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WO2008013618A1 - Procédé pour la préparation d'intermédiaires alcynes pour des polymères dendritiques - Google Patents

Procédé pour la préparation d'intermédiaires alcynes pour des polymères dendritiques Download PDF

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Publication number
WO2008013618A1
WO2008013618A1 PCT/US2007/014404 US2007014404W WO2008013618A1 WO 2008013618 A1 WO2008013618 A1 WO 2008013618A1 US 2007014404 W US2007014404 W US 2007014404W WO 2008013618 A1 WO2008013618 A1 WO 2008013618A1
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Prior art keywords
reagents
propargyl
reacting
ethyl
aryl
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PCT/US2007/014404
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English (en)
Inventor
Donald A. Tomalia
Douglas R. Swanson
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Dendritic Nanotechnologies Inc
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Dendritic Nanotechnologies Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles

Definitions

  • This invention relates to a process for preparing acetylene or alkyne intermediates to make dendritic polymers.
  • the present invention provides an improved process to generate inexpensive acetylene intermediates based on commercially available propargyl alcohol. These intermediates can then be reacted by click chemistry using azides to form desired dendrimers, such a PEHAM dendrimers or other dendritic polymers.
  • the present process prepares an alkyne compounds, useful as "clickable intermediates" to produce novel core reagents, branch cell reagents, surface group reagents, dendron reagents, oligomeric extender reagents, dendrimer core reagents, or dendrimer shell reagents suitable for preparing dendritic polymers, which comprises:
  • BR branch cell reagent (C) or C means core cm means centimeter(s)
  • C branch cell reagent
  • C core cm means centimeter(s)
  • Dendritic polymer means all dendritic architectures, including but not limited to PAMAM and PEHAM dendrimers, and dendronized polymers
  • Dendronized polymers means where the (C) moiety has dendons on its surface, where such cores include, but are not limited to, linear polymers, latex particles, cage molecules such as macrocycles, cyclodextrins, and others, and the dendron can be a portion of a dendritic polymer
  • Dendron means a portion of a dendrimer DETA means diethylenetriamine DI water means deionized water Equiv. means equivalents)
  • G means dendrimer generation, which is indicated by the number of concentric branch cell shells surrounding the core (usually counted sequentially from the core)
  • g means gram(s)
  • h means hour(s)
  • HCI hydrochloric acid
  • HPLC means high pressure liquid chromatography IF or (IF) means interior functionality
  • MALDI-TOF matrix-assisted laser desorption ionization time of flight mass spectroscopy
  • MeOH means methanol mg means milligram(s) min. means minute(s) mL means milliliters)
  • MWCO molecular weight cut off nm means nanometers
  • NMR nuclear magnetic resonance
  • N-SIS means nanoscale sterically induced stoichiometry
  • PAMAM means poly(amidoamine) dendrimers, including linear and branched polymers or dendrimers with primary amine terminal groups or other surface groups, or dendrons
  • PEHAM means poly(etherhydroxylamine) dendrimer
  • PEI poly(ethyleneimine) dendrimer
  • PIPZ means piperazine
  • POPAM means a PPI core surrounded by PAMAM dendrons
  • PPI means poly(propyleneimine) dendrimer
  • % w/v means Percent weight by volume
  • RT means room temperature or ambient temperature, about 20-2S 0 C
  • SEC means size exclusion chromatography
  • TLC thin layer chromatraphy
  • TMPTA trimethylolpropane
  • UV means ultraviolet spectroscopy ⁇ means micron(s) ⁇ m means micrometers
  • the dendritic polymer structures of the present invention may be any dendritic polymer, including without limitation, PAMAM dendrimers, PEHAM dendrimers,
  • PEI dendrimers POPAM dendrimers, PPI dendrimers, polyether dendrimers, dendrigrafts, random hyperbranched dendrimers, polylysine dendritic polymers, arborols, cascade polymers, avidimers or other dendritic architectures.
  • dendritic polymers there are numerous examples of such dendritic polymers in the literature, such as those described in Dendrimers and other
  • Dendritic Polymers eds. J.M.J. Frechet, D. A. Tomalia, pub. John Wiley and Sons, (2001) and other such sources.
  • dendritic polymers can be any physical shape, such as for example spheres, rods, tubes, or any other shape possible.
  • the interior structure may have an internal cleavable bond (such as a disulfide) or an internal functionality such as a hydroxide or other group to associate with it.
  • the dendritic polymer can be a dendron. This dendron can have any dendritic polymer constituents desired.
  • Dendritic Polymers Most of these dendritic polymers have been taught in the literature. See Dendrimers and other Dendritic Polymers, eds. J.M.J. Fr ⁇ chet, D. A. Tomalia, pub. John Wiley and
  • the dendritic polymer is a PEHAM dendritic polymer it has the following general formula
  • (C) means a core
  • FF focal point functionality component of the core
  • x is independently 0 or an integer from 1 to N c -1 ;
  • (BR) means a branch cell, which, if p is greater than 1, then (BR) may be the same or a different moiety; p is the total number of branch cells (BR) in the dendrimer and is an integer from 1 to 2000 derived by the following equation
  • (IF) means interior functionality, which, if q is greater than 1, then (IF) may be the same or a different moiety; q is independently 0 or an integer from 1 to 4000;
  • (EX) means an extender, which, if m is greater than 1, then (BX) may be the same or a different moiety; m is independently 0 or an integer from 1 to 2000;
  • the PEHAM of Formula I can be prepared by an acrylate-amine reaction system which comprises:
  • a process to prepare the dendritic polymers can be by ring-opening reaction system which comprises:
  • Steps A and B the addition of an extender (EX) group to a core, the mole ratio of (EX)/(C) is defined as the moles of extender molecules (EX) to the moles of reactive functional groups on the simple core, scaffolding core, super core, or current generation structure (i.e. N c ) where an excess of (EX) is used when full coverage is desired; the addition of a branch cell (BR) to a simple core, scaffolding core, super core, or current generation structure (BR)/(C) is defined as the moles of branch cell molecules (BR) to the moles of reactive functional groups on the simple core, scaffolding core, super core, or current generation structure ⁇ i.e.
  • N c where an excess of (BR) is used when full coverage is desired; and the level of addition of branch cells (BR) or extenders (EX) to a core, scaffolding core, super core or current generational product can be controlled by the mole ratio added or by N-SIS.
  • BR branch cells
  • EX extenders
  • An orthogonal chemical approach is the 1,3-dipolar cyclo-addition of azides containing (C) and (BR) to alkynes containing (C) and (BR).
  • the alkyne containing (C) may have from 1 to N c alkyne moieties present and alkyne containing (BR) may have from 1 to N b -I alkyne moieties.
  • the other reactive groups present in (C) or (BR) can be any of the (BR) groups listed herein before.
  • Azide containing (C) and (BR) are produced by nucleophilic ring-opening of epoxy rings with azide ions.
  • the present strategy involves conversion of propargyl alcohol to propargyl tosylate, which may be used directly or converted to appropriate propargyl halides ⁇ i.e., bromides/iodides) by the Finkelstein reaction .
  • These intermediates allow transformation into a variety of critical compounds useful for 1,3-cyclo-addition (Huisgen type) "click chemistry".
  • propargyl initiated poly(oxazolines) could be grown to any desireable degree of polymerization and then terminated with a wide variety of nucleophiles.
  • These important acetylenic intermediates could then be "clicked” to various azide functional ized PEHAM products. ⁇ i.e., core reagents, branch cell reagents, dendrons, extenders or dendrimers) to produce valuable intermediates to a final PEHAM dendrimer product.
  • propargyl tosylate with either sodium bromide or sodium iodide in acetonitrile
  • the corresponding propargyl bromide/iodide can be obtained in quantitative yield.
  • These propargyl halides can be reacted with monoprotected piperazines (i.e., ethyl 1-piperazine carboxylate), morpholine or solvent protected DETA to make some very interesting and clickable intermediates for modifying PEHAM dendrimers or intermediates.
  • ⁇ AH reactions performed were successful producing apparently clean reaction mixtures at each step as determined by mass spectroscopy and TLC.
  • the reaction to form the propargyl ethyl oxazolinium cation from propargyl tosylate is relatively rapid with NaI versus NaBr.
  • the characteristic signals for the propargyl group are present in the 13 C NMR spectrum for the propargyl initiated poly(ethyl oxazoline) and form the ring opened product derived from propargyl ethyl oxazolinium cation.
  • the product mixture derived from the 3- butyne-1,4- ditosylate shows the desired product derived from a ring opening reaction of ethyl 1-piperazine carboxylate with 3-butyne -1 ,4-di-2-ethyI-2-oxazolinium cation.
  • Mass spectra were obtained on a Broker Autoflex LRF MALDI-TOF mass spectrometer with Pulsed Ion Extraction. Mass ranges below 20 kDa were acquired in the reflector mode using a 19 kV sample voltage and 20 kV reflector voltage. Polyethylene oxide was used for calibration. Higher mass ranges were acquired in the linear mode using a 20 kV sample voltage. Size Exclusion Chromatography (SEO)
  • a methanolic solution of dendrimer compositions was evaporated and reconstituted with the mobile phase used in the SEC experiment (1 mg/mL concentration). All the samples were prepared fresh and used immediately for SEC. Dendrimers were analyzed qualitatively by SEC. SEC system (Waters 1515) was operated in an isocratic mode with refractive index detector (Waters 2400) and Waters 717 Plus Auto Sampler. The analysis was performed at RT on two serially aligned TSK gel columns (Supelco), G3000PW and G2500PW, particle size lO ⁇ m, 30cm * 7.5 mm. The mobile phase of acetate buffer (0.5M) was pumped at a flow rate of lmL/min. The elution volume of dendrimer was observed to be 11-16 mL, according to the generation and surface of dendrimer.
  • UV-VIS Ultraviolet/Visible Spectrometry
  • UV-VIS spectral data were obtained on a Perkin Elmer Lambda 2 UV/VIS Spectrometer.
  • Sample preparation To 50-100 mg of a dry sample was add 800-900 ⁇ L of a deuterated solvent to dissolve. Typical reference standards are used, i.e., trimethylsilane. Typical solvents are CDCl 3 , CD 3 OD, D 2 O, DMSO-d6, and acetone-d ⁇ - The dissolved sample was transferred to an NMR tube to a height of— 5.5 cm in the tube.
  • 300MHz NMR data were obtained on a 300MHz 2-channel VarianTM Mercury Plus NMR spectrometer system using an Automation Triple Resonance Broadband (ATB) probe, H/X (where X is tunable from 15 N to 31 P). Data acquisition was obtained on a Sun BladeTM 150 computer with a SolarisTM 9 operating system. The software used was VNMR v6.1C.
  • 500MHz NMR data were obtained on a 500MHz 3-channel VarianTM Inova 500MHz NMR spectrometer system using a Switchable probe, H/X (X is tunable from 15 N to 31 P). Data acquisition was obtained on a Sun BladeTM 150 computer with a SolarisTM 9 operating system.
  • the software used was VNMR v ⁇ .lC. Polvacrylamide Gel Electrophoresis (PAGE)
  • Dendrimers that were stored in solvent are dried under vacuum and then dissolved or diluted with water to a concentration about 100 mg in 4 mL of water.
  • the water solution is frozen using dry ice and the sample dried using a lyophilizer (freeze dryer) (LABCONCO Corp. Model number is Free Zone 4.5 Liter, Freeze Dry System 77510) at about -47°C and 60 x 10 "3 mBar.
  • Freeze dried dendrimer (1-2 mg) is diluted with water to a concentration of 1 mg/mL.
  • Tracking dye is added to each dendrimer sample at 10% v/v concentration and includes (1) methylene blue dye (1% w/v) for basic compounds (2) bromophenol blue dye (0.1% w/v) for acid compounds (3) bromophenol blue dye (0.1%w/v) with 0.1% (w/V) SDS for neutral compounds.
  • Pre-cast 4-20% gradient gels were purchased from ISC BioExpress. Gel sizes were 100 mm (W) X 80 mm (H) X 1 mm (Thickness) with ten pre-numbered sample wells formed in the cassette. The volume of the sample well is 50 ⁇ L. Gels not obtained commercially were prepared as 10% homogeneous gels using 30% acrylamide (3.33 mL), 4 X TBE buffer (2.5 mL), water (4.17 mL), 10% APS (100 ⁇ L), TEMED (3.5 ⁇ L).
  • TBE buffer used for gel electrophoresis is prepared using /m(hydroxymethyl)aminomethane (43.2 g), boric acid (22.08 g), disodium EDTA (3.68 g) in 1 L of water to form a solution of pH 8.3.
  • the buffer is diluted 1 :4 prior to use.
  • Electrophoresis is done using a PowerPacTM 300 165-5050 power supply and BIO- RADTM Mini Protean 3 Electrophoresis Cells. Prepared dendrimer/dye mixtures (5 ⁇ L each) are loaded into separate sample wells and the electrophoresis experiment run. Dendrimers with amine surfaces are fixed with a glutaraldehyde solutions for about one hour and then stained with Coomassie Blue R-250 (Aldrich) for about one hour. Gels are then destained for about one hour using a glacial acetic acid solution. Images are recorded using an hp ScanJetTM 5470C scanner.
  • Thin Layer Chromatography was used to monitor the progress of chemical reactions.
  • One drop of material generally O.OSM to 0.4M solution in organic solvent, is added to a silica gel plate and placed into a solvent chamber and allowed to develop for generally 10- IS mins. After the solvent has been eluted, the TLC plate is generally dried and then stained (as described below). Because the silica gel is a polar polymer support, less polar molecules will travel farther up the plate. "R f " value is used to identify how far material has traveled on a TLC plate. Changing solvent conditions will subsequently change the R f value. This R f is measured by the ratio of the length the product traveled to the length the solvent traveled.
  • TLC plates used were either (1) "Thin Layer Chromatography Plates - Whatman®” PK6F Silica Gel Glass backed, size 20 x 20 cm, layer thickness: 250 ⁇ m or (2) "Thin Layer Chromatography Plate Plastic sheets — EM Science” Alumina backed, Size 20 x 20 cm, layer thickness 200 ⁇ m. Staining conditions were: (1) Ninhydrin: A solution is made with 1.5 g of ninhydrin,
  • reaction vial was put in a 900W domestic microwave and heated for a certain amount of time. Reaction results were checked by TLC immediately after the heating. When the TLC result is rated the TLC ratings are from 0 to 10 (10 is the best result on TLC, but is not meant to mean 100% yield).
  • the invention will be further clarified by a consideration of the following examples, which are intended to be purely exemplary of the present invention.
  • Example 1 Preparation of Poly(ethyloxazoline) Initiated from Propargyl Tosylate and Terminated with Morpholine
  • MALDI-TOF MS distribution from 918 to 2009 with peak at 1315 amu, DP ⁇ 12.
  • a MALDI — TOF mass spectrum indicated the complete disappearance of the peak at 136 amu for the N-propargyl-2-ethyl-2-oxazolinium cation and the appearance of a new peak at 296 amu for the desired product.
  • the volatiles of the reaction mixture were removed on a rotary evaporator.
  • the resulting mixture was mixed with IS mL of MeOH and sodium carbonate (500 mg, 4.7 mmol) and purified through a plug of silica gel in MeOH to give 1.3 g (89% yield) of a light brown liquid. Its spectra are as follows:
  • a MALDI-TOF mass spectrum of this crude material showed the desired product at 566 amu and an unidentified peak at 218 amu.
  • Example 7 PETGE-tetra-azide "Click Reaction" with N-Propargyl Initiated Poly(ethyl oxazoline) that was Terminated with Morpholine
  • a 13 C NMR spectrum of this crude material indicated signals for the triazole ring at 125.89 and 129.27 ppm and 140.91 and 141.80 ppm.
  • An IR of the crude reaction mixture after irradiation with microwave showed a large decrease in the azide signal at 2100 cm '1 relative to the reaction mixture before irradiation.
  • Example 9 Polymerization of 3-Butyne— 1,4-diol ditosylate with Ethyl Oxazoline, Sodium Iodide and Quenching with Triethylmethanecarboxylate Sodium Salt
  • Example 10 Polymerization of 3— Butyne-1,4— diol ditosylate with Ethyl Oxazoline, Sodium Iodide and Quenching with Sodium Azide
  • Example 11 Polymerization of 3— Butyne— 1,4— diol ditosylate with Ethyl Oxazoline, Sodium Iodide and Ethyl 1-piperazine carboxylate

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

La présente invention concerne un procédé pour la préparation d'intermédiaires alcynes utilisés pour fabriquer des polymères dendritiques. Ce procédé concerne des composés alcynes, utiles en tant qu'« intermédiaires cliquables » pour produire de nouveaux réactifs de cœur, réactifs de cellule ramifiée, réactifs de groupe de surface, réactifs de dendrite, réactifs extenseurs oligomères, réactifs de cœur de dendrimère ou réactifs d'enveloppe de dendrimère convenant pour la préparation de polymères dendritiques, qui comprend : 1) la mise en réaction d'halogénures acétyléniques (c'est-à-dire des chlorures, des bromures ou des iodures) ou de mésylates/tosylates acétyléniques avec des 2-alkyl/aryl-2-oxazolines ou oxazines pour produire des sels cationiques de N-acétylenique-2-oxazolinium ou 2-oxazinium ; et 2) la mise en réaction de sels cationiques de N-acétylenique-2-oxazolinium ou 2-oxazinium en tant qu'agents catalytiques pour la polymérisation de 2-alkyl/aryl-2-oxazolines ou 2-alkyl/aryl-2-oxazines ; ou 3) la mise en réaction de tosylate de propargyle ou d'halogénures de propargyle avec la 2-éthyl-2-oxazoline, puis de les polymériser afin d'obtenir des poly(2-éethyl-2-oxazolines) à substitution alcyne avec un degré de polymérisation (c'est-à-dire, dp=1-100) ; ou 4) la mise en réaction de tosylate de propargyle avec de la 2-ethyl-2-oxazoline (1:1) en présence de bromure de sodium ou de iodure de sodium, respectivement ; ou 5) la mise en réaction de 3-butyne-1,4-ditosylate en présence de iodure de sodium ou de bromure de sodium dans de l'acétonitrile pour obtenir du iodure ou du bromure de 3-butyne1,4-dioxazolinium, respectivement.
PCT/US2007/014404 2006-06-21 2007-06-20 Procédé pour la préparation d'intermédiaires alcynes pour des polymères dendritiques Ceased WO2008013618A1 (fr)

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US8034396B2 (en) 2008-04-01 2011-10-11 Tyco Healthcare Group Lp Bioadhesive composition formed using click chemistry
US8512728B2 (en) 2009-02-21 2013-08-20 Sofradim Production Method of forming a medical device on biological tissue
US8535477B2 (en) 2009-02-21 2013-09-17 Sofradim Production Medical devices incorporating functional adhesives
US8648144B2 (en) 2009-02-21 2014-02-11 Sofradim Production Crosslinked fibers and method of making same by extrusion
US8663689B2 (en) 2009-02-21 2014-03-04 Sofradim Production Functionalized adhesive medical gel
US8795331B2 (en) 2010-03-25 2014-08-05 Covidien Lp Medical devices incorporating functional adhesives
US8865857B2 (en) 2010-07-01 2014-10-21 Sofradim Production Medical device with predefined activated cellular integration
US8877170B2 (en) 2009-02-21 2014-11-04 Sofradim Production Medical device with inflammatory response-reducing coating
US8956603B2 (en) 2009-02-21 2015-02-17 Sofradim Production Amphiphilic compounds and self-assembling compositions made therefrom
US8969473B2 (en) 2009-02-21 2015-03-03 Sofradim Production Compounds and medical devices activated with solvophobic linkers
US8968733B2 (en) 2009-02-21 2015-03-03 Sofradim Production Functionalized surgical adhesives
US8968818B2 (en) 2009-02-21 2015-03-03 Covidien Lp Medical devices having activated surfaces
US9039979B2 (en) 2009-02-21 2015-05-26 Sofradim Production Apparatus and method of reacting polymers passing through metal ion chelated resin matrix to produce injectable medical devices
US9247931B2 (en) 2010-06-29 2016-02-02 Covidien Lp Microwave-powered reactor and method for in situ forming implants
US9272074B2 (en) 2010-03-25 2016-03-01 Sofradim Production Surgical fasteners and methods for sealing wounds
US9273191B2 (en) 2009-02-21 2016-03-01 Sofradim Production Medical devices with an activated coating
US9375699B2 (en) 2009-02-21 2016-06-28 Sofradim Production Apparatus and method of reacting polymers by exposure to UV radiation to produce injectable medical devices
US9523159B2 (en) 2009-02-21 2016-12-20 Covidien Lp Crosslinked fibers and method of making same using UV radiation
US9555154B2 (en) 2009-02-21 2017-01-31 Covidien Lp Medical devices having activated surfaces
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US9987297B2 (en) 2010-07-27 2018-06-05 Sofradim Production Polymeric fibers having tissue reactive members

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US8034396B2 (en) 2008-04-01 2011-10-11 Tyco Healthcare Group Lp Bioadhesive composition formed using click chemistry
US9517291B2 (en) 2009-02-21 2016-12-13 Covidien Lp Medical devices having activated surfaces
US8512728B2 (en) 2009-02-21 2013-08-20 Sofradim Production Method of forming a medical device on biological tissue
US8648144B2 (en) 2009-02-21 2014-02-11 Sofradim Production Crosslinked fibers and method of making same by extrusion
US8663689B2 (en) 2009-02-21 2014-03-04 Sofradim Production Functionalized adhesive medical gel
US10632207B2 (en) 2009-02-21 2020-04-28 Sofradim Production Compounds and medical devices activated with solvophobic linkers
US10167371B2 (en) 2009-02-21 2019-01-01 Covidien Lp Medical devices having activated surfaces
US8877170B2 (en) 2009-02-21 2014-11-04 Sofradim Production Medical device with inflammatory response-reducing coating
US8956603B2 (en) 2009-02-21 2015-02-17 Sofradim Production Amphiphilic compounds and self-assembling compositions made therefrom
US8969473B2 (en) 2009-02-21 2015-03-03 Sofradim Production Compounds and medical devices activated with solvophobic linkers
US8968733B2 (en) 2009-02-21 2015-03-03 Sofradim Production Functionalized surgical adhesives
US8968818B2 (en) 2009-02-21 2015-03-03 Covidien Lp Medical devices having activated surfaces
US9039979B2 (en) 2009-02-21 2015-05-26 Sofradim Production Apparatus and method of reacting polymers passing through metal ion chelated resin matrix to produce injectable medical devices
US9216226B2 (en) 2009-02-21 2015-12-22 Sofradim Production Compounds and medical devices activated with solvophobic linkers
US9555154B2 (en) 2009-02-21 2017-01-31 Covidien Lp Medical devices having activated surfaces
US8535477B2 (en) 2009-02-21 2013-09-17 Sofradim Production Medical devices incorporating functional adhesives
US9375699B2 (en) 2009-02-21 2016-06-28 Sofradim Production Apparatus and method of reacting polymers by exposure to UV radiation to produce injectable medical devices
US9550164B2 (en) 2009-02-21 2017-01-24 Sofradim Production Apparatus and method of reacting polymers passing through metal ion chelated resin matrix to produce injectable medical devices
US9421296B2 (en) 2009-02-21 2016-08-23 Covidien Lp Crosslinked fibers and method of making same by extrusion
US9510810B2 (en) 2009-02-21 2016-12-06 Sofradim Production Medical devices incorporating functional adhesives
US9511175B2 (en) 2009-02-21 2016-12-06 Sofradim Production Medical devices with an activated coating
US9273191B2 (en) 2009-02-21 2016-03-01 Sofradim Production Medical devices with an activated coating
US9523159B2 (en) 2009-02-21 2016-12-20 Covidien Lp Crosslinked fibers and method of making same using UV radiation
US9272074B2 (en) 2010-03-25 2016-03-01 Sofradim Production Surgical fasteners and methods for sealing wounds
US9554782B2 (en) 2010-03-25 2017-01-31 Covidien Lp Medical devices incorporating functional adhesives
US10143471B2 (en) 2010-03-25 2018-12-04 Sofradim Production Surgical fasteners and methods for sealing wounds
US8795331B2 (en) 2010-03-25 2014-08-05 Covidien Lp Medical devices incorporating functional adhesives
US9247931B2 (en) 2010-06-29 2016-02-02 Covidien Lp Microwave-powered reactor and method for in situ forming implants
US8865857B2 (en) 2010-07-01 2014-10-21 Sofradim Production Medical device with predefined activated cellular integration
US9987297B2 (en) 2010-07-27 2018-06-05 Sofradim Production Polymeric fibers having tissue reactive members
US9775928B2 (en) 2013-06-18 2017-10-03 Covidien Lp Adhesive barbed filament

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