US20100028260A1 - Color-Coded Polymeric Particles of Predetermined Size for Therapeutic and/or Diagnostic Applications and Related Methods - Google Patents

Color-Coded Polymeric Particles of Predetermined Size for Therapeutic and/or Diagnostic Applications and Related Methods Download PDF

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US20100028260A1
US20100028260A1 US12/467,229 US46722909A US2010028260A1 US 20100028260 A1 US20100028260 A1 US 20100028260A1 US 46722909 A US46722909 A US 46722909A US 2010028260 A1 US2010028260 A1 US 2010028260A1
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poly
color
calibrated
acrylate
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US20210299056A9 (en
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Ulf Fritz
Olaf Fritz
Thomas A. Gordy
Ronald Wojcik
Jacques BLÜMMEL
Alexander KÜLLER
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Celonova Bioscience Inc
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Celonova Bioscience Inc
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Priority claimed from US11/257,535 external-priority patent/US8318209B2/en
Priority claimed from US11/924,674 external-priority patent/US9107850B2/en
Application filed by Celonova Bioscience Inc filed Critical Celonova Bioscience Inc
Priority to US12/467,229 priority Critical patent/US20210299056A9/en
Publication of US20100028260A1 publication Critical patent/US20100028260A1/en
Priority to US14/720,428 priority patent/US10973770B2/en
Priority to US17/065,319 priority patent/US11426355B2/en
Publication of US20210299056A9 publication Critical patent/US20210299056A9/en
Priority to US17/814,896 priority patent/US20220362161A1/en
Abandoned legal-status Critical Current

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005Wall or coating material
    • A61K9/5021Organic macromolecular compounds
    • A61K9/5026Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00Preparations for testing in vivo
    • A61K49/04X-ray contrast preparations
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00Preparations for testing in vivo
    • A61K49/04X-ray contrast preparations
    • A61K49/0404X-ray contrast preparations containing barium sulfate
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00Preparations for testing in vivo
    • A61K49/06Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1818Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
    • A61K49/1821Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
    • A61K49/1824Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00Preparations for testing in vivo
    • A61K49/22Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
    • A61K49/222Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
    • A61K49/225Microparticles, microcapsules
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/007Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests for contrast media
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00General characteristics of the apparatus
    • A61M2205/60General characteristics of the apparatus with identification means

Definitions

  • This disclosure relates to various polymeric particles incorporating chromophores and other agents of interest that can be employed as implantable devices in animal subjects, for various diagnostic and therapeutic applications.
  • various cosmetic, clinical, and interventional procedures involve in vivo administration of synthetic particles, manufactured in various sizes and compositions.
  • various blends of polymeric embolic particles can be introduced into the lumen of blood vessels to intentionally impede blood flow through various tissues/organs affected with physical trauma, tumor, or any condition in which blood-flow intervention can provide an effective and noninvasive form of temporary or permanent mode of therapy (“embolization”).
  • the manufactured products containing such synthetic particles require further manipulation by the practitioner prior to in vivo administration.
  • the particle-based products provided by a manufacturer need to be combined with other reagents in order to make a final sample preparation suitable for in vivo administration.
  • Substantial human errors can be inadvertently introduced during the preparatory procedures that may increase the overall risk associated with performing a given treatment.
  • Practitioners need particles formulated to minimize various types of risks introduced during sample preparations for various particle-mediated diagnostic and/or therapeutic applications.
  • color-coded and size-calibrated polymeric particles comprising an acrylate-based hydrogel core incorporating one or more chromophores of interest, and an outer shell comprising polyphosphazenes of formula I, useful for various therapeutic and/or diagnostic procedures.
  • the color-coded and size-calibrated polymeric particles can be employed in any particle-mediated procedure, including as embolic agents, dermal fillers, and various implantable devices for a broad range of clinical and cosmetic applications.
  • FIG. 1 is a schematic of an exemplary color-coded and size-calibrated polymeric particle comprising an acrylate-based hydrogel core incorporating one or more chromophores of interest, and an outer shell comprising a polyphosphazene coating of formula I.
  • FIG. 2 is an exemplary reaction scheme for the incorporation of reactive dye molecules by forming activated groups within reactive dye molecules before reacting with acrylate-based hydrogels in the presence of a coupling agent.
  • FIG. 3 is an exemplary reaction scheme for the incorporation of reactive dye molecules by forming activated groups within acrylate-based hydrogels before reacting with reactive dye molecules.
  • FIG. 4 is a schematic of an interventional occlusion of a hypothetical blood vessel employing particles of at least three different diameter sizes, each set of particles labeled according to a different color scheme.
  • particle-mediated procedure refers to any procedure that involves the utilization of disclosed particles in order to facilitate a diagnostic purpose and/or a therapeutic purpose.
  • Exemplary particle-mediated procedures include various intravascular interventional procedures (“embolization”) involving in vivo administration of synthetically made particles of various compositions for reducing or stopping blood flow into the affected tissue/organ, including: for controlling gastrointestinal bleeding of any cause, for controlling bleeding into the abdomen or pelvis from any physical trauma injuries, for controlling bleeding resulting from long menstrual periods or heavy menstrual bleeding caused by uterine fibroid tumors, for occluding vessels that are supplying blood to tumors, for eliminating arteriovenous malformation (AVM) or arteriovenous fistula (AVF) caused by abnormal connection or connections between arteries and veins, for treating various types of aneurysms, and various other conditions and diseases suitable for such particle-mediated interventional procedures.
  • AMM arteriovenous malformation
  • AVF arteriovenous fistula
  • the contemplated “particle-mediated procedures” include any procedure in which a benefit can be conferred by the targeted delivery of particles of interest for any form of therapy, including various diagnostic, therapeutic, and cosmetic applications.
  • the particles can be delivered to any tissue or organ of a recipient.
  • the type of optimal particles (size range, color, composition) suitable for a given condition under contemplation would need to be determined by the practitioner.
  • particle(s),” “color-coded particles,” and “color-coded and size-calibrated particles” can be used interchangeably to refer to any synthetically made particle of any shape or surface contour, with an average diameter size ranging from approximately 10 ⁇ m to approximately 1500 ⁇ m, that can be employed for any particle-based procedure, and includes various embolic particles and dermal-filler particles.
  • the particles refer to substantially polymeric bodies shaped or formed as substantially spherical or ellipsoid articles manufactured to a particular size or diameter of interest and incorporating one or more chromophores of interest in order to produce a set of particles characterized by a particular predetermined size and color.
  • embolic particles refers to any synthetically made particle of any shape or surface contour, with an average diameter size ranging from approximately 10 ⁇ m to approximately 1500 ⁇ m, suitable for any embolization procedure, and exemplifies “color-coded and size-calibrated particles.”
  • each set of particles calibrated for a particular size/dimension can be manufactured to incorporate a particular color desired to match the size-calibrated particles so that each set of such particles can be visually identified by the particular color exhibited (“color-coded”).
  • Suitable embolic particles can be composed of any material amendable to controlled manufacturing and production specifications according to shaping and sizing requirements.
  • Embolic particles are typically suspended in a transport medium containing various components that stabilize the particles during storage and shipment by manufacturers.
  • the color-coded and size-calibrated particles can be employed as embolic agents for treating hypertrophic obstructive cardiomyopathy (HCM), having an average diameter size ranging from approximately 50 ⁇ m to approximately 90 ⁇ m, preferably from approximately 60 ⁇ m to approximately 80 ⁇ m, and most preferably from approximately 70 ⁇ m to approximately 75 ⁇ m.
  • HCM hypertrophic obstructive cardiomyopathy
  • skin-filler particles refers to any synthetically made particle of any shape or surface contour, with an average diameter size ranging from approximately 50 ⁇ m to approximately 500 ⁇ m, from approximately 50 ⁇ m to approximately 400 ⁇ m, from approximately 50 ⁇ m to approximately 300 ⁇ m, from approximately 50 ⁇ m to approximately 200 ⁇ m, suitable for any cosmetic application procedure, and exemplifies “color-coded and size-calibrated particles.”
  • Suitable dermal-filler particles can be composed of any material amendable to controlled manufacturing and production specifications according to shaping and sizing requirements.
  • Dermal-filler particles can be administered to a recipient in need of cosmetic and/or therapeutic enhancement in appearance, including the removal of wrinkles, dermal texture imperfections, dermal blot clots, dermal age-related disease or damage, and other equivalent conditions known by persons skilled in the art of dermal cosmetic enhancement and dermal diagnostic/clinical/therapeutic applications.
  • Mixtures of chromophores formulated to resemble various skin tones can be incorporated into the acrylate-based hydrogel cores of color-coded and size-calibrated particles manufactured for use as dermal fillers.
  • acrylate-based hydrogel refers to any polymer chain, formed in part or entirely, through the polymerization of an acrylate based monomer and (optionally) through subsequent and/or parallel reactions, can be three-dimensionally crosslinked, and having pendant side groups to confer the resulting cross-linked polymeric network with a substantial affinity for particular solvents, such as water, and to enable swelling.
  • gel refers to an elastic colloid or polymeric network capable of expanding throughout the volume by the absorption of fluid.
  • the polymer network can be a network formed by covalent bonds or by physical aggregation with region of local order acting as network junctions. Both by weight and volume, gels can be mostly liquid in composition and thus exhibit densities similar to that of liquids, however, gels have the structural coherence of a solid.
  • hydrogel refers to a polymeric network capable of absorbing water.
  • crosslink refers to a small region in a macromolecule from which at least three chains emanate, and formed by reactions involving sites or groups on existing macromolecules or by interactions between existing macromolecules.
  • the small region may be an atom, a group of atoms, or a number of branch points connected by bonds, groups of atoms, or oligomeric chains.
  • a crosslink is a covalent structure but the term can describe sites of weaker chemical interactions, portions of crystallites, and even physical entanglements.
  • chromophores refers to any molecule that can absorb certain wavelengths of visible light, and can transmit or reflect other wavelengths as understood by persons skilled in the art, and includes various nontoxic pigments and dyes of medical grade that can be incorporated into food and/or medical devices for implantation into human and/or animal subjects without imposing the risk of substantial harm
  • the chromophores suitable for incorporation into particles of interest include dyes that have been approved or have been exempt from certification by the FDA, which are listed under TITLE 21—FOOD AND DRUGS, CHAPTER I—FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES, SUBCHAPTER A, GENERAL, PART 73 LISTING OF COLOR ADDITIVES EXEMPT FROM CERTIFICATION, Subpart D—Medical Devices, the disclosure of which is incorporated herein by reference.
  • incorpora refers to any process involving the physical or chemical affixation of one or more species, including atoms, molecular entities, agents such as dyes, oligo- and polymeric species together.
  • the term refers to processes involving impregnation, precipitation, covalent binding, grafting in- or onto, fixing in- or onto, diffusion, permeation, temporary or permanent, partial or complete localization within, around, throughout a given article.
  • the color-coded and size-calibrated polymeric particles comprising an acrylate-based hydrogel core incorporating one or more chromophores of interest, and an outer shell comprising polyphosphazenes of formula I, useful for various therapeutic and/or diagnostic procedures are provided.
  • the color-coded and size-calibrated polymeric particles comprising an acrylate-based hydrogel core incorporating one or more chromophores of interest and an outer shell comprising polyphosphazenes of formula I, can be employed as embolic particles for mediating various interventional procedures.
  • the color-coded and size-calibrated polymeric particles comprising an acrylate-based hydrogel core incorporating one or more chromophores of interest and an outer shell comprising polyphosphazenes of formula I, can be employed as embolic agents for treating hypertrophic obstructive cardiomyopathy (HCM).
  • HCM hypertrophic obstructive cardiomyopathy
  • the color-coded and size-calibrated polymeric particles comprising an acrylate-based hydrogel core incorporating one or more chromophores of interest and an outer shell comprising polyphosphazenes of formula I, can be employed as dermal fillers.
  • the biocompatible and loadable polymeric particles comprises an acrylate-based hydrogel core incorporating one or more chromophores of interest and an outer shell comprising poly[bis(trifluoroethoxy) phosphazene] and/or a derivative thereof.
  • a particular chromophore formulation that correlates with a predetermined size range of implantable and loadable polymeric particles of interest (“color-coded” particles) permit a convenient and accurate visual identification of particles of interest and minimizes user-introduced errors.
  • FIG. 1 is a schematic of an exemplary color-coded and size-calibrated polymeric particle comprising an acrylate-based hydrogel core incorporating one or more chromophores of interest, and an outer shell comprising a polyphosphazene coating of formula I.
  • a hypothetical particle 100 comprising an acrylate-based hydrogel core 110 and an outer shell 120 is shown.
  • the acrylate-based hydrogel core 110 can be manufactured to incorporate various chromophores present in a sufficient amount to permit the detection of a “color” by a human eye or by an instrument.
  • the total amount of chromophores sufficient to be visually detected can vary depending on particular chromophores selected.
  • the total amount of chromophores that can be incorporated into the color-coded and size-calibrated particles can range up to about 20%, about 15%, about 10%, about 8%, about 6%, about 5%, or about 2.5% of the total dry weight of the hydrogel.
  • An outer shell 120 comprising at least one polyphosphazene of formula I, can be formed on the surface of the acrylate-based hydrogel core 110 to provide a biocompatible coating layer.
  • the color-coded and size-calibrated polymeric particles can be manufactured to be substantially uniform in size.
  • the smallest average diameter of a set of particles for a first product line can be about 10 ⁇ m
  • the largest average diameter of a set of particles for a second product line can be about 1500 ⁇ m.
  • the average diameter size range of particles of interest can be selected from about 10 ⁇ m to about 1500 ⁇ m; from about 10 ⁇ m to about 1100 ⁇ m; from about 10 ⁇ m to about 1000 ⁇ m; from about 10 ⁇ m to about 900 ⁇ m; from about 10 ⁇ m to about 800 ⁇ m; from about 10 ⁇ m to about 700 ⁇ m; from about 10 ⁇ m to about 600 ⁇ m; from about 10 ⁇ m to about 500 ⁇ m; from about 10 ⁇ m to about 400 ⁇ m; from about 10 ⁇ m to about 300 ⁇ m; from about 10 ⁇ m to about 200 ⁇ m; from about 10 ⁇ m to about 175 ⁇ m; from about 10 ⁇ m to about 150 ⁇ m; from about 10 ⁇ m to about 120 ⁇ m; from about 10 ⁇ m to about 80 ⁇ m; and from about 10 ⁇ m to about 40 ⁇ m.
  • Suitable range in average diameter size of a particle of interest include: from about 20 ⁇ m to about 1500 ⁇ m; from about 20 ⁇ m to about 1200 ⁇ m; from about 20 ⁇ m to about 1000 ⁇ m; from about 20 ⁇ m to about 900 ⁇ m; from about 20 ⁇ m to about 800 ⁇ m; from about 20 ⁇ m to about 700 ⁇ m; from about 20 ⁇ m to about 600 ⁇ m; from about 20 ⁇ m to about 500 ⁇ m; from about 20 ⁇ m to about 400 ⁇ m; from about 20 ⁇ m to about 300 ⁇ m; from about 20 ⁇ m to about 200 ⁇ m; from about 20 ⁇ m to about 175 ⁇ m; from about 20 ⁇ m to about 150 ⁇ m; from about 20 ⁇ m to about 120 ⁇ m; from about 20 ⁇ m to about 80 ⁇ m; and from about 20 ⁇ m to about 40 ⁇ m.
  • Suitable range in average diameter size of a particle of interest include: from about 30 ⁇ m to about 1500 ⁇ m; from about 30 ⁇ m to about 1300 ⁇ m; from about 30 ⁇ m to about 3000 ⁇ m; from about 30 ⁇ m to about 900 ⁇ m; from about 30 ⁇ m to about 800 ⁇ m; from about 30 ⁇ m to about 700 ⁇ m; from about 30 ⁇ m to about 600 ⁇ m; from about 30 ⁇ m to about 500 ⁇ m; from about 30 ⁇ m to about 400 ⁇ m; from about 30 ⁇ m to about 300 ⁇ m; from about 30 ⁇ m to about 300 ⁇ m; from about 30 ⁇ m to about 175 ⁇ m; from about 30 ⁇ m to about 150 ⁇ m; from about 30 ⁇ m to about 130 ⁇ m; from about 30 ⁇ m to about 80 ⁇ m; and from about 30 ⁇ m to about 40 ⁇ m.
  • the color-coded and size-calibrated polymeric particles can be calibrated to a predetermined deviation tolerance of less than or equal to about ⁇ 5%, less than or equal to about ⁇ 10%, less than or equal to about ⁇ 15%, less than or equal to about ⁇ 20%, less than or equal to about ⁇ 25%, less than or equal to about ⁇ 30%, or less than or equal to about ⁇ 35% from the design specification.
  • the color-coded and size-calibrated polymeric particles can be manufactured to exhibit a narrow size distribution proportional to the average size of the particles.
  • the particles within the range from about 700 ⁇ m to about 1000 ⁇ m can vary less than or equal to only about ⁇ 3-5% from the design specification, whereas particles within the size range from about 40 ⁇ m to about 100 ⁇ m can vary less than or equal to about ⁇ 20-25% from the design specification.
  • the color-coded and size-calibrated polymeric particles can be manufactured to exhibit uniformity in shape, and preferably, the particles can be manufactured to be substantially spherical in shape.
  • the color-coded and size-calibrated polymeric particles comprise an acrylate-based hydrogel, as a core component, that can be manufactured utilizing various polymers known to persons skilled in the art, including polymers selected from poly(methacrylic acid), poly(methyl acrylate), poly(methyl methacrylate) (PMMA), poly(ethyl methacrylate), poly(hexamethyl methacrylate), poly(hydroxyethyl methacrylate), poly(acrylic acid), poly(butyl acrylate), poly(2-ethylhexyl acrylate), poly(ethyl acrylate), poly(acrylonitrile), poly(trimethylolpropane triacrylate), or an equivalent known by persons skilled in the art, a copolymer thereof, and/or a combination thereof.
  • FIG. 2 is an exemplary reaction scheme for the incorporation of reactive dye molecules by forming activated groups within reactive dye molecules before reacting with acrylate-based hydrogels in the presence of a coupling agent.
  • a suitable reactive dye 200 can be amino-activated with an aliphatic diamine (ethylene diamine) 210 to form an aliphatic amino group within the reactive dye 220 , which can be reacted with a hypothetical acrylate-based hydrogel 230 in the presence of a coupling promoter agent 240 , such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), to produce color-coded and size-calibrated particles 250 incorporated with reactive dye molecules by a stable covalent linkage.
  • a coupling promoter agent 240 such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)
  • Exemplary reactive dyes used in production FDA exempt from certification: Reactive Red 11 (dichlorotriazine), Reactive Yellow 86 (dichlorotriazine), Reactive Blue 4 (dichlorotriazine), Reactive Black 5 (vinyl sulfone), Reactive Red 180 (vinyl sulfone), Reactive Yellow 15 (vinyl sulfone), Reactive Blue 19 (vinyl sulfone), Reactive Blue 21 (vinyl sulfone), Reactive Blue 163 (vinyl sulfone), Reactive Orange 78 (vinyl sulfone), and others known to persons skilled in the art.
  • These examples can be accordingly reformulated by replacing the nucleophilic group H 2 N— with —OH, —SH or any other arbitrary nucleophilic group.
  • An exemplary formula for an amino activator spacer molecule is provided by: H 2 N—CH 2 —R—CH 2 —NH 2 , wherein the R is an alkylene, alkoxylene, alkenylene, alkinylene, arylene, and alkylarylene; includes carrying organic and heteroorganic side groups (such as hydroxyl, silyl, thiol, sulfonyl, sulfoxyl, sulfate, amine, immine, amide, nitro, nitroso, phosphine, phosphonate, phosphate).
  • organic and heteroorganic side groups such as hydroxyl, silyl, thiol, sulfonyl, sulfoxyl, sulfate, amine, immine, amide, nitro, nitroso, phosphine, phosphonate, phosphate.
  • FIG. 3 is an exemplary reaction scheme for the incorporation of reactive dye molecules by forming activated groups within acrylate-based hydrogels before reacting with reactive dye molecules.
  • the carboxylic acid groups of the PMAA 300 as an hypothetical acrylate-based hydrogel, can be amino-activated by reacting with 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) 310 in the presence of an aliphatic diamine (ethylene diamine) 320 .
  • EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide
  • the resulting free amino group within the activated acrylate-based hydrogel 330 can react with the reactive dyes 340 to produce the color-coded and size-calibrated particles 350 incorporated with reactive dye molecules by a stable covalent linkage.
  • active anchor groups can be created within the PMAA core of color-coded and size-calibrated particles during the polymerization process of PMMA.
  • co-polymerization of MMA in the presence of a small amount (about 1-10%) of amino (—NH 2 ) or hydroxyl (—OH) groups (or protected forms of both) containing unsaturated species can generate active anchor groups so that reactive dyes can be directly bound to the hydrogel core without prior activation without requiring ethylene diamine via EDC to activate the hydrogel core or amino activation of dye molecules.
  • exemplary co-polymers include unsaturated alcohols, unsaturated amines, and unsaturated thiols.
  • the generalized formula for unsaturated alcohols is R 5 O—R 1 —CR 2 ⁇ CR 3 R 4
  • R 1 is any bivalent group with no electron withdrawing impact on —OH; this includes but is not limited to alkylene, alkoxylene, alkenylene, alkinylene, arylene, and alkylarylene, also including organic and heteroorganic side groups (e.g. hydroxyl, silyl, thiol, sulfonyl, suloxyl, sulfate, amine, immine, amide, nitro, nitroso, phosphine, phosphonate, phosphate);
  • organic and heteroorganic side groups e.g. hydroxyl, silyl, thiol, sulfonyl, suloxyl, sulfate, amine, immine, amide, nitro, nitroso, phosphine, phosphonate, phosphate
  • R 2 , R 3 and/or R 4 enable copolymerization and include but are not limited to hydrogen, halogen, alkyl, alkoxyl, alkenyl, alkinyl, aryl, and alkylaryl, or any combinations or derivatives thereof, also including any organic and heteroorganic side groups (e.g. silyl, thiol, sulfonyl, suloxyl, sulfate, amine, immine, amide, nitro, nitroso, phosphine, phosphonate, phosphate); and
  • R 5 includes hydrogen or any protecting group.
  • the generalized formula for unsaturated amine is: R 5 HN—R 1 —CR 2 ⁇ CR 3 R 4
  • R 1 is any bivalent group with no electron withdrawing impact on —OH; this includes but is not limited to alkylene, alkoxylene, alkenylene, alkinylene, arylene, and alkylarylene, also including organic and heteroorganic side groups (e.g. hydroxyl, silyl, thiol, sulfonyl, suloxyl, sulfate, amine, immine, amide, nitro, nitroso, phosphine, phosphonate, phosphate);
  • organic and heteroorganic side groups e.g. hydroxyl, silyl, thiol, sulfonyl, suloxyl, sulfate, amine, immine, amide, nitro, nitroso, phosphine, phosphonate, phosphate
  • R 2 , R 3 and/or R 4 enable copolymerization and include but are not limited to hydrogen, halogen, alkyl, alkoxyl, alkenyl, alkinyl, aryl, and alkylaryl, or any combinations or derivatives thereof, also including any organic and heteroorganic side groups (e.g. silyl, thiol, sulfonyl, suloxyl, sulfate, amine, immine, amide, nitro, nitroso, phosphine, phosphonate, phosphate); and
  • R 5 includes hydrogen or any protecting group.
  • Exemplary unsaturated amines include vinyl amine (H 2 C ⁇ CH—NH 2 ) or derivatives [H 2 C ⁇ CH—(CH 2 ) n —NH 2 ] (n ⁇ 1).
  • R 1 is any bivalent group with no electron withdrawing impact on —OH; this includes but is not limited to alkylene, alkoxylene, alkenylene, alkinylene, arylene, and alkylarylene, also including organic and heteroorganic side groups (e.g. hydroxyl, silyl, thiol, sulfonyl, suloxyl, sulfate, amine, immine, amide, nitro, nitroso, phosphine, phosphonate, phosphate);
  • organic and heteroorganic side groups e.g. hydroxyl, silyl, thiol, sulfonyl, suloxyl, sulfate, amine, immine, amide, nitro, nitroso, phosphine, phosphonate, phosphate
  • R 2 , R 3 and/or R 4 enable copolymerization and include but are not limited to hydrogen, halogen, alkyl, alkoxyl, alkenyl, alkinyl, aryl, and alkylaryl, or any combinations or derivatives thereof, also including any organic and heteroorganic side groups (e.g. silyl, thiol, sulfonyl, suloxyl, sulfate, amine, immine, amide, nitro, nitroso, phosphine, phosphonate, phosphate); and
  • R 5 includes hydrogen or any protecting group.
  • the acrylate-based hydrogel core of the color-coded and size-calibrated particles can incorporate any compound/agent of interest suitable for various therapeutic and/or diagnostic applications.
  • the acrylate-based hydrogel core of the color-coded and size-calibrated particles can incorporate any bioactive and pharmaceutical agents, such as peptides, proteins, hormones, carbohydrates, polysaccharides, nucleic acids, lipids, vitamins, steroids, organic or inorganic drugs, and/or equivalents, and combinations thereof.
  • bioactive and pharmaceutical agents such as peptides, proteins, hormones, carbohydrates, polysaccharides, nucleic acids, lipids, vitamins, steroids, organic or inorganic drugs, and/or equivalents, and combinations thereof.
  • the acrylate-based hydrogel core of the color-coded and size-calibrated particles can incorporate various fluorescent dyes, radiopaque reagents, and/or equivalents to permit contemporaneous monitoring, and combinations thereof.
  • the acrylate-based hydrogel core of the color-coded and size-calibrated particles can incorporate magnetic, diamagnetic, paramagnetic, ferromagnetic and/or antiferromagnetic elements to impart certain magnetic properties.
  • the acrylate-based hydrogel core of the color-coded and size-calibrated particles can incorporate various excipients, such as dextranes, other sugars, polyethylene glycol, glucose, and various salts.
  • excipients such as dextranes, other sugars, polyethylene glycol, glucose, and various salts.
  • contrast agent refers to various compounds, suspended in contrast medium/media, that enables radiopaque visibility by highlighting specific tissue/organ of interest during various diagnostic medical imaging examinations and/or treatment procedures that require simultaneous monitoring, by various means including: x-ray exams, computed tomography scans, and magnetic resonance imaging.
  • contrast agents include iobitridol, iodixanol, iomeprol, iopamidol, iopentol, iopromide, ioversol, and other iodine-formulated compositions, which have iodine concentrations between about 240 mg/ml to about 400 mg/ml, or more.
  • a larger volume of contrast medium may be required to sufficiently saturate the particles with an iodine threshold level necessary to provide adequate radiopaque visibility when monitoring particle transport following in vivo administration.
  • the acrylate-based hydrogel core of the color-coded and size-calibrated particles can incorporate barium sulfate, which can be utilized for increasing the density of the particle, so that the particle can be properly suspended within a dense medium, such as a contrast agent-containing solution, for modulating or enhancing the added chromophore by creating varying degrees of translucency, contributing to the intensity of the color perceived, for changing the elastic and mechanic properties of a particle as an inelastic component, and/or for increasing the radiopaqueness of a particle, without the use of separate contrast agent, capable of acting as a contrast agent in itself.
  • barium sulfate which can be utilized for increasing the density of the particle, so that the particle can be properly suspended within a dense medium, such as a contrast agent-containing solution, for modulating or enhancing the added chromophore by creating varying degrees of translucency, contributing to the intensity of the color perceived, for changing the elastic and mechanic properties of a particle as an inelastic component, and/
  • Various embodiments are directed to color-coded and size-calibrated particles comprising an acrylate-based hydrogel core incorporating one or more chromophores of interest, and an outer shell comprising polyphosphazenes having the general formula (I):
  • Suitable substituents for R 1 to R 6 can be independently selected from the group consisting of: halide substituents, such as fluorine, chlorine bromine, or iodine; pseudohalide substituents, such as cyano (—CN), isocyano (—NC), thiocyano (—SCN), isothiocyano (—NCS), cyanato (—OCN), isocyanato (—NCO), or azido (—N 3 ) groups; substituents such as nitro- (—NO 2 ) or nitrito (—NO) groups; partially substituted alkyl groups, such as haloalkyl; heteroaryl such as imidazoyl, oxazolyl, thiazolyl, or pyrazolyl derivatives; and purine and pyrimidine bases such as guanidines, amidines or other ureido derivatives of the base structure.
  • halide substituents such as fluorine, chlorine bromine, or iod
  • R can be selected independently from a linear, branched, and/or cyclic (“cycloalkyl”) hydrocarbyl moieties, including alkyl (saturated hydrocarbons) as well as alkenyl and alkynyl moieties, having from 1 to about 20 (for example, from 1 to about 12, or 1 to about 6) carbon atoms.
  • cycloalkyl cyclic hydrocarbyl moieties, including alkyl (saturated hydrocarbons) as well as alkenyl and alkynyl moieties, having from 1 to about 20 (for example, from 1 to about 12, or 1 to about 6) carbon atoms.
  • alkenyl and alkynyl moieties provides, among other things, the capability to cross-link the polyphosphazene moieties to any extent desired.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl and dodecyl.
  • Cycloalkyl moieties may be monocyclic or multicyclic, and examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl. Additional examples of alkyl moieties have linear, branched and/or cyclic portions (e.g. 1-ethyl-4-methyl-cyclohexyl).
  • R (alkyl) groups include unsubstituted alkyl, substituted alkyl such as halo-substituted alkyl (haloalkyl), unsubstituted alkenyl, substituted alkenyl such as halo-substituted alkenyl, and unsubstituted alkynyl, and substituted alkynyl such as halo-substituted alkynyl.
  • alkoxy (OR) substituents can be unsubstituted alkoxy (“alkyloxy”), substituted alkoxy such as halo-substituted alkoxy (haloalkoxy), unsubstituted alkenyloxy, substituted alkenyloxy such as halo-substituted alkenyloxy, unsubstituted alkynyloxy, and substituted alkynyloxy such as halo-substituted alkynyloxy.
  • vinyloxy and allyloxy can be useful.
  • a silyl group is a —SiR 3 group and a silyloxy group is an —OSiR 3 group, where each R moiety is selected independently from the R groups defined supra. That is, R in each occurrence is selected independently from a linear, branched, and/or cyclic (“cycloalkyl”) hydrocarbyl moieties, including alkyl (saturated hydrocarbons) as well as alkenyl and alkynyl moieties, having from 1 to about 20 (for example, from 1 to about 12, or 1 to about 6) carbon atoms.
  • cycloalkyl cyclic hydrocarbyl moieties, including alkyl (saturated hydrocarbons) as well as alkenyl and alkynyl moieties, having from 1 to about 20 (for example, from 1 to about 12, or 1 to about 6) carbon atoms.
  • any R group can be unsubstituted or substituted independently with at least one substituent selected from a halogen (fluorine, chlorine, bromine, or iodine), an alkyl, an alkylsulfonyl, an amino, an alkylamino, a dialkylamino, an amidino (—N ⁇ C(NH 2 ) 2 ), an alkoxide, or an aryloxide, any of which can have up to about 6 carbon atoms, if applicable.
  • a halogen fluorine, chlorine, bromine, or iodine
  • an alkyl an alkylsulfonyl
  • an amino, an alkylamino, a dialkylamino an amidino (—N ⁇ C(NH 2 ) 2 )
  • an alkoxide or an aryloxide, any of which can have up to about 6 carbon atoms, if applicable.
  • substituted “alkyl” and moieties which encompass substituted alkyl, such as “alkoxy,” include haloalkyl and haloalkoxy, respectively, including any fluorine-, chlorine-, bromine-, and iodine-substituted alkyl and alkoxy.
  • haloalkyl and haloalkoxy refers to alkyl and alkoxy groups substituted with one or more halogen atoms, namely fluorine, chlorine, bromine, or iodine, including any combination thereof.
  • aryl means an aromatic ring or an aromatic or partially aromatic ring system composed of carbon and hydrogen atoms, which may be a single ring moiety, or may contain multiple rings bound or fused together.
  • aryl moieties include, but are not limited to, phenyl, anthracenyl, azulenyl, biphenyl, fluorenyl, indan, indenyl, naphthyl, phenanthrenyl, 1,2,3,4-tetrahydro-naphthalene, tolyl, and the like, any of which having up to about 20 carbon atoms.
  • An aryloxy group refers to an —O(aryl) moiety.
  • haloaryl and haloaryloxy refer to aryl and aryloxy groups, respectively, substituted with one or more halogen atoms, namely fluorine, chlorine, bromine, or iodine, including any combination thereof.
  • a heterocyclic alkyl group with at least one nitrogen as a heteroatom refers to a non-aromatic heterocycle and includes a cycloalkyl or a cycloalkenyl moiety in which one or more of the atoms in the ring structure is nitrogen rather than carbon, and which may be monocyclic or multicyclic, and may include exo-carbonyl moieties and the like.
  • heterocyclic alkyl group with nitrogen as a heteroatom examples include, but are not limited to, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydropyrimidinyl, morpholinyl, aziridinyl, imidazolidinyl, 1-pyrroline, 2-pyrroline, or 3-pyrroline, pyrrolidinonyl, piperazinonyl, hydantoinyl, piperidin-2-one, pyrrolidin-2-one, azetidin-2-one, and the like.
  • these groups include heterocyclic exocyclic ketones as well.
  • a heteroaryl group with at least one nitrogen as the heteroatom refers to an aryl moiety in which one or more of the atoms in the ring structure is nitrogen rather than carbon, and which may be monocyclic or multicyclic.
  • heterocyclic alkyl group with nitrogen as a heteroatom include, but are not limited to, acridinyl, benzimidazolyl, quinazolinyl, benzoquinazolinyl, imidazolyl, indolyl, isothiazolyl, isoxazolyl, oxazolyl or oxadiazolyl, phthalazinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolinyl, tetrazolyl, thiazolyl, triazinyl, and the like.
  • this disclosure includes or encompasses chemical moieties found as subunits in a wide range of pharmaceutical agents, natural moieties, natural biomolecules, and biomacromolecules.
  • this disclosure encompasses a number of pharmaceutical agents available with the tetrazole group (for example, losartan, candesartan, irbesartan, and other Angiotensin receptor antagonists); the triazole group (for example, fluconazole, isavuconazole, itraconazole, voriconazole, pramiconazole, posaconazole, and other antifungal agents); diazoles (for example, fungicides such as Miconazole, Ketoconazole, Clotrimazole, Econazole, Bifonazole, Butoconazole, Fenticonazole, Isoconazole, Oxiconazole, Sertaconazole, Sulconazole, Tioconazole, and the like); and imidazoles (h
  • a heterocyclic alkyl group with at least one phosphorus, oxygen, sulfur, or selenium as a heteroatom refers to a non-aromatic heterocycle and includes a cycloalkyl or a cycloalkenyl moiety in which one or more of the atoms in the ring structure is phosphorus, oxygen, sulfur, or selenium rather than carbon, and which may be monocyclic or multicyclic, and may include exo-carbonyl moieties and the like.
  • heteroaryl group with at least one phosphorus, oxygen, sulfur, or selenium as the heteroatom refers to an aryl moiety in which one or more of the atoms in the ring structure is phosphorus, oxygen, sulfur, or selenium rather than carbon, and which may be monocyclic or multicyclic.
  • heterocyclic alkyl groups or heteroaryls with phosphorus, oxygen, sulfur, or selenium as a heteroatom include, but are not limited to, substituted or unsubstituted ethylene oxide (epoxides, oxiranes), oxirene, oxetane, tetrahydrofuran (oxolane), dihydrofuran, furan, pyran, tetrahydropyran, dioxane, dioxin, thiirane (episulfides), thietane, tetrahydrothiophene (thiolane) dihydrothiophene, thiophene, thiane, thiine (thiapyrane), oxazine, thiazine, dithiane, dithietane, and the like.
  • substituted or unsubstituted ethylene oxide epoxides, oxiranes
  • oxirene oxetane
  • these groups include all isomers, including regioisomers of the recited compounds.
  • these groups include 1,2- and 1,3-oxazoles, thiazoles, selenazoles, phosphazoles, and the like, which include different heteroatoms from the group 15 or group 16 elements.
  • polymers other than the poly[bis(trifluoroethoxy) phosphazene] and/or its derivative may be included and/or combined with in the particle.
  • examples of polymers may include poly(lactic acid), poly(lactic-co-glycolic acid), poly(caprolactone), polycarbonates, polyamides, polyanhydrides, polyamino acids, polyorthoesters, polyacetals, polycyanoacrylates, and polyurethanes.
  • polymers include polyacrylates, ethylene-vinyl acetate co-polymers, acyl substituted cellulose acetates and derivatives thereof, degradable or non-degradable polyurethanes, polystyrenes, polyvinylchloride, polyvinyl fluoride, poly(vinyl imidazole), chlorosulphonated polyolefins, and polyethylene oxide.
  • polyacrylates include, but are not limited to, acrylic acid, butyl acrylate, ethylhexyl acrylate, methyl acrylate, ethyl acrylate, acrylonitrile, methyl methacrylate, TMPTA (trimethylolpropane triacrylate), and the like.
  • the particle may be coated with an additional polymer layer or layers, including polymers such as those mentioned hereinabove.
  • PTFEP or derivatives thereof may be used to form such a coating on a particle formed of other suitable polymers or copolymers known or to be developed in the art.
  • PTFEP is applied as a coating on a microparticle(s) formed of an acrylic-based polymer as set forth in further detail below.
  • FIG. 4 is a schematic of an interventional occlusion of a hypothetical blood vessel employing particles of at least three different diameter sizes, each set of particles labeled according to a different color scheme.
  • a hypothetical blood vessel 400 that can transport blood from point 405 to point 410 as shown. If occlusion of blood vessel 400 at point 410 , for example, is necessary for treatment, efficient occlusion can be achieved by deploying a first set A of smallest particles such as 420 and 422 , followed immediately by a second set B of intermediate particles such as 430 and 432 , followed immediately by a third set C of largest particles such as 440 and 442 of a given range of particles calibrated to a particular size of interest.
  • a method of selective embolization at a site in need of comprising administering color-coded and size-calibrated particles described herein to a patient in need of.
  • an alkyl substituent or group can have from 1 to 20 carbon atoms
  • Applicants intent is to recite that the alkyl group have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms, including any range or sub-range encompassed therein.
  • Applicants reserve the right to proviso out or exclude any individual members of such a group, including any sub-ranges or combinations of sub-ranges within the group, that can be claimed according to a range or in any similar manner, if for any reason Applicants choose to claim less than the full measure of the disclosure, for example, to account for a reference that Applicants are unaware of at the time of the filing of the application.
  • Indigo dye can be incorporated into acrylate-based microparticles as follows.
  • the vat can be prepared by mixing 5 g Indigo, 2.5 ml ethanol, 150 ml hot water, 6.5 ml concentrated sodium hydroxide solution and 7.5 g sodium dithionite. The mixture can be stirred for 15 minutes at 50-60° C. until the mixture converts to yellow-greenish.
  • the concentrated solution can be given into 3 L of hot (50-60° C.) water with 3 ml of ammonia (25% solution) and additional 2 g of sodium dithionite. The amount of water can be varied from 0 to 31 to receive different color intensity. After stirring of the solution becomes yellow-greenish the particles can be added, and gently stirred for additional 15 minutes. After decanting and rinsing of the particles with water they become blue.
  • Indigo red can be incorporated following the same protocol.
  • Dyes containing sulfonic acid side groups can be incorporated into acrylate-based microparticles as follows. Dyes containing sulfonic acid side groups have a high capacity in precipitating with barium ions to form a water insoluble compound. For example, 3 ml Reactive Blue 21 (20 mg/ml physiological saline) can be added to 3 ml hydrated polymethylacrylate beads (400-600 ⁇ m) in physiological saline (total volume 6 ml). The suspension can be gently shaken for 10 to 15 min to reach diffusion equilibrium. Afterwards, the aqueous phase can be removed. 5 ml 0.5 molar aqueous barium chloride can be added to the particles and shaken over 30 min at ambient temperature.
  • the suspension was stored over night at 70° C., than extensively washed with physiological saline until the solution remained optically colorless.
  • the solution can be substituted by 0.5 molar barium chloride and heated for 30 min to approximately 125° C. at 1.5 bar. Afterwards the particles can be extensively washed with physiological saline.
  • Different color intensities can be prepared by varying aqueous Reactive Blue 21 concentrations from 2 to 30 mg/ml physiological saline and from 0.5 ml to 5 ml hydrated polymethylacrylate beads.
  • Dyes containing sulfonic acid side groups can be incorporated into acrylate-based microparticles as follows. Reactive Blue, Reactive Blue 4, Reactive Blue 19, Reactive Blue 163, Reactive Black 5, Reactive Yellow 86, Reactive Yellow 15, Reactive Orange 78, Reactive Red 11, Reactive Red 180, Chinolin Yellow, Allura Red AC, and any combinations thereof can be used to obtain different color shades by using mixtures of various ratios/percentage. Color intensities can be altered by varying the total dye amount (1 mg to 400 mg).
  • a mixture of methyl methacrylate (MMA), allyl methacrylate (AMA), and the crosslinker triethyleneglycol dimethacrylate (TEGDMA) is copolymerized in presence of a radical initiator (lauroyl peroxide, LP) can be performed by suspension polymerization.
  • a radical initiator laroyl peroxide, LP
  • 200 g freshly destilled MMA, 670 mg LP, 2.875 g TEGDMA, and 10 g AMA can be mixed until a clear solution is obtained.
  • the aqueous phase composed of 23 g polyvinylalcohol (PVA; 26/88), 5 g disodium hydrogen phosphate, and 290 mg sodium dihydrogen phosphate can be dissolved in 1000 ml deionized water.
  • Polymerization can be performed by stirring at 130 rpm (initial 250 rpm for 5 to 10 min) at 67° C. for 1 h, than 2 h at 70° C., and finally 80° C. for 2 h. Particle sizes in the range of 50 to 1000 ⁇ m can be obtained.
  • Hydrolysis can be performed with 5 g of the particles (taken from sieve fraction 212 to 350 ⁇ m) in 1500 ml ethylene glycol containing 75 g potassium hydroxide under reflux for 2 h. Afterwards, the particles can be washed extensively with deionized water until pH7 results. The water can be substituted by physiological saline, and osmolarity measured at 290 ⁇ 50 mOsmol/kg.
  • 20 ml hydrated particles in physiological saline
  • 20 ml hydrated particles can be colored by adding 150 mg Reactive Blue 4 and Reactive Blue 19, respectively.
  • the first dyeing can be performed at ambient temperature, the latter reaction at 70° C.; after 14 h, the particles can be washed with physiological saline until the solution remains optically colorless.
  • a mixture of methyl methacrylate (MMA), diallylurea (DAU) and the crosslinker triethyleneglycol dimethacrylate (TEGDMA) is copolymerized in presence of a radical initiator (lauroyl peroxide, LP) can be performed by suspension polymerization.
  • a radical initiator laroyl peroxide, LP
  • 100 g freshly distilled MMA, 330 mg LP, 1.43 g TEGDMA, and 1.0 g DAU can be mixed until a clear solution is obtained.
  • the aqueous phase composed of 11.5 g polyvinylalcohol (PVA; 26/88), 2.5 g disodium hydrogen phosphate, and 145 mg sodium dihydrogen phosphate can be dissolved in 500 ml deionized water.
  • Polymerization can be performed by stirring at 130 rpm (initial 250 rpm for 5 to 10 min) at 67° C. for 1 h, than 2 h at 70° C. and finally 80° C. for 2 h. Particle sizes in the range of 50 to 800 ⁇ m.
  • Hydrolysis can be performed with 5 g of the particles in 1500 ml ethylene glycol containing 75 g potassium hydroxide under reflux for 2 h. Afterwards, the particles can be washed extensively with deionized water until pH of 7 results. The water can be substituted by physiological saline, and osmolarity measured at 290 ⁇ 50 mOsmol/kg.
  • 20 ml hydrated particles in physiological saline
  • 20 ml hydrated particles can be colored by adding 150 mg Reactive Blue 4 and Reactive Blue 19, respectively.
  • the first dyeing can be performed at ambient temperature, the latter reaction at 70° C.; after 16 h, the particles can be washed with physiological saline until the solution remains optically colorless.
  • Reactive Dyes can bind to nucleophilic groups such as amines (primary amines preferred) or hydroxyl groups.
  • nucleophilic groups such as amines (primary amines preferred) or hydroxyl groups.
  • amine groups primary amines preferred
  • hydroxyl groups 100 mg dry particles can be hydrated in 5 ml deionized water for 10 to 15 min.
  • 100 mg 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and 100 ⁇ m ethylene diamine (EDA) can be added and shaken gently for 2 h at ambient temperature. After extensive washing with potable water the beads can be dyed in 5 ml deionized water by adding 200 mg Reactive Blue 4 and Reactive Blue 19, respectively.
  • the first mixture can be kept at room temperature and the latter reaction at 70° C., both over night.
  • the dye solution can be removed and the particles can be washed with potable water and afterwards 3-4 times with 8-9 ml 0.9% NaCl aq until the transport solution (TS) is almost colorless.
  • Different color intensities can be prepared by varying EDA (20 ⁇ l to 200 ⁇ l), EDC (20 mg to 200 mg), and dye amount (10 mg to 40 0 mg); other colors can be also created by using Reactive Red 11, Reactive Red 180, Reactive Yellow 86, Reactive Yellow 15, Reactive Black 5, and Reactive Blue 21.
  • a broader range of colors such as green, purple, and orange beads can be prepared as follows.
  • various mixtures of dyes can be employed together to create the colors of interest, for example: (i) orange can be made by mixing red and yellow (ii) green can be made by mixing blue and yellow, and (iii) purple can be made by mixing blue and red.
  • Dyes can be chosen within the same dye family (Remazol®: Reactive Yellow 15, Reactive Red 180, Reactive Black 5, Reactive Blue 21 and Reactive Blue 19; Procion®: Reactive Red 11, Reactive Yellow 86, Reactive Blue 4). Different color shades can be obtained by using mixtures of different ratios in the range of about 1:100 to about 100:1.
  • Color intensities can be altered by varying EDA (20 ⁇ l to 200 ⁇ l), EDC (20 mg to 200 mg), and adjusting the total dye amount from about 10 mg to about 400 mg.
  • a broader range of colors such as green, purple, pink, orange, grey, olive, smurf-blue, brown, ivory, black, burgundy, crimson, turquoise, orange beads can be prepared.
  • Mixtures of at least two dyes can be utilized to create the described colors.
  • Amino activated Reactive Yellow 86, Reactive Yellow 15, Reactive Blue 19, Reactive Red 180, Reactive Orange 78, Reactive Blue 163, Reactive Black 5, Reactive Blue 21, Reactive Blue 4, Reactive Blue 19, and Reactive Red 11 can be used. Different color shades can be obtained by using mixtures of all percentage ratios.
  • Color intensities can be altered by varying EDC (20 mg to 500 mg), and adjusting the total dye amount from about 1 mg to about 400 mg.
  • a broader range of colors such as green, purple, pink, orange, grey, olive, smurf-blue, brown, ivory, black, burgundy, crimson, turquoise, and orange beads can be prepared.
  • additional dyeing procedures can be applied utilizing another dye.
  • Amino activated Reactive Yellow 86, Reactive Yellow 15, Reactive Blue 19, Reactive Red 180, Reactive Orange 78, Reactive Blue 163, Reactive Black 5, Reactive Blue 21, Reactive Blue 4, Reactive Blue 19, and Reactive Red 11 can be utilized, for example.
  • Different color shades can be obtained altering dye amounts (0.1 mg to 20 mg) during the different dyeing procedures.
  • Color intensities can be altered by varying EDC (20 mg to 500 mg), and adjusting the total dye amount from about 1 mg to 100 mg.
  • Approximately 20 ml particles (900 ⁇ m) can be immersed in 80 ml 0.9% aqueous sodium chloride solution (physiological saline). First 2.6 ml aqueous iron(III) chloride (45%) can be added to this suspension, and then followed by 4 ml of 1 molar aqueous iron(II) sulfate. The suspension can be gently shaken for 10 to 15 min to reach diffusion equilibrium. 100 ml of 0.1 molar aqueous sodium hydroxide solution (containing 0.9% sodium chloride) can be added drop wise to allow iron hydroxide precipitation. The particles can be extensively washed with physiological saline. Rusty colored particles can be obtained.
  • Different color intensities can be prepared by varying aqueous iron(III) chloride (45%) from 0.1 ml to 10 ml, 1 molar aqueous iron(II) sulfate from 0.15 ml to 15.5 ml, and aqueous sodium hydroxide from 0.1 molar to 1 molar and 4 ml to 400 ml, respectively.
  • the particles can be prepared as described above, substituting 0.1 to 1 molar aqueous ammonia (NH 3aq ) in the place of sodium hydroxide.
  • Different color intensities can be prepared by varying aqueous iron(III) chloride (45%) from 0.1 ml to 10 ml, 1 molar aqueous iron(II) sulfate from 0.15 ml to 15.5 ml, and aqueous ammonia from 0.1 molar to 1 molar and 4 ml to 400 ml, respectively.
  • Different color intensities can be prepared by varying saturated aqueous iron(II) sulfate from 0.1 ml to 10 ml, hydrogen peroxide concentration from 0.1% to 5% utilizing an amount from 0.5 ml to 10 ml.

Abstract

Various embodiments are directed to color-coded and size-calibrated polymeric particles comprising an acrylate-based hydrogel core incorporating one or more chromophores of interest, and an outer shell comprising polyphosphazenes of formula I, useful for various therapeutic and/or diagnostic procedures. In various embodiments, the color-coded and size-calibrated polymeric particles can be employed in any particle-mediated procedure, including as embolic agents, dermal fillers, and various implantable devices for a broad range of clinical and cosmetic applications. The incorporation of a particular chromophore formulation that correlates with a pre-determined size specificity for implantable and loadable polymeric particles (“color-coded and size-calibrated”) enables the visual detection and identification of particles exhibiting a particular size of interest, and minimizes the probability of user-introduced or procedural errors.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • This application is a continuation-in-part of U.S. patent application Ser. No. 11/924,674, filed on Oct. 26, 2007, currently pending, which:
  • is a continuation-in-part of U.S. patent application Ser. No. 11/257,535, filed Oct. 25, 2005, currently pending, which claims the benefit of U.S. Provisional Patent Applications: No. 60/621,729, filed Oct. 25, 2004; and the No. 60/684,307, filed May 24, 2005; and
  • also which claims the benefit of U.S. Provisional Patent Application No. 60/962,015, filed Jul. 25, 2007;
  • the entire disclosures of which are incorporated herein by reference.
  • TECHNICAL FIELD
  • This disclosure relates to various polymeric particles incorporating chromophores and other agents of interest that can be employed as implantable devices in animal subjects, for various diagnostic and therapeutic applications.
  • BACKGROUND
  • Various cosmetic, clinical, and interventional procedures involve in vivo administration of synthetic particles, manufactured in various sizes and compositions. For example, various blends of polymeric embolic particles can be introduced into the lumen of blood vessels to intentionally impede blood flow through various tissues/organs affected with physical trauma, tumor, or any condition in which blood-flow intervention can provide an effective and noninvasive form of temporary or permanent mode of therapy (“embolization”).
  • In general, the manufactured products containing such synthetic particles require further manipulation by the practitioner prior to in vivo administration. The particle-based products provided by a manufacturer need to be combined with other reagents in order to make a final sample preparation suitable for in vivo administration. Substantial human errors can be inadvertently introduced during the preparatory procedures that may increase the overall risk associated with performing a given treatment. Practitioners need particles formulated to minimize various types of risks introduced during sample preparations for various particle-mediated diagnostic and/or therapeutic applications.
  • SUMMARY OF THE INVENTION
  • Various embodiments are directed to color-coded and size-calibrated polymeric particles comprising an acrylate-based hydrogel core incorporating one or more chromophores of interest, and an outer shell comprising polyphosphazenes of formula I, useful for various therapeutic and/or diagnostic procedures. In various embodiments, the color-coded and size-calibrated polymeric particles can be employed in any particle-mediated procedure, including as embolic agents, dermal fillers, and various implantable devices for a broad range of clinical and cosmetic applications. The incorporation of a particular chromophore formulation that correlates with a pre-determined size specificity for implantable and loadable polymeric particles (“color-coded and size-calibrated”) enables the visual detection and identification of particles exhibiting a particular size of interest, and minimizes the probability of user-introduced or procedural errors.
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1 is a schematic of an exemplary color-coded and size-calibrated polymeric particle comprising an acrylate-based hydrogel core incorporating one or more chromophores of interest, and an outer shell comprising a polyphosphazene coating of formula I.
  • FIG. 2 is an exemplary reaction scheme for the incorporation of reactive dye molecules by forming activated groups within reactive dye molecules before reacting with acrylate-based hydrogels in the presence of a coupling agent.
  • FIG. 3 is an exemplary reaction scheme for the incorporation of reactive dye molecules by forming activated groups within acrylate-based hydrogels before reacting with reactive dye molecules.
  • FIG. 4 is a schematic of an interventional occlusion of a hypothetical blood vessel employing particles of at least three different diameter sizes, each set of particles labeled according to a different color scheme.
  • DETAILED DESCRIPTION A. Definitions
  • In addition to the definition of terms provided below, the terms “a” or “an” can mean one or more of the referenced subject matter.
  • The term “particle-mediated procedure” refers to any procedure that involves the utilization of disclosed particles in order to facilitate a diagnostic purpose and/or a therapeutic purpose. Exemplary particle-mediated procedures include various intravascular interventional procedures (“embolization”) involving in vivo administration of synthetically made particles of various compositions for reducing or stopping blood flow into the affected tissue/organ, including: for controlling gastrointestinal bleeding of any cause, for controlling bleeding into the abdomen or pelvis from any physical trauma injuries, for controlling bleeding resulting from long menstrual periods or heavy menstrual bleeding caused by uterine fibroid tumors, for occluding vessels that are supplying blood to tumors, for eliminating arteriovenous malformation (AVM) or arteriovenous fistula (AVF) caused by abnormal connection or connections between arteries and veins, for treating various types of aneurysms, and various other conditions and diseases suitable for such particle-mediated interventional procedures. The contemplated “particle-mediated procedures” include any procedure in which a benefit can be conferred by the targeted delivery of particles of interest for any form of therapy, including various diagnostic, therapeutic, and cosmetic applications. The particles can be delivered to any tissue or organ of a recipient. The type of optimal particles (size range, color, composition) suitable for a given condition under contemplation would need to be determined by the practitioner.
  • The terms “particle(s),” “color-coded particles,” and “color-coded and size-calibrated particles” can be used interchangeably to refer to any synthetically made particle of any shape or surface contour, with an average diameter size ranging from approximately 10 μm to approximately 1500 μm, that can be employed for any particle-based procedure, and includes various embolic particles and dermal-filler particles. In various embodiments, the particles refer to substantially polymeric bodies shaped or formed as substantially spherical or ellipsoid articles manufactured to a particular size or diameter of interest and incorporating one or more chromophores of interest in order to produce a set of particles characterized by a particular predetermined size and color.
  • The term “embolic particles” refers to any synthetically made particle of any shape or surface contour, with an average diameter size ranging from approximately 10 μm to approximately 1500 μm, suitable for any embolization procedure, and exemplifies “color-coded and size-calibrated particles.” In producing embolic particles of a broad size range, each set of particles calibrated for a particular size/dimension can be manufactured to incorporate a particular color desired to match the size-calibrated particles so that each set of such particles can be visually identified by the particular color exhibited (“color-coded”). Suitable embolic particles can be composed of any material amendable to controlled manufacturing and production specifications according to shaping and sizing requirements. Embolic particles are typically suspended in a transport medium containing various components that stabilize the particles during storage and shipment by manufacturers. In particular, the color-coded and size-calibrated particles can be employed as embolic agents for treating hypertrophic obstructive cardiomyopathy (HCM), having an average diameter size ranging from approximately 50 μm to approximately 90 μm, preferably from approximately 60 μm to approximately 80 μm, and most preferably from approximately 70 μm to approximately 75 μm.
  • The term “dermal-filler particles” refers to any synthetically made particle of any shape or surface contour, with an average diameter size ranging from approximately 50 μm to approximately 500 μm, from approximately 50 μm to approximately 400 μm, from approximately 50 μm to approximately 300 μm, from approximately 50 μm to approximately 200 μm, suitable for any cosmetic application procedure, and exemplifies “color-coded and size-calibrated particles.” Suitable dermal-filler particles can be composed of any material amendable to controlled manufacturing and production specifications according to shaping and sizing requirements. Dermal-filler particles can be administered to a recipient in need of cosmetic and/or therapeutic enhancement in appearance, including the removal of wrinkles, dermal texture imperfections, dermal blot clots, dermal age-related disease or damage, and other equivalent conditions known by persons skilled in the art of dermal cosmetic enhancement and dermal diagnostic/clinical/therapeutic applications. Mixtures of chromophores formulated to resemble various skin tones can be incorporated into the acrylate-based hydrogel cores of color-coded and size-calibrated particles manufactured for use as dermal fillers.
  • The term “acrylate-based hydrogel” refers to any polymer chain, formed in part or entirely, through the polymerization of an acrylate based monomer and (optionally) through subsequent and/or parallel reactions, can be three-dimensionally crosslinked, and having pendant side groups to confer the resulting cross-linked polymeric network with a substantial affinity for particular solvents, such as water, and to enable swelling.
  • The term “gel” refers to an elastic colloid or polymeric network capable of expanding throughout the volume by the absorption of fluid. The polymer network can be a network formed by covalent bonds or by physical aggregation with region of local order acting as network junctions. Both by weight and volume, gels can be mostly liquid in composition and thus exhibit densities similar to that of liquids, however, gels have the structural coherence of a solid. The term “hydrogel” refers to a polymeric network capable of absorbing water.
  • The term “crosslink” refers to a small region in a macromolecule from which at least three chains emanate, and formed by reactions involving sites or groups on existing macromolecules or by interactions between existing macromolecules. The small region may be an atom, a group of atoms, or a number of branch points connected by bonds, groups of atoms, or oligomeric chains. In general, a crosslink is a covalent structure but the term can describe sites of weaker chemical interactions, portions of crystallites, and even physical entanglements.
  • The term “chromophores” refers to any molecule that can absorb certain wavelengths of visible light, and can transmit or reflect other wavelengths as understood by persons skilled in the art, and includes various nontoxic pigments and dyes of medical grade that can be incorporated into food and/or medical devices for implantation into human and/or animal subjects without imposing the risk of substantial harm The chromophores suitable for incorporation into particles of interest include dyes that have been approved or have been exempt from certification by the FDA, which are listed under TITLE 21—FOOD AND DRUGS, CHAPTER I—FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES, SUBCHAPTER A, GENERAL, PART 73 LISTING OF COLOR ADDITIVES EXEMPT FROM CERTIFICATION, Subpart D—Medical Devices, the disclosure of which is incorporated herein by reference.
  • The term “incorporate” refers to any process involving the physical or chemical affixation of one or more species, including atoms, molecular entities, agents such as dyes, oligo- and polymeric species together. For example, the term refers to processes involving impregnation, precipitation, covalent binding, grafting in- or onto, fixing in- or onto, diffusion, permeation, temporary or permanent, partial or complete localization within, around, throughout a given article.
  • B. Manufacturing Implantable and Loadable Polymeric Particles of Various Sizes Labeled with Chromophores to Facilitate Visual Identification
  • In various embodiments, the color-coded and size-calibrated polymeric particles comprising an acrylate-based hydrogel core incorporating one or more chromophores of interest, and an outer shell comprising polyphosphazenes of formula I, useful for various therapeutic and/or diagnostic procedures are provided.
  • In various embodiments, the color-coded and size-calibrated polymeric particles, comprising an acrylate-based hydrogel core incorporating one or more chromophores of interest and an outer shell comprising polyphosphazenes of formula I, can be employed as embolic particles for mediating various interventional procedures.
  • In various embodiments, the color-coded and size-calibrated polymeric particles, comprising an acrylate-based hydrogel core incorporating one or more chromophores of interest and an outer shell comprising polyphosphazenes of formula I, can be employed as embolic agents for treating hypertrophic obstructive cardiomyopathy (HCM).
  • In various embodiments, the color-coded and size-calibrated polymeric particles, comprising an acrylate-based hydrogel core incorporating one or more chromophores of interest and an outer shell comprising polyphosphazenes of formula I, can be employed as dermal fillers.
  • In various embodiments, the biocompatible and loadable polymeric particles comprises an acrylate-based hydrogel core incorporating one or more chromophores of interest and an outer shell comprising poly[bis(trifluoroethoxy) phosphazene] and/or a derivative thereof. The incorporation of a particular chromophore formulation that correlates with a predetermined size range of implantable and loadable polymeric particles of interest (“color-coded” particles) permit a convenient and accurate visual identification of particles of interest and minimizes user-introduced errors.
  • C. Manufacturing a Hydrogel Core
  • 1. Acrylate-Based Hydrogels
  • FIG. 1 is a schematic of an exemplary color-coded and size-calibrated polymeric particle comprising an acrylate-based hydrogel core incorporating one or more chromophores of interest, and an outer shell comprising a polyphosphazene coating of formula I. In FIG. 1, a hypothetical particle 100 comprising an acrylate-based hydrogel core 110 and an outer shell 120 is shown. The acrylate-based hydrogel core 110 can be manufactured to incorporate various chromophores present in a sufficient amount to permit the detection of a “color” by a human eye or by an instrument. The total amount of chromophores sufficient to be visually detected can vary depending on particular chromophores selected. The total amount of chromophores that can be incorporated into the color-coded and size-calibrated particles can range up to about 20%, about 15%, about 10%, about 8%, about 6%, about 5%, or about 2.5% of the total dry weight of the hydrogel. An outer shell 120 comprising at least one polyphosphazene of formula I, can be formed on the surface of the acrylate-based hydrogel core 110 to provide a biocompatible coating layer.
  • In various embodiments, the color-coded and size-calibrated polymeric particles can be manufactured to be substantially uniform in size. For example, the smallest average diameter of a set of particles for a first product line can be about 10 μm, and the largest average diameter of a set of particles for a second product line can be about 1500 μm. The average diameter size range of particles of interest can be selected from about 10 μm to about 1500 μm; from about 10 μm to about 1100 μm; from about 10 μm to about 1000 μm; from about 10 μm to about 900 μm; from about 10 μm to about 800 μm; from about 10 μm to about 700 μm; from about 10 μm to about 600 μm; from about 10 μm to about 500 μm; from about 10 μm to about 400 μm; from about 10 μm to about 300 μm; from about 10 μm to about 200 μm; from about 10 μm to about 175 μm; from about 10 μm to about 150 μm; from about 10 μm to about 120 μm; from about 10 μm to about 80 μm; and from about 10 μm to about 40 μm. Suitable range in average diameter size of a particle of interest include: from about 20 μm to about 1500 μm; from about 20 μm to about 1200 μm; from about 20 μm to about 1000 μm; from about 20 μm to about 900 μm; from about 20 μm to about 800 μm; from about 20 μm to about 700 μm; from about 20 μm to about 600 μm; from about 20 μm to about 500 μm; from about 20 μm to about 400 μm; from about 20 μm to about 300 μm; from about 20 μm to about 200 μm; from about 20 μm to about 175 μm; from about 20 μm to about 150 μm; from about 20 μm to about 120 μm; from about 20 μm to about 80 μm; and from about 20 μm to about 40 μm. Suitable range in average diameter size of a particle of interest include: from about 30 μm to about 1500 μm; from about 30 μm to about 1300 μm; from about 30 μm to about 3000 μm; from about 30 μm to about 900 μm; from about 30 μm to about 800 μm; from about 30 μm to about 700 μm; from about 30 μm to about 600 μm; from about 30 μm to about 500 μm; from about 30 μm to about 400 μm; from about 30 μm to about 300 μm; from about 30 μm to about 300 μm; from about 30 μm to about 175 μm; from about 30 μm to about 150 μm; from about 30 μm to about 130 μm; from about 30 μm to about 80 μm; and from about 30 μm to about 40 μm. The color-coded and size-calibrated polymeric particles can be calibrated to a predetermined deviation tolerance of less than or equal to about ±5%, less than or equal to about ±10%, less than or equal to about ±15%, less than or equal to about ±20%, less than or equal to about ±25%, less than or equal to about ±30%, or less than or equal to about ±35% from the design specification. In a preferred embodiment, the color-coded and size-calibrated polymeric particles can be manufactured to exhibit a narrow size distribution proportional to the average size of the particles. For example, the particles within the range from about 700 μm to about 1000 μm can vary less than or equal to only about ±3-5% from the design specification, whereas particles within the size range from about 40 μm to about 100 μm can vary less than or equal to about ±20-25% from the design specification.
  • In another embodiment, the color-coded and size-calibrated polymeric particles can be manufactured to exhibit uniformity in shape, and preferably, the particles can be manufactured to be substantially spherical in shape.
  • Various methods for manufacturing acrylate-based hydrogel cores have been previously described by the present Applicants in U.S. Patent Publication Nos. 2006/0088476 and 2008/0113029, the entire disclosures of which are incorporated herein by reference.
  • 2. Acrylate-Based Hydrogels as the Core Component of Color-Coded and Size-Calibrated Particles
  • The color-coded and size-calibrated polymeric particles comprise an acrylate-based hydrogel, as a core component, that can be manufactured utilizing various polymers known to persons skilled in the art, including polymers selected from poly(methacrylic acid), poly(methyl acrylate), poly(methyl methacrylate) (PMMA), poly(ethyl methacrylate), poly(hexamethyl methacrylate), poly(hydroxyethyl methacrylate), poly(acrylic acid), poly(butyl acrylate), poly(2-ethylhexyl acrylate), poly(ethyl acrylate), poly(acrylonitrile), poly(trimethylolpropane triacrylate), or an equivalent known by persons skilled in the art, a copolymer thereof, and/or a combination thereof.
  • 3. Exemplary Chromophores and Methods for Incorporating into Acrylate-Based Hydrogels
  • FIG. 2 is an exemplary reaction scheme for the incorporation of reactive dye molecules by forming activated groups within reactive dye molecules before reacting with acrylate-based hydrogels in the presence of a coupling agent. In FIG. 2, a suitable reactive dye 200 can be amino-activated with an aliphatic diamine (ethylene diamine) 210 to form an aliphatic amino group within the reactive dye 220, which can be reacted with a hypothetical acrylate-based hydrogel 230 in the presence of a coupling promoter agent 240, such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), to produce color-coded and size-calibrated particles 250 incorporated with reactive dye molecules by a stable covalent linkage.
  • Table of Exemplary Reactive Dyes:
  • Table of Exemplary Reactive Dyes:
    Monochlorotriazines
    R1 = chromophore R2 = 2nd chromophore or any other
    Figure US20100028260A1-20100204-C00001
    Mono-
    fluorochlorotriazines
    R = chromophore
    Figure US20100028260A1-20100204-C00002
    Dichlorotriazines
    R = chromophore
    Figure US20100028260A1-20100204-C00003
    Dichloroquinoxaline
    R1 = chromophore or any other R2 = chromophore or any other R3 = chromophore or any other R4 = chromophore or any other
    Figure US20100028260A1-20100204-C00004
    Trichloropyrimidine
    R = chromophore
    Figure US20100028260A1-20100204-C00005
    Vinyl sulfone
    R = chromophore
    Figure US20100028260A1-20100204-C00006
    Vinyl amide
    R1 = chromophore or any other R2 = chromophore or any other R3 = chromophore or any other R4 = chromophore or any other
    Figure US20100028260A1-20100204-C00007
  • Exemplary reactive dyes used in production (FDA exempt from certification): Reactive Red 11 (dichlorotriazine), Reactive Yellow 86 (dichlorotriazine), Reactive Blue 4 (dichlorotriazine), Reactive Black 5 (vinyl sulfone), Reactive Red 180 (vinyl sulfone), Reactive Yellow 15 (vinyl sulfone), Reactive Blue 19 (vinyl sulfone), Reactive Blue 21 (vinyl sulfone), Reactive Blue 163 (vinyl sulfone), Reactive Orange 78 (vinyl sulfone), and others known to persons skilled in the art.
  • Exemplary spacer molecules to link the reactive dye to the polymer in the hydrogel include any di-functional, tri-functional, or multi-functional species, the functional species comprising a nucleophilic group, including H2N—(CH2)n—NH2 (n≧2) [in production n=2 (ethylene diamine)], [H—2N—(CH2)n]3—CH (n≧1), [H2N—(CH2)n]4—C (n≧1). These examples can be accordingly reformulated by replacing the nucleophilic group H2N— with —OH, —SH or any other arbitrary nucleophilic group.
  • An exemplary formula for an amino activator spacer molecule is provided by: H2N—CH2—R—CH2—NH2, wherein the R is an alkylene, alkoxylene, alkenylene, alkinylene, arylene, and alkylarylene; includes carrying organic and heteroorganic side groups (such as hydroxyl, silyl, thiol, sulfonyl, sulfoxyl, sulfate, amine, immine, amide, nitro, nitroso, phosphine, phosphonate, phosphate).
  • Figure US20100028260A1-20100204-C00008
  • FIG. 3 is an exemplary reaction scheme for the incorporation of reactive dye molecules by forming activated groups within acrylate-based hydrogels before reacting with reactive dye molecules. In the first reaction of FIG. 3, the carboxylic acid groups of the PMAA 300, as an hypothetical acrylate-based hydrogel, can be amino-activated by reacting with 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) 310 in the presence of an aliphatic diamine (ethylene diamine) 320. In the second reaction of FIG. 3, the resulting free amino group within the activated acrylate-based hydrogel 330 can react with the reactive dyes 340 to produce the color-coded and size-calibrated particles 350 incorporated with reactive dye molecules by a stable covalent linkage.
  • Alternatively, active anchor groups can be created within the PMAA core of color-coded and size-calibrated particles during the polymerization process of PMMA. For example, co-polymerization of MMA in the presence of a small amount (about 1-10%) of amino (—NH2) or hydroxyl (—OH) groups (or protected forms of both) containing unsaturated species can generate active anchor groups so that reactive dyes can be directly bound to the hydrogel core without prior activation without requiring ethylene diamine via EDC to activate the hydrogel core or amino activation of dye molecules. Exemplary co-polymers include unsaturated alcohols, unsaturated amines, and unsaturated thiols.
  • The generalized formula for unsaturated alcohols is R5O—R1—CR2═CR3R4
  • wherein R1 is any bivalent group with no electron withdrawing impact on —OH; this includes but is not limited to alkylene, alkoxylene, alkenylene, alkinylene, arylene, and alkylarylene, also including organic and heteroorganic side groups (e.g. hydroxyl, silyl, thiol, sulfonyl, suloxyl, sulfate, amine, immine, amide, nitro, nitroso, phosphine, phosphonate, phosphate);
  • wherein R2, R3 and/or R4 enable copolymerization and include but are not limited to hydrogen, halogen, alkyl, alkoxyl, alkenyl, alkinyl, aryl, and alkylaryl, or any combinations or derivatives thereof, also including any organic and heteroorganic side groups (e.g. silyl, thiol, sulfonyl, suloxyl, sulfate, amine, immine, amide, nitro, nitroso, phosphine, phosphonate, phosphate); and
  • wherein R5 includes hydrogen or any protecting group.
  • Exemplary unsaturated alcohols include vinyl alcohol (H2C═CH—OH) or derivatives [H2C═CH—(CH2)n—OH] (n≧1) [n=1: allyl alcohol].
  • The generalized formula for unsaturated amine is: R5HN—R1—CR2═CR3R4
  • wherein R1 is any bivalent group with no electron withdrawing impact on —OH; this includes but is not limited to alkylene, alkoxylene, alkenylene, alkinylene, arylene, and alkylarylene, also including organic and heteroorganic side groups (e.g. hydroxyl, silyl, thiol, sulfonyl, suloxyl, sulfate, amine, immine, amide, nitro, nitroso, phosphine, phosphonate, phosphate);
  • wherein R2, R3 and/or R4 enable copolymerization and include but are not limited to hydrogen, halogen, alkyl, alkoxyl, alkenyl, alkinyl, aryl, and alkylaryl, or any combinations or derivatives thereof, also including any organic and heteroorganic side groups (e.g. silyl, thiol, sulfonyl, suloxyl, sulfate, amine, immine, amide, nitro, nitroso, phosphine, phosphonate, phosphate); and
  • wherein R5 includes hydrogen or any protecting group.
  • Exemplary unsaturated amines include vinyl amine (H2C═CH—NH2) or derivatives [H2C═CH—(CH2)n—NH2] (n≧1).
  • The generalized formula for unsaturated thiols is R5S—R1—CR2═CR3R4
  • wherein R1 is any bivalent group with no electron withdrawing impact on —OH; this includes but is not limited to alkylene, alkoxylene, alkenylene, alkinylene, arylene, and alkylarylene, also including organic and heteroorganic side groups (e.g. hydroxyl, silyl, thiol, sulfonyl, suloxyl, sulfate, amine, immine, amide, nitro, nitroso, phosphine, phosphonate, phosphate);
  • wherein R2, R3 and/or R4 enable copolymerization and include but are not limited to hydrogen, halogen, alkyl, alkoxyl, alkenyl, alkinyl, aryl, and alkylaryl, or any combinations or derivatives thereof, also including any organic and heteroorganic side groups (e.g. silyl, thiol, sulfonyl, suloxyl, sulfate, amine, immine, amide, nitro, nitroso, phosphine, phosphonate, phosphate); and
  • wherein R5 includes hydrogen or any protecting group.
  • Exemplary unsaturated amines include vinyl mercaptane (H2C═CH—SH) or derivatives [H2C═CH—(CH2)n—SH] (n≧1) [n=1: allyl mercaptane].
  • 4. Exemplary Agents of Interest
  • In various embodiments, the acrylate-based hydrogel core of the color-coded and size-calibrated particles can incorporate any compound/agent of interest suitable for various therapeutic and/or diagnostic applications.
  • In various embodiments, the acrylate-based hydrogel core of the color-coded and size-calibrated particles can incorporate any bioactive and pharmaceutical agents, such as peptides, proteins, hormones, carbohydrates, polysaccharides, nucleic acids, lipids, vitamins, steroids, organic or inorganic drugs, and/or equivalents, and combinations thereof.
  • In various embodiments, the acrylate-based hydrogel core of the color-coded and size-calibrated particles can incorporate various fluorescent dyes, radiopaque reagents, and/or equivalents to permit contemporaneous monitoring, and combinations thereof.
  • In various embodiments, the acrylate-based hydrogel core of the color-coded and size-calibrated particles can incorporate magnetic, diamagnetic, paramagnetic, ferromagnetic and/or antiferromagnetic elements to impart certain magnetic properties.
  • In various embodiments, the acrylate-based hydrogel core of the color-coded and size-calibrated particles can incorporate various excipients, such as dextranes, other sugars, polyethylene glycol, glucose, and various salts. The term “contrast agent” refers to various compounds, suspended in contrast medium/media, that enables radiopaque visibility by highlighting specific tissue/organ of interest during various diagnostic medical imaging examinations and/or treatment procedures that require simultaneous monitoring, by various means including: x-ray exams, computed tomography scans, and magnetic resonance imaging. Exemplary contrast agents include iobitridol, iodixanol, iomeprol, iopamidol, iopentol, iopromide, ioversol, and other iodine-formulated compositions, which have iodine concentrations between about 240 mg/ml to about 400 mg/ml, or more. In general, as the average size of particles increases, a larger volume of contrast medium may be required to sufficiently saturate the particles with an iodine threshold level necessary to provide adequate radiopaque visibility when monitoring particle transport following in vivo administration.
  • In various embodiments, the acrylate-based hydrogel core of the color-coded and size-calibrated particles can incorporate barium sulfate, which can be utilized for increasing the density of the particle, so that the particle can be properly suspended within a dense medium, such as a contrast agent-containing solution, for modulating or enhancing the added chromophore by creating varying degrees of translucency, contributing to the intensity of the color perceived, for changing the elastic and mechanic properties of a particle as an inelastic component, and/or for increasing the radiopaqueness of a particle, without the use of separate contrast agent, capable of acting as a contrast agent in itself.
  • D. High Molecular Weight Polyphosphazenes of Formula I as an Outer Shell for Color-Coded and Size-Calibrated Polymeric Particles
  • The definition for high molecular weight polyphosphazenes of formula I and methods for coating acrylate-based hydrogel cores have been previously described by the present Applicants in U.S. Patent Publication Nos. 2006/0088476 and 2008/0113029, the entire disclosures of which are incorporated herein by reference.
  • Various embodiments are directed to color-coded and size-calibrated particles comprising an acrylate-based hydrogel core incorporating one or more chromophores of interest, and an outer shell comprising polyphosphazenes having the general formula (I):
  • Figure US20100028260A1-20100204-C00009
      • in which the n value is an integer from 2 to ∞;
      • R1 to R6 are independently selected from the group consisting of:
      • a substituted or unsubstituted alkyl, alkoxy, aryl, aryloxy, silyl, silyloxy, alkylsulfonyl, alkyl amino, dialkyl amino, ureido, carboxylic acid ester, alkylmonoamidine, alkylbisamidine, alkoxymonoamidine, alkoxybisamidine; and an amino;
      • a heterocyclic alkyl group with at least one nitrogen, phosphorus, oxygen, sulfur, or selenium as a heteroatom;
      • a heteroaryl group with at least one nitrogen, phosphorus, oxygen, sulfur, or selenium as the heteroatom;
      • a nucleotide or a nucleotide residue;
      • a biomacromolecule; and
      • a pyrimidine or a purine base.
  • Suitable substituents for R1 to R6 can be independently selected from the group consisting of: halide substituents, such as fluorine, chlorine bromine, or iodine; pseudohalide substituents, such as cyano (—CN), isocyano (—NC), thiocyano (—SCN), isothiocyano (—NCS), cyanato (—OCN), isocyanato (—NCO), or azido (—N3) groups; substituents such as nitro- (—NO2) or nitrito (—NO) groups; partially substituted alkyl groups, such as haloalkyl; heteroaryl such as imidazoyl, oxazolyl, thiazolyl, or pyrazolyl derivatives; and purine and pyrimidine bases such as guanidines, amidines or other ureido derivatives of the base structure.
  • As used herein, alkyl (R), alkoxy (—OR), alkylsulfonyl (—SO2R), alkyl amino (—NHR), dialkyl amino (—NR2), carboxylic acid ester (-(alkadiyl)C(O)OR or -alkadiyl)OC(O)R)), ureido (—NHC(O)NH2, —NRC(O)NH2, —NHC(O)NHR, —NRC(O)NHR, —NHC(O)NR2, —NRC(O)NR2, and their alkadiyl-linked analogs), alkylmonoamidine (including —N═C(NR2)R, —(alkadiyl)N═C(NR2)R, —C(NR2)═NR, and -(alkadiyl)C(NR2)═NR), alkylbisamidine (including —N═C(NR2)2, -(alkadiyl)N═C(NR2)2, —NRC(NR2)═NR, and -(alkadiyl)NRC(NR2)═NR), alkoxymonoamidine (—O(alkadiyl)N═C(NR2)R, —OC(NR2)═NR, and —O(alkadiyl)C(NR2)═NR)), and alkoxybisamidine (—O(alkadiyl)N═C(NR2)2. —O(alkadiyl)NRC(NR2)—NR, and —O(alkadiyl)NRC(NR2)═NR) moieties are defined by the corresponding formula shown, in which R can be selected independently from a linear, branched, and/or cyclic (“cycloalkyl”) hydrocarbyl moieties, including alkyl (saturated hydrocarbons) as well as alkenyl and alkynyl moieties, having from 1 to about 20 (for example, from 1 to about 12, or 1 to about 6) carbon atoms.
  • The inclusion of alkenyl and alkynyl moieties provides, among other things, the capability to cross-link the polyphosphazene moieties to any extent desired. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl and dodecyl. Cycloalkyl moieties may be monocyclic or multicyclic, and examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl. Additional examples of alkyl moieties have linear, branched and/or cyclic portions (e.g. 1-ethyl-4-methyl-cyclohexyl).
  • According to this definition and usage (supra), specific examples of R (alkyl) groups include unsubstituted alkyl, substituted alkyl such as halo-substituted alkyl (haloalkyl), unsubstituted alkenyl, substituted alkenyl such as halo-substituted alkenyl, and unsubstituted alkynyl, and substituted alkynyl such as halo-substituted alkynyl.
  • Furthermore, these examples of R (alkyl) provide that the alkoxy (OR) substituents can be unsubstituted alkoxy (“alkyloxy”), substituted alkoxy such as halo-substituted alkoxy (haloalkoxy), unsubstituted alkenyloxy, substituted alkenyloxy such as halo-substituted alkenyloxy, unsubstituted alkynyloxy, and substituted alkynyloxy such as halo-substituted alkynyloxy. In this aspect, vinyloxy and allyloxy can be useful.
  • A silyl group is a —SiR3 group and a silyloxy group is an —OSiR3 group, where each R moiety is selected independently from the R groups defined supra. That is, R in each occurrence is selected independently from a linear, branched, and/or cyclic (“cycloalkyl”) hydrocarbyl moieties, including alkyl (saturated hydrocarbons) as well as alkenyl and alkynyl moieties, having from 1 to about 20 (for example, from 1 to about 12, or 1 to about 6) carbon atoms.
  • Unless otherwise specified, any R group can be unsubstituted or substituted independently with at least one substituent selected from a halogen (fluorine, chlorine, bromine, or iodine), an alkyl, an alkylsulfonyl, an amino, an alkylamino, a dialkylamino, an amidino (—N═C(NH2)2), an alkoxide, or an aryloxide, any of which can have up to about 6 carbon atoms, if applicable. Thus, the term substituted “alkyl” and moieties which encompass substituted alkyl, such as “alkoxy,” include haloalkyl and haloalkoxy, respectively, including any fluorine-, chlorine-, bromine-, and iodine-substituted alkyl and alkoxy. Thus, terms haloalkyl and haloalkoxy refers to alkyl and alkoxy groups substituted with one or more halogen atoms, namely fluorine, chlorine, bromine, or iodine, including any combination thereof.
  • Unless otherwise indicated, the term “aryl” means an aromatic ring or an aromatic or partially aromatic ring system composed of carbon and hydrogen atoms, which may be a single ring moiety, or may contain multiple rings bound or fused together. Examples of aryl moieties include, but are not limited to, phenyl, anthracenyl, azulenyl, biphenyl, fluorenyl, indan, indenyl, naphthyl, phenanthrenyl, 1,2,3,4-tetrahydro-naphthalene, tolyl, and the like, any of which having up to about 20 carbon atoms. An aryloxy group refers to an —O(aryl) moiety.
  • The terms haloaryl and haloaryloxy refer to aryl and aryloxy groups, respectively, substituted with one or more halogen atoms, namely fluorine, chlorine, bromine, or iodine, including any combination thereof.
  • A heterocyclic alkyl group with at least one nitrogen as a heteroatom refers to a non-aromatic heterocycle and includes a cycloalkyl or a cycloalkenyl moiety in which one or more of the atoms in the ring structure is nitrogen rather than carbon, and which may be monocyclic or multicyclic, and may include exo-carbonyl moieties and the like. Examples of heterocyclic alkyl group with nitrogen as a heteroatom include, but are not limited to, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydropyrimidinyl, morpholinyl, aziridinyl, imidazolidinyl, 1-pyrroline, 2-pyrroline, or 3-pyrroline, pyrrolidinonyl, piperazinonyl, hydantoinyl, piperidin-2-one, pyrrolidin-2-one, azetidin-2-one, and the like. Thus, these groups include heterocyclic exocyclic ketones as well.
  • A heteroaryl group with at least one nitrogen as the heteroatom refers to an aryl moiety in which one or more of the atoms in the ring structure is nitrogen rather than carbon, and which may be monocyclic or multicyclic. Examples of heterocyclic alkyl group with nitrogen as a heteroatom include, but are not limited to, acridinyl, benzimidazolyl, quinazolinyl, benzoquinazolinyl, imidazolyl, indolyl, isothiazolyl, isoxazolyl, oxazolyl or oxadiazolyl, phthalazinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolinyl, tetrazolyl, thiazolyl, triazinyl, and the like. In this aspect, this disclosure includes or encompasses chemical moieties found as subunits in a wide range of pharmaceutical agents, natural moieties, natural biomolecules, and biomacromolecules. For example, this disclosure encompasses a number of pharmaceutical agents available with the tetrazole group (for example, losartan, candesartan, irbesartan, and other Angiotensin receptor antagonists); the triazole group (for example, fluconazole, isavuconazole, itraconazole, voriconazole, pramiconazole, posaconazole, and other antifungal agents); diazoles (for example, fungicides such as Miconazole, Ketoconazole, Clotrimazole, Econazole, Bifonazole, Butoconazole, Fenticonazole, Isoconazole, Oxiconazole, Sertaconazole, Sulconazole, Tioconazole, and the like); and imidazoles (histidine, histamine, and the like). Thus in one aspect, some of the R1 to R6 moieties in the formula I can encompass chemical moieties found as subunits in a wide range of pharmaceutical agents, natural moieties, natural biomolecules, and biomacromolecules.
  • A heterocyclic alkyl group with at least one phosphorus, oxygen, sulfur, or selenium as a heteroatom refers to a non-aromatic heterocycle and includes a cycloalkyl or a cycloalkenyl moiety in which one or more of the atoms in the ring structure is phosphorus, oxygen, sulfur, or selenium rather than carbon, and which may be monocyclic or multicyclic, and may include exo-carbonyl moieties and the like. Similarly, a heteroaryl group with at least one phosphorus, oxygen, sulfur, or selenium as the heteroatom refers to an aryl moiety in which one or more of the atoms in the ring structure is phosphorus, oxygen, sulfur, or selenium rather than carbon, and which may be monocyclic or multicyclic. Examples of heterocyclic alkyl groups or heteroaryls with phosphorus, oxygen, sulfur, or selenium as a heteroatom include, but are not limited to, substituted or unsubstituted ethylene oxide (epoxides, oxiranes), oxirene, oxetane, tetrahydrofuran (oxolane), dihydrofuran, furan, pyran, tetrahydropyran, dioxane, dioxin, thiirane (episulfides), thietane, tetrahydrothiophene (thiolane) dihydrothiophene, thiophene, thiane, thiine (thiapyrane), oxazine, thiazine, dithiane, dithietane, and the like. Thus, these groups include all isomers, including regioisomers of the recited compounds. For example, these groups include 1,2- and 1,3-oxazoles, thiazoles, selenazoles, phosphazoles, and the like, which include different heteroatoms from the group 15 or group 16 elements.
  • Additionally, if desired, polymers other than the poly[bis(trifluoroethoxy) phosphazene] and/or its derivative may be included and/or combined with in the particle. Examples of polymers may include poly(lactic acid), poly(lactic-co-glycolic acid), poly(caprolactone), polycarbonates, polyamides, polyanhydrides, polyamino acids, polyorthoesters, polyacetals, polycyanoacrylates, and polyurethanes. Other polymers include polyacrylates, ethylene-vinyl acetate co-polymers, acyl substituted cellulose acetates and derivatives thereof, degradable or non-degradable polyurethanes, polystyrenes, polyvinylchloride, polyvinyl fluoride, poly(vinyl imidazole), chlorosulphonated polyolefins, and polyethylene oxide. Examples of polyacrylates include, but are not limited to, acrylic acid, butyl acrylate, ethylhexyl acrylate, methyl acrylate, ethyl acrylate, acrylonitrile, methyl methacrylate, TMPTA (trimethylolpropane triacrylate), and the like. One may incorporate the selected compounds by any means known in the art, including diffusing, inserting or entrapping the additional compounds in the matrix of an already formed particle or by adding the additional compound to a polymer melt or to a polymer solvent in the preparation of the particle such as described herein.
  • The particle may be coated with an additional polymer layer or layers, including polymers such as those mentioned hereinabove. Further, PTFEP or derivatives thereof, may be used to form such a coating on a particle formed of other suitable polymers or copolymers known or to be developed in the art. Preferably, when coating a particle such as a microparticle, PTFEP is applied as a coating on a microparticle(s) formed of an acrylic-based polymer as set forth in further detail below.
  • E. Various Methods for Utilizing Color-Coded and Size-Calibrated Polymeric Particles
  • FIG. 4 is a schematic of an interventional occlusion of a hypothetical blood vessel employing particles of at least three different diameter sizes, each set of particles labeled according to a different color scheme. In FIG. 4, a hypothetical blood vessel 400 that can transport blood from point 405 to point 410 as shown. If occlusion of blood vessel 400 at point 410, for example, is necessary for treatment, efficient occlusion can be achieved by deploying a first set A of smallest particles such as 420 and 422, followed immediately by a second set B of intermediate particles such as 430 and 432, followed immediately by a third set C of largest particles such as 440 and 442 of a given range of particles calibrated to a particular size of interest.
  • A method of selective embolization at a site in need of, the method comprising administering color-coded and size-calibrated particles described herein to a patient in need of.
  • All publications and patents mentioned in this disclosure are incorporated herein by reference in their entireties, for the purpose of describing and disclosing, for example, the constructs and methodologies that are described in the publications, which might be used in connection with the presently described methods, compositions, articles, and processes. The publications discussed throughout the text are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention. Should the usage or terminology used in any reference that is incorporated by reference conflict with the usage or terminology used in this disclosure, the usage and terminology of this disclosure controls. The Abstract of the disclosure is provided to satisfy the requirements of 37 C.F.R. §1.72 and the purpose stated in 37 C.F.R. §1.72(b) “to enable the United States Patent and Trademark Office and the public generally to determine quickly from a cursory inspection the nature and gist of the technical disclosure.” The Abstract is not intended to be used to construe the scope of the appended claims or to limit the scope of the subject matter disclosed herein. Moreover, any headings are not intended to be used to construe the scope of the appended claims or to limit the scope of the subject matter disclosed herein. Any use of the past tense to describe an example otherwise indicated as constructive or prophetic is not intended to reflect that the constructive or prophetic example has actually been carried out.
  • Also unless indicated otherwise, when a range of any type is disclosed or claimed, for example a range of molecular weights, layer thicknesses, concentrations, temperatures, and the like, it is intended to disclose or claim individually each possible number that such a range could reasonably encompass, including any sub-ranges encompassed therein. For example, when the Applicants disclose or claim a chemical moiety having a certain number of atoms, for example carbon atoms, Applicants' intent is to disclose or claim individually every possible number that such a range could encompass, consistent with the disclosure herein. Thus, by the disclosure that an alkyl substituent or group can have from 1 to 20 carbon atoms, Applicants intent is to recite that the alkyl group have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms, including any range or sub-range encompassed therein. Accordingly, Applicants reserve the right to proviso out or exclude any individual members of such a group, including any sub-ranges or combinations of sub-ranges within the group, that can be claimed according to a range or in any similar manner, if for any reason Applicants choose to claim less than the full measure of the disclosure, for example, to account for a reference that Applicants are unaware of at the time of the filing of the application.
  • EXAMPLES Example 1 Physical Incorporation of Indigo Dyes as Precipitates
  • Indigo dye can be incorporated into acrylate-based microparticles as follows. The vat can be prepared by mixing 5 g Indigo, 2.5 ml ethanol, 150 ml hot water, 6.5 ml concentrated sodium hydroxide solution and 7.5 g sodium dithionite. The mixture can be stirred for 15 minutes at 50-60° C. until the mixture converts to yellow-greenish. The concentrated solution can be given into 3 L of hot (50-60° C.) water with 3 ml of ammonia (25% solution) and additional 2 g of sodium dithionite. The amount of water can be varied from 0 to 31 to receive different color intensity. After stirring of the solution becomes yellow-greenish the particles can be added, and gently stirred for additional 15 minutes. After decanting and rinsing of the particles with water they become blue. Alternatively, Indigo red can be incorporated following the same protocol.
  • Example 2 Physical Incorporation of Dyes Containing Sulfonic Acid Side Groups as Precipitates
  • Dyes containing sulfonic acid side groups can be incorporated into acrylate-based microparticles as follows. Dyes containing sulfonic acid side groups have a high capacity in precipitating with barium ions to form a water insoluble compound. For example, 3 ml Reactive Blue 21 (20 mg/ml physiological saline) can be added to 3 ml hydrated polymethylacrylate beads (400-600 μm) in physiological saline (total volume 6 ml). The suspension can be gently shaken for 10 to 15 min to reach diffusion equilibrium. Afterwards, the aqueous phase can be removed. 5 ml 0.5 molar aqueous barium chloride can be added to the particles and shaken over 30 min at ambient temperature. The suspension was stored over night at 70° C., than extensively washed with physiological saline until the solution remained optically colorless. The solution can be substituted by 0.5 molar barium chloride and heated for 30 min to approximately 125° C. at 1.5 bar. Afterwards the particles can be extensively washed with physiological saline. Different color intensities can be prepared by varying aqueous Reactive Blue 21 concentrations from 2 to 30 mg/ml physiological saline and from 0.5 ml to 5 ml hydrated polymethylacrylate beads.
  • Example 3 Physical Incorporation of Dyes Containing Sulfonic Acid Side Groups as Precipitates
  • Dyes containing sulfonic acid side groups can be incorporated into acrylate-based microparticles as follows. Reactive Blue, Reactive Blue 4, Reactive Blue 19, Reactive Blue 163, Reactive Black 5, Reactive Yellow 86, Reactive Yellow 15, Reactive Orange 78, Reactive Red 11, Reactive Red 180, Chinolin Yellow, Allura Red AC, and any combinations thereof can be used to obtain different color shades by using mixtures of various ratios/percentage. Color intensities can be altered by varying the total dye amount (1 mg to 400 mg).
  • Example 4 Chemical Incorporation of Dyes to Activated Hydrogels Exhibiting Reactive Groups
  • A mixture of methyl methacrylate (MMA), allyl methacrylate (AMA), and the crosslinker triethyleneglycol dimethacrylate (TEGDMA) is copolymerized in presence of a radical initiator (lauroyl peroxide, LP) can be performed by suspension polymerization. For example, 200 g freshly destilled MMA, 670 mg LP, 2.875 g TEGDMA, and 10 g AMA can be mixed until a clear solution is obtained. The aqueous phase composed of 23 g polyvinylalcohol (PVA; 26/88), 5 g disodium hydrogen phosphate, and 290 mg sodium dihydrogen phosphate can be dissolved in 1000 ml deionized water. Polymerization can be performed by stirring at 130 rpm (initial 250 rpm for 5 to 10 min) at 67° C. for 1 h, than 2 h at 70° C., and finally 80° C. for 2 h. Particle sizes in the range of 50 to 1000 μm can be obtained. Hydrolysis can be performed with 5 g of the particles (taken from sieve fraction 212 to 350 μm) in 1500 ml ethylene glycol containing 75 g potassium hydroxide under reflux for 2 h. Afterwards, the particles can be washed extensively with deionized water until pH7 results. The water can be substituted by physiological saline, and osmolarity measured at 290±50 mOsmol/kg. 20 ml hydrated particles (in physiological saline) can be colored by adding 150 mg Reactive Blue 4 and Reactive Blue 19, respectively. The first dyeing can be performed at ambient temperature, the latter reaction at 70° C.; after 14 h, the particles can be washed with physiological saline until the solution remains optically colorless.
  • Example 5 Chemical Incorporation of Dyes to Activated Hydrogels Exhibiting Reactive Groups
  • A mixture of methyl methacrylate (MMA), diallylurea (DAU) and the crosslinker triethyleneglycol dimethacrylate (TEGDMA) is copolymerized in presence of a radical initiator (lauroyl peroxide, LP) can be performed by suspension polymerization. For example, 100 g freshly distilled MMA, 330 mg LP, 1.43 g TEGDMA, and 1.0 g DAU can be mixed until a clear solution is obtained. The aqueous phase composed of 11.5 g polyvinylalcohol (PVA; 26/88), 2.5 g disodium hydrogen phosphate, and 145 mg sodium dihydrogen phosphate can be dissolved in 500 ml deionized water. Polymerization can be performed by stirring at 130 rpm (initial 250 rpm for 5 to 10 min) at 67° C. for 1 h, than 2 h at 70° C. and finally 80° C. for 2 h. Particle sizes in the range of 50 to 800 μm. Hydrolysis can be performed with 5 g of the particles in 1500 ml ethylene glycol containing 75 g potassium hydroxide under reflux for 2 h. Afterwards, the particles can be washed extensively with deionized water until pH of 7 results. The water can be substituted by physiological saline, and osmolarity measured at 290±50 mOsmol/kg. 20 ml hydrated particles (in physiological saline) can be colored by adding 150 mg Reactive Blue 4 and Reactive Blue 19, respectively. The first dyeing can be performed at ambient temperature, the latter reaction at 70° C.; after 16 h, the particles can be washed with physiological saline until the solution remains optically colorless.
  • Example 6 Chemical Incorporation of Reactive Dyes to Activated Hydrogels
  • Reactive Dyes can bind to nucleophilic groups such as amines (primary amines preferred) or hydroxyl groups. To introduce amine groups to an acrylate-based hydrogels, 100 mg dry particles can be hydrated in 5 ml deionized water for 10 to 15 min. Afterwards, 100 mg 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and 100 μm ethylene diamine (EDA) can be added and shaken gently for 2 h at ambient temperature. After extensive washing with potable water the beads can be dyed in 5 ml deionized water by adding 200 mg Reactive Blue 4 and Reactive Blue 19, respectively. The first mixture can be kept at room temperature and the latter reaction at 70° C., both over night. The dye solution can be removed and the particles can be washed with potable water and afterwards 3-4 times with 8-9 ml 0.9% NaClaq until the transport solution (TS) is almost colorless. Different color intensities can be prepared by varying EDA (20 μl to 200 μl), EDC (20 mg to 200 mg), and dye amount (10 mg to 40 0 mg); other colors can be also created by using Reactive Red 11, Reactive Red 180, Reactive Yellow 86, Reactive Yellow 15, Reactive Black 5, and Reactive Blue 21.
  • Example 7 Chemical Incorporation of Reactive Dyes to Activated Hydrogels
  • To expand the color palette, a broader range of colors such as green, purple, and orange beads can be prepared as follows. As described above, various mixtures of dyes can be employed together to create the colors of interest, for example: (i) orange can be made by mixing red and yellow (ii) green can be made by mixing blue and yellow, and (iii) purple can be made by mixing blue and red. Dyes can be chosen within the same dye family (Remazol®: Reactive Yellow 15, Reactive Red 180, Reactive Black 5, Reactive Blue 21 and Reactive Blue 19; Procion®: Reactive Red 11, Reactive Yellow 86, Reactive Blue 4). Different color shades can be obtained by using mixtures of different ratios in the range of about 1:100 to about 100:1. Color intensities can be altered by varying EDA (20 μl to 200 μl), EDC (20 mg to 200 mg), and adjusting the total dye amount from about 10 mg to about 400 mg.
  • Example 8 Chemical Incorporation of Reactive Dyes to Activated Hydrogels
  • To expand the color palette, a broader range of colors such as green, purple, pink, orange, grey, olive, smurf-blue, brown, ivory, black, burgundy, crimson, turquoise, orange beads can be prepared. Mixtures of at least two dyes can be utilized to create the described colors. Amino activated Reactive Yellow 86, Reactive Yellow 15, Reactive Blue 19, Reactive Red 180, Reactive Orange 78, Reactive Blue 163, Reactive Black 5, Reactive Blue 21, Reactive Blue 4, Reactive Blue 19, and Reactive Red 11 can be used. Different color shades can be obtained by using mixtures of all percentage ratios. Color intensities can be altered by varying EDC (20 mg to 500 mg), and adjusting the total dye amount from about 1 mg to about 400 mg.
  • Example 9 Chemical Incorporation of Reactive Dyes to Activated Hydrogels
  • To expand the color palette, a broader range of colors such as green, purple, pink, orange, grey, olive, smurf-blue, brown, ivory, black, burgundy, crimson, turquoise, and orange beads can be prepared. After the first dyeing procedure, additional dyeing procedures can be applied utilizing another dye. Amino activated Reactive Yellow 86, Reactive Yellow 15, Reactive Blue 19, Reactive Red 180, Reactive Orange 78, Reactive Blue 163, Reactive Black 5, Reactive Blue 21, Reactive Blue 4, Reactive Blue 19, and Reactive Red 11 can be utilized, for example. Different color shades can be obtained altering dye amounts (0.1 mg to 20 mg) during the different dyeing procedures. Color intensities can be altered by varying EDC (20 mg to 500 mg), and adjusting the total dye amount from about 1 mg to 100 mg.
  • Example 10 Physical Incorporation of Iron(III) Chloride as Metal Oxide Precipitate to Hydrogels
  • Approximately 20 ml particles (900 μm) can be immersed in 80 ml 0.9% aqueous sodium chloride solution (physiological saline). First 2.6 ml aqueous iron(III) chloride (45%) can be added to this suspension, and then followed by 4 ml of 1 molar aqueous iron(II) sulfate. The suspension can be gently shaken for 10 to 15 min to reach diffusion equilibrium. 100 ml of 0.1 molar aqueous sodium hydroxide solution (containing 0.9% sodium chloride) can be added drop wise to allow iron hydroxide precipitation. The particles can be extensively washed with physiological saline. Rusty colored particles can be obtained. Different color intensities can be prepared by varying aqueous iron(III) chloride (45%) from 0.1 ml to 10 ml, 1 molar aqueous iron(II) sulfate from 0.15 ml to 15.5 ml, and aqueous sodium hydroxide from 0.1 molar to 1 molar and 4 ml to 400 ml, respectively.
  • Example 11 Physical Incorporation of Iron(III) Chloride as Metal Oxide Precipitate to Hydrogels
  • The particles can be prepared as described above, substituting 0.1 to 1 molar aqueous ammonia (NH3aq) in the place of sodium hydroxide. Different color intensities can be prepared by varying aqueous iron(III) chloride (45%) from 0.1 ml to 10 ml, 1 molar aqueous iron(II) sulfate from 0.15 ml to 15.5 ml, and aqueous ammonia from 0.1 molar to 1 molar and 4 ml to 400 ml, respectively.
  • Example 12 Physical Incorporation of Iron(III) Chloride as Metal Oxide Precipitate to Hydrogels
  • The particles can be prepared as described above, as follows. 3 ml hydrated particles (900 μm) can be immersed in 6 ml 0.9% aqueous sodium chloride solution (physiological saline). 2 ml of a saturated aqueous iron(II) sulfate solution (T=20° C.) can be added to the suspension and shaken gently for 10 to 15 min to reach diffusion equilibrium. 2 ml hydrogen peroxide (3%) can be added to the suspension for 5 to 6 min; afterwards the particles can be extensively washed with physiological saline, resulting in brownish colored particles. Different color intensities can be prepared by varying saturated aqueous iron(II) sulfate from 0.1 ml to 10 ml, hydrogen peroxide concentration from 0.1% to 5% utilizing an amount from 0.5 ml to 10 ml.
  • The foregoing description, for purposes of explanation, used specific nomenclature to provide a thorough understanding of the invention. However, it will be apparent to one skilled in the art that the specific details are not required in order to practice the invention. The foregoing descriptions of specific embodiments of the present invention are presented for purpose of illustration and description. They are not intended to be exhaustive or to limit the invention to the precise forms disclosed. Obviously many modifications and variations are possible in view of the above teachings. The embodiments are shown and described in order to best explain the principles of the invention and its practical applications, to thereby enable others skilled in the art to best utilize the invention and various embodiments with various modifications as are suited to the particular use contemplated. It is intended that the scope of the invention be defined by the following claims and their equivalent.

Claims (12)

1. Color-coded and size-calibrated polymeric particles, each particle comprising:
an acrylate-based hydrogel core incorporating one or more chromophores; and
an outer shell comprising a polyphosphazenes having the general formula (I):
Figure US20100028260A1-20100204-C00010
in which the n value is an integer from 2 to ∞;
R1 to R6 are independently selected from the group consisting of:
a substituted or unsubstituted alkyl, alkoxy, aryl, aryloxy, silyl, silyloxy, alkylsulfonyl, alkyl amino, dialkyl amino, ureido, carboxylic acid ester, alkylmonoamidine, alkylbisamidine, alkoxymonoamidine, or alkoxybisamidine, aminoalkyl, haloalkyl, thioalkyl, thioaryl, haloalkoxy, aryloxy, haloaryloxy, alkylthiolate, arylthiolate, alkylsulphonyl, alkylamino, dialkylamino, heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, sulfur, phosphorus, and combinations thereof, heteroaryl comprising one or more heteroatoms selected from nitrogen, oxygen, sulfur, phosphorus, and combinations thereof.
2. The color-coded and size-calibrated polymeric particles of claim 1, wherein R1 to R6 are selected independently from the group consisting of OCH3, OCH2CH3, OCH2CH2CH3, OCF3, OCH2CF3, OCH2CH2CF3, OCH2CF2CF3, OCH(CF3)2, OCCH3(CF3)2, OCH2CF2CF2CF3, OCH2(CF2)3CF3, OCH2(CF2)4CF3, OCH2(CF2)5CF3, OCH2(CF2)6CF3, OCH2(CF2)7CF3, OCH2CF2CHF2, OCH2CF2CF2CHF2, OCH2(CF2)3CHF2, OCH2(CF2)4CHF2, OCH2(CF2)5CHF2, OCH2(CF2)6CHF2, OCH2(CF2)7CHF2, OCH2CH═CH2, OCH2CH2CH═CH2, and any combinations thereof.
3. The color-coded and size-calibrated polymeric particles of claim 1, wherein the polyphosphazene is poly[bis(2,2,2-trifluoroethoxy)]phosphazene or a derivative of poly[bis(2,2,2-trifluoroethoxy)]phosphazene.
4. The color-coded and size-calibrated polymeric particles of claim 1, wherein the acrylate-based hydrogel core comprises a polymer selected from the group consisting of poly(methacrylic acid), poly(methyl acrylate), poly(methyl methacrylate), poly(ethyl methacrylate), poly(hexamethyl methacrylate), poly(hydroxyethyl methacrylate), poly(acrylic acid), poly(butyl acrylate), poly(2-ethylhexyl acrylate), poly(ethyl acrylate), poly(acrylonitrile), poly(trimethylolpropane triacrylate), copolymers thereof, and combinations thereof.
5. The color-coded and size-calibrated polymeric particles of claim 1 calibrated to have an average diameter selected from the group consisting of: from about 10 μm to about 1500 μm; from about 10 μm to about 1100 μm; from about 10 μm to about 1000 μm; from about 10 μm to about 900 μm; from about 10 μm to about 800 μm; from about 10 μm to about 700 μm; from about 10 μm to about 600 μm; from about 10 μm to about 500 μm; from about 10 μm to about 400 μm; from about 10 μm to about 300 μm; from about 10 μm to about 200 μm; from about 10 μm to about 175 μm; from about 10 μm to about 150 μm; from about 10 μm to about 120 μm; from about 10 μm to about 80 μm; and from about 10 μm to about 40 μm.
6. The color-coded and size-calibrated polymeric particles of claim 1, wherein the acrylate-based hydrogel core comprises an agent of interest selected from the group consisting of barium sulfate, an imaging agent, a bioactive agent, a pharmaceutical agent, a contrast agent, a steroid, a hormone, a nucleic acid, an antibiotic, an antiseptic, an analgesic, an anti-neoplastic, an anesthetic, and combinations thereof.
7. A method of making color-coded and size-calibrated polymeric particles, the method comprising:
incorporating one or more chromophores into an acrylate-based hydrogel core; and
coating the acrylate-based hydrogel core with a polyphosphazene having the general formula (I):
Figure US20100028260A1-20100204-C00011
in which the n value is an integer from 2 to ∞;
R1 to R6 are independently selected from the group consisting of:
a substituted or unsubstituted alkyl, alkoxy, aryl, aryloxy, silyl, silyloxy, alkylsulfonyl, alkyl amino, dialkyl amino, ureido, carboxylic acid ester, alkylmonoamidine, alkylbisamidine, alkoxymonoamidine, or alkoxybisamidine, aminoalkyl, haloalkyl, thioalkyl, thioaryl, haloalkoxy, aryloxy, haloaryloxy, alkylthiolate, arylthiolate, alkylsulphonyl, alkylamino, dialkylamino, heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, sulfur, phosphorus, and combinations thereof, heteroaryl comprising one or more heteroatoms selected from nitrogen, oxygen, sulfur, phosphorus, and combinations thereof.
8. The method of claim 7, wherein R1 to R6 are selected independently from the group consisting of OCH3, OCH2CH3, OCH2CH2CH3, OCF3, OCH2CF3, OCH2CH2CF3, OCH2CF2CF3, OCH(CF3)2, OCCH3(CF3)2, OCH2CF2CF2CF3, OCH2(CF2)3CF3, OCH2(CF2)4CF3, OCH2(CF2)5CF3, OCH2(CF2)6CF3, OCH2(CF2)7CF3, OCH2CF2CHF2, OCH2CF2CF2CHF2, OCH2(CF2)3CHF2, OCH2(CF2)4CHF2, OCH2(CF2)5CHF2, OCH2(CF2)6CHF2, OCH2(CF2)7CHF2, OCH2CH═CH2, OCH2CH2CH═CH2, and combinations thereof.
9. The method of claim 7, wherein the acrylate-based hydrogel core comprises a polymer selected from the group consisting of poly(methacrylic acid), poly(methyl acrylate), poly(methyl methacrylate), poly(ethyl methacrylate), poly(hexamethyl methacrylate), poly(hydroxyethyl methacrylate), poly(acrylic acid), poly(butyl acrylate), poly(2-ethylhexyl acrylate), poly(ethyl acrylate), poly(acrylonitrile), poly(trimethylolpropane triacrylate), copolymers thereof, and combinations thereof.
10. The method of claim 7, wherein the color-coded and size-calibrated polymeric particles are calibrated to have an average diameter selected from the group consisting of: from about 10 μm to about 1500 μm; from about 10 μm to about 1100 μm; from about 10 μm to about 1000 μm; from about 10 μm to about 900 μm; from about 10 μm to about 800 μm; from about 10 μm to about 700 μm; from about 10 μm to about 600 μm; from about 10 μm to about 500 μm; from about 10 μm to about 400 μm; from about 10 μm to about 300 μm; from about 10 μm to about 200 μm; from about 10 μm to about 175 μm; from about 10 μm to about 150 μm; from about 10 μm to about 120 μm; from about 10 μm to about 80 μm; and from about 10 μm to about 40 μm.
11. The color-coded and size-calibrated polymeric particles of claim 1, wherein the acrylate-based hydrogel core comprises an agent of interest selected from the group consisting of barium sulfate, an imaging agent, a bioactive agent, a pharmaceutical agent, a contrast agent, a steroid, a hormone, a nucleic acid, an antibiotic, an antiseptic, an analgesic, an anti-neoplastic, an anesthetic, and combinations thereof.
12. A method of selective embolization at a site in need of, the method comprising,
administering color-coded and size-calibrated particles of claim 1 to a patient in need of.
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9408916B2 (en) 2013-09-19 2016-08-09 Microvention, Inc. Polymer films
US9546236B2 (en) 2013-09-19 2017-01-17 Terumo Corporation Polymer particles
US9688788B2 (en) 2013-11-08 2017-06-27 Terumo Corporation Polymer particles
US9907880B2 (en) 2015-03-26 2018-03-06 Microvention, Inc. Particles
US10201632B2 (en) 2016-09-28 2019-02-12 Terumo Corporation Polymer particles

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11426355B2 (en) 2004-10-25 2022-08-30 Varian Medical Systems, Inc. Color-coded and sized loadable polymeric particles for therapeutic and/or diagnostic applications and methods of preparing and using the same

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4774189A (en) * 1984-12-24 1988-09-27 Flow Cytometry Standards Corp. Fluorescent calibration microbeads simulating stained cells
US20020068089A1 (en) * 1998-03-06 2002-06-06 Biosphere Medical, Inc. Implantable particles for tissue bulking and the treatment of gastroesophageal reflux disease, urinary incontinence, and skin wrinkles
US20030099683A1 (en) * 2000-03-18 2003-05-29 Michael Grunze Polyphosphazene derivatives
US20030157142A1 (en) * 2000-08-11 2003-08-21 Stefan Nagel Implants with a phosphazene-containing coating
US20030211165A1 (en) * 2000-03-24 2003-11-13 Jean-Marie Vogel Microspheres for active embolization
US20090011073A1 (en) * 2007-07-04 2009-01-08 Fanuc Ltd Stationary platen of injection molding machine
US20090025601A1 (en) * 2007-07-27 2009-01-29 Sundar Vasudevan Polymerizable dye-monomer conjugates for encapsulating pigment particles
US20090110730A1 (en) * 2007-10-30 2009-04-30 Celonova Biosciences, Inc. Loadable Polymeric Particles for Marking or Masking Individuals and Methods of Preparing and Using the Same
US20110150954A1 (en) * 2003-03-14 2011-06-23 Sol-Gel Technologies Ltd. Agent-encapsulating micro-and nanoparticles, methods for preparation of same and products containing same

Family Cites Families (296)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE420565B (en) 1974-06-06 1981-10-19 Pharmacia Ab AID FOR INTRAVASCULAR ADMINISTRATION FOR USE IN CONNECTION WITH INTRAVASCULAR ADMINISTRATION OF A SOLUTION OR SUSPENSION OF A DIAGNOSTIC AGENT
US4107288A (en) 1974-09-18 1978-08-15 Pharmaceutical Society Of Victoria Injectable compositions, nanoparticles useful therein, and process of manufacturing same
US3949073A (en) 1974-11-18 1976-04-06 The Board Of Trustees Of Leland Stanford Junior University Process for augmenting connective mammalian tissue with in situ polymerizable native collagen solution
US4166800A (en) 1977-08-25 1979-09-04 Sandoz, Inc. Processes for preparation of microspheres
DE2905878A1 (en) 1979-02-16 1980-08-28 Merck Patent Gmbh IMPLANTATION MATERIALS AND METHOD FOR THEIR PRODUCTION
US4311736A (en) 1979-03-19 1982-01-19 The Kendall Company Article having organo-phosphonitrile rubber coating bonded to natural or synthetic rubber and method of making
US4341844A (en) 1979-10-25 1982-07-27 The Kendall Company Article having organo-phosphonitrile rubber coating bonded to natural or synthetic rubber and method of making
US4318947A (en) 1979-12-26 1982-03-09 The Kendall Company Polymer coating and curing process for catheters
FR2482112B1 (en) 1980-05-09 1985-06-07 Pharmindustrie NOVEL HYDROPHILIC COPOLYMERS BASED ON N- (TRIS (HYDROXYMETHYL) METHYL) ACRYLAMIDE, PROCESSES FOR THEIR PREPARATION, AQUEOUS GELS OF SAID COPOLYMERS AND THEIR USE AS ION EXCHANGERS
US4698373A (en) 1981-01-21 1987-10-06 Dentsply Research & Development Corp. Stable one part dental compositions employing ipn technology
JPS5879915A (en) 1981-11-09 1983-05-13 Nippon Soda Co Ltd Preparation of rod-shaped drug
US4424208A (en) 1982-01-11 1984-01-03 Collagen Corporation Collagen implant material and method for augmenting soft tissue
US4440750A (en) 1982-02-12 1984-04-03 Collagen Corporation Osteogenic composition and method
US4582640A (en) 1982-03-08 1986-04-15 Collagen Corporation Injectable cross-linked collagen implant material
US4424395A (en) 1982-03-11 1984-01-03 The Dow Chemical Company Carbamates of biphenyls
US4535485A (en) 1982-03-12 1985-08-20 Medical Biological Sciences, Inc. Polymeric acrylic prothesis
US4547390A (en) 1982-03-12 1985-10-15 Medical Biological Sciences, Inc. Process of making implantable prosthesis material of modified polymeric acrylic (PMMA) beads coated with PHEMA and barium sulfate
JPS58206759A (en) 1982-05-28 1983-12-02 テルモ株式会社 Medical container
US4451647A (en) 1982-06-21 1984-05-29 Research Corporation Heparinized polyorganophosphazenes
US4480642A (en) 1982-07-26 1984-11-06 Health Products Research, Inc. Dilation device for the cervix
SU1085993A1 (en) 1983-01-24 1984-04-15 Московский ордена Ленина и ордена Трудового Красного Знамени химико-технологический институт им.Д.И.Менделеева Process for preparing hydrophylic polyorganophosphasenes
JPS59164723A (en) 1983-03-10 1984-09-17 Koken:Kk Substrate containing regenerated collagen fibril and its preparation
CA1225585A (en) 1983-06-30 1987-08-18 Maria T. Litvinova Composition for embolization of blood vessels
JPS6038307A (en) 1983-08-11 1985-02-27 Nippon Daigaku Composite material for plugging
US4728345A (en) 1983-12-28 1988-03-01 Monsanto Company Multicomponent gas separation membranes having polyphosphazene coatings
US4837285A (en) 1984-03-27 1989-06-06 Medimatrix Collagen matrix beads for soft tissue repair
US4537916A (en) 1984-06-25 1985-08-27 The Dow Chemical Company Structured latex particles which are film forming and a process for their preparation
US4557764A (en) 1984-09-05 1985-12-10 Collagen Corporation Process for preparing malleable collagen and the product thereof
US4883699A (en) 1984-09-21 1989-11-28 Menlo Care, Inc. Polymeric article having high tensile energy to break when hydrated
US4911691A (en) 1984-09-21 1990-03-27 Menlo Care, Inc. Assembly for adminstering IV solution
US4595713A (en) 1985-01-22 1986-06-17 Hexcel Corporation Medical putty for tissue augmentation
DE3503584C1 (en) 1985-02-02 1986-06-12 Degussa Ag, 6000 Frankfurt Process for the preparation of suspension polymers
US4592755A (en) 1985-06-11 1986-06-03 Ethyl Corporation Mammary implant
US4851046A (en) 1985-06-19 1989-07-25 University Of Florida Periodontal osseous defect repair
JPH0678434B2 (en) 1985-10-14 1994-10-05 チッソ株式会社 Spherical particulate polyphosphazene and method for producing the same
US4728570A (en) 1985-10-29 1988-03-01 United States Surgical Corporation Calcium-hydroxide-treated polymeric implant matrial
US4798876A (en) 1985-11-12 1989-01-17 Tyndale Plains-Hunter Ltd. Hydrophilic polyurethane composition
JPS6322843A (en) 1986-02-14 1988-01-30 Teijin Ltd Polyphosphazene molding and production thereof
US4880622A (en) 1986-05-20 1989-11-14 Research Corporation Technologies, Inc. Water-soluble phosphazene polymers having pharmacological applications
US4803075A (en) 1986-06-25 1989-02-07 Collagen Corporation Injectable implant composition having improved intrudability
US4849285A (en) 1987-06-01 1989-07-18 Bio Med Sciences, Inc. Composite macrostructure of ceramic and organic biomaterials
WO1988009664A1 (en) 1987-06-10 1988-12-15 Massachusetts Institute Of Technology Polyphosphazene matrix erosion and diffusion release systems
US4912141A (en) 1987-07-28 1990-03-27 Kronman Joseph H Fibrous and cartilaginous tissue replacement
US4902511A (en) 1987-07-28 1990-02-20 Kronman Joseph H Fibrous and cartilaginous tissue replacement
JPH01265970A (en) 1988-04-19 1989-10-24 Shiseido Co Ltd Collagen water solution or water dispersion solution including hyaluronic acid
US5634946A (en) 1988-08-24 1997-06-03 Focal, Inc. Polymeric endoluminal paving process
US4938763B1 (en) 1988-10-03 1995-07-04 Atrix Lab Inc Biodegradable in-situ forming implants and method of producing the same
US5510418A (en) 1988-11-21 1996-04-23 Collagen Corporation Glycosaminoglycan-synthetic polymer conjugates
US5306500A (en) 1988-11-21 1994-04-26 Collagen Corporation Method of augmenting tissue with collagen-polymer conjugates
US5304595A (en) 1988-11-21 1994-04-19 Collagen Corporation Collagen-polymer conjugates
US5162430A (en) 1988-11-21 1992-11-10 Collagen Corporation Collagen-polymer conjugates
DE3841401A1 (en) 1988-12-08 1990-06-13 Martin Lemperle ALLOPLASTIC IMPLANT
US5258028A (en) 1988-12-12 1993-11-02 Ersek Robert A Textured micro implants
US4975280A (en) 1989-01-23 1990-12-04 Ethyl Corporation Bioerodable sustained release implants
US5395620A (en) 1989-01-31 1995-03-07 Coletica Biodegradable microcapsules having walls composed of crosslinked atelocollagen and polyholoside
US5019400A (en) 1989-05-01 1991-05-28 Enzytech, Inc. Very low temperature casting of controlled release microspheres
US5007940A (en) 1989-06-09 1991-04-16 American Medical Systems, Inc. Injectable polymeric bodies
US5116387A (en) 1989-06-09 1992-05-26 American Medical Systems, Inc. Preparation of injectable polymeric bodies
US5158573A (en) 1989-06-09 1992-10-27 American Medical Systems, Inc. Injectable polymeric bodies
JPH0351200A (en) 1989-07-20 1991-03-05 Maruishi Kasei Kk Palette with paint
US5077049A (en) 1989-07-24 1991-12-31 Vipont Pharmaceutical, Inc. Biodegradable system for regenerating the periodontium
US5487897A (en) 1989-07-24 1996-01-30 Atrix Laboratories, Inc. Biodegradable implant precursor
WO1991001720A1 (en) 1989-08-07 1991-02-21 Herman Wade Schlameus Composition and method of promoting hard tissue healing
US5439446A (en) 1994-06-30 1995-08-08 Boston Scientific Corporation Stent and therapeutic delivery system
US5143724A (en) 1990-07-09 1992-09-01 Biomatrix, Inc. Biocompatible viscoelastic gel slurries, their preparation and use
US5246698A (en) 1990-07-09 1993-09-21 Biomatrix, Inc. Biocompatible viscoelastic gel slurries, their preparation and use
DE4024371C2 (en) 1990-08-01 1994-10-13 Degussa Process for the preparation of suspension polymers using phosphonic acids or their ammonium or alkali metal salts as dispersing aid additives
US5487390A (en) 1990-10-05 1996-01-30 Massachusetts Institute Of Technology Gas-filled polymeric microbubbles for ultrasound imaging
US5149543A (en) 1990-10-05 1992-09-22 Massachusetts Institute Of Technology Ionically cross-linked polymeric microcapsules
US5562099A (en) 1990-10-05 1996-10-08 Massachusetts Institute Of Technology Polymeric microparticles containing agents for imaging
US5342557A (en) 1990-11-27 1994-08-30 United States Surgical Corporation Process for preparing polymer particles
US6391343B1 (en) 1991-01-15 2002-05-21 Hemosphere, Inc. Fibrinogen-coated particles for therapeutic use
AU652022B2 (en) 1991-02-12 1994-08-11 C.R. Bard Inc. Injectable medical device
JPH04337328A (en) 1991-05-13 1992-11-25 Shin Etsu Chem Co Ltd Production of phosphazene polymer
FR2676927B1 (en) 1991-05-29 1995-06-23 Ibf MICROSPHERES FOR USE IN THERAPEUTIC VASCULAR OCCLUSIONS AND INJECTABLE SOLUTIONS CONTAINING THEM.
CA2071137A1 (en) 1991-07-10 1993-01-11 Clarence C. Lee Composition and method for revitalizing scar tissue
FR2679466B1 (en) 1991-07-25 1994-04-15 Ceramique Technique FILTRATION MEMBRANE AND MANUFACTURING METHOD.
US6515009B1 (en) 1991-09-27 2003-02-04 Neorx Corporation Therapeutic inhibitor of vascular smooth muscle cells
JP3356447B2 (en) 1991-10-16 2002-12-16 テルモ株式会社 Vascular lesion embolic material composed of dried polymer gel
DE4138513A1 (en) 1991-11-23 1993-05-27 Basf Ag SOLID PHARMACEUTICAL RETARD FORM
US6537574B1 (en) 1992-02-11 2003-03-25 Bioform, Inc. Soft tissue augmentation material
US7968110B2 (en) 1992-02-11 2011-06-28 Merz Aesthetics, Inc. Tissue augmentation material and method
US7060287B1 (en) 1992-02-11 2006-06-13 Bioform Inc. Tissue augmentation material and method
US5204382A (en) 1992-02-28 1993-04-20 Collagen Corporation Injectable ceramic compositions and methods for their preparation and use
DK0632820T3 (en) 1992-02-28 2000-10-02 Collagen Corp Highly concentrated, homogenized collagen compositions
DE69331096T2 (en) 1992-02-28 2002-08-14 Cohesion Tech Inc INJECTABLE, CERAMIC COMPOUNDS AND METHOD FOR THE PRODUCTION AND USE THEREOF
US6235313B1 (en) 1992-04-24 2001-05-22 Brown University Research Foundation Bioadhesive microspheres and their use as drug delivery and imaging systems
DE69332500T2 (en) 1992-04-24 2004-01-29 Chienna Bv DEVICE FOR AVOIDING TISSUE ADHESIONS
AU4926193A (en) 1992-09-21 1994-04-12 Vitaphore Corporation Embolization plugs for blood vessels
AU660852B2 (en) 1992-11-25 1995-07-06 Elan Pharma International Limited Method of grinding pharmaceutical substances
DE784487T1 (en) 1993-03-19 1999-11-04 Q Med Ab Uppsala A PREPARATION AND TISSUE PROPAGATION METHOD
US5562909A (en) 1993-07-12 1996-10-08 Massachusetts Institute Of Technology Phosphazene polyelectrolytes as immunoadjuvants
ATE502664T1 (en) 1993-07-19 2011-04-15 Angiotech Pharm Inc METHOD OF PRODUCTION OF A STENT WITH ANTI-ANGIOGENIC COMPOSITION
US5994341A (en) 1993-07-19 1999-11-30 Angiogenesis Technologies, Inc. Anti-angiogenic Compositions and methods for the treatment of arthritis
US5397352A (en) 1993-08-27 1995-03-14 Burres; Steven Method of recollagenation
US5500161A (en) 1993-09-21 1996-03-19 Massachusetts Institute Of Technology And Virus Research Institute Method for making hydrophobic polymeric microparticles
US5681873A (en) 1993-10-14 1997-10-28 Atrix Laboratories, Inc. Biodegradable polymeric composition
WO1995020362A1 (en) 1994-01-26 1995-08-03 Reiley Mark A Improved inflatable device for use in surgical protocol relating to fixation of bone
US5962427A (en) 1994-02-18 1999-10-05 The Regent Of The University Of Michigan In vivo gene transfer methods for wound healing
US6235061B1 (en) 1994-04-04 2001-05-22 The Penn State Research Foundation Poly(organophosphazene) matrices for bone replacement
US5464932A (en) 1994-04-15 1995-11-07 The Penn State Research Foundation Photocrosslinkable polyphosphazenes and their use as microencapsulation materials
GB9407812D0 (en) 1994-04-20 1994-06-15 Nycomed Salutar Inc Compounds
FR2721198B1 (en) 1994-06-16 1996-10-31 Caravel Jean Baudoin Flexible implantable prosthesis, used in surgery for volume increase or soft tissue reconstruction, in particular breast prosthesis.
ATE296140T1 (en) 1994-06-27 2005-06-15 Bard Peripheral Vascular Inc RADIALLY EXPANDABLE POLYTETRAFLUORETHYLENE AND EXPANDABLE ENDOVASCULAR STENTS MOLDED THEREFROM
US5855895A (en) 1995-06-07 1999-01-05 Virus Research Institute Polyphosphazene polyelectrolyte immunoadjuvants
US5451406A (en) 1994-07-14 1995-09-19 Advanced Uroscience, Inc. Tissue injectable composition and method of use
US5788979A (en) 1994-07-22 1998-08-04 Inflow Dynamics Inc. Biodegradable coating with inhibitory properties for application to biocompatible materials
DE4428056A1 (en) 1994-07-29 1996-02-08 Schering Ag Use of microparticle preparations to eliminate dissolved, non-renal substances from the blood
US5516532A (en) 1994-08-05 1996-05-14 Children's Medical Center Corporation Injectable non-immunogenic cartilage and bone preparation
US5548060A (en) 1994-08-08 1996-08-20 Penn State Research Foundation, Inc. Sulfonation of polyphosphazenes
AU706434B2 (en) 1994-10-18 1999-06-17 Ethicon Inc. Injectable liquid copolymers for soft tissue repair and augmentation
US5599852A (en) 1994-10-18 1997-02-04 Ethicon, Inc. Injectable microdispersions for soft tissue repair and augmentation
US6335383B1 (en) 1994-10-18 2002-01-01 Ethicon, Inc. Microdispersions for coating surgical devices
EP0713707A1 (en) 1994-11-23 1996-05-29 Collagen Corporation In situ crosslinkable, injectable collagen composition for tissue augmention
US6281015B1 (en) 1994-12-16 2001-08-28 Children's Medical Center Corp. Localized delivery of factors enhancing survival of transplanted cells
CA2213403C (en) 1995-02-22 2007-01-16 Menlo Care, Inc. Covered expanding mesh stent
US6962979B1 (en) 1995-03-14 2005-11-08 Cohesion Technologies, Inc. Crosslinkable biomaterial compositions containing hydrophobic and hydrophilic crosslinking agents
US6337389B1 (en) 1995-03-17 2002-01-08 Bioscience Consultants, L.L.C. Method and process for the production of collagen preparations from invertebrate marine animals and compositions thereof
US5686113A (en) 1995-03-21 1997-11-11 Temple University Of The Commonwealth System Of Higher Education Microcapsules of predetermined peptide(s) specificity (ies), their preparation and uses
DE19613048C2 (en) 1995-03-30 1997-12-18 Michael Prof Dr Grunze Artificial implants with antithrombogenic properties and processes for their production
US5605696A (en) 1995-03-30 1997-02-25 Advanced Cardiovascular Systems, Inc. Drug loaded polymeric material and method of manufacture
US5914388A (en) 1995-04-26 1999-06-22 The Penn State Research Foundation Synthesis polyphosphazenes with controlled molecular weight and polydisperity
US6214331B1 (en) 1995-06-06 2001-04-10 C. R. Bard, Inc. Process for the preparation of aqueous dispersions of particles of water-soluble polymers and the particles obtained
US6284284B1 (en) 1995-06-06 2001-09-04 Advanced Tissue Sciences, Inc. Compositions and methods for production and use of an injectable naturally secreted extracellular matrix
CA2178541C (en) 1995-06-07 2009-11-24 Neal E. Fearnot Implantable medical device
US6413536B1 (en) 1995-06-07 2002-07-02 Southern Biosystems, Inc. High viscosity liquid controlled delivery system and medical or surgical device
US5776193A (en) 1995-10-16 1998-07-07 Orquest, Inc. Bone grafting matrix
US6458889B1 (en) 1995-12-18 2002-10-01 Cohesion Technologies, Inc. Compositions and systems for forming crosslinked biomaterials and associated methods of preparation and use
US5752974A (en) 1995-12-18 1998-05-19 Collagen Corporation Injectable or implantable biomaterials for filling or blocking lumens and voids of the body
US5955143A (en) 1995-12-21 1999-09-21 Drexel University Hollow polymer microcapsules and method of producing the same
FR2747682B1 (en) 1996-04-17 1998-06-05 Atochem Elf Sa PROCESS FOR THE PREPARATION OF POLYMER POWDERS BY SUSPENSION POLYMERIZATION
US5718159A (en) 1996-04-30 1998-02-17 Schneider (Usa) Inc. Process for manufacturing three-dimensional braided covered stent
US6190684B1 (en) 1996-05-30 2001-02-20 University Of Florida Research Foundation, Inc. Injectable bio-active glass in a dextran suspension
US5840290A (en) 1996-05-30 1998-11-24 University Of Florida Research Foundation Injectable bio-active glass in a dextran suspension
US6383500B1 (en) 1996-06-27 2002-05-07 Washington University Particles comprising amphiphilic copolymers, having a crosslinked shell domain and an interior core domain, useful for pharmaceutical and other applications
US5807757A (en) 1996-07-02 1998-09-15 Virus Research Institute, Inc. Preparation of ionically cross-linked polyphosphazene microspheresy by coacervation
US5792478A (en) 1996-07-08 1998-08-11 Advanced Uro Science Tissue injectable composition and method of use
US6666892B2 (en) 1996-08-23 2003-12-23 Cook Biotech Incorporated Multi-formed collagenous biomaterial medical device
US6066325A (en) 1996-08-27 2000-05-23 Fusion Medical Technologies, Inc. Fragmented polymeric compositions and methods for their use
US6063061A (en) 1996-08-27 2000-05-16 Fusion Medical Technologies, Inc. Fragmented polymeric compositions and methods for their use
US6254628B1 (en) 1996-12-09 2001-07-03 Micro Therapeutics, Inc. Intracranial stent
US6007573A (en) 1996-09-18 1999-12-28 Microtherapeutics, Inc. Intracranial stent and method of use
WO1998012274A1 (en) 1996-09-23 1998-03-26 Chandrashekar Pathak Methods and devices for preparing protein concentrates
US5785642A (en) 1996-10-18 1998-07-28 Micro Therapeutics, Inc. Methods for treating urinary incontinence in mammals
US5707597A (en) 1996-11-13 1998-01-13 Virus Research Institute, Inc. Polyhalophosphazene solutions stable against gelation
BR9606075C1 (en) 1996-12-19 2002-05-07 Mateus Sommer Neto Injectable composition for medical use.
US5980972A (en) 1996-12-20 1999-11-09 Schneider (Usa) Inc Method of applying drug-release coatings
US5814704A (en) 1997-03-04 1998-09-29 Virus Research Institute, Inc. Recovery of polyphosphazene polyacids or acids salts thereof
BR9808109A (en) 1997-03-31 2000-03-08 Neorx Corp Therapeutic smooth muscle vascular cell inhibitor
US6210715B1 (en) 1997-04-01 2001-04-03 Cap Biotechnology, Inc. Calcium phosphate microcarriers and microspheres
US6273913B1 (en) 1997-04-18 2001-08-14 Cordis Corporation Modified stent useful for delivery of drugs along stent strut
US20030153985A1 (en) 1997-04-26 2003-08-14 Lee Yong Chan Medical implant
TW586934B (en) 1997-05-19 2004-05-11 Sumitomo Pharma Immunopotentiating composition
US6077916A (en) 1997-06-04 2000-06-20 The Penn State Research Foundation Biodegradable mixtures of polyphoshazene and other polymers
WO1998055100A1 (en) 1997-06-05 1998-12-10 Roland Bodmeier Multiphase system
WO1998056312A1 (en) 1997-06-13 1998-12-17 Scimed Life Systems, Inc. Stents having multiple layers of biodegradable polymeric composition
GB9712525D0 (en) 1997-06-16 1997-08-20 Nycomed Imaging As Method
US7192984B2 (en) 1997-06-17 2007-03-20 Fziomed, Inc. Compositions of polyacids and polyethers and methods for their use as dermal fillers
US20020197250A1 (en) 2001-04-10 2002-12-26 Renal Tech International Biocompatible devices, systems, and methods for reducing levels of pro-inflammatory or anti-inflammatory stimulators or mediators in the blood
DE19735368A1 (en) 1997-08-14 1999-02-18 Univ Karlsruhe New soluble polymeric thiosulphate(s)
DE19744135C1 (en) 1997-09-29 1999-03-25 Schering Ag Medical implants coated with epothilone
DE19743373A1 (en) 1997-09-30 1999-04-15 Univ Heidelberg · 3 ·· 2 · P-polyphosphazene
FR2769223B1 (en) 1997-10-03 2003-08-22 Oreal OXIDIZING COMPOSITION AND USES FOR DYING, FOR PERMANENT DEFORMATION OR FOR DECOLORATION OF KERATINIC FIBERS
US6309420B1 (en) 1997-10-14 2001-10-30 Parallax Medical, Inc. Enhanced visibility materials for implantation in hard tissue
US6485514B1 (en) 1997-12-12 2002-11-26 Supergen, Inc. Local delivery of therapeutic agents
US6423343B1 (en) 1998-01-23 2002-07-23 Usbiomaterials Corporation Bioactive glass treatment of inflammation in skin conditions
RU2215542C2 (en) 1998-02-23 2003-11-10 Массачусетс Инститьют Оф Текнолоджи Biodecomposing polymers able recovery of form
US6660301B1 (en) 1998-03-06 2003-12-09 Biosphere Medical, Inc. Injectable microspheres for dermal augmentation and tissue bulking
US6207171B1 (en) 1998-03-27 2001-03-27 Avant Immunotherapeutics, Inc. Polyphosphazene microspheres
AU3552099A (en) 1998-04-09 1999-11-01 Charlotte-Mecklenburg Hospital Authority Creation of three-dimensional tissues
US8029561B1 (en) 2000-05-12 2011-10-04 Cordis Corporation Drug combination useful for prevention of restenosis
US20010029351A1 (en) 1998-04-16 2001-10-11 Robert Falotico Drug combinations and delivery devices for the prevention and treatment of vascular disease
DE69935716T2 (en) 1998-05-05 2007-08-16 Boston Scientific Ltd., St. Michael STENT WITH SMOOTH ENDS
US6254634B1 (en) 1998-06-10 2001-07-03 Surmodics, Inc. Coating compositions
US6933326B1 (en) 1998-06-19 2005-08-23 Lifecell Coporation Particulate acellular tissue matrix
BR9815931A (en) 1998-06-30 2001-02-20 Dow Chemical Co Polymeric polyols, a process for their production, and polyurethane foam obtained
US6153252A (en) 1998-06-30 2000-11-28 Ethicon, Inc. Process for coating stents
US6514534B1 (en) 1998-08-14 2003-02-04 Incept Llc Methods for forming regional tissue adherent barriers and drug delivery systems
DE19843254C2 (en) 1998-09-10 2000-07-06 Schering Ag Use of polymer mixtures containing cyanoacrylate or methylene malonic ester for coating medical devices and implants, medical implants and processes for their production
GB2345638A (en) 1998-09-11 2000-07-19 Tissue Science Lab Limited Injectable collagen compositions
US6531152B1 (en) 1998-09-30 2003-03-11 Dexcel Pharma Technologies Ltd. Immediate release gastrointestinal drug delivery system
AU759016B2 (en) 1998-10-05 2003-04-03 Penn State Research Foundation, The Compositions and methods for enhancing receptor-mediated cellular internalization
FR2784580B1 (en) 1998-10-16 2004-06-25 Biosepra Inc POLYVINYL-ALCOHOL MICROSPHERES AND METHODS OF MAKING THE SAME
US5997301A (en) 1998-10-20 1999-12-07 Linden; Lars Ake Treatment of tooth surfaces and substances therefor
US6261573B1 (en) 1998-10-30 2001-07-17 Avant Immunotherapeutics, Inc. Immunoadjuvants
CA2353606A1 (en) 1998-12-03 2000-06-08 Boston Scientific Limited Stent having drug crystals thereon
US6251064B1 (en) 1998-12-11 2001-06-26 Enteric Medical Technologies, Inc. Method for creating valve-like mechanism in natural body passageway
US6238335B1 (en) 1998-12-11 2001-05-29 Enteric Medical Technologies, Inc. Method for treating gastroesophageal reflux disease and apparatus for use therewith
US20020016637A1 (en) 1998-12-16 2002-02-07 Mark A. Anton Soft tissue filler
IT1302534B1 (en) 1998-12-21 2000-09-05 Fidia Advanced Biopolymers Srl INJECTABLE, BIOCOMPATIBLE AND BIODEGRADABLE COMPOSITIONS INCLUDING AT LEAST A DERIVATIVE OF HYALURONIC ACID, CHONDROGENIC CELLS, FOR
EP1031354A3 (en) 1999-01-19 2003-02-05 Rohm And Haas Company Polymeric MRI Contrast agents
US6662805B2 (en) 1999-03-24 2003-12-16 The Johns Hopkins University Method for composite cell-based implants
WO2000056254A1 (en) 1999-03-24 2000-09-28 Parallax Medical, Inc. Non-compliant system for delivery of implant material
US6689823B1 (en) 1999-03-31 2004-02-10 The Brigham And Women's Hospital, Inc. Nanocomposite surgical materials and method of producing them
US20030007954A1 (en) 1999-04-12 2003-01-09 Gail K. Naughton Methods for using a three-dimensional stromal tissue to promote angiogenesis
US6258121B1 (en) 1999-07-02 2001-07-10 Scimed Life Systems, Inc. Stent coating
JP2001017121A (en) 1999-07-05 2001-01-23 Anpureenu Europe:Kk Coated granule and its production
JP3910314B2 (en) 1999-07-23 2007-04-25 エーザイ・アール・アンド・ディー・マネジメント株式会社 Natural colorant
US6423818B1 (en) 1999-07-30 2002-07-23 Takehisa Matsuda Coumarin endcapped absorbable polymers
US6503556B2 (en) 2000-12-28 2003-01-07 Advanced Cardiovascular Systems, Inc. Methods of forming a coating for a prosthesis
US6713119B2 (en) 1999-09-03 2004-03-30 Advanced Cardiovascular Systems, Inc. Biocompatible coating for a prosthesis and a method of forming the same
US6790228B2 (en) 1999-12-23 2004-09-14 Advanced Cardiovascular Systems, Inc. Coating for implantable devices and a method of forming the same
US7025980B1 (en) 1999-09-14 2006-04-11 Tepha, Inc. Polyhydroxyalkanoate compositions for soft tissue repair, augmentation, and viscosupplementation
US6277392B1 (en) 1999-09-16 2001-08-21 Carbon Medical Technologies, Inc. Tissue injectable composition
US6431174B1 (en) 2000-08-10 2002-08-13 Pi Medical, Inc. Method and apparatus to treat conditions of the naso-pharyngeal area
US6203551B1 (en) 1999-10-04 2001-03-20 Advanced Cardiovascular Systems, Inc. Chamber for applying therapeutic substances to an implant device
US6458387B1 (en) 1999-10-18 2002-10-01 Epic Therapeutics, Inc. Sustained release microspheres
KR100315630B1 (en) 1999-11-17 2001-12-12 박호군 Biodegradable and thermosensitive polyphosphazenes and their preparation method
AU1609701A (en) 1999-11-18 2001-05-30 Sts Biopolymers, Inc. Flexible sealed coil-like devices
US7004977B2 (en) 1999-11-24 2006-02-28 A Enterprises, Inc. Soft tissue substitute and method of soft tissue reformation
US6355058B1 (en) 1999-12-30 2002-03-12 Advanced Cardiovascular Systems, Inc. Stent with radiopaque coating consisting of particles in a binder
AU4566001A (en) 2000-03-13 2001-09-24 Biocure Inc Embolic compositions
US7160931B2 (en) 2000-03-15 2007-01-09 Yu-Ling Cheng Thermally reversible implant and filler
US6436424B1 (en) 2000-03-20 2002-08-20 Biosphere Medical, Inc. Injectable and swellable microspheres for dermal augmentation
US7338657B2 (en) 2001-03-15 2008-03-04 Biosphere Medical, Inc. Injectable microspheres for tissue construction
US6263930B1 (en) 2000-04-11 2001-07-24 Scott A. Wiley Stump grinder
DE10019982A1 (en) 2000-04-22 2001-10-25 Univ Heidelberg Use of antithrombogenic phosphazene polymer films or coverings on stents, catheters or other implants to reduce cell proliferation and hence to limit restenosis
AU2001263760A1 (en) 2000-04-11 2001-11-07 Polyzenix Gmbh Poly-tri-fluoro-ethoxypolyphosphazene coverings and films
US6682760B2 (en) 2000-04-18 2004-01-27 Colbar R&D Ltd. Cross-linked collagen matrices and methods for their preparation
US6869445B1 (en) 2000-05-04 2005-03-22 Phillips Plastics Corp. Packable ceramic beads for bone repair
US20020005206A1 (en) 2000-05-19 2002-01-17 Robert Falotico Antiproliferative drug and delivery device
US6528586B2 (en) 2000-05-16 2003-03-04 Gordon Mark Cohen Compositions of elastomeric ethylene/(meth)acrylic (acid) ester copolymer and polylactone or polyether
AU2001255438B2 (en) 2000-05-16 2005-03-24 Ortho-Mcneil Pharmaceutical, Inc. Process for coating medical devices using super-critical carbon dioxide
US6423332B1 (en) 2000-05-26 2002-07-23 Ethicon, Inc. Method and composition for deforming soft tissues
US7144414B2 (en) 2000-06-27 2006-12-05 Smith & Nephew, Inc. Surgical procedures and instruments
US6620185B1 (en) 2000-06-27 2003-09-16 Smith & Nephew, Inc. Surgical procedures and instruments
WO2002011696A2 (en) 2000-08-08 2002-02-14 Ev & M Active tissue augmentation materials and method
US6858634B2 (en) 2000-09-15 2005-02-22 Monsanto Technology Llc Controlled release formulations and methods for their production and use
AU2001286940A1 (en) 2000-09-22 2002-04-02 Kensey Nash Corporation Drug delivering prostheses and methods of use
ATE343969T1 (en) 2000-09-29 2006-11-15 Cordis Corp COATED MEDICAL DEVICES
US7261735B2 (en) 2001-05-07 2007-08-28 Cordis Corporation Local drug delivery devices and methods for maintaining the drug coatings thereon
US20020111590A1 (en) 2000-09-29 2002-08-15 Davila Luis A. Medical devices, drug coatings and methods for maintaining the drug coatings thereon
US6746773B2 (en) 2000-09-29 2004-06-08 Ethicon, Inc. Coatings for medical devices
US20040047892A1 (en) 2000-11-15 2004-03-11 Desrosiers Eric Andre Filler composition for soft tissue augmentation and reconstructive surgery
US6767637B2 (en) 2000-12-13 2004-07-27 Purdue Research Foundation Microencapsulation using ultrasonic atomizers
DE10100961B4 (en) 2001-01-11 2005-08-04 Polyzenix Gmbh Body-compatible material and substrate coated with this material for the cultivation of cells and artificial organic implants constructed or grown from cells
US6949251B2 (en) 2001-03-02 2005-09-27 Stryker Corporation Porous β-tricalcium phosphate granules for regeneration of bone tissue
US20070191964A1 (en) 2001-04-04 2007-08-16 Arthrocare Corporation Enhanced visibility materials for implantation in hard tissue
US20050209629A1 (en) 2001-04-19 2005-09-22 Kerr Sean H Resorbable containment device and process for making and using same
GB0115320D0 (en) 2001-06-22 2001-08-15 Univ Nottingham Matrix
BR0210722A (en) 2001-06-29 2004-07-20 Medgraft Microtech Inc Biodegradable Injectable Implants and Related Methods of Production and Use
US6967234B2 (en) 2002-12-18 2005-11-22 Ethicon, Inc. Alkyd-lactone copolymers for medical applications
ATE340551T1 (en) 2001-08-17 2006-10-15 Polyzenix Gmbh DEVICE BASED ON NITINOL WITH POLYPHOSPHAZENE COVER
US7195640B2 (en) 2001-09-25 2007-03-27 Cordis Corporation Coated medical devices for the treatment of vulnerable plaque
US20030065345A1 (en) 2001-09-28 2003-04-03 Kevin Weadock Anastomosis devices and methods for treating anastomotic sites
US20030065377A1 (en) 2001-09-28 2003-04-03 Davila Luis A. Coated medical devices
US8133501B2 (en) 2002-02-08 2012-03-13 Boston Scientific Scimed, Inc. Implantable or insertable medical devices for controlled drug delivery
US6887270B2 (en) 2002-02-08 2005-05-03 Boston Scientific Scimed, Inc. Implantable or insertable medical device resistant to microbial growth and biofilm formation
US7094369B2 (en) 2002-03-29 2006-08-22 Scimed Life Systems, Inc. Processes for manufacturing polymeric microspheres
US7131997B2 (en) 2002-03-29 2006-11-07 Scimed Life Systems, Inc. Tissue treatment
US7053134B2 (en) 2002-04-04 2006-05-30 Scimed Life Systems, Inc. Forming a chemically cross-linked particle of a desired shape and diameter
US6713646B2 (en) 2002-04-12 2004-03-30 Biosphere Medical Degradable crosslinkers, and degradable crosslinked hydrogels comprising them
US7271234B2 (en) 2002-04-24 2007-09-18 Rutgers, The State University Of New Jersey Polyarylates for drug delivery and tissue engineering
US7838699B2 (en) 2002-05-08 2010-11-23 Biosphere Medical Embolization using degradable crosslinked hydrogels
US20040028676A1 (en) 2002-08-06 2004-02-12 Klein Dean A. Swallowing system tissue modifier
US7026374B2 (en) 2002-06-25 2006-04-11 Aruna Nathan Injectable microdispersions for medical applications
US7272144B2 (en) 2002-06-26 2007-09-18 Arris International, Inc. Method and apparatus for queuing data flows
AU2003281270B2 (en) * 2002-07-02 2010-07-22 Universitair Medisch Centrum Utrecht Scanning suspension comprising a particle with a diameter of at least 1 micrometer
DK1534352T3 (en) 2002-07-05 2008-12-15 Celonova Biosciences Germany G Implant for transporting and delivering pharmacologically active agents as well as a method for preparing the same
US20050136093A1 (en) 2002-07-05 2005-06-23 Polyzenix Gmbh Implant for transport and release for pharmacologically active agents as well as a process for producing the same
US6884905B2 (en) 2002-07-23 2005-04-26 Biosphere Medical Degradable carbamate-containing bis(acryloyl) crosslinkers, and degradable crosslinked hydrogels comprising them
US7588825B2 (en) 2002-10-23 2009-09-15 Boston Scientific Scimed, Inc. Embolic compositions
JP4337328B2 (en) 2002-11-01 2009-09-30 ソニー株式会社 Encryption strength index calculation method, encryption strength evaluation processing device, and computer program
US20040161470A1 (en) 2002-11-22 2004-08-19 Alexander Andrianov Preparation of polyphosphazene microspheres
WO2004060283A2 (en) 2002-12-16 2004-07-22 Nitromed, Inc. Nitrosated and nitrosylated rapamycin compounds, compositions and methods of use
US6872799B2 (en) 2002-12-18 2005-03-29 Ethicon, Inc. Functionalized polymers for medical applications
US6866860B2 (en) 2002-12-19 2005-03-15 Ethicon, Inc. Cationic alkyd polyesters for medical applications
JP2004250376A (en) 2003-02-20 2004-09-09 Lion Corp Coloring matter for pharmaceutical composition, method for producing the same, the pharmaceutical composition and method for preventing its discoloration
US20040186437A1 (en) 2003-03-20 2004-09-23 Frenette Claude E. Content-coded medical syringe, syringe set and syringe content identification method
KR20050120665A (en) 2003-03-26 2005-12-22 폴리제닉스 게엠베하 Coated dental implants
US7655048B2 (en) 2003-04-02 2010-02-02 Furlow Jr Leonard T Materials and methods for soft tissue augmentation
US20050037047A1 (en) 2003-08-11 2005-02-17 Young-Ho Song Medical devices comprising spray dried microparticles
WO2005065079A2 (en) 2003-11-10 2005-07-21 Angiotech International Ag Medical implants and fibrosis-inducing agents
US20050208095A1 (en) 2003-11-20 2005-09-22 Angiotech International Ag Polymer compositions and methods for their use
TW200603843A (en) 2004-04-20 2006-02-01 Technology Dev Company Ltd Tissue enhancement implant and method
US7217781B2 (en) 2004-04-20 2007-05-15 Parallel Solutions, Inc. Polyphosphazenes including ionic or ionizable moieties and fluorine-containing moieties
US20060246109A1 (en) 2005-04-29 2006-11-02 Hossainy Syed F Concentration gradient profiles for control of agent release rates from polymer matrices
EP1809349B1 (en) 2004-07-05 2009-10-14 Ziscoat N.V. Biocompatible coating of medical devices comprising molecular sieves
US20060008529A1 (en) 2004-07-12 2006-01-12 Meyerhoff Mark E Use of additive sites to control nitric oxide release from nitric oxide donors contained within polymers
US7244270B2 (en) 2004-09-16 2007-07-17 Evera Medical Systems and devices for soft tissue augmentation
WO2006036269A2 (en) 2004-09-24 2006-04-06 Biosphere Medical, Inc. Microspheres capable of binding radioisotopes, optionally comprising metallic microparticles, and methods of use thereof
US20060147895A1 (en) 2004-10-22 2006-07-06 Cryofacets, Inc. System, chamber, and method for fractionation, elutriation, and decontamination of fluids containing cellular components
JP4885866B2 (en) 2004-10-25 2012-02-29 セロノヴァ バイオサイエンスィズ ジャーマニー ゲーエムベーハー Fillable polyphosphazene-containing particles for therapeutic and / or diagnostic applications and methods for their preparation and use
US9114162B2 (en) * 2004-10-25 2015-08-25 Celonova Biosciences, Inc. Loadable polymeric particles for enhanced imaging in clinical applications and methods of preparing and using the same
US20070009612A1 (en) 2004-12-16 2007-01-11 Barefoot Robert R Method for administering a composition to an animal
US7308939B2 (en) 2005-03-09 2007-12-18 Halliburton Energy Services, Inc. Methods of using polymer-coated particulates
JP2005199723A (en) 2005-03-10 2005-07-28 Pilot Ink Co Ltd Cap for ball-point pen
CN104815331A (en) 2005-05-09 2015-08-05 生物领域医疗公司 Compositions and methods using microspheres and non-ionic contrast agents
US8263109B2 (en) 2005-05-09 2012-09-11 Boston Scientific Scimed, Inc. Injectable bulking compositions
US20070003584A1 (en) 2005-06-16 2007-01-04 Russell Anderson Liquid crystal polymer syringes and containers and methods of use for long term storage of filler materials
WO2006138669A2 (en) 2005-06-16 2006-12-28 Artes Medical, Inc. Life-like anatomic feature for testing injection of soft tissue fillers
US20070100449A1 (en) 2005-10-31 2007-05-03 O'neil Michael Injectable soft tissue fixation technique
WO2007056316A2 (en) 2005-11-04 2007-05-18 University Of Virginia Patent Foundation Injectable physiological temperature setting cement composites for spinal fusion and related method thereof
US20070142786A1 (en) * 2005-12-16 2007-06-21 Lampropoulos Fred P System with color-coded medical syringes and basins
US8673019B2 (en) 2006-04-13 2014-03-18 Warsaw Orthopedic, Inc. Use of anti-inflammatory compounds with allograft tissue implantation
US20080058954A1 (en) 2006-08-22 2008-03-06 Hai Trieu Methods of treating spinal injuries using injectable flowable compositions comprising organic materials

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4774189A (en) * 1984-12-24 1988-09-27 Flow Cytometry Standards Corp. Fluorescent calibration microbeads simulating stained cells
US20020068089A1 (en) * 1998-03-06 2002-06-06 Biosphere Medical, Inc. Implantable particles for tissue bulking and the treatment of gastroesophageal reflux disease, urinary incontinence, and skin wrinkles
US20030099683A1 (en) * 2000-03-18 2003-05-29 Michael Grunze Polyphosphazene derivatives
US20030211165A1 (en) * 2000-03-24 2003-11-13 Jean-Marie Vogel Microspheres for active embolization
US20030157142A1 (en) * 2000-08-11 2003-08-21 Stefan Nagel Implants with a phosphazene-containing coating
US20110150954A1 (en) * 2003-03-14 2011-06-23 Sol-Gel Technologies Ltd. Agent-encapsulating micro-and nanoparticles, methods for preparation of same and products containing same
US20090011073A1 (en) * 2007-07-04 2009-01-08 Fanuc Ltd Stationary platen of injection molding machine
US20090025601A1 (en) * 2007-07-27 2009-01-29 Sundar Vasudevan Polymerizable dye-monomer conjugates for encapsulating pigment particles
US20090110730A1 (en) * 2007-10-30 2009-04-30 Celonova Biosciences, Inc. Loadable Polymeric Particles for Marking or Masking Individuals and Methods of Preparing and Using the Same

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11135167B2 (en) 2013-09-19 2021-10-05 Terumo Corporation Polymer particles
US11104772B2 (en) 2013-09-19 2021-08-31 Microvention, Inc. Polymer films
US11786630B2 (en) 2013-09-19 2023-10-17 Terumo Corporation Polymer particles
US9408916B2 (en) 2013-09-19 2016-08-09 Microvention, Inc. Polymer films
US9938367B2 (en) 2013-09-19 2018-04-10 Terumo Corporation Polymer particles
US9546236B2 (en) 2013-09-19 2017-01-17 Terumo Corporation Polymer particles
US10144793B2 (en) 2013-09-19 2018-12-04 Terumo Corporation Polymer particles
US10227463B2 (en) 2013-09-19 2019-03-12 Microvention, Inc. Polymer films
US10118980B1 (en) 2013-11-08 2018-11-06 Terumo Corporation Polymer particles
US9688788B2 (en) 2013-11-08 2017-06-27 Terumo Corporation Polymer particles
US10519264B2 (en) 2013-11-08 2019-12-31 Terumo Corporation Polymer particles
US11261274B2 (en) 2013-11-08 2022-03-01 Terumo Corporation Polymer particles
US10543295B2 (en) 2015-03-26 2020-01-28 Microvention, Inc. Particles
US10792390B2 (en) 2015-03-26 2020-10-06 Microvention, Inc. Particles
US11857694B2 (en) 2015-03-26 2024-01-02 Microvention, Inc. Particles
US10155064B2 (en) 2015-03-26 2018-12-18 Microvention, Inc. Particles
US9907880B2 (en) 2015-03-26 2018-03-06 Microvention, Inc. Particles
US11759545B2 (en) 2016-09-28 2023-09-19 Terumo Corporation Polymer particles
US10201632B2 (en) 2016-09-28 2019-02-12 Terumo Corporation Polymer particles
US11110198B2 (en) 2016-09-28 2021-09-07 Terumo Corporation Polymer particles
US11617814B2 (en) 2016-09-28 2023-04-04 Terumo Corporation Methods of treatment comprising administering polymer particles configured for intravascular delivery of pharmaceutical agents
US10632226B2 (en) 2016-09-28 2020-04-28 Terumo Corporation Polymer particles
US10729805B2 (en) 2016-09-28 2020-08-04 Terumo Corporation Drug delivery polymer particles with hydrolytically degradable linkages
US10328175B2 (en) 2016-09-28 2019-06-25 Terumo Corporation Polymer particles

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