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WO2008115694A2 - Polymérisation d'azides multifonctionnels et polymères dérivés de ceux-ci - Google Patents

Polymérisation d'azides multifonctionnels et polymères dérivés de ceux-ci Download PDF

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Publication number
WO2008115694A2
WO2008115694A2 PCT/US2008/055905 US2008055905W WO2008115694A2 WO 2008115694 A2 WO2008115694 A2 WO 2008115694A2 US 2008055905 W US2008055905 W US 2008055905W WO 2008115694 A2 WO2008115694 A2 WO 2008115694A2
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WIPO (PCT)
Prior art keywords
polymer
multifunctional
azide
medical device
tissue
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PCT/US2008/055905
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English (en)
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WO2008115694A3 (fr
Inventor
Michael E. Benz
Metasebia T. Munie
Lian L. Luo
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Medtronic, Inc.
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Application filed by Medtronic, Inc. filed Critical Medtronic, Inc.
Publication of WO2008115694A2 publication Critical patent/WO2008115694A2/fr
Publication of WO2008115694A3 publication Critical patent/WO2008115694A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00—Compounds containing azido groups
    • C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C247/04—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being saturated

Definitions

  • polymers or other materials that can solidify e.g., gel
  • gel e.g., gel
  • many materials known in the art that gel after injection in or application to a tissue have drawbacks that limit their usefulness.
  • polymers that solidify upon exposure to ultraviolet (UV) light have been disclosed; however methods of using these polymers can require UV active primers and/or curing agents, multiple steps, and additional curing equipment.
  • systems that form certain hydrogels have also been disclosed; however such systems can require precise stoichiometry control for multiple reagents, and the reagents, upon mixing, may have limited pot life, which can further require that the reagents be mixed in the operating room.
  • Bioorthogonal reactions are reactions of materials with each other, wherein each material has limited or substantially no reactivity with functional groups found in vivo.
  • the efficient reaction between an azide and a terminal alkyne, i.e., the most widely studied example of "click" chemistry is known as a useful example of a bioorthogonal reaction, and has also been reported for use in modifying and/or preparing polymers.
  • click a useful example of a bioorthogonal reaction
  • the preparation of materials that that solidify after injection in, or application to, a tissue using "click" chemistry has not been widely reported.
  • the polymers can be prepared ex vivo or in vivo by introducing at least some of the reactants into a tissue.
  • the term "in vivo” refers to a reaction that is within the body of a subject.
  • the term “ex vivo” refers to a reaction in tissue (e.g., cells) that has been removed, for example, isolated, from the body of a subject.
  • Tissue that can be removed includes, for example, primary cells (e.g., cells that have recently been removed from a subject and are capable of limited growth or maintenance in tissue culture medium), cultured cells (e.g., cells that are capable of extended growth or maintenance in tissue culture medium), and combinations thereof.
  • primary cells e.g., cells that have recently been removed from a subject and are capable of limited growth or maintenance in tissue culture medium
  • cultured cells e.g., cells that are capable of extended growth or maintenance in tissue culture medium
  • the present invention provides a method of preparing a polymer in a tissue.
  • the method includes: introducing at least one multifunctional azide into the tissue; introducing at least one multifunctional azide-reactant into the tissue; and allowing the at least one multifunctional azide and the at least one multifunctional azide-reactant to react ex vivo and/or in vivo under conditions effective to form the polymer.
  • the at least one multifunctional azide-reactant includes at least one multifunctional alkyne (e.g., a terminal alkyne), and the polymer formed is a polytriazole.
  • the method further includes providing a source of Cu(I) in the tissue. Such methods can be used, for example, to repair, augment, or replace tissue in need of repair, augmentation, or replacement.
  • the present invention provides a method of preparing a polymer.
  • the method includes: combining at least one multifunctional azide and at least one multifunctional cyclic alkyne; and allowing the at least one multifunctional azide and the at least one multifunctional cyclic alkyne to react under conditions effective to form the polymer (e.g., a polytriazole).
  • the at least one multifunctional cyclic alkyne is a multifunctional strained cyclic alkyne, and conditions effective for forming the polymer include the substantial absence of added polymerization agent.
  • the polymer is substantially resistant to hydrolysis under physiological conditions.
  • the method includes: combining at least one multifunctional azide and at least one multifunctional ⁇ -phosphine ester; and allowing the at least one multifunctional azide and the at least one multifunctional ⁇ -phosphine ester to react under conditions effective to form the polymer (e.g., a polyamide).
  • conditions effective for forming the polymer include the substantial absence of added polymerization agent.
  • the polymer is substantially resistant to hydrolysis under physiological conditions.
  • the present invention provides a medical device including at least one polymer (e.g., a homopolymer or copolymer) including at least two repeat units of the formula (Formula III):
  • each R 1 and R 3 independently represents an organic group.
  • the at least one polymer is substantially biostable.
  • the medical device further includes at least one biologically active agent that can be at least partially disposed in the at least one polymer.
  • the present invention provides a composition (e.g., a pharmaceutical composition) including: at least one biologically active agent; and at least one polytriazole including at least two repeat units of the formula (Formula III):
  • each R 1 and R 3 independently represents an organic group.
  • the present invention provides a polymer (e.g., a homopolymer or copolymer); compositions including the polymer and at least one biologically active agent (e.g., pharmaceutical compositions); and medical devices including the polymer.
  • the polymer includes at least two repeat units of the formula (Formula VI):
  • the polymer can be applied to a medical device to provide a medical device having the device thereon.
  • the polymer can be applied to a tissue to provide a polymeric coating on the tissue.
  • the present invention provides a polymer (e.g., a homopolymer or copolymer); compositions including the polymer and at least one biologically active agent (e.g., pharmaceutical compositions); and medical devices including the polymer.
  • the polymer includes at least two repeat units of the formula (Formula VII):
  • each R 1 and R 10 independently represents an organic group; the ring structure represents an aryl or heteroaryl group; and each Ar independently represents an aryl or a heteroaryl group.
  • the polymer can be applied to a medical device to provide a medical device having the polymer thereon.
  • the polymer can be applied to a tissue to provide a polymeric coating on the tissue.
  • the present invention provides a method of preparing a medical device.
  • the method includes combining components including: at least one multifunctional azide; and at least one multifunctional azide-reactant, wherein combining includes conditions effective to react the at least one multifunctional azide with the at least one multifunctional azide-reactant to form a polymer.
  • the method further includes combining a source of Cu(I).
  • the present invention provides a method of preparing an active agent delivery system (e.g., a polymeric coating on a medical device).
  • the method includes combining components including: at least one multifunctional azide; at least one multifunctional azide-reactant; and at least one biologically active agent, wherein combining includes conditions effective to react the at least one multifunctional azide with the at least one multifunctional azide-reactant to form a polymer.
  • the method further includes combining a source of Cu(I).
  • the invention provides a method of preparing a medical device having a polymer thereon.
  • the method includes: providing a medical device; and applying components including at least one multifunctional azide and at least one multifunctional azide-reactant to the device, wherein applying includes conditions effective to react the at least one multifunctional azide with the at least one multifunctional azide-reactant to form a polymer.
  • the present invention provides a method of preparing a polymeric coating on a tissue.
  • the method includes: providing a tissue; and applying components including at least one multifunctional azide and at least one multifunctional azide-reactant to the tissue, wherein applying includes conditions effective to react the at least one multifunctional azide with the at least one multifunctional azide-reactant to form a polymer.
  • the present invention provides a method of preparing a medical device having a polymer thereon.
  • the method includes: providing a medical device; and applying at least one polytriazole to at least a portion of the device, wherein the at least one polytriazole includes at least two repeat units of the formula (Formula III):
  • each R 1 and R 3 independently represents an organic group.
  • the present invention provides a method of preparing a polymeric coating on a tissue. The method includes: providing a tissue; and applying at least one polytriazole to at least a portion of the device, wherein the at least one polytriazole includes at least two repeat units of the formula (Formula III):
  • each R 1 and R 3 independently represents an organic group.
  • the methods and polymers disclosed herein can be used for a wide variety of applications including, for example, delivery of cells, drugs, and/or proteins; repair of intervertebral discs; treatment of vulnerable plaque (gel paving); filling of voids; reinforcement of the esophageal valve; treatment of diabetes through cell implants; repair, augmentation, or replacement of tissue using tissue engineering; repair, augmentation, or replacement of cartilage; and prevention of formation of surgical adhesions.
  • a medical device including a polymer as disclosed herein can be used, for example, to control the release rate of one or more biologically active agents from the device. Definitions
  • Described herein are methods for preparing polymers by reacting at least one multifunctional azide with at least one multifunctional azide-reactant (e.g., multifunctional alkynes, multifunctional ⁇ -phosphine esters, and combinations thereof).
  • at least one multifunctional azide-reactant e.g., multifunctional alkynes, multifunctional ⁇ -phosphine esters, and combinations thereof.
  • multifunctional azide refers to a compound that includes two or more azide (-N 3 ) groups.
  • exemplary classes of multifunctional azides includes, for example, difunctional azides, trifunctional azides, tetrafunctional azides, pentafunctional azides, hexafunctional azides, heptafunctional azides, octafunctional azides, and combinations thereof.
  • multifunctional azide-reactant refers to a compound that includes two or more groups that can react with an azide group.
  • exemplary classes of multifunctional azide-reactants include, for example, difunctional azide-reactants, trifunctional azide-reactants, tetrafunctional azide-reactants, pentafunctional azide- reactants, hexafunctional azide-reactants, heptafunctional azide-reactants, octafunctional azide-reactants, and combinations thereof.
  • the term "polymer” is intended to be broadly interpreted to include materials having two or more repeat units, and preferably three or more repeat units.
  • polymer is intended to include materials ranging from oligomers through high molecular weight materials (e -g- > materials having a number average molecular weight of at least 1,000 daltons, preferably at least 5,000 daltons, and more preferably at least 10,000 daltons).
  • the term polymer is also intended to encompass both non-crosslinked and crosslinked materials including networks.
  • the term polymer is also intended to include linear, branched, and highly branched materials.
  • the polymers prepared and/or disclosed herein can be a solid or gel.
  • the polymers disclosed herein can be hydrophobic or hydrophilic.
  • the polymers prepared and/or disclosed herein can include hydrogels, e.g., polymeric materials that exhibit the ability to swell in water and to retain a significant fraction (e.g., greater than 20 volume%) of water within their structure, but do not dissolve in water), and non-hydrogels.
  • the polymers prepared and/or disclosed herein can include biodegradable materials (e.g., biodegradable materials that do not include ester groups) or biostable materials.
  • biodegradable and “bioerodible” are used interchangeably and are intended to broadly encompass materials that include, for example, those that tend to break down upon exposure to physiological environments.
  • biostable is intended to broadly encompass materials that are substantially resistant to hydrolysis under physiological conditions.
  • a single multifunctional azide and a single multifunctional azide-reactant as described herein can be used to prepare a homopolymer.
  • two or more multifunctional azides and/or two or more multifunctional azide -reactants can be used to prepare copolymers.
  • the two or more azides can each be azides having, for example, different structures and/or different functionalities (e.g., difunctional, trifunctional, tetrafunctional, pentafunctional, hexafunctional, heptafunctional, or octafunctional).
  • the two or more azide -reactants can each be, for example, terminal alkynes, cyclic alkynes, strained cyclic alkynes, and/or ⁇ -phosphine esters having different structures and/or different functionalities (e.g., difunctional, trifunctional, tetrafunctional, pentafunctional, hexafunctional, heptafunctional, or octafunctional).
  • the two or more azide - reactants can include combinations of, for example, terminal alkynes, cyclic alkynes, strained cyclic alkynes, and/or ⁇ -phosphine esters.
  • Copolymers as disclosed herein can be random copolymers, alternating copolymers, block copolymers, graft copolymers, or combinations thereof.
  • Copolymers as disclosed herein can include hard and/or soft segments. For example, mixtures of azides and/or azide-reactants can be combined to prepare random and/or alternating copolymers.
  • the at least one multifunctional azide and the at least one multifunctional azide -reactant are each introduced into a tissue and allowed to react ex vivo and/or in vivo, and in certain embodiments in vivo.
  • the at least one multifunctional azide and the at least one multifunctional azide-reactant can be introduced into the tissue substantially simultaneously, or sequentially (e.g., introducing the at least one multifunctional azide occurs prior to introducing the at least one multifunctional azide- reactant, or introducing the at least one multifunctional azide occurs subsequent to introducing the at least one multifunctional azide-reactant).
  • Conditions effective for the reaction of at least one multifunctional azide with at least one multifunctional azide-reactant can include a polymerization agent (e.g., an added catalyst).
  • a polymerization agent can be used to initiate and/or propagate the polymerization reactions described herein.
  • a wide variety of polymerization agents can be used that are known in the art to catalyze addition polymerizations.
  • the polymerization agent provides for polymerization through a cationic, an anionic, a free radical, and/or an organometallic pathway.
  • the polymerization agent may be present in catalytic amounts, or alternatively, may be used in stoichiometric amounts with partial or total consumption of the polymerization agent during the polymerization reaction.
  • conditions effective for the reaction of at least one multifunctional azide with at least one multifunctional azide-reactant can be in the substantial absence of added polymerization agent.
  • the "substantial absence" of added polymerization agent means that any added polymerization agent increases the rate of polymerization by no more than 10%, preferably by no more than 5%, and more preferably no increase, compared to the rate of polymerization in the complete absence of added polymerization agent.
  • the at least one azide and the at least one azide-reactant are introduced in a ratio such that the azide and azide-reactant groups are present in approximately a 1 : 1 equivalent ratio (e.g., from a 0.95:1 to a 1.05:1 equivalent ratio).
  • the at least one multifunctional azide includes at least one azide of the formula N 3 -R ⁇ N 3 , wherein R 1 represents an organic group.
  • R 1 can include, for example, a polyether group (e.g., a poly(ethylene glycol)).
  • An exemplary azide including a polyether group is a diazide of the formula (Formula I):
  • n 2 to 20,000.
  • organic group is used for the purpose of this invention to mean a hydrocarbon group that is classified as an aliphatic group, cyclic group, or combination of aliphatic and cyclic groups (e.g., alkaryl and aralkyl groups).
  • suitable organic groups for methods and polymers of this invention are those that do not interfere with the polymerization reactions disclosed herein.
  • aliphatic group means a saturated or unsaturated linear or branched hydrocarbon group. This term is used to encompass alkyl, alkenyl, and alkynyl groups, for example.
  • alkyl group means a saturated linear or branched monovalent hydrocarbon group including, for example, methyl, ethyl, n- propyl, isopropyl, tert-butyi, amyl, heptyl, and the like.
  • alkenyl group means an unsaturated, linear or branched monovalent hydrocarbon group with one or more olefmically unsaturated groups (i.e., carbon-carbon double bonds), such as a vinyl group.
  • alkynyl group means an unsaturated, linear or branched monovalent hydrocarbon group with one or more carbon-carbon triple bonds.
  • cyclic group means a closed ring hydrocarbon group that is classified as an alicyclic group, aromatic group, or heterocyclic group.
  • alicyclic group means a cyclic hydrocarbon group having properties resembling those of aliphatic groups.
  • aromatic group or “aryl group” means a mono- or polynuclear aromatic hydrocarbon group.
  • heterocyclic group means a closed ring hydrocarbon in which one or more of the atoms in the ring is an element other than carbon (e.g., nitrogen, oxygen, sulfur, etc.).
  • group and “moiety” are used to differentiate between chemical species that allow for substitution or that may be substituted and those that do not so allow for substitution or may not be so substituted.
  • group when the term “group” is used to describe a chemical substituent, the described chemical material includes the unsubstituted group and that group with nonperoxidic O, N, S, Si, or F atoms, for example, in the chain as well as carbonyl groups or other conventional substituents.
  • moiety is used to describe a chemical compound or substituent, only an unsubstituted chemical material is intended to be included.
  • alkyl group is intended to include not only pure open chain saturated hydrocarbon alkyl substituents, such as methyl, ethyl, propyl, tert-butyi, and the like, but also alkyl substituents bearing further substituents known in the art, such as hydroxy, alkoxy, alkylsulfonyl, halogen atoms, cyano, nitro, amino, carboxyl, etc.
  • alkyl group includes ether groups, haloalkyls, nitroalkyls, carboxyalkyls, hydroxy alky Is, sulfoalkyls, etc.
  • the phrase “alkyl moiety” is limited to the inclusion of only pure open chain saturated hydrocarbon alkyl substituents, such as methyl, ethyl, propyl, tert- butyl, and the like.
  • any of the R substituents that are "organic groups” can include as at least a portion thereof, for example, additional functionality (e.g., azide functionality or azide-reactant functionality).
  • additional functionality e.g., azide functionality or azide-reactant functionality.
  • R 1 represents an organic group that can include, for example, additional azide groups
  • the formula N 3 -R 1 -N 3 represents not only difunctional azides, but can also represent additional multifunctional azides.
  • any of the R substituents that are "organic groups” can include as at least a portion thereof, for example, a group that includes one or more ether groups, ester groups, orthoester groups, ketal groups, carbonate groups, and combinations thereof.
  • Any of the R substituents that are "organic groups” can optionally be polymeric groups including, for example, polyethers, polyesters, poly(orthoesters), polyketals, polycarbonates, and combinations thereof.
  • any of the R substituents that are "organic groups” can include as at least a portion thereof, for example, an imagable functionality (i.e., a functionality visible in an imaging system, such as, for example, one or more radiopaque functionalities such as iodinated groups, ferromagnetic functionalities, and magnetic susceptible functionalities such as Fe, Cr, Ni, and Gd); a latent reactive functionality (e.g., ethylenic unsaturation and/or oxygen-containing rings suitable for latent crosslinking after polymerization); or combinations thereof.
  • an imagable functionality i.e., a functionality visible in an imaging system, such as, for example, one or more radiopaque functionalities such as iodinated groups, ferromagnetic functionalities, and magnetic susceptible functionalities such as Fe, Cr, Ni, and Gd
  • a latent reactive functionality e.g., ethylenic unsaturation and/or oxygen-containing rings suitable for latent crosslinking after polymerization
  • the at least one multifunctional azide-reactant can include a multifunctional alkyne, wherein one or more azide groups (-N 3 ) of the multifunctional azide can react with one or more alkyne groups (-C ⁇ C-) of the multifunctional alkyne to
  • a "multifunctional alkyne” refers to a compound that includes two or more alkyne (-C ⁇ C-) groups.
  • the alkyne groups can be terminal alkyne groups (R-C ⁇ C-H), or internal alkyne groups (R-C ⁇ C-R'), which can be either cyclic (e.g., strained or non-strained) or non-cyclic.
  • Exemplary classes of multifunctional alkynes include, for example, difunctional alkynes, trifunctional alkynes, tetrafunctional alkynes, pentafunctional alkynes, hexafunctional alkynes, heptafunctional alkynes, octafunctional alkynes, and combinations thereof.
  • the reaction of at least one multifunctional azide with at least one multifunctional alkyne can form a polymer having at least two triazole-containing repeat units (i.e., a polytriazole).
  • the multifunctional alkyne can be a multifunctional terminal alkyne.
  • a “multifunctional terminal alkyne” refers to a compound that includes two or more terminal alkyne (-C ⁇ C-H) groups.
  • Exemplary classes of multifunctional terminal alkynes include, for example, difunctional terminal alkynes, trifunctional terminal alkynes, tetrafunctional terminal alkynes, pentafunctional terminal alkynes, hexafunctional terminal alkynes, heptafunctional terminal alkynes, octafunctional terminal alkynes, and combinations thereof.
  • An exemplary class of multifunctional terminal alkynes are alkynes of the formula N-(R 2 -C ⁇ CH) 3 , wherein each R 2 independently represents an organic group (e.g., an organic moiety), a class of which includes, for example, a trialkyne of the formula (Formula II):
  • Multifunctional terminal alkynes can be prepared by suitable methods known to one of skill in the art. For example, a polyol can be reacted with a propargyl halide (e.g., propargyl bromide) in the presence of a base.
  • a propargyl halide e.g., propargyl bromide
  • conditions effective for the reaction with the at least one multifunctional azide can sometimes preferably include a polymerization agent (e.g., an added catalyst).
  • Suitable polymerization agents include a source of Cu(I).
  • Cu(I) is added as a polymerization agent, typically at least 0.1% by weight is added, based on the total weight of the reactants.
  • Cu(I) is added as a polymerization agent, typically at most 10% by weight is added, based on the total weight of the reactants.
  • it may be desirable to generate the Cu(I) catalyst in situ for example, by reduction of a Cu(II) compound.
  • CuSO 4 can be reduced by sodium ascorbate to generate the desired Cu(I) catalyst in situ.
  • the reaction of at least one multifunctional azide with at least one multifunctional terminal alkyne can form a polytriazole polymer.
  • exemplary polymers include those having at least two repeat units of the formula (Formula III):
  • each R 1 and R 3 independently represents an organic group.
  • the formed polymer is not a hydrogel. In certain embodiments, the formed polymer is substantially biostable.
  • the multifunctional alkyne can be a multifunctional cyclic alkyne.
  • a "multifunctional cyclic alkyne” refers to a compound that includes two or more cyclic alkyne (-C ⁇ C-) groups.
  • Exemplary classes of multifunctional cyclic alkynes include, for example, difunctional cyclic alkynes, trifunctional cyclic alkynes, tetrafunctional cyclic alkynes, pentafunctional cyclic alkynes, hexafunctional cyclic alkynes, heptafunctional cyclic alkynes, octafunctional cyclic alkynes, and combinations thereof.
  • the multifunctional cyclic alkyne is a multifunctional strained cyclic alkyne.
  • a “multifunctional strained cyclic alkyne” refers to a compound that includes two or more strained cyclic alkyne (-C ⁇ C-) groups.
  • a "strained cyclic alkyne” refers to a cyclic alkyne having at least 8 Kcal/mole strain energy.
  • strain energy is defined as the difference between the measured heat of formation of the strained cyclic alkyne and the calculated heat of formation of the molecule in a hypothetical strain- free state.
  • Exemplary multifunctional strained cyclic alkynes include alkynes of the formula (Formula IV):
  • each R 5 and R 6 independently represents hydrogen or an organic moiety; each R 7 represents an optional organic linking moiety; and each R 8 represents an organic moiety.
  • Multifunctional strained cyclic alkynes can be prepared by suitable methods known to one of skill in the art. See, for example, Agard et al, J. American Chem. Soc, 126:15046-15047 (2004).
  • conditions effective for the reaction with the at least one multifunctional azide can include the substantial absence of added polymerization agent.
  • the substantial absence of added polymerization agent e.g., added Cu(I)
  • the reaction of at least one multifunctional azide with at least one multifunctional strained cyclic alkyne can form a polytriazole polymer.
  • the at least one multifunctional azide-reactant can include a multifunctional ⁇ -phosphine ester, wherein one or more azide groups (-N 3 ) of the
  • multifunctional azide can react with one or more ⁇ -phosphine ester groups (e.g., ° ) of the multifunctional ⁇ -phosphine ester to form one or more amide groups (e.g., - C(O)NH-).
  • a "multifunctional ⁇ -phosphine ester" refers to a compound that includes two or more ⁇ -phosphine ester groups.
  • Exemplary classes of multifunctional ⁇ -phosphine esters include, for example, difunctional ⁇ -phosphine esters, trifunctional ⁇ - phosphine esters, tetrafunctional ⁇ -phosphine esters, pentafunctional ⁇ -phosphine esters, hexafunctional ⁇ -phosphine esters, heptafunctional ⁇ -phosphine esters, octafunctional ⁇ - phosphine esters, and combinations thereof.
  • the reaction of at least one multifunctional azide with at least one multifunctional ⁇ -phosphine ester can form a polymer having at least two amide-containing repeat units (i.e., a polyamide).
  • Exemplary multifunctional ⁇ -phosphine esters include ⁇ -phosphine esters of the formula (Formula V):
  • each R 9 and R 10 independently represents an organic group; each Ar
  • each R 9 and R 10 independently represents an organic moiety; the ring
  • Multifunctional ⁇ -phosphine esters can be prepared by suitable methods known to one of skill in the art. See, for example, Saxon et al, Science, 287:2007-2010 (2000).
  • conditions effective for the reaction with the at least one multifunctional azide can include the substantial absence of added polymerization agent.
  • the substantial absence of added polymerization agent can be particularly advantageous in avoiding unintended effects in ex vivo and/or in vivo reaction conditions.
  • the reaction of at least one multifunctional azide with at least one multifunctional ⁇ -phosphine ester can form a polyamide polymer.
  • exemplary polymers include those having at least two repeat units of the formula (Formula VII):
  • each R 1 and R 10 independently represents an organic group; the ring structure represents an aryl or heteroaryl group; and each Ar independently represents an aryl or a heteroaryl group.
  • one or more polymers as disclosed herein can be blended with another polymer (e.g., the same or different than the polymers disclosed herein) to provide the desired physical and/or chemical properties.
  • another polymer e.g., the same or different than the polymers disclosed herein
  • two polytriazole or polyamide polymers having different molecular weights can be blended to optimize the release rate of one or more biologically active agents.
  • two polytriazole or polyamide polymers having different repeat units can be blended to provide desired physical and/or chemical properties.
  • a polytriazole polymer and a polyamide polymer can be blended to provide desired physical and/or chemical properties.
  • a polytriazole or polyamide polymer can be blended with another polymer that is not a polytriazole or polyamide polymer to provide desired physical and/or chemical properties.
  • Polymers as disclosed herein can be used in various combinations for various applications. They can be used as tissue-bulking agents in urological applications for bulking the urinary sphincter to prevent stress incontinence or in gastrological applications for bulking of the lower esophageal sphincter to prevent gastroesophageal reflux disease. They can be used for replacements for nucleus pulposis or repair of annulus in intervertebral disc repair procedures. They can be used as tissue adhesives or sealants. They can be used as surgical void fillers, for example, in reconstructive or cosmetic surgery (e.g., for filling a void after tumor removal).
  • Polymers as disclosed herein can further be used for applications such as scaffolds or supports for the development and/or growth of cells for applications including, for example, tissue engineering and the fabrication of artificial organs.
  • injectable compositions can be used in injectable compositions.
  • injectable compositions could be used as tissue bulking agents (e.g., for the treatment of urinary stress incontinence, for the treatment of gastroesophageal reflux disease, or serving to augment a degenerated intervertebral disc), void fillers (e.g., in cosmetic or reconstructive surgery, such as serving as a replacement for the nucleus pulposis), or as an injectable drug delivery matrix.
  • one or more polymers can be combined with a solvent such as N-methyl-2-pyrrolidone or dimethylsulfoxide (DMSO), which are fairly biocompatible solvents. The solvent can diffuse away after injection and the polymer can remain in place.
  • a solvent such as N-methyl-2-pyrrolidone or dimethylsulfoxide (DMSO), which are fairly biocompatible solvents. The solvent can diffuse away after injection and the polymer can remain in place.
  • DMSO dimethylsulfoxide
  • injectable materials can be applied to a desired site (e.g., a surgical site) using a syringe, catheter, or by hand.
  • injectable compositions could include crosslinkers (such as diacrylates), plasticizers (such as triethyl citrate), lipids (soybean oil), poly(ethylene glycol) (including those with the ends blocked with methyls or similar groups), silicone oil, partially or fully fluorinated hydrocarbons, N-methyl-2-pyrrolidone, or mixtures thereof.
  • crosslinkers such as diacrylates
  • plasticizers such as triethyl citrate
  • lipids such asybean oil
  • poly(ethylene glycol) including those with the ends blocked with methyls or similar groups
  • silicone oil such as silicone oil
  • partially or fully fluorinated hydrocarbons such as those with the ends blocked with methyls or similar groups
  • silicone oil such as silicone oil
  • polymers as disclosed herein can be used, for example, to repair, augment, or replace tissue in need of repair, augmentation, or replacement.
  • At least one multifunctional azide and at least one multifunctional azide- reactant can be introduced proximate a tissue in need of repair, augmentation, or replacement; and the at least one multifunctional azide and the at least one multifunctional azide -reactant allowed to react ex vivo and/or in vivo under conditions effective to form a polymer.
  • Polymers as disclosed herein can be used in combination with a variety of particulate materials.
  • they can be used with moisture curing ceramic materials (e.g., tricalcium phosphate) for vertebroplasty cements, bone void filling (due to disease such as cancer or due to fracture).
  • They can be used in combination with inorganic materials such as hydroxylapatite to form pastes for use in bone healing, sealing, filling, repair, augmentation, and replacement.
  • They can be used as or in combination with polymer microspheres that can be reservoirs for one or more biologically active agents such as a protein, DNA plasmid, RNA plasmid, antisense agent, etc.
  • polymers as disclosed herein can be used in combination with other materials to form a composite (e.g., a polymer having an additive therein).
  • composites can include a wide variety of additives, and particularly particulate additives, such as, for example, fillers (e.g., including particulate, fiber, and/or platelet material), other polymers (e.g., polymer particulate materials such as polytetrafluoroethylene can result in higher modulus composites), imaging particulate materials (e.g., barium sulfate for visualizing material placement using, for example, fluoroscopy), biologically derived materials (e.g., bone particles, cartilage, demineralized bone matrix, platelet gel, and combinations thereof), and combinations thereof.
  • Additives can be dissolved, suspended, and/or dispersed within the composite. For particulate additives, the additive is typically dispersed within the composite.
  • Polymers as disclosed herein can be combined with fibers, woven or nonwoven fabric for reconstructive surgery, such as the in situ formation of a bone plate or a bone prosthesis.
  • one or more polymers as disclosed herein can be shaped to form a medical device.
  • the one or more polymers can be shaped by methods known in the art including compression molding, injection molding, casting, extruding, milling, blow molding, or combinations thereof.
  • a "medical device” includes devices that have surfaces that contact tissue, bone, blood, or other bodily fluids in the course of their operation, which fluids are subsequently used in patients. This can include, for example, extracorporeal devices for use in surgery such as blood oxygenators, blood pumps, blood sensors, tubing used to carry blood, and the like which contact blood which is then returned to the patient.
  • a medical device can also be fabricated by reacting at least one azide and at least one azide-reactant in a suitable mold under conditions effective to form a polymer. Polymers as disclosed herein can also be coated onto a substrate if desired.
  • a coating mixture of the polymer can be prepared using a wide variety of solvents including, but not limited to, water, ether, ethyl acetate, alcohols, toluene, chloroform, tetrahydrofuran, perfluorinated solvents, and combinations thereof.
  • Preferred solvents include water, ether, ethyl acetate and low molecular weight alcohols (less than eight carbons).
  • the coating mixture can be applied to an appropriate substrate such as uncoated or polymer coated medical wires, catheters, stents, prostheses, penile inserts, and the like, by conventional coating application methods. Such methods include, but are not limited to, dipping, spraying, wiping, painting, solvent swelling, and the like.
  • the solvent is preferably allowed to evaporate from the coated substrate.
  • a suitable substrate include, but are not limited to, polymers, metal, glass, ceramics, composites, and multilayer laminates of these materials.
  • the coating may be applied to metal substrates such as the stainless steel used for guide wires, stents, catheters and other devices.
  • Organic substrates that may be coated with the polymers of this invention include, but are not limited to, polyether-polyamide block copolymers, polyethylene terephthalate, polyetherurethane, polyesterurethane, other polyurethanes, silicone, natural rubber, rubber latex, synthetic rubbers, polyester-polyether copolymers, polycarbonates, and other organic materials.
  • Additives that can be combined with a polymer as disclosed herein to form a composition include, but are not limited to, wetting agents for improving wettability to hydrophobic surfaces, viscosity and flow control agents to adjust the viscosity and thixotropy of the mixture to a desired level, tackifiers, adhesion promoters, antioxidants to improve oxidative stability of the coatings, dyes or pigments to impart color or radiopacity, and air release agents or defoamers, cure catalysts, cure accelerants, plasticizers, solvents, stabilizers (cure inhibitors, pot-life extenders), and adhesion promoters.
  • the one or more multifunctional azides and the one or more multifunctional azide-reactants are selected so that they also do not react with a therapeutic agent of interest (that is, they are also pharmaorthogonal), they can be used to create matrices to deliver drugs, proteins, DNA, or other therapeutic agents.
  • compositions that include one or more polymers as disclosed herein and at least one biologically active agent.
  • a biologically active agent is intended to be broadly interpreted as any agent capable of eliciting a response in a biological system such as, for example, living cell(s), tissue(s), organ(s), and being(s).
  • Biologically active agents can include natural and/or synthetic agents.
  • a biologically active agent is intended to be inclusive of any substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease or in the enhancement of desirable physical or mental development and conditions in a subject.
  • subject as used herein is taken to include humans, sheep, horses, cattle, pigs, dogs, cats, rats, mice, birds, reptiles, fish, insects, arachnids, protists (e.g., protozoa), and prokaryotic bacteria.
  • subject is a human or other mammal.
  • a preferred class of biologically active agents includes drugs.
  • drug means any therapeutic agent.
  • Suitable drugs include inorganic and organic drugs, without limitation, and include drugs that act on the peripheral nerves, adrenergic receptors, cholinergic receptors, nervous system, skeletal muscles, cardiovascular system, smooth muscles, blood circulatory system, synaptic sites, neuro-effector junctional sites, endocrine system, hormone systems, immunological system, reproductive system, skeletal system, autocoid systems, alimentary and excretory systems (including urological systems), histamine systems, and the like.
  • drugs include inorganic and organic drugs, without limitation, and include drugs that act on the peripheral nerves, adrenergic receptors, cholinergic receptors, nervous system, skeletal muscles, cardiovascular system, smooth muscles, blood circulatory system, synaptic sites, neuro-effector junctional sites, endocrine system, hormone systems, immunological system, reproductive system, skeletal system, autocoid systems, alimentary and excretory systems (including urological systems), histamine systems, and the like.
  • Such conditions, as well as others, can be
  • Suitable drugs include, for example, polypeptides (which is used herein to encompass a polymer of L- or D- amino acids of any length including peptides, oligopeptides, proteins, enzymes, hormones, etc.), polynucleotides (which is used herein to encompass a polymer of nucleic acids of any length including oligonucleotides, single- and double-stranded DNA, single- and double-stranded RNA, DNA/RNA chimeras, etc.), saccharides (e.g., mono-, di-, poly-saccharides, and mucopolysaccharides), vitamins, viral agents, and other living material, radionuclides, and the like.
  • polypeptides which is used herein to encompass a polymer of L- or D- amino acids of any length including peptides, oligopeptides, proteins, enzymes, hormones, etc.
  • polynucleotides which is used herein to encompass a polymer of nucle
  • antithrombogenic and anticoagulant agents such as heparin, Coumadin, protamine, and hirudin
  • antimicrobial agents such as antibiotics
  • antineoplastic agents and antiproliferative agents such as etoposide, podophylotoxin
  • antiplatelet agents including aspirin and dipyridamole
  • antimitotics (cytotoxic agents) and antimetabolites such as methotrexate, colchicine, azathioprine, vincristine, vinblastine, fluorouracil, adriamycin, and mutamycinnucleic acids
  • antidiabetic such as rosiglitazone maleate
  • antiinflammatory agents such as heparin, Coumadin, protamine, and hirudin
  • antimicrobial agents such as antibiotics
  • antineoplastic agents and antiproliferative agents such as etoposide, podophylotoxin
  • antiplatelet agents including aspirin and dipyridamole
  • Anti-inflammatory agents for use in the present invention include glucocorticoids, their salts, and derivatives thereof, such as Cortisol, cortisone, fludrocortisone, Prednisone, Prednisolone, 6 ⁇ -methylprednisolone, triamcinolone, betamethasone, dexamethasone, beclomethasone, aclomethasone, amcinonide, clebethasol and clocortolone.
  • glucocorticoids such as Cortisol, cortisone, fludrocortisone, Prednisone, Prednisolone, 6 ⁇ -methylprednisolone, triamcinolone, betamethasone, dexamethasone, beclomethasone, aclomethasone, amcinonide, clebethasol and clocortolone.
  • Illustrative classes of drugs include, for example, Plasmid DNA, genes, antisense oligonucleotides and other antisense agents, peptides, proteins, protein analogs, siRNA, shRNA, miRNA, ribozymes, DNAzymes and other DNA based agents, viral and non-viral vectors, lyposomes, cells, stem cells, antineoplastic agents, antiproliferative agents, antithrombogenic agents, anticoagulant agents, antiplatelet agents, antibiotics, antiinflammatory agents, antimitotic agents, immunosuppressants, growth factors, cytokines, hormones, and combinations thereof.
  • Suitable drugs can have a variety of uses including, but are not limited to, anticonvulsants, analgesics, antiparkinsons, antiinflammatories (e.g., ibuprofen, fenbufen, cortisone, and the like), calcium antagonists, anesthetics (e.g., benoxinate, benzocaine, procaine, and the like), antibiotics (e.g., ciprofloxacin, norfloxacin, clofoctol, and the like), antimalarials, antiparasitics, antihypertensives, antihistamines, antipyretics, alpha- adrenergic agonists, alpha-blockers, biocides, bactericides, bronchial dilators, beta- adrenergic blocking drugs, contraceptives, cardiovascular drugs, calcium channel inhibitors, depressants, diagnostics, diuretics, electrolytes, enzymes, hypnotics, hormones, hypog
  • Certain embodiments include a drug selected from the group consisting of indomethacin, sulindac, diclofenal, etodolac, meclofenate, mefenamic acid, nambunetone, piroxicam, phenylgutazone, meloxicam, dexamethoasone, betamethasone, dipropionate, diflorsasone diacetate, clobetasol propionate, galobetasol propionate, amcinomide, beclomethasone dipropionate, fluocinomide, betamethasone valerate, triamcinolone acetonide, penicillamine, hydroxychloroquine, sulfasalazine, azathioprine, minocycline, cyclophosphamide, methotrexate, cyclosporine, leflunomide, etanercept, infliximab, ascomycin, beta-estradiol
  • Certain embodiments include a drug selected from the group consisting of podophyllotoxin, mycophenolic acid, teniposide, etoposide, trans-retinoic acids, 9-cis retinoic acid, 13-cis retinoic acid, rapamycin, a rapalog (e.g., Everolimus, ABT-578), camptothecin, irinotecan, topotecan, tacromilus, mithramycin, mitobronitol, thiotepa, treosulfan, estramusting, chlormethine, carmustine, lomustine, busultan, mephalan, chlorambucil, ifosfamide, cyclophosphamide, doxorubicin, epirubicin, aclarubicin, daunorubicin, mitosanthrone, bleomycin, cepecitabine, cytarabine, fludarabine, cladribine
  • Certain embodiments include a drug selected from the group consisting of salicylic acid, fenbufen, cortisone, ibuprofen, diflunisal, sulindac, difluprednate, prednisone, medrysone, acematacin, indomethacin, meloxicam, camptothecin, benoxinate, benzocaine, procaine, ciprofloxacin, norfloxacin, clofoctol, dexamethasone, fluocinolone, ketorolac, pentoxifylline, rapamycin, ABT-578, gabapentin, baclofen, sulfasalazine, bupivacaine, sulindac, clonidine, etanercept, pegsunercept, and combinations thereof.
  • a drug selected from the group consisting of salicylic acid, fenbufen, cortisone, ibuprofen,
  • compositions including at least one biologically active agent and at least one polymer as disclosed herein can be prepared by suitable methods known in the art.
  • such compositions can be prepared by solution processing, milling, extruding, and/or reacting components including multifunctional azides and multifunctional azide-reactants in the presence of at least one biologically active agent.
  • Compositions including polymers as disclosed herein can further include additional components.
  • additional components include fillers, dyes, pigments, inhibitors, accelerators, viscosity modifiers, tackifiers, adhesion promoters, wetting agents, buffering agents, stabilizers, biologically active agents, polymeric materials, excipients, and combinations thereof.
  • Medical devices that include one or more polymers as disclosed herein and one or more biologically active agents can have a wide variety of uses.
  • the one or more biologically active agents are preferably disposed in the one or more polymers.
  • the term "disposed" is intended to be broadly interpreted as inclusive of dispersed, dissolved, suspended, or otherwise contained at least partially therein or thereon.
  • such devices can be used to deliver one or more biologically active agents to a tissue by positioning at least a portion of the device including the one or more polymers proximate the tissue and allowing the one or more polymers to deliver the one or more biologically active agents disposed therein.
  • such devices can be used to control the release rate of one or more biologically active agents from a medical device by disposing the one or more biologically active agents in at least one of the one or more polymers.
  • Polyethylene glycol diglycidyl ether, M n -526 (7.89 g; 0.015 mole) was added to a solution of sodium azide (NaN 3 ; 9.75 g; 0.15 mole) in 60 milliliters (ml) water. The pH of the solution was measured to be 12.2. The solution was allowed to stir overnight. A small sample of the solution was taken out and concentrated under full vacuum. The product was then dissolved in D 2 O, and 1 H and 13 C NMR spectra were acquired. The 13 C NMR spectrum was consistent with the formation of an azido alcohol of Formula I.
  • Polyethylene glycol, M n 600 (PEG 600) was dried using a rotary evaporator at a pressure of 20 torr (2.7 kilopascals) and heating at 80 0 C in an oil bath.
  • the reaction mixture was warmed to room temperature and stirred overnight under a nitrogen atmosphere. The precipitate was then filtered out of solution, and the filtrate concentrated under full vacuum at 50 0 C. A sample of the dried product was dissolved in dg-THF, and 1 H and 13 C NMR spectra were acquired, which were consistent with the mesylated-PEG 600 (25.34 g; 0.0335moles).
  • the mesylated-PEG 600 was dissolved in acetone (50 ml), sodium azide (5.45 g; 0.0838 moles; 2.5 equivalents of azide to mesylate) was added, and the reaction mixture was stirred for 2 days.
  • Polyethylene glycol, M n 600 (PEG 600) was dried using a rotary evaporator at a pressure of 20 torr (2.7 kilopascals) and heating at 80 0 C in an oil bath.
  • the reaction mixture was stirred over the weekend to allow all the Na metal to react, then cooled to 0 0 C in an ice bath.
  • Tripropargyl amine (0.33 g; 0.0025 mole) was added to the azido alcohol prepared in Preparatory Example 1 (2.31 g; 0.0038 moles) in a round bottomed flask (2: 3 molar ratio of the tripropargyl amine to the azido alcohol).
  • CuSO 4 (0.139 g; 5% by weight) and sodium ascorbate (0.293 g; 10% by weight) were dissolved in 15 ml of water to generate a Cu(I) catalyst in situ.
  • the aqueous Cu(I) catalyst solution was then added to the flask containing the azido alcohol and the tripropargyl amine, and the reaction mixture was stirred until becoming thick overnight. Additional water (30 ml) was added to the flask, and the product was separated by centrifuging the reaction mixture. The resulting polymer was then dried at ambient temperature under full vacuum.

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Abstract

L'invention concerne des procédés de préparation de polymères à partir d'azides multifonctionnels et de réactifs aux azides multifonctionnels. Des exemples de réactifs aux azides multifonctionnels comprennent des alcynes multifonctionnels et/ou des esters d'a-phosphine multifonctionnels. Dans certains modes de réalisation, de tels polymères peuvent être préparés in vivo. De tels polymères peuvent être utiles dans une grande variété d'applications biomédicales.
PCT/US2008/055905 2007-03-16 2008-03-05 Polymérisation d'azides multifonctionnels et polymères dérivés de ceux-ci WO2008115694A2 (fr)

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