WO2008089256A2 - Polymeric therapeutics - Google Patents

Polymeric therapeutics Download PDF

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Publication number
WO2008089256A2
WO2008089256A2 PCT/US2008/051193 US2008051193W WO2008089256A2 WO 2008089256 A2 WO2008089256 A2 WO 2008089256A2 US 2008051193 W US2008051193 W US 2008051193W WO 2008089256 A2 WO2008089256 A2 WO 2008089256A2
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WIPO (PCT)
Prior art keywords
polymer
compound
paclitaxel
composition
acid
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Application number
PCT/US2008/051193
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French (fr)
Other versions
WO2008089256A3 (en
Inventor
Rachit Ohri
Mark Steckel
Shrirang Ranade
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Cappella, Inc.
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Publication of WO2008089256A2 publication Critical patent/WO2008089256A2/en
Publication of WO2008089256A3 publication Critical patent/WO2008089256A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6957—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a device or a kit, e.g. stents or microdevices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/593—Polyesters, e.g. PLGA or polylactide-co-glycolide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/605—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the macromolecule containing phosphorus in the main chain, e.g. poly-phosphazene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid

Definitions

  • the present invention relates to biodegradable polymers covalently bonded to one or more pharmaceutically active agents typically for use as coatings on medical devices that are inserted within the body and subject to internal body, organ or blood conditions.
  • DES drug eluting stents
  • catheters catheters
  • guidewires guidewires
  • DES drug eluting stents
  • commercially available DES comprise a coated device where the coating includes a single drug eluted from a polymeric carrier.
  • One embodiment provides a polymer comprising a chemical moiety covalently linked to at least one branch of the polymer, the chemical moiety being linked through a covalent bond, wherein the chemical moiety forms a pharmaceutically active agent upon degradation of the covalent bond, and wherein the polymer is chosen from star polymers, dendrimers, and hyperbranched polymers.
  • the polymer is less soluble in an aqueous medium, e.g., a physiological medium, than is the free form of the pharmaceutically active agent.
  • the polymer has a Tg greater than 37°C. In one embodiment, the polymer has a Tg greater than 40 0 C, e.g., a Tg greater than 50 0 C, or greater than 60°C.
  • Another embodiment provides a star polymer comprising a chemical moiety covalently linked to at least one branch of the polymer, the chemical moiety being linked through a covalent bond, wherein the chemical moiety forms a pharmaceutically active agent upon degradation of the covalent bond.
  • the chemical moiety is incorporated in the main chain (backbone) of the at least one branch of the star polymer.
  • the chemical moiety is a pendant (side chain and/or terminus) group of the at least one branch of the star polymer.
  • the chemical moiety is linked to the terminus of the at least one branch of the star polymer.
  • each branch of the star polymer have substantially the same molecular weight and length.
  • branches of the star polymer have different molecular weights and different lengths.
  • the star polymer comprises branches of substantially the same molecular weight and length and one branch of substantially higher molecular weight and length.
  • the molecular weight of one or more branches of the star polymer ranges from 10,000 Da to 100,000 Da.
  • the covalent bond is hydrolytically degradable.
  • the covalent link between the star polymer and the pharmaceutically active agent is selected from anhydride, ester, carbonate, amide, and thioester linkages.
  • the chemical moiety is linked to the star polymer via a linking group.
  • the linking group is selected from aliphatic C 4 -C2o chains, polylactide, poly(lactide-co-galactide), polyethylene glycol, polycaprolactone, polyethyleneimine, polycaprolactone/polyethyleneimine, and phospholipids.
  • the linking group is biodegradable.
  • At least one branch contains a stimuli-responsive linking group.
  • the stimuli-responsive linking group is selected from temperature responsive polymers and pH responsive polymers.
  • the temperature responsive polymers are selected from poly(N-isopropylacrylamide).
  • the pH responsive polymers are selected from polypropyl acrylic acid.
  • the star polymer comprises a monomer selected from ethylenimine, ethylene glycol, amphiphilic scorpion-like macromolecules, phosphazenes, amidoamines, and propyleneimine.
  • the star polymer comprises a polymer selected from polyethyleneimine, polyethylene glycol, polyethyleneimine/polyethylene glycol, amphiphilic scorpion-like macromolecules, polyphosphazenes, polyamidoamines, and polypropyleneimine, and the chemical moiety is covalently linked as a pendant group (e.g., a side chain) or terminus group.
  • the star polymer is biodegradable.
  • the pharmaceutically active agent is selected from taxanes, limus derivatives, and non-steroidal anti-inflammatory agents.
  • the pharmaceutically active agent is selected from paclitaxel, sirolimus, everolimus, biolimus, zotarolimus, and AP23573.
  • the star polymer is less soluble in an aqueous medium than is the free form of the pharmaceutically active agent.
  • the pharmaceutically active agent is hydrophobic.
  • the pharmaceutically active agent is present in a dose density ranging from 0.05 to 10 ⁇ g/mm 2 .
  • the star polymer has a Tg greater than 37°C. In one embodiment, the compound has a Tg greater than 40 0 C. In one embodiment, the compound has a Tg greater than 50 0 C, or greater than 60°C.
  • At least one branch of the star polymer comprises two or more different chemical moieties that form pharmaceutically active agents.
  • At least one branch of the star polymer comprises at least three different chemical moieties that form pharmaceutically active agents.
  • the at least three chemical moieties comprises a first chemical moiety that forms an antiproliferative pharmaceutically active agent, at second chemical moiety forms an anti-inflammatory agent, and a third chemical moiety that forms a healing promoter.
  • At least one branch of the star polymer comprises a first chemical moiety, and at least one branch of the star polymer comprises a second chemical moiety.
  • At least one branch of the star polymer comprises a first chemical moiety
  • at least one branch of the star polymer comprises a second chemical moiety
  • at least one branch of the star polymer comprises a third chemical moiety
  • the first chemical moiety forms an antiproliferative pharmaceutically active agent
  • the second chemical moiety forms an antiinflammatory agent
  • the third chemical moiety forms a healing promoter
  • a polymer comprising at least two covalently linked star polymers comprising at least two covalently linked star polymers.
  • Another embodiment provides an implantable medical device having at least one coating covering at least a portion of the device, the at least one coating comprising a polymer selected from star polymers, dendhmers, and hyperbranched polymers as disclosed herein.
  • the device is implantable into a mammalian lumen.
  • the device is a stent.
  • the stent is either balloon expandable or self-expanding.
  • the composition is coated on the stent to form a conformal coating around all surfaces of the stent.
  • the composition is coated only on the abluminal surface of the stent. In one embodiment, the composition is coated only on the abluminal surface of the stent and the composition resides partially or completely within micro-reservoirs or pores in the stent surface.
  • the device is selected from pacemaker leads, valve replacement and repair devices, vena cava filters, and embolic coils and beads.
  • the device is an angioplasty balloon having coated thereon the coating comprising the composition, wherein the balloon is used to deliver the composition to an endoluminal surface.
  • the at least one coating comprises at least two coatings to provide a multi-layered structure.
  • the at least one coating comprises at least three coatings.
  • each of the at least three coatings provides a different chemical moiety that forms a different pharmaceutically active agent.
  • the composition in one of the at least three coatings comprises a chemical moiety that forms an antiproliferative pharmaceutically active agent.
  • the composition in one of the at least three coatings comprises a chemical moiety that forms an anti-inflammatory agent.
  • the composition in one of the at least three coatings comprises a chemical moiety that forms a healing promoter.
  • the at least one coating directly contacts the device.
  • the device further comprises an inner coating free of a pharmaceutically active agent that directly contacts the device, wherein the inner coating also directly contacts the at least one coating.
  • Another embodiment provides a polymer comprising: one or more of a star polymer, a dendrimer polymer and a hyperbranched polymer having a plurality of branches, one more of the branches comprising a biodegradable polymer comprising a chemical moiety bonded to a linker group; wherein the chemical moiety is bonded to the linker group via a linkage that is naturally hydrolysable in an in vivo environment, the polymer being less soluble in vivo than the free form of the pharmaceutically active agent is soluble in vivo.
  • the pharmaceutically active agent is incorporated into a backbone of one or more of the branches.
  • the pharmaceutically active agent is bonded in pendant relationship to one or more of the branches.
  • the hydrolysable linkage is preselected to produce a selected concentration of the pharmaceutically active moieties over a selected period of time in an in vivo environment.
  • one or more of the number and length of the one or more branches is preselected to produce a selected concentration of the pharmaceutically active moieties over a selected period of time in an in vivo environment.
  • the linker group comprises one or more of an aliphatic chain of 2-20 carbon atoms, a lactide, a glycolide, a glycol, a caprolactide, an alkylene oxide and co-monomers and copolymers of all of the foregoing.
  • One embodiment provides a composition comprising a biocompatible polymer, the polymer being linked to a chemical moiety through a covalent bond, wherein, the chemical moiety forms a pharmaceutically active agent upon degradation of the covalent bond, the chemical moiety is linked to a polysaccharide or phospholipid.
  • the polymer has a Tg greater than 37°C, e.g., greater than 40 0 C, greater than 50 0 C, or greater than 60°C.
  • the chemical moiety is incorporated into the backbone of the polymer.
  • the covalent bond is hydrolytically degradable or biodegradable.
  • the covalent bond comprises an ester, amide, carbonate, anhydride or thioester linkage.
  • the composition is used for at least one coating for an implantable medical device, the at least one coating covering at least a portion of the device.
  • the biodegradable polymer further comprises a linker group linking the polysaccharide or phospholipid to the chemical moiety, the linker group being linked to the polysaccharide or phospholipid via an ester, amide, carbonate, anhydride or thioester linkage and to the chemical moiety via an ester, amide, carbonate, anhydride or thioester linkage.
  • the polysaccharide includes a plurality of hydroxyl groups, a selected number of such plurality of hydroxyl groups being reacted with a second chemical moiety to form a second biodegradable linkage, the second chemical moiety forming a second pharmaceutically active agent on degradation of the second biodegradable linkage.
  • the pharmaceutically active agent is selected from taxanes, limus derivatives, and non-steroidal anti-inflammatory agents.
  • the pharmaceutically active agent is selected from paclitaxel, rapamycin and their analogs and derivatives.
  • the biodegradable polymer is present in an amount ranging from 40% to 95% by weight relative to the total weight of the composition.
  • the pharmaceutically active agent is present in a dose density ranging from 0.05 to 10 ⁇ g/mm 2 .
  • the number average molecular weight of the polymer is between about 10,000 daltons and about 100,000 daltons.
  • the structure and molecular weight of the polysaccharide is pre-selected to impart a pre-selected degree of hydrophilicity to the polymer.
  • the polysaccharide is pre-selected to impart or possess a predetermined bioactivity on degradation of the covalent bond.
  • the structure and molecular weight of the phospholipid is pre-selected to impart a pre-selected degree of hydrophobicity to the polymer.
  • the phospholipid is pre-selected to impart or possess a predetermined bioactivity on degradation of the covalent bond.
  • polymer comprises both a phospholipid and a polysaccharide, each linked to the same or different chemical moieties, the chemical moieties forming a pharmaceutically active agent upon degradation of the covalent bond.
  • the structure, molecular weight and relative amounts of the polysaccharide and phospholipid are pre-selected to impart a pre-selected degree of hydrophilicity or hydrophobicity to the polymer.
  • Another embodiment provides a method of making a polymer having therapeutic properties, the method comprising: selecting a first chemical moiety having a selected pharmaceutical activity; covalently bonding a first reactive site on the first chemical moiety to a first reactive site on a selected polysaccharide or phospholipid; and, covalently bonding a second reactive site on the first chemical moiety to a second reactive site on the selected polysaccharide or phospholipid to form a polymer of alternating sequence of the first chemical moiety and the selected polysaccharide or phospholipid.
  • a method of making a polymer having therapeutic properties comprising: selecting a first chemical moiety having a selected pharmaceutical activity; selecting a polysaccharide or a phospholipid having multiple reactive sites capable of linking to the first chemical moiety; protecting all but two of the reactive sites of the selected polysaccharide or phospholipid; and linking the first chemical moiety to at least one of the two unprotected sites of the selected polysaccharide or phospholipid.
  • the selected polysaccharide or phospholipid is polymerized in alternating sequence with the first chemical moiety alone or together with a second chemical moiety having a second selected pharmaceutical activity.
  • the selected polysaccharide or phospholipid can be copolymehzed together with the first and second selected chemical moieties to form a straight or branched chain polymer of the first and/or second chemical moieties in alternating sequence with one or both of the polysaccharide and/or phospholipid.
  • the first and/or second selected chemical moieties have at least two reactive sites for forming covalent linkages to the selected polysaccharide and/or phopholipid.
  • Such linkages can be selected from direct ester, amide, carbonate, anhydride and/or thioester linkages.
  • the linkages between the one or more selected chemical moieties and the polysaccharide or phospholipid can be created via a linker having two reactive groups capable of forming an ester, amide, carbonate, anhydride or thioester linkage with a corresponding reactive group of the selected chemical moiety(ies) and the selected polysaccharide and/or phospholipid.
  • the structure and molecular weight of the polysaccharide or phospholipid is selected to impart a pre-selected degree of hydrophilicity and/or hydrophobicity to the polymer so formed.
  • the polysaccharide and/or phospholipid has a preselected biologic therapeutic activity such as an anti-restenotic, anti-inflammatory or anti-thrombotic activity.
  • a preselected biologic therapeutic activity such as an anti-restenotic, anti-inflammatory or anti-thrombotic activity.
  • Another embodiment provides an implantable medical device having at least one coating covering at least a portion of the device, the at least one coating comprising a compound according to any of the above described polymers..
  • the at least one coating comprises at least two coatings to provide a multi-layered structure.
  • the at least one coating comprises at least three coatings.
  • each of the at least two or three coatings provides a different chemical moiety that forms a different pharmaceutically active agent.
  • the composition in one of the at least two or three coatings comprises a chemical moiety that forms an antiproliferative pharmaceutically active agent.
  • the composition in one of the at least two or three coatings comprises a chemical moiety that forms an anti-inflammatory agent.
  • the at least one coating directly contacts the device.
  • an inner coating free of a pharmaceutically active agent that directly contacts the device wherein the inner coating also directly contacts the at least one coating.
  • the device is implantable into a mammalian lumen.
  • the device is a stent.
  • the stent is either balloon expandable or self-expanding.
  • the composition is coated on the stent to form a conformal coating around all surfaces of the stent.
  • the composition is coated only on the abluminal surface of the stent. In one embodiment, the composition is coated only on the abluminal surface of the stent and the composition resides partially or completely within micro-reservoirs or pores in the stent surface.
  • the device is selected from pacemaker leads, valve replacement and repair devices, vena cava filters, and embolic coils and beads.
  • the device is an angioplasty balloon having coated thereon the coating comprising the composition, wherein the balloon is used to deliver the composition to an endoluminal surface.
  • Another embodiment provides a polymer comprising the repeat unit:
  • L 1 and L 2 are the same or different, and each are linking groups selected from the group of polysaccharides and phospholipids and are covalently linked to D 1 and D 2 via one or more of an amide, ester, anhydride, carbonate and thioester linkage;
  • D 1 and D 2 are the same or different and are a chemical moiety that upon degradation of a linkage to the linking groups form a pharmaceutically active agent.
  • Another embodiment provides a polymer comprising the repeat unit:
  • L 1 and L 2 are the same or different, and each are linking groups selected from the group of polysaccharides and phospholipids and are covalently linked to D 1 and D 2 via one or more of an amide, ester, anhydride, carbonate and thioester linkage;
  • L 3 , L 4 , L 5 and L 6 can be the same or different, and each are one or the other of an amide, ester, anhydride, carbonate and thioester linkage or are a linking group that are linked to an adjacent group via one or the other of an amide, ester, anhydride, carbonate and thioester linkage;
  • D 1 and D 2 are the same or different and are a chemical moiety that upon degradation of a linkage to the linking groups form a pharmaceutically active agent.
  • Another embodiment provides a polymer comprising the repeat unit:
  • L 1 and L 2 and L 3 are the same or different, and each are linking groups selected from the group of polysaccharides and phospholipids and are covalently linked to D 1 and D 2 via one or more of an amide, ester, anhydride, carbonate and thioester linkage;
  • Di and D 2 and D 3 are the same or different and are a chemical moiety that upon degradation of a linkage to the linking groups form a pharmaceutically active agent.
  • Another embodiment provides a polymer comprising the repeat unit:
  • Li and L 2 and L 3 are the same or different, and each are linking groups selected from the group of polysaccharides and phospholipids
  • L 4 , L 5 , L 6 , L 7 , L 8 and L 9 can be the same or different, and each are one or the other of an amide, ester, anhydride, carbonate and thioester linkage or are a linking group that are linked to an adjacent group via one or the other of an amide, ester, anhydride, carbonate and thioester linkage;
  • Di and D 2 and D 3 are the same or different and are a chemical moiety that upon degradation of a linkage to the linking groups form a pharmaceutically active agent.
  • Di and D 2 and D 3 are each selected from taxanes, limus derivatives, and non-steroidal anti-inflammatory agents.
  • D 1 and D 2 and D 3 are each selected from paclitaxel, rapamycin and their analogs and derivatives.
  • D 1 and D 2 and D 3 are each selected from taxanes, limus derivatives, non-steroidal anti-inflammatory agents and healing promoters.
  • composition comprising the above described polymer, the polymer being present in an amount ranging from 40% to 95% by weight relative to the total weight of the composition.
  • the pharmaceutically active agent is present in a dose density ranging from 0.05 to 10 ⁇ g/mm 2 .
  • the number average molecular weight of the polymer is between about 10,000 daltons and about 100,000 daltons.
  • the structure and molecular weight of the polysaccharide is pre-selected to impart a pre-selected degree of hydrophilicity to the polymer.
  • the polysaccharide is pre-selected to impart or possess a predetermined bioactivity on degradation of the covalent bond.
  • the structure and molecular weight of the phospholipid is pre-selected to impart a pre-selected degree of hydrophobicity to the polymer.
  • the phospholipid is pre-selected to impart or possess a predetermined bioactivity on degradation of the covalent bond.
  • the relative molar or weight ratios of the polysaccharide and phospholipid contained within the polymer are pre-selected to impart a preselected degree of hydrophilicity or hydrophobicity to the polymer.
  • compositions comprising a biodegradable polymer, the polymer comprising: a backbone having a first chemical moiety incorporated into the backbone of the polymer via one or more biodegradable covalent linkages, a pendant arm (side chain and/or terminus group) linked to the backbone via a biodegradable linkage, the pendant arm having a second chemical moiety bonded to the pendant arm via a single biodegradable covalent linkage, wherein the first and second chemical moieties are the same or different and each forms a pharmaceutically active agent upon degradation of their biodegradable linkages.
  • the pendant arm is linked to the backbone via an ester, amide, carbonate, anhydride or thioester linkage.
  • the backbone of the biodegradable polymer further comprises one or more of an aliphatic chain of 4 to 20 carbon atoms, a polylactide, a polyether, a polyglycolide, a polyethyleneimine, a polycaprolactone, a polysaccharide, a polyphospholipid or a polyamino acid linked to the first chemical moiety via one or more of an ester, amide, carbonate, anhydride or thioester linkage.
  • the polylactide, polyether, polyglycolide, polyethyleneimine, polycaprolactone, polysaccharide or polyphospholipid is incorporated into the backbone via a linker group, the linker group being linked to both the first chemical moiety and to the polylactide, polyether, polyglycolide, polysaccharide and/or polyphospholipid via an ester, amide, carbonate, anhydride or thioester linkage.
  • a linker group typically comprises an aliphatic chain of 4 to 20 carbon atoms.
  • the pendant arm comprises one or more of an aliphatic chain of 4 to 20 carbon atoms, a polylactide, a polyether, a polyglycolide, a polyethyleneimine, a polycaprolactone, a polysaccharide, a polyphospholipid or a polyamino acid linked to the second chemical moiety via one or more of an ester, amide, carbonate, anhydride or thioester linkage.
  • the polymer has a Tg greater than 37°C, e.g., a Tg greater than 40 0 C, greater than 50 0 C, or even greater than 60°C.
  • the covalent bond is hydrolytically degradable or biodegradable.
  • the covalent comprises an ester, amide, carbonate, anhydride or thioester linkage.
  • the composition is used for at least one coating for an implantable medical device, the at least one coating covering at least a portion of the device.
  • the pharmaceutically active agent is selected from taxanes, limus derivatives, and non-steroidal anti-inflammatory agents.
  • the pharmaceutically active agent is selected from paclitaxel, rapamycin and their analogs and derivatives.
  • the biodegradable polymer is present in an amount ranging from 40% to 95% by weight relative to the total weight of the composition.
  • the pharmaceutically active agent is present in a dose density ranging from 0.05 to 10 ⁇ g/mm 2 .
  • the number average molecular weight of the polymer is between about 5,000 daltons and about 100,000 daltons.
  • the structure and molecular weight of the aliphatic chain of 4 to 20 carbon atoms, a polylactide, a polyether, a polyglycolide, a polyethyleneimine, a polycaprolactone, a polysaccharide, a polyphospholipid or a polyamino acid is pre-selected to impart a pre-selected degree of hydrophilicity, hydrophobicity or rate of degradation to the polymer.
  • the aliphatic chain of 4 to 20 carbon atoms, a polylactide, a polyether, a polyglycolide, a polyethyleneimine, a polycaprolactone, a polysaccharide, a polyphospholipid or a polyamino acid is pre-selected to impart or possess a predetermined bioactivity on degradation of the covalent linkages.
  • the polymer comprises two or more of an aliphatic chain of 4 to 20 carbon atoms, a polylactide, a polyether, a polyglycolide, a polyethyleneimine, a polycaprolactone, a polysaccharide, a polyphospholipid or a polyamino acid, each linked to the same or different first chemical moieties, the first chemical moieties forming a pharmaceutically active agent upon degradation of the covalent bond.
  • molecular weight and relative amounts of the two or more of an aliphatic chain of 4 to 20 carbon atoms, a polylactide, a polyether, a polyglycolide, a polyethyleneimine, a polycaprolactone, a polysaccharide, a polyphospholipid or a polyamino acid are pre-selected to impart a pre-selected degree of hydrophilicity, hydrophobicity or rate of degradation to the polymer.
  • a method of making a polymer having therapeutic properties comprising: selecting a first chemical moiety having a selected pharmaceutical activity; covalently bonding a first reactive site on the first chemical moiety via a first biodegradable linkage to a selected aliphatic chain of 4 to 20 carbon atoms, a polylactide, a polyether, a polyglycolide, a polyethyleneimine, a polycaprolactone, a polysaccharide, a polyphospholipid or a polyamino acid; and, covalently bonding a second reactive site on the first chemical moiety via a second biodegradable linkage to the selected aliphatic chain of 4 to 20 carbon atoms, polylactide, polyether, polyglycolide, polyethyleneimine, polycaprolactone, polysaccharide, polyphospholipid or polyamino acid to form a polymer of alternating sequence of the first chemical moiety and the selected polylactide, poly
  • a method of making a polymer having therapeutic properties comprising: selecting a second chemical moiety having a selected pharmaceutical activity; selecting a pendant arm comprising one or more of an aliphatic chain of 4 to 20 carbon atoms, a polylactide, a polyether, a polyglycolide, a polyethyleneimine, a polycaprolactone, a polysaccharide, a polyphospholipid or a polyamino acid; linking the second chemical moiety via a single biodegradable linkage to the pendant arm via one or more of an ester, amide, carbonate, anhydride or thioester linkage; linking the pendant arm to the backbone of the polymer via an ester, amide, carbonate, anhydride or thioester linkage.
  • the selected aliphatic chain of 4 to 20 carbon atoms, polylactide, polyether, polyglycolide, polyethyleneimine, polycaprolactone, polysaccharide, polyphospholipid or polyamino acid can be polymerized in alternating sequence with the first chemical moiety alone or together with a third chemical moiety having a third selected pharmaceutical activity.
  • the selected aliphatic chain of 4 to 20 carbon atoms, polylactide, polyether, polyglycolide, polyethyleneimine, polycaprolactone, polysaccharide, polyphospholipid or polyamino acid can be copolymehzed together with each other and with the first and third selected chemical moieties.
  • the aliphatic chains of 4 to 20 carbon atoms, polylactide, polyether, polyglycolide, polyethyleneimine, polycaprolactone, polysaccharide, polyphospholipid or polyamino acid can be pre-selected to impart or possess a predetermined temperature or pH responsive property.
  • the first, second, and/or third selected chemical moieties have at least two reactive sites for forming covalent linkages to the selected aliphatic chain of 4 to 20 carbon atoms, polylactide, polyether, polyglycolide, polyethyleneimine, polycaprolactone, polysaccharide, polyphospholipid or polyamino acid.
  • linkages can be direct ester, amide, carbonate, anhydride and/or thioester linkages.
  • the linkages between the one or more selected first, second, and/or third chemical moieties and the polylactide, polyether, polyglycolide, polyethyleneimine, polycaprolactone, polysaccharide, polyphospholipid or polyamino acid can be created via a linker having two reactive groups each capable of forming an ester, amide, carbonate, anhydride or thioester linkage with a corresponding reactive group of the selected chemical moiety(ies) as well as with a corresponding next one of the poly moieties in the chain.
  • the structure and molecular weight of the aliphatic chain of 4 to 20 carbon atoms, polylactide, polyether, polyglycolide, polyethyleneimine, polycaprolactone, polysaccharide, polyphospholipid or polyamino acid is selected to impart a pre-selected degree of hydrophilicity and/or hydrophobicity to the polymer so formed.
  • the polylactide, polyether, polyglycolide, polyethyleneimine, polycaprolactone, polysaccharide, polyphospholipid or polyamino acid has a pre-selected rate of biodegradability.
  • Another embodiment provides an implantable medical device having at least one coating covering at least a portion of the device, the at least one coating comprising a compound according to any of the above described polymers.
  • the at least one coating comprises at least two coatings to provide a multi-layered structure.
  • the at least one coating comprises at least three coatings.
  • each of the at least two or three coatings provides a different chemical moiety that forms a different pharmaceutically active agent.
  • the composition in one of the at least two or three coatings comprises a chemical moiety that forms an antiproliferative pharmaceutically active agent.
  • the composition in one of the at least two or three coatings comprises a chemical moiety that forms an anti-inflammatory agent.
  • the at least one coating directly contacts the device.
  • an inner coating free of a pharmaceutically active agent that directly contacts the device wherein the inner coating also directly contacts the at least one coating.
  • the device is implantable into a mammalian lumen.
  • the device is a stent.
  • the stent is either balloon expandable or self-expanding.
  • the composition is coated on the stent to form a conformal coating around all surfaces of the stent.
  • the composition is coated only on the abluminal surface of the stent. In one embodiment, the composition is coated only on the abluminal surface of the stent and the composition resides partially or completely within micro-reservoirs or pores in the stent surface.
  • the device is selected from pacemaker leads, valve replacement and repair devices, vena cava filters, and embolic coils and beads.
  • the device is an angioplasty balloon having coated thereon the coating comprising the composition, wherein the balloon is used to deliver the composition to an endoluminal surface.
  • Another embodiment provides a polymer comprising the repeat unit:
  • L 1 , L 2 and L 3 are the same or different, and each are linking groups selected from the group of aliphatic chains of 4 to 20 carbon atoms, polysaccharide, polyphospholipid or polyamino acid and are covalently linked to D 1 , D 2 and D 3 via one or more of an amide, ester, anhydride, carbonate and thioester linkage;
  • D 1 , D 2 and D 3 are the same or different and are a chemical moiety that upon degradation of a linkage to the linking groups form a pharmaceutically active agent.
  • L 3 can be linked to L 1 via a biodegradable linkage such as an amide, ester, anhydride, carbonate and thioester linkage.
  • a "polymer comprising the repeat unit” can have additional linking groups and repeat units other than the repeat unit listed herein.
  • Another embodiment provides a polymer comprising the repeat unit:
  • L 1 , L 2 and L 7 are the same or different, and each are linking groups selected from the group of aliphatic chains of 4 to 20 carbon atoms, polylactide, polyether, polyglycolide, polyethyleneimine, polycaprolactone, polysaccharide, polyphospholipid or polyamino acid and are covalently linked to D 1 , D 2 and D 3 via one or more of an amide, ester, anhydride, carbonate and thioester linkage;
  • L 3 , L 4 , L 5 and L 6 are the same or different, and each are one or the other of an amide, ester, anhydride, carbonate and thioester linkage or are a linking group that are linked to an adjacent group via one or the other of an amide, ester, anhydride, carbonate and thioester linkage;
  • D 1 , D 2 and D 3 are the same or different and are a chemical moiety that upon degradation of a linkage to the linking groups form a pharmaceutically active agent.
  • L 7 can be linked to L 1 via a biodegradable linkage such as an amide, ester, anhydride, carbonate and thioester linkage.
  • Another embodiment provides a polymer comprising the repeat unit:
  • L 1 and L 2 and L 3 and L 7 are the same or different, and each are linking groups selected from the group of aliphatic chains of 4 to 20 carbon atoms, polysaccharide, polyphospholipid or polyamino acid and are covalently linked to D 1 and D 2 and D 3 and D 4 via one or more of an amide, ester, anhydride, carbonate and thioester linkage; D 1 and D 2 and D 3 and D 4 are the same or different and are a chemical moiety that upon degradation of a linkage to the linking groups form a pharmaceutically active agent.
  • L 7 can be linked to Li via a biodegradable linkage such as an amide, ester, anhydride, carbonate and thioester linkage.
  • Another embodiment provides a polymer comprising the repeat unit: -[Di- L 4 -Li- L 5 -D 2 - L 6 -L 2 - L 7 -D 3 - L 8 -L 3 -L 9 ] I
  • L 1 and L 2 and L 10 are the same or different, and each are linking groups selected from the group of aliphatic chains of 4 to 20 carbon atoms, polylactide, polyether, polyglycolide, polyethyleneimine, polycaprolactone, polysaccharide, polyphospholipid or polyamino acid;
  • L 4 , L 5 , L 6 , L 7 , L 8 and L 9 can be the same or different, and each are one or the other of an amide, ester, anhydride, carbonate and thioester linkage or are a linking group that are linked to an adjacent group via one or the other of an amide, ester, anhydride, carbonate and thioester linkage;
  • Di and D 2 and D 3 are the same or different and are a chemical moiety that upon degradation of a linkage to the linking groups form a pharmaceutically active agent.
  • Li 0 can be linked to Li via a biodegradable linkage such as an amide, ester, anhydride, carbonate and thioester linkage.
  • D 1 and D 2 and D 3 are each selected from taxanes, limus derivatives, and non-steroidal anti-inflammatory agents.
  • D 1 and D 2 and D 3 are each selected from paclitaxel, rapamycin and their analogs and derivatives.
  • D 1 and D 2 and D 3 are each selected from taxanes, limus derivatives, non-steroidal anti-inflammatory agents and healing promoters.
  • a composition comprising the above described polymer, the polymer being present in an amount ranging from 40% to 95% by weight relative to the total weight of the composition.
  • the pharmaceutically active agent is present in a dose density ranging from 0.05 to 10 ⁇ g/mm 2 .
  • the number average molecular weight of the polymer is between about 10,000 daltons and about 100,000 daltons.
  • the polymer is a linear, star or hyperbranched or dendrimer polymer in structure.
  • the aliphatic chain of 4 to 20 carbon atoms, polylactide, polyether, polyglycolide, polyethyleneimine, polycaprolactone, polysaccharide, polyphospholipid or polyamino acid is pre-selected to impart or possess a predetermined temperature or pH response property.
  • the relative molar or weight ratios of the aliphatic chains of 4 to 20 carbon atoms, polylactide, polyether, polyglycolide, polyethyleneimine, polycaprolactone, polysaccharide, polyphospholipid or polyamino acid contained within the polymer are pre-selected to impart a preselected degree of hydrophilicity or hydrophobicity or glass transition temperature to the polymer.
  • FIG. 1 is a schematic showing a paclitaxel polymer via a covalent linking group
  • FIG. 2 is a schematic of a multi-layered coating containing different pharmaceutically active agents
  • FIG. 3 is a schematic showing a star polymer containing pharmaceutically active agents incorporated in the main chain (backbone) of the branches;
  • FIG. 4 is a schematic showing pharmaceutically active agents as pendant groups (side chain and terminal groups) covalently bonded to a star polymer
  • FIG. 5 is a schematic showing a pharmaceutically active agents covalently bonded to the end of branches (terminus) of a star polymer
  • FIG. 6 is a schematic showing a pharmaceutically active agents covalently bonded to the end of branches (terminus) of a star polymer, where the branches have varying lengths
  • FIG. 7 is a schematic showing star polymers of FIGs. 3-5 and including an additional branch having a high molecular weight.
  • One embodiment provides a prodrug for at least one coating covering all or a portion of an implantable medical device.
  • the at least one coating comprises a composition comprising a biodegradable polymer.
  • the biodegradable polymer comprises one or more moieties covalently linked in a polymeric chain.
  • the chemical moiety forms a pharmaceutically active agent.
  • the polymeric chain can be straight or branched, or can be a star polymer, a dendrimer, or a hyperbranched polymer.
  • the chemical moiety is linked to a polysaccharide or phospholipid.
  • the chemical moiety can be present in a pendant arm (side chain and/or terminus group) or in the polymer backbone.
  • the biodegradable polymer is linked to the chemical moiety. In one embodiment, the biodegradable polymer is linked to a pendant chemical moiety. In another embodiment, a "biodegradable polymer linked to a chemical moiety” refers to a chemical moiety incorporated in the backbone of the biodegradable polymer.
  • the degradation of the covalent bond occurs via hydrolysis.
  • the hydrolysis can involve a direct reaction with an aqueous medium, or can be catalyzed chemically or enzymatically.
  • Aqueous medium refers to water, aqueous solutions, physiological media or biological fluids (e.g., body fluids), and other pharmaceutically acceptable media.
  • Suitable hydrolysable covalent bonds include those forming esters, amides, urethanes, carbamates, carbonates, azo linkages, anhydrides, thioesters, and combinations thereof.
  • the hydrolysis rate can be controlled by choice of linker chemistry (as discussed below). Additional control of active agent release can be obtained by variables that are unique to these polymer structures, e.g., density and length of polymer branches, the hydrophobicity/hydrophilicity profile of the polymer branches, combination of polymer branches of various lengths, and stimuli responsiveness of the polymer branches (such as stimuli-responsiveness to pH, temperature, light, ultrasound etc.).
  • stimuli-responsive polymeric linker segments include those composed of temperature responsive polymers like poly(N- isopropylacrylamide) (poly-NIPAAM) or pH responsive polymers like polypropyl acrylic acid (PPAc).
  • the polymer is less soluble in an aqueous medium, e.g., a physiological medium, than is the free form of the pharmaceutically active agent.
  • the "free form" of the pharmaceutically active agent can refer to the neutral compound, or salts thereof, e.g., the isolable or stable form of the agent.
  • the compositions (comprising the chemical moiety) have a lower solubility in aqueous media (or in physiological media) than the free form of the pharmaceutically active agent.
  • a coating comprising a drug in a form affording it reduced solubility can provide a lesser probability of the drug being inadvertently eliminated by dissolution (or partial dissolution) prior to its reaching the target site.
  • the polymer is more soluble in an aqueous medium, e.g., a physiological medium, than is the free form of the pharmaceutically active agent.
  • a product of the degradation or hydrolysis is the pharmaceutically active agent, e.g., the free form of the agent.
  • the pharmaceutically active agent has a different structure than the free form of the pharmaceutically active agent but is the true active species that treats the disease or condition, e.g., the form of the agent in vivo.
  • the polymer comprises a monomer selected from ethylenimine, ethylene glycol, amphiphilic scorpion-like macromolecules, phosphazenes, amidoamines, and propyleneimine.
  • the polymer links the chemical moiety as a pendant group, is selected from polyethyleneimine (PEI), polyethylene glycol (PEG), polyethyleneimine/polyethylene glycol, amphiphilic scorpion-like macromolecules (AScMs), polyphosphazenes, polyamidoamines (PAMAM), and polypropyleneimine (PPI).
  • PEI polyethyleneimine
  • PEG polyethylene glycol
  • AScMs amphiphilic scorpion-like macromolecules
  • PAMAM polyphosphazenes
  • PPI polypropyleneimine
  • the polymer i.e., the polymer containing the covalently linked chemical moiety
  • the polymer containing the covalently linked chemical moiety is biodegradable.
  • Biodegradable polymer refers to a polymer capable of hydrolyzing or otherwise degrading in an aqueous medium, as opposed to being soluble in an aqueous medium without degradation.
  • the resulting product(s) of biodegradation is soluble in the resulting body fluid or, if insoluble, can be suspended in a body fluid and transported away from the implantation site without clogging the flow of the body fluid.
  • the body fluid can be any fluid in the body of a mammal including, but not limited to, blood, serum, urine, saliva, lymph, plasma, gastric, biliary, or intestinal fluids, seminal fluids, and mucosal fluids, humors, and extracellular fluids.
  • the biodegradable polymer is soluble, degradable as defined above, or is an aggregate of soluble and/or degradable matehal(s) with insoluble matehal(s) such that, with the resorption of the soluble and/or degradable materials, the residual insoluble materials are of sufficiently fine size such that they can be suspended in a body fluid and transported away from the implantation site without clogging the flow of the body fluid.
  • the degraded compounds can be eliminated from the body either by excretion in perspiration, urine or feces, or dissolved, degraded, corroded or otherwise metabolized into soluble components that are then excreted from the body.
  • the biodegradable polymers are degraded through cleavage of functional groups such as esters, anhydrides, carbonates, thioesters, orthoesters, glycosidic bonds, phosphate esters, and amides.
  • Suitable biodegradable polymers include those in the FDA GRAS (Generally Regarded As Safe) list, the disclosure of which is incorporated herein by reference.
  • the biodegradable polymer comprises one or more monomers that form the following biodegradable polymers: polyglycolides, polylactides (e.g., poly-l-lactide (PLLA)), polycaprolactones, polydioxanones, poly(lactide-co-glycolide) (PLGA), polyhydroxybutyrate, polyhydroxyvalerate, polyphosphoesters, polyphosphoester-urethane, polyamino acids, polycyanoacrylates, poly(trimethylene carbonate), biomolecules such as fibrin, fibrinogen, cellulose, starch, collagen, and blends and copolymers thereof.
  • biodegradable polymers polyglycolides, polylactides (e.g., poly-l-lactide (PLLA)), polycaprolactones, polydioxanones, poly(lactide-co-glycolide) (PLGA), polyhydroxybutyrate, polyhydroxyvalerate, polyphosphoesters, polyphosphoester-urethan
  • the "chemical moiety” is a fragment of a pharmaceutically active agent.
  • the portion of the agent that is covalently bonded is the chemical moiety of the agent.
  • the polymer "linked to a chemical moiety through a covalent bond” can refer to one or more covalent bonds.
  • the chemical moiety is linked directly to the polymer (or monomers) via one or more covalent bonds. "Linked directly” as used herein refers to the product of a reaction between the polymer (or monomer unit) and the pharmaceutically active agent, where the linking atom originates from the starting materials.
  • the chemical moiety is linked to the polymer or monomer through covalent bond(s) to a linking group (comprising one or more molecules) or spacer that is covalently bonded to the polymer or monomer unit.
  • the linking group comes from an external reagent and does not originate from either the polymer (or monomer unit) or the pharmaceutically active agent.
  • Suitable linking groups bind the biodegradable polymer to the chemical moiety through covalent bonds, such as those covalent linkages described herein, e.g., ester, amide, carbamate, carbonate, azo, anhydride, and thioester linkages.
  • FIG. 1 shows a schematic of a chemical moiety covalently linked to a biodegradable polymer.
  • the chemical moiety of FIG. 1 is paclitaxel (PAC), shown below:
  • PAC paclitaxel
  • a linking group containing two carbonyl chloride functional groups (acyl chlorides if L is, e.g., an alkyl group), is reacted with a hydroxyl group of paclitaxel in the presence of triethylamine (TEA).
  • TAA triethylamine
  • a polymer e.g., a biodegradable polymer
  • the L is a biodegradable polymer, resulting in the paclitaxel being directly bonded to the polymer.
  • the paclitaxel is bonded to the polymer via a series of carbonate/ester linkages, and other linkages such as anhydride, carbamate, etc., depending on the linking group and polymers.
  • the linking group can impart mechanical properties and release kinetics for the selected therapeutic application.
  • the linking group is a divalent organic radical having a molecular weight ranging from 25 daltons to 400 daltons, e.g., a molecular weight ranging from 40 daltons to 200 daltons.
  • the linking group has a length ranging from 5 angstroms to 100 angstroms using standard bond lengths and angles, e.g., a length ranging from 10 angstroms to 50 angstroms.
  • the linking group may be biologically inactive, or may itself possess biological activity.
  • the linking group can also comprise other functional groups (including hydroxy groups, mercapto groups, amine groups, carboxylic acids, as well as others) that can be used to modify the properties of the polymer (e.g. for branching, for cross linking, for appending other molecules (e.g. another biologically active compound) to the polymer, for reducing the solubility of the polymer, or for effecting the biodisthbution of the polymer).
  • the linking group is selected from aliphatic C 4 -C2o chains, such as C 4 -C2o chains, polylactide, poly(lactide-co-galactide), polyethylene glycol, polycaprolactone, polyethyleneimine, polycaprolactone/polyethyleneimine, and phospholipids.
  • linkers examples include PLLA, PLGA, PDLA and PDLLA and co-polymers and mixtures of all of the foregoing with each other and with caprolactone, etheyleneimine, thmethylenecarbonate, amino acids, and the like.
  • Other linkers include phospholipids and polysaccharides, as described herein.
  • polycaprolactones usable as linkers include polycaprolactone, polydiaxonone and copolymers and mixtures of all of the foregoing with lactides, ethyleneimine, glycolides, thmethylenecarbonate, amino acids and the like.
  • polyethylenimines usable as linkers include polyethyleneimine and copolymers and mixtures of all of the foregoing with lactides, caprolactones, glycolides, trimethylenecarbonate, amino acids and the like.
  • polyglycolides usable as linkers include PLGA, polyglyconate and copolymers and mixtures of glycolides with lactides, caprolactones, ethyleneimine, trimethylenecarbonate, amino acids and the like.
  • the linking group is: a (Ci -C ⁇ jalkyl, e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, 3-pentyl, or hexyl;
  • (C 3 - C 6 )cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
  • (C 3 - C 6 )cycloalkyl(Ci -C 6 )alkyl can be cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2- cyclopentylethyl, or 2-cyclohexylethyl;
  • (Ci -C 6 )alkoxy can be methoxy, e
  • the linking group is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 1 to 20 carbon atoms, wherein the chain is optionally substituted on carbon with one or more (e.g.
  • substituents selected from (Ci -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, (Ci - C 6 )alkanoyl, (Ci -C 6 )alkanoyloxy, (Ci -C 6 )alkoxycarbonyl, (Ci -C 6 )alkylthio, azido, cyano, nitro, halo, hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl, and heteroaryloxy.
  • the linking group is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 1 to 20 carbon atoms, wherein one or more (e.g. 1 , 2, 3, or 4) of the carbon atoms is optionally replaced by (-O-) or (-NR-).
  • the linking group is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 3 to 15 carbon atoms, wherein one or more (e.g. 1 , 2, 3, or 4) of the carbon atoms is optionally replaced by (-O-) or NR-), and wherein the chain is optionally substituted on carbon with one or more (e.g.
  • substituents selected from the group consisting of (Ci -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, (C1 -C 6 )alkanoyl, (Ci - C ⁇ jalkanoyloxy, (Ci -C ⁇ jalkoxycarbonyl, (Ci -C ⁇ jalkylthio, azido, cyano, nitro, halo, hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl, and heteroaryloxy.
  • the linking group is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 3 to 15 carbon atoms, wherein one or more (e.g. 1 , 2, 3, or 4) of the carbon atoms is optionally replaced by (-O-) or (-NR-).
  • the linking group is selected from amino acids and peptides.
  • the linking group is present in an amount ranging from 5% to 50% by weight relative to the total weight of the composition.
  • the biodegradable polymers are degraded through cleavage of the linkages between the linker groups and the bioactive chemical moieties, the linkages including functional groups such as esters, anhydrides, carbonates, thioesters, and amides.
  • the polymers containing the chemical moieties can be linked with other such polymers.
  • more than one pharmaceutically active agents other than the agent covalently bonded can be incorporated in the polymer.
  • the additional agents can be either covalently bonded to the polymer or even admixed with the polymer, so long as at least one agent is covalently bonded to the polymer.
  • the number average molecular weight of the polymer is 20,000 Da or less, such as a number average molecular weight of 10,000 Da or less, or 5,000 Da or less. In one embodiment, the number average molecular weight of the polymer ranges from 5,000 daltons to 100,000 daltons. In another embodiment, the number average molecular weight of the polymer is 25,000 Da or less. In yet another embodiment, the number average molecular weight of the polymer ranges from 25,000 daltons to 100,000 daltons.
  • One embodiment of the at least one coating comprises a polymer comprising a chemical moiety covalently linked to at least one branch of the polymer, where the polymer is chosen from star polymers, dendrimers, and hyperbranched polymers.
  • the chemical moiety is linked through a covalent bond, wherein the chemical moiety forms a pharmaceutically active agent upon degradation of the covalent bond.
  • Star polymers have a three-dimensional structure of linear arms extending from a central core.
  • the linear arms can be of the same or different molecular weight.
  • Dendrimers also have a three-dimensional structure where a repetitive series of branched units emanate from an extended core. Each new branch unit is termed a "generation.”
  • Hyperbranched polymers have a less regular three-dimensional structure than either dendrimers or star polymers, and have been characterized as having a combination of the two polymer types. Like dendrimers, hyperbranched polymers can have generations; however, each successive "generation" can have varying molecular weights, branching or nonbranching groups, and different chemical functional groups.
  • hyperbranched polymers A description of hyperbranched polymers is provided in Gao et al., "Hyperbranched polymers: from synthesis to applications," Prog. Polym. Sci., pp. 183-275 (2004), the disclosure of which is incorporated herein by reference.
  • a review of the different polymer types and methods for covalently incorporating pharmaceuticals are provided in Qiu et al., "Polymer Architecture and Drug Delivery,” Pharmaceutical Research, Vol. 23, No. 1 , pp. 1 -30 (2006), the disclosure of which is incorporated herein by reference.
  • the chemical moiety is incorporated in the main chain (backbone) of the at least one branch of the polymer. As shown schematically in FIG. 3, all branches of an exemplary star polymer incorporate the chemical moiety in the main chain.
  • the chemical moiety (“D") is a pendant group of the at least one branch of the polymer, as shown schematically in FIG. 4 for a star polymer.
  • the chemical moiety is linked to the terminus of the at least one branch, as shown schematically in FIG. 5 for a star polymer.
  • these linking modes can also be provided in dendrimers or hyperbranched polymers
  • these star, dendrimers, or hyperbranched polymer systems can offer the prospect of high drug loading at the same time as achieving appropriate duration and profile of drug-delivery.
  • High polymer drug-loading may allow a minimal coat-weight to achieve delivery of appropriate levels of drug.
  • the biodegradation can eliminate the polymer after the drug-delivery and revert back to the bare-metal stent surface, which is desirable for healing.
  • structures with therapeutic agent(s) attached as pendant groups offer the prospect of minimal perturbation to the drug molecule(s).
  • Pendant attachment of the drug molecules to the star polymer branches may allow for chemically reacting with only one site on the molecule. Being able to minimize perturbation of the drug molecules in this manner may result in better drug activity upon release.
  • the site of reaction could be the 2'-OH group or a 7'-OH group, each offering unique kinetics of drug-release.
  • the molecular weight of the one or more branches of the polymer ranges from 10,000 Da to 100,000 Da.
  • the polymer is a star polymer.
  • Each branch of the star polymer can have substantially the same molecular weight and length.
  • branches of the star polymer have different molecular weights and different lengths, as shown schematically in FIG. 6.
  • FIG. 6 depicts different size branches having a terminal chemical moiety, it is understood that the chemical moiety can be linked to the star polymer having varying branch sizes as pendant groups, or incorporated in the backbone of the branch.
  • the star polymer comprises branches of substantially the same molecular weight and length and one branch of substantially higher molecular weight and length, as shown in FIG. 7. This structure may allow mutual entanglement of the star polymer structures and facilitate forming of polymer films, thus, potentially providing an additional variable for tuning the physical properties of the polymer.
  • the branch of substantially higher molecular weight and length has at least a 25% greater molecular weight or length, such as at least a 50% greater molecular weight or length compared to the other branches of substantially the same molecular weight and length.
  • Star polymers can be prepared by a "core first” method or an “arm-first” method.”
  • a core-first method the arms are propagated by polymerizing from a reactive core.
  • An arm-first method comprises joining the already polymerized arms to a core.
  • a core first method is typically used when a more homogeneous structure is desired, e.g., where each branch has substantially the same chemical structure.
  • An arm first method can be used to prepare a polymer of varying sized branches and/or chemistries.
  • hyperbranched polymer systems include the chemistry and molecular architecture represented by PEI / PEI-PEG systems, AScMs, and polyphosphazenes.
  • dendhmehc polymer structures include the chemistry and polymer architecture represented by PAMAM, PPI, and/or PEG systems (via multifunctional linkers if necessary).
  • At least one branch of the polymer comprises two or more different chemical moieties that form pharmaceutically active agents.
  • at least one branch of the polymer comprises at least three different chemical moieties that form pharmaceutically active agents.
  • the at least three chemical moieties comprises a first chemical moiety that forms an antiproliferative pharmaceutically active agent, at second chemical moiety forms an anti-inflammatory agent, and a third chemical moiety that forms a healing promoter.
  • At least one branch of the star polymer comprises a first chemical moiety, and at least one branch of the star polymer comprises a second chemical moiety.
  • at least one branch of the star polymer comprises a first chemical moiety
  • at least one branch of the star polymer comprises a second chemical moiety
  • at least one branch of the star polymer comprises a third chemical moiety.
  • the first chemical moiety can form an antiproliferative pharmaceutically active agent
  • the second chemical moiety can form an anti-inflammatory agent
  • the third chemical moiety can form a healing promoter.
  • these polymers can offer several variables for controlling the release of the pharmaceutically active agent, such as: (a) choice and combinations of linker/conjugation chemistry; (b) lengths of the polymer branches; (c) hydrophobicity/hydrophilicity of the polymer branches; (d) density of polymer branches; and (e) stimuli responsiveness of the polymer branches.
  • These polymers may offer one or more of greater control over the release profile of the therapeutic agent, better processability and physical characteristics of the polymer, and the prospect of eliminating the polymer after drug delivery, if biodegradable.
  • the chemical moiety is positioned in the backbone of the polymer.
  • the composition comprises a polymer selected from star polymers, dendrimers, and hyperbranched polymers in which at least one arm of the polymer comprises the repeat unit:
  • L is a linker derived from one or more molecules selected from diacids, diols, diamines, hydroxyacids, amino acids, and other difunctional molecules that can be bonded to D;
  • D is a chemical moiety that releases a pharmaceutically active agent upon degradation of the covalent bond, e.g., upon hydrolysis of covalent bonds binding it to L.
  • L is derived from one or more molecules selected from carbonic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, pimelic acid, adipic acid or sebacic acid.
  • D is a chemical moiety that releases rapamycin and/or paclitaxel.
  • the chemical moiety is in a side chain.
  • the composition comprises a polymer selected from star polymers, dendrimers, and hyperbranched polymers in which at least one arm of the polymer comprises the repeat unit:
  • L is a linker derived from one or more molecules selected from dihydroxyacids, amino diacids, diamino acids, and other thfunctional molecules that can be bonded to each other and to D; and D is a chemical moiety that releases a pharmaceutically active agent upon degradation of the covalent bond, e.g., upon hydrolysis of covalent bonds binding it to L.
  • L is derived from glutamic and/or aspartic acid.
  • D is a chemical moiety that releases rapamycin and/or paclitaxel.
  • the chemical moiety can be positioned in a side chain and terminal group, as shown in the structure below:
  • L is a linker as defined in (b) above.
  • L is derived from glutamic and/or aspartic acid and D is a chemical moiety that releases rapamycin and/or paclitaxel.
  • a linker may be used to bind the terminal group that is different from the linker used to bind the side chain, as shown in the structure below:
  • L 1 is a linker as in (b) above and L 2 is a linker as in (a) above.
  • L 1 is derived from glutamic and/or aspartic acid
  • L 2 is derived from at least one linker selected from carbonic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, pimelic acid, adipic acid, and sebacic acid
  • D is a chemical moiety that releases rapamycin and/or paclitaxel.
  • the chemical moiety can be positioned in both the backbone and side chain.
  • the composition comprises a polymer selected from star polymers, dendhmers, and hyperbranched polymers in which at least one arm of the polymer comprises the repeat unit: D I -[D-L]- wherein:
  • L is a linker derived from one or more molecules selected from dihydroxyacids, amino diacids, diamino acids, and other thfunctional molecules that can be bonded to each other and to D;
  • D is a chemical moiety that releases a pharmaceutically active agent upon degradation of the covalent bond, e.g., upon hydrolysis of covalent bonds binding it to L.
  • L is derived from 2-carboxyglutaric acid and D is a chemical moiety that releases rapamycin and/or paclitaxel.
  • the same chemistry can be used to position the chemical moiety in a terminal group.
  • two different linkers can be used to position the chemical moiety in the backbone, side chain and terminal groups, as shown in the structure below:
  • L 1 is a linker as in (b) above
  • L 2 is a linker as in (a) above
  • n is either 1 , 2, 1 -5, 1 -20, 1 -50, 1 -100 or 1 -500.
  • L 1 is derived from glutamic and/or aspartic acid
  • L 2 is a diacid
  • D is a chemical moiety that releases rapamycin and/or paclitaxel.
  • L 1 is derived from glutamic and/or aspartic acid
  • L 2 is derived from at least one molecule selected from carbonic acid, oxalic acid, malonic acid, succinic acid, glutahc acid, pimelic acid, adipic acid, and sebacic acid
  • D is a chemical moiety that releases rapamycin and/or paclitaxel.
  • a linker can be used to link the chemical moiety in the side chain, as shown in the structure below: -(L 1 ) H -L 2 -D-(L 1 ) H -L 2 -D I I
  • L 1 is a linker as in (b) above
  • L 2 is a linker as in (a) above
  • n is either 1 , 2, 1 -5, 1 -20, 1 -50, 1 -100 or 1 -500.
  • L 1 is derived from glyceric acid
  • L 2 is derived from a diacid
  • D is a chemical moiety that releases rapamycin and/or paclitaxel.
  • L 1 is derived from at least one molecule selected from glyceric acid, lysine, serine, threonine, tyrosine, cysteine, and ornithine
  • L 2 is derived from at least one molecule selected from carbonic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, pimelic acid, adipic acid, and sebacic acid
  • D is a chemical moiety that releases rapamycin or paclitaxel.
  • D is positioned in the terminal groups and side chains only, as shown in the structure below:
  • L 1 is a linker as in defined (b) above
  • L 2 is a biodegradable polymer
  • L 3 is a linker as defined in (a) above
  • D is a chemical moiety that releases rapamycin and/or paclitaxel.
  • L 2 is derived from at least one biodegradable polymer selected from PLLA, PDLA, PDLLA, PGA, PLGA, polycaprolactone, polydioxinone, poly amino acids prepared from at least one monomer selected from glycine, alanine, leucine, isoleucine, norleucine, valine, norvaline, methionine, phenylalanine, and tryptophan
  • L 1 is derived from at least one molecule selected from glyceric acid, lysine, serine, threonine, tyrosine, cysteine, and ornithine
  • L 3 is derived from at least one molecule selected from carbonic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, pimelic acid, adipic acid, and sebacic acid
  • D is a chemical moiety which releases rapamycin or paclitaxel.
  • the biodegradable polymer comprises one or more moieties covalently linked in a chain, straight or branched, to one or the other or both of a polysaccharide or phospholipid linker group, e.g., via one or the other of an ester, amide, carbonate, anhydride or thioester.
  • the polymer has a Tg greater than 37°C, such as a Tg greater than 40 0 C, a Tg greater than 50 0 C, or a Tg greater than 60°C.
  • compositions comprising a biocompatible polymer, the polymer being linked to a chemical moiety through a covalent bond, wherein, the chemical moiety forms a pharmaceutically active agent upon degradation of the covalent bond, the chemical moiety is linked to a polysaccharide or phospholipid.
  • the molar or weight ratio of polysaccharide and/or phospholipid to each other and/or to the chemical moiety contained within the polymer are preselected to impart a predetermined hydrophilicity and/or hydrophobicity to the polymer.
  • Examples of polysaccharides usable as linkers in the invention include hyaluronic acid, chitosan, cellulose, alginate, cyclodextrin, GAGs (GAG: glycosaminoglycan) and the like.
  • Examples of phospholipids usable as linkers in the invention include phosphatylcholine / phosphatidylcholine (Lecithin), phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, phosphatidylethanolamine etc.
  • the invention provides a polymer comprising the repeat unit:
  • L 1 and L 2 are the same or different, and each are linking groups selected from the group of polysaccharides and phospholipids and are covalently linked to of D 1 and D 2 via one or more of an amide, ester, anhydride, carbonate and thioester linkage;
  • D 1 and D 2 are the same or different and are a chemical moiety that upon degradation of a linkage to the linking groups form a pharmaceutically active agent.
  • the invention also provides a polymer comprising the repeat unit:
  • L 3 , L 4 , L 5 and L 6 can be the same or different, and each are one or the other of an amide, ester, anhydride, carbonate and thioester linkage or are a linking group that are linked to an adjacent group via one or the other of an amide, ester, anhydride, carbonate and thioester linkage.
  • the linker groups L 3 , L 4 L 5 or L 6 are typically an aliphatic moiety having at least two reactive groups capable of forming one or the other of an ester, amide, carbonate, anhydride or thioester linkage with an adjacent drug, polysaccharide or phospholipid group.
  • the invention provides a polymer comprising the repeat unit:
  • L 4 , L 5 , L 6 , L 7 , L 8 and L 9 can be the same or different, and each are one or the other of an amide, ester, anhydride, carbonate and thioester linkage or are a linking group that are linked to an adjacent group via one or the other of an amide, ester, anhydride, carbonate and thioester linkage
  • linker groups L 4 , L 5 , L 6 , L 7 , L 8 and L 9 are typically an aliphatic moiety having at least two reactive groups capable of forming one or the other of an ester, amide, carbonate, anhydride or thioester linkage with an adjacent drug, polysaccharide or phospholipid group.
  • linking groups are: a (Ci -C 6 )alkyl, e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, 3-pentyl, or hexyl; (C 3 -C 6 )cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (C 3 -C 6 )cycloalkyl(Ci -C 6 )alkyl can be cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2- cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, or 2-cyclohexylethy
  • such aliphatic linking groups are a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 1 to 20 carbon atoms, wherein the chain is optionally substituted on carbon with one or more (e.g.
  • substituents selected from (Ci -C ⁇ jalkoxy, (C3 - C 6 )cycloalkyl, (Ci -C 6 )alkanoyl, (Ci -C 6 )alkanoyloxy, (Ci -C 6 )alkoxycarbonyl, (Ci - C 6 )alkylthio, azido, cyano, nitro, halo, hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl, and heteroaryloxy.
  • such aliphatic linking groups are a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 1 to 20 carbon atoms, wherein one or more (e.g. 1 , 2, 3, or 4) of the carbon atoms is optionally replaced by (-O-) or (-NR-).
  • such aliphatic linking groups are a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 3 to 15 carbon atoms, wherein one or more (e.g. 1 , 2, 3, or 4) of the carbon atoms is optionally replaced by (-O-) or NR-), and wherein the chain is optionally substituted on carbon with one or more (e.g.
  • substituents selected from (Cr C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, (Ci -C 6 )alkanoyl, (Ci -C 6 )alkanoyloxy, (Cr C ⁇ jalkoxycarbonyl, (Ci -C ⁇ jalkylthio, azido, cyano, nitro, halo, hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl, and heteroaryloxy.
  • such aliphatic linking groups are a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 3 or 4 to 15 carbon atoms, wherein one or more (e.g. 1 , 2, 3, or 4) of the carbon atoms is optionally replaced by (-O-) or (-NR-).
  • Polysaccharides usually have more than the two functional groups required for synthesis of a polymer of the form ...-drug-linker-drug-linker-...
  • chitosan depicted above has three functional groups per monosaccharide monomer plus an extra group (total of 4) on each end monomer.
  • all functional groups of a molecule except the one which is being reacted are blocked by protecting groups which are removed when the reaction is complete.
  • protecting groups which are removed when the reaction is complete.
  • the following examples are given without using these protection- deprotection reactions so the resulting polymers may be complex mixtures, highly branched or crosslinked with multiple types of linkages due to the many functional groups available.
  • Carbonate, amide and ester linkage examples are set forth below.
  • alginic acid could be used as the polysaccharide but all OH groups would have to be protected to derivatize its carboxylic acid groups into anhydrides.
  • the chemical moiety that forms an active pharmaceutical agent on degradation is incorporated into the backbone of the polymer and is linked directly via one or more covalent bonds.
  • Linked directly refers to the product of a reaction between the polysaccharide, phospholipid or other linking groups disclosed herein and the pharmaceutically active agent. Methods for covalently incorporating pharmaceuticals are provided in Qiu et al., "Polymer Architecture and Drug Delivery," Pharmaceutical Research, Vol. 23, No. 1 , pp. 1 -30 (2006), the disclosure of which is incorporated herein by reference.
  • [244] For purposes of illustration of the formation of an ester linkage to a paclitaxel molecule, there is shown in FIG.
  • an aliphatic linking group containing two carbonyl chloride functional groups e.g. acyl chlorides if L is, e.g., an alkyl group or a polysaccharide or phospholipid having a carbonyl group
  • TAA triethylamine
  • another linking group such as a polysaccharide or phospholipid linker group via its residual carbonyl chloride group or through another subsequently introduced second linker group.
  • the linking groups may be biologically inactive, or may themselves possess biological activity.
  • High-Molecular-Weight-Hyaluronic-Acid a natural polysaccharide
  • phosphatidylcholine a natural phospholipid
  • pharmaceutically active agents in addition to Di, D 2 , and D 3 can also be present in the composition, e.g., any other agents useful for treating vascular injury, e.g., restenosis.
  • pharmaceutically active agents in addition to D 1 , D 2 , and D 3 can be incorporated in the polymer, e.g., either covalently linked to the polymer or admixed with the polymer.
  • each coating contains a different pharmaceutically active agent.
  • each layer contains a unique agent, e.g., D 1 , D 2 , and D 3 as described herein, or any other agents useful for treating vascular injury, e.g., restenosis.
  • pharmaceutically active agents in addition to D 1 , D 2 , and D 3 can be incorporated in the polymer, e.g., either covalently linked to the polymer or admixed with the polymer.
  • polysaccharides and phospholipids in addition to polysaccharides and phospholipids, several of the advantages offered by polysaccharides and phospholipids as linkers are also offered by other natural molecules such as structural natural polymers (e.g. collagen, keratin); amino-acids etc. and analogs thereof.
  • structural natural polymers e.g. collagen, keratin
  • amino-acids etc. and analogs thereof.
  • compositions comprising a biodegradable polymer, the polymer comprising: a backbone having a first chemical moiety incorporated into the backbone of the polymer via one or more biodegradable covalent linkages, a pendant arm linked to the backbone via a biodegradable linkage, the pendant arm having a second chemical moiety bonded to the pendant arm via a single biodegradable covalent linkage, wherein the first and second chemical moieties are the same or different and each forms a pharmaceutically active agent upon degradation of their biodegradable linkages.
  • the pendant arm is typically linked to the backbone via an ester, amide, carbonate, anhydride or thioester linkage.
  • the invention provides a polymer comprising any one or the other of the following repeat units:
  • Another embodiment includes polymers having one or the other of the following structures:
  • the l_i, L 2 , L 3 , L 7 , Li 0 chains can have two functional groups that are capable of forming a direct amide, ester, anhydride, carbonate or thioester linkage with an adjacent group.
  • Such chains can comprise for example a C4-C20 aliphatic chain as described above.
  • Li, L 2 , L 3 , L 7 , L 10 can comprise a chain that is linked to the drug molecules via an intermediate linker group L 3 , L 4 , L 5 , L 6 , L 7 , L 8 or L 9 as shown in the above structures.
  • the linkages between the chains Li, L 2 , L 3 , L 7 , Li 0 and the linker groups are via an amide, ester, anhydride, carbonate or thioester linkage.
  • Typical examples of such chains that are linked to the drugs via intermediate linker groups are polylactide, polyether, polyglycolide, polyethyleneimine, polycaprolactone, polysaccharide and polyphospholipid chains.
  • the linkages between such intermediate linker groups and a drug molecule may be an amide, ester, anhydride, carbonate or thioester linkage.
  • Intermediate linker groups such as L 3 , L 4, L 5, L 6, L 7, L 8 or L 9 above typically comprise chains of 1 -20 carbon atoms.
  • pharmaceutically active agents in addition to Di, D 2 , D 3 and D 4 can also be present in the composition, e.g., any other agents useful for treating vascular injury, e.g., restenosis.
  • pharmaceutically active agents in addition to Di, D 2 , D 3 and D 4 can be incorporated in the polymer, e.g., either covalently linked to the polymer or admixed with the polymer.
  • the polymer chains have drug molecules, i.e. moieties that are pharmaceutically active on hydrolysis of the amide, ester, anhydride, carbonate or thioester linkage, incorporated by two linkages into a backbone portion of the polymers and also have a pendant group having a drug molecule having a single linkage to the pendant group.
  • drug molecules i.e. moieties that are pharmaceutically active on hydrolysis of the amide, ester, anhydride, carbonate or thioester linkage, incorporated by two linkages into a backbone portion of the polymers and also have a pendant group having a drug molecule having a single linkage to the pendant group.
  • L 1 and L 2 and L 3 and L 7 are chains that have two functional groups that are capable of forming a direct amide, ester, anhydride, carbonate or thioester linkage with an adjacent group.
  • linker chains or moieties are aliphatic linker groups, such as any of the aliphatic linker groups disclosed herein.
  • an aliphatic linking group containing two carbonyl chloride functional groups e.g. acyl chlorides if L is, e.g., an alkyl group or a polysaccharide or phospholipid having a carbonyl group
  • TAA triethylamine
  • another linking group such as a polysaccharide or phospholipid linker group via its residual carbonyl chloride group or through another subsequently introduced second linker group.
  • the polymers disclosed herein can be used to form a coating for an implantable medical device.
  • the polymers can offer one or more of: (a) tunable and controllable release profile for therapeutic agent(s) for optimal therapeutic effect; (b) polymer physical properties amenable to polymer-processing leading to a viable stent coating for optimal coating viability and performance; and (c) biodegradation along with high drug-loading to be able to deliver the therapeutic agent(s) over a long period of avoiding polymer-mediated negative effects (e.g. thrombosis).
  • the device treats narrowing or obstruction of a body passageway in a subject in need thereof.
  • the method comprises inserting the device into the passageway, the device comprising a generally tubular structure, the surface of the structure being coated with a composition disclosed herein, such that the passageway is expanded.
  • the body passageway may be selected from arteries, veins, lacrimal ducts, trachea, bronchi, bronchiole, nasal passages, sinuses, eustachian tubes, the external auditory canal, oral cavities, the esophagus, the stomach, the duodenum, the small intestine, the large intestine, biliary tracts, the ureter, the bladder, the urethra, the fallopian tubes, uterus, vagina, the vasdeferens, and the ventricular system.
  • Exemplary devices include sutures, staples, anastomosis devices, vertebral disks, bone pins, suture anchors, hemostatic barriers, clamps, screws, plates, clips, vascular implants, urological implants, tissue adhesives and sealants, tissue scaffolds, bone substitutes, intraluminal devices, and vascular supports.
  • the device can be a cardiovascular device, such as venous catheters, venous ports, tunneled venous catheters, chronic infusion lines or ports, including hepatic artery infusion catheters, pacemakers and pace maker leads, and implantable defibrillators.
  • the device can be a neurologic/neurosurgical device such as ventricular peritoneal shunts, ventricular atrial shunts, nerve stimulator devices, dural patches and implants to prevent epidural fibrosis post- laminectomy, and devices for continuous subarachnoid infusions.
  • the device can be a gastrointestinal device, such as chronic indwelling catheters, feeding tubes, portosystemic shunts, shunts for ascites, peritoneal implants for drug delivery, peritoneal dialysis catheters, and suspensions or solid implants to prevent surgical adhesions.
  • the device can be a genitourinary device, such as uterine implants, including intrauterine devices (IUDs) and devices to prevent endometrial hyperplasia, fallopian tubal implants, including reversible sterilization devices, fallopian tubal stents, artificial sphincters and periurethral implants for incontinence, ureteric stents, chronic indwelling catheters, bladder augmentations, or wraps or splints for vasovasostomy, central venous catheters.
  • IUDs intrauterine devices
  • devices to prevent endometrial hyperplasia include reversible sterilization devices, fallopian tubal stents, artificial sphincters and periurethral implants for incontinence, ureteric stents, chronic indwelling catheters, bladder augmentations, or wraps or splints for vasovasostomy, central venous catheters.
  • IUDs intrauterine devices
  • the device is selected from pacemaker leads, valve replacement and repair devices, vena cava filters, and embolic coils and beads.
  • Other exemplary devices include prosthetic heart valves, vascular grafts ophthalmologic implants (e.g., multino implants and other implants for neovascular glaucoma, drug eluting contact lenses for pterygiums, splints for failed dacrocystalrhinostomy, drug eluting contact lenses for corneal neovascularity, implants for diabetic retinopathy, drug eluting contact lenses for high risk corneal transplants), otolaryngology devices (e.g., ossicular implants, Eustachian tube splints or stents for glue ear or chronic otitis as an alternative to transtempanic drains), plastic surgery implants (e.g., breast implants or chin implants), and catheter cuffs and orthopedic implants (e.g., cemented orthopedic prostheses).
  • vascular grafts ophthalmologic implants e.g., multino implants and other implants for neovascular gla
  • a stent such as a stent comprising a generally tubular structure.
  • a stent is commonly used as a tubular structure disposed inside the lumen of a duct to relieve an obstruction.
  • the stent is either balloon expandable or self-expanding.
  • stents are inserted into the lumen in a non-expanded form and are then expanded autonomously, or with the aid of a second device in situ.
  • a typical method of expansion occurs through the use of a catheter-mounted angioplasty balloon which is inflated within the stenosed vessel or body passageway in order to shear and disrupt the obstructions associated with the wall components of the vessel and to obtain an enlarged lumen.
  • An exemplary stent is a stent for treating narrowing or obstruction of a body passageway in a human or animal in need thereof.
  • Body passageway refers to any of number of passageways, tubes, pipes, tracts, canals, sinuses or conduits which have an inner lumen and allow the flow of materials within the body.
  • body passageways include arteries and veins, lacrimal ducts, the trachea, bronchi, bronchiole, nasal passages (including the sinuses) and other airways, eustachian tubes, the external auditory canal, oral cavities, the esophagus, the stomach, the duodenum, the small intestine, the large intestine, biliary tracts, the ureter, the bladder, the urethra, the fallopian tubes, uterus, vagina and other passageways of the female reproductive tract, the vasdeferens and other passageways of the male reproductive tract, and the ventricular system (cerebrospinal fluid) of the brain and the spinal cord.
  • Exemplary devices of the invention are for these above-mentioned body passageways, such as stents, e.g., vascular stents.
  • stents e.g., vascular stents.
  • vascular stents There is a multiplicity of different vascular stents known in the art that may be utilized following percutaneous transluminal coronary angioplasty.
  • stents Any number of stents may be utilized in accordance with the present invention and the invention is not limited to the specific stents that are described in exemplary embodiments of the present invention. The skilled artisan will recognize that any number of stents may be utilized in connection with the present invention. In addition, as stated above, other medical devices may be utilized, such as e.g., orthopedic implants.
  • the composition is coated on the stent to form a conformal coating around all surfaces of the stent. In another embodiment, the composition is coated only on the abluminal surface of the stent. In one embodiment, the composition resides partially or completely within micro-reservoirs or pores in the stent surface.
  • the device is an angioplasty balloon having coated thereon the coating comprising the composition, wherein the balloon is used to deliver the composition to an endoluminal surface.
  • the devices of the invention may be coated partially or wholly with the above defined compositions in any manner known in the art, e.g., dipping, spraying, rolling, brushing, electrostatic plating or spinning, vapor deposition (e.g., physical or chemical), air spraying including atomized spray coating, and spray coating using an ultrasonic nozzle.
  • the compositions can be applied by these methods either as a solid (e.g., film or particles), a suspension, a solution, or as a vapor.
  • the device can be coated with a first substance (such as a hydrogel) that is capable of absorbing the composition.
  • the device can be constructed from a material comprising a polymer/drug composition.
  • the device comprises at least two coatings to provide a multi-layered structure.
  • the device has at least three coatings.
  • Each of the at least three coatings can provide a different chemical moiety that forms a different pharmaceutically active agent.
  • one of the at least three coatings comprises a chemical moiety that forms an antiproliferative pharmaceutically active agent
  • a second of the three coatings comprises a chemical moiety that forms an anti-inflammatory agent
  • a third of the at least three coatings comprises a chemical moiety that forms a healing promoter.
  • FIG. 2 is a schematic showing a multi-layered coating arrangement, where each of layers 1 , 2, and 3 contain either a unique pharmaceutically active agent, or if two or more layers contain the same agent, the agent is linked to the polymer via a different linking chemistry. This arrangement allows control of the release profile of the agents and can provide control of the sequence of release of different pharmaceutically active agents.
  • each layer can be individually customized by choice of agents, linking chemistry, polymer structure, thickness, etc. for controlling the release profile and kinetics.
  • each layer contains a unique agent, or any other agents useful for treating vascular injury, e.g., restenosis.
  • the method is used for treating at least one disease or condition associated with vascular injury or angioplasty, e.g., one or more of atherosclerosis, restenosis, neointima, neointimal hyperplasia and thrombosis.
  • vascular injury or angioplasty e.g., one or more of atherosclerosis, restenosis, neointima, neointimal hyperplasia and thrombosis.
  • the implantable devices disclosed herein are implanted in a subject in need thereof to achieve a therapeutic effect, e.g., therapeutic treatment and/or prophylactic/preventative measures.
  • a therapeutic effect e.g., therapeutic treatment and/or prophylactic/preventative measures.
  • Those in need of treatment may include individuals already having a particular medical disease as well as those at risk for the disease (e.g., those who are likely to ultimately acquire the disorder).
  • a therapeutic method can also result in the prevention or amelioration of symptoms, or an otherwise desired biological outcome, and may be evaluated by improved clinical signs, delayed onset of disease, reduced/elevated levels of lymphocytes and/or antibodies.
  • Exemplary pharmaceutically active agents include antiproliferative agents (e.g., those active against smooth muscle cells), anti-inflammatory agents, and healing promoters.
  • Exemplary antiproliferative agents include paclitaxel, sirolimus, everolimus, biolimus, zotarolimus, AP23573 (a sirolimus analog), and other limus derivatives.
  • anti-inflammatory agents include non-steroidal agents (e.g., 3-amino-4-hydroxybutyric acid, aceclofenac, alminoprofen, bromfenac, bumadizon, carprofen, diclofenac, diflunisal, enfenamic acid, etodolac, fendosal, flufenamic acid, gentisic acid, meclofenamic acid, mefenamic acid, mesalamine, niflumic acid, olsalazine oxaceprol, S-adenosylmethionine, salicylic acid, salsalate, sulfasalazine, tolfenamic acid).
  • non-steroidal agents e.g., 3-amino-4-hydroxybutyric acid, aceclofenac, alminoprofen, bromfenac, bumadizon, carprofen, diclofenac, diflunisal,
  • Exemplary healing promoters include nitric oxide donors such as halofuganone, S-nitrosothiols, and glyceryl thnitrite 1 -[N-(3- aminopropyl)-N-(3-ammoniopropyl]diazen-1 -ium-1 ,2-diolate, 1 -[N-(2-aminoethyl)-N- (2-ammonioethyl)amino]diazen-1 -ium-1 ,2-diolate, as well as epidermal growth factor and other growth factors.
  • nitric oxide donors such as halofuganone, S-nitrosothiols, and glyceryl thnitrite 1 -[N-(3- aminopropyl)-N-(3-ammoniopropyl]diazen-1 -ium-1 ,2-diolate, 1 -[N-(2-aminoethyl)-N- (2-am
  • exemplary pharmaceutically active agents include analgesics, anesthetics, anti acne agents, antibiotics, synthetic antibacterial agents, anticholinergics, anticoagulants, antidyskinetics, antifibrotics, antifungal agents, antiglaucoma agents, anti-inflammatory agents, antineoplastics, antiosteoporotics, antipagetics, anti-Parkinson's agents, antisporatics, antipyretics, antiseptics/disinfectants, antithrombotics, bone resorption inhibitors, calcium regulators, keratolytics, sclerosing agents and ultraviolet screening agents.
  • exemplary antithrombotics and anticoagulants include aspirin and plavix.
  • the pharmaceutically active agent is a drug useful for treating diseases and conditions associated with restenosis, e.g., antithrombotics, anticoagulants, antiplatelet agents, thrombolytics, antiproliferatives, antiinflammatories, antimitotic, antimicrobial, agents that inhibit restenosis, smooth muscle cell inhibitors, antibiotics, fibrinolytic, immunosuppressive, and anti-antigenic agents.
  • a drug useful for treating diseases and conditions associated with restenosis e.g., antithrombotics, anticoagulants, antiplatelet agents, thrombolytics, antiproliferatives, antiinflammatories, antimitotic, antimicrobial, agents that inhibit restenosis, smooth muscle cell inhibitors, antibiotics, fibrinolytic, immunosuppressive, and anti-antigenic agents.
  • anti-bacterial compounds suitable for use in the present invention include, but are not limited to, 4-sulfanilamidosalicylic acid, acediasulfone, amfenac, amoxicillin, ampicillin, apalcillin, apicycline, aspoxicillin, aztreonam, bambermycin(s), biapenem, carbenicillin, carumonam, cefadroxil, cefamandole, cefatrizine, cefbuperazone, cefclidin, cefdinir, cefditoren, cefepime, cefetamet, cefixime, cefinenoxime, cefminox, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotetan, cefotiam, cefozopran, cefpimizole, cefpiramide, cefpirome, cefprozil, cefroxadine, cef
  • anti-fungal compounds suitable for use in the present invention include, but are not limited to amphotericin B, azasehne, candicidin(s), lucensomycin, natamycin, and nystatin.
  • anti-neoplastic compounds suitable for use in the present invention include, but are not limited to 6-diazo-5-oxo-L-norleucine, azaserine, carzinophillin A, denoptehn, edatrexate, eflomithine, melphalan, methotrexate, mycophenolic acid, podophyllinic acid 2-ethylhydrazide, pteropterin, streptonigrin, Tomudex.RTM.
  • anti-thrombotic compounds for use in the present invention include, but are not limited to, argatroban, iloprost, lamifiban, taprostene, and tirofiban.
  • immunosuppressive compounds suitable for use in the present invention include, but are not limited to bucillamine, mycophenolic acid, procodazole, romurtide, and ubenimex.
  • Dosages of the pharmaceutically active agent may be determined by means known in the art. Typically, the dosage is dependent upon the particular drug employed and medical condition being treated to achieve a therapeutic result. In one embodiment, the amount of drug represents about 0.001 percent to about seventy percent of the total coating weight, or about 0.01 percent to about sixty percent of the total coating weight. In one embodiment, the weight percent of the therapeutic agents in the carrier or polymer coating is 1 % to 50%, 2% to 45%, 5% to 40%, or 10% to 25% by weight relative to the total coating weight. In another embodiment, it is possible that the drug may represent as little as 0.0001 percent to the total coating weight. In another embodiment, the dosage is determined per coated surface area of the device.
  • the dose density may range from 0.05 to 10 ⁇ g/mm 2 , such as a dose-density ranging from 0.05 to 1.0 ⁇ g/mm 2 , or ranging from 0.1 to 4 ⁇ g/mm 2 , or ranging from 0.2 to 4 ⁇ g/mm 2 .
  • the device delivers the agent over a selected period of time, such as days, weeks or months, e.g., such as a period of at least one week, at least two weeks, at least one month, at least six months, or at least one year.
  • a selected period of time such as days, weeks or months, e.g., such as a period of at least one week, at least two weeks, at least one month, at least six months, or at least one year.
  • the biodegradable polymer functions to reduce the solubility of the pharmaceutically active agent in an aqueous medium.
  • the polymer covalently linked to the chemical moiety is less soluble in an aqueous medium than the free form of the agent.
  • the at least one pharmaceutically active agent is hydrophobic or amphipathic (e.g., paclitaxel). Although hydrophobic agents may have some solubility in water, generally a hydrophobic agent generally dissolves more readily in oils or non-polar solvents than in water or polar solvents.
  • the agent is hydrophilic, e.g., dissolves more readily in water or polar solvents than in oils or non-polar solvents.
  • two or more different chemical moieties are incorporated in the polymer to impart different therapeutic effects based on the resulting drug.
  • the choice of drug, and the monomer(s) can allow control of release profile and kinetics of pharmaceutically active agents from the medical device.
  • the release profile and kinetics can be controlled by the hydrolysis rates and chemistry of the various hydrolytic linkages.
  • the period of time of drug delivery and drug dosage can be controlled to substantially prevent undesirable burst release.
  • the linking groups and biodegradable polymer can be chosen to provide desirable mechanical properties.
  • Example 1 Polymer with activated carboxyl terminated cellulose and paclitaxel
  • One example of a method of preparation of such a polymer is one that uses enzyme-catalyzed synthesis and protection-deprotection of the polysaccharide hydroxyl groups and does not employ any linkers between the polysaccharide and drug.
  • the polysaccharide is coupled only on its terminal ends to the drug via biodegradable carboxylic ester bonds.
  • the polymer prepared is a cellulose-paclitaxel-cellulose-paclitaxel... polymer.
  • Cellulose is a linear un-branched polymer of ⁇ -D-glucose with a reducing and a non-reducing end.
  • Paclitaxel is dissolved in dichloromethane with a catalytic amount of 4- dimethylaminopyhdine and added to the protected, cellulose dicarboxylic acid solution. The mixture is stirred at room temperature until unreacted paclitaxel is almost consumed. Addition of water precipitates the polymer which is washed carefully with dichloromethane to remove the unreacted paclitaxel. The polymer is dissolved in dichloromethane/methanol or another suitable solvent and stirred at room temperature with an excess of 1 ,2-dichloro-4,5-dicyanoquinone to remove all the naphthylmethyl protecting groups.
  • paclitaxel is reacted with 2/3 equivalent of triphosgene in a minimum amount of chloroform at 0 0 C in the presence of 2 equivalents of triethylamine to give paclitaxel activated with one chloro-carbonyl group on each of its reactive hydroxyl groups (2' and 7).
  • triphosgene contains 3 equivalents of phosgene.
  • the solution is stirred overnight at room temperature, rotary evaporated to dryness, dissolved in water, adjusted to pH 5 and extracted 3 times with chloroform to remove excess paclitaxel.
  • the aqueous phase is lyophilized to give a polymer with mixed ester and amide bonds joining paclitaxel to chitosan, of the form ...-paclitaxel-chitosan- paclitaxel-chitosan-... along with more complex polymers, i.e. branched/hyperbranched .
  • rapamycin is derivatized with two equivalents of sebacic acid dichloride similar to Example 3 to give rapamycin activated on each of its two reactive hydroxyl groups with a chlorosebacoyl group.
  • Dextran is dissolved in dimethylformamide and reacted with the activated rapamycin similarly to Example 2.
  • the solution is rotary evaporated to dryness, dissolved in water and extracted with chloroform to remove excess rapamycin.
  • the aqueous phase is lyophilized to yield a polymer with ester bonds joining rapamycin to dextran, of the form ...-rapamycin- dextran-rapamycin-dextran-... along with more complex polymers.
  • chitosan One equivalent of chitosan is dissolved in pyridine and reacted with 2/3 equivalent of triphosgene at 0 0 C to give, on average, activated chitosan with two chlorocarbonyl groups per chitosan molecule.
  • Paclitaxel dissolved in dimethylformamide is added dropwise at 0 0 C with stirring. The mixture is stirred overnight and worked up as in Example 2 to yield a polymer with mixed ester and amide bonds joining paclitaxel to chitosan, of the form ...-paclitaxel-chitosan- paclitaxel-chitosan-... along with more complex polymers.
  • Example 5 Polymer with activated paclitaxel and di-acyl phosphatidylethanolamine (mixed carboxylic-phosphoric anhydride and amide (urethane)-type bonds using triphosgene)
  • paclitaxel is reacted with 2/3 equivalent of triphosgene in a minimum amount of chloroform at 0 0 C in the presence of 2 equivalents of triethylamine to yield paclitaxel activated with one chloro-carbonyl group on each of its two reactive hydroxyl groups (2' and 7).
  • Phosphatidylethanoamine (1 equivalent) dissolved in a minimum amount of dimethylformamide with 2 equivalents of triethylamine is added dropwise at 0 0 C with stirring to the activated paclitaxel solution.
  • Example 6 Polymer with activated paclitaxel and di-acyl phosphatidylethanolamine (mixed carboxylic-phosphoric anhydride, ester and amide (urethane)-type bonds using sebacic acid dichloride
  • Paclitaxel is reacted with 2 equivalents of sebacic acid dichloride in a minimum amount of chloroform at 0 0 C in the presence of 2 equivalents of triethylamine to yield paclitaxel activated with one chlorosebacoyl group on each of its two reactive hydroxyl groups (2' and 7).
  • Phosphatidylethanoamine (1 equivalent) dissolved in a minimum amount of dimethylformamide with 2 equivalents of triethylamine is added dropwise at 0 0 C with stirring to the activated paclitaxel solution.
  • Example 7 Polymer with activated phosphatidylethanolamine dimer and paclitaxel (phosphoric anhydride and amide (urethane) and carbonate bonds) using triphosqene
  • N- carbobenzoxy phosphatidylethanolamine Two equivalents of N- carbobenzoxy phosphatidylethanolamine are dissolved in tetrahydrofuran/dimethylformamide, cooled to 0 0 C and reacted with 1 equivalent of dicyclohexyl carbodiimide, then stirred overnight at room temperature.
  • the solid dicyclohexyl urea is removed by filtration and the solvent evaporated to dryness to give the pyrophosphate (phosphoric anhydride) dimer of N-carbobenzoxy phosphatidylethanolamine.
  • the carbobenzoxy groups are removed by hydrogenolysis in tetrahydrofuran over a palladium on carbon catalyst to yield the pyrophosphate dimer of phosphatidylethanolamine.
  • paclitaxel is reacted with 2/3 equivalent of triphosgene in a minimum amount of chloroform at 0 0 C in the presence of 2 equivalents of triethylamine to give paclitaxel activated with one chloro-carbonyl group on each of its two reactive hydroxyl groups (2' and 7).
  • One equivalent of the dimer of phosphatidylethanolamine is dissolved in tetrahydrofuran/dimethylformamide with two equivalents of triethylamine and added dropwise to the solution of paclitaxel at 0 0 C. The mixture is stirred overnight at room temperature, rotary evaporated to dryness, and the residue triturated with ether to remove excess paclitaxel.
  • the product is a polymer of the form ...paclitaxel- phosphatidylethanolamine dimer-paclitaxel-phosphatidylethanolamine dimer-....
  • Example 8 Polymer with activated paclitaxel and phosphatidylqlvcerol (ester- tvpe bonds using sebacic acid dichloride
  • Paclitaxel is reacted with 2 equivalents of sebacic acid dichloride in a minimum amount of chloroform at 0 0 C in the presence of 2 equivalents of triethylamine to give paclitaxel activated with one chlorosebacoyl group on each of its two reactive hydroxyl groups (2' and 7).
  • Phosphatidylglycerol (1 equivalent) dissolved in a minimum amount of pyridine is added dropwise at 0 0 C with stirring to the activated paclitaxel solution.
  • Star polymers branch only at the central star core and have linear arms in contrast to dendrimers which continue branching and thus have branched arms.
  • P represents paclitaxel or any of the therapeutic agents of the invention.
  • the 16 arm star polymer has a central core of pentaerythritol with 4 hydroxyl groups. This central core is extended with 2,2-(dihydroxymethyl)propanoic acid for two generations to give a star core with 16 hydroxy groups.
  • One arm of the star polymer is attached to each of the 16 hydroxyl groups via a short oligomer and linkers. Either the linker or the oligomer has pendant functional side chains to which the pendant therapeutic agent is attached.
  • Therapeutic agent is also incorporated into the polymer backbone via linkers.
  • Scheme 1 shows a second generation, drug-bearing star polymer with therapeutic agent both pendant and within the polymer backbone.
  • the second generation star polymer can be extended for additional generations by addition of oligomers, linkers and therapeutic agent to each of the 16 arms.
  • Drug- bearing star polymers with more than 16 arms can be prepared by adding additional generations of 2,2-(dihydroxymethyl)propanoic acid to the star core before chain extension.
  • Paclitaxel is protected on its 2' hydroxyl group with 2-napthylmethyl, leaving its 7-hydroxyl group free.
  • a second batch of paclitaxel is protected on its 2'- hydroxyl with acetyl, leaving its 7-hydroxyl free.
  • Cis-aconitic acid anhydride is catalytically reduced with hydrogen to give the corresponding anhydride of 2- carboxy-glutaric acid.
  • the anhydride of 2-carboxy-glutaric acid is activated on its free carboxylic acid group by stirring with one equivalent of oxalyl chloride in dichloromethane.
  • the anhydride/acid chloride solution is treated with an excess of a dichloromethane solution of 2'-O-(2-napthylmethyl) and 2'-O-acetyl- paclitaxels (molar ratio 1 :1 ) in the presence of dimethylaminopyridine until all the activated glutaric anhydride is converted to a dipaclitaxel diester.
  • the diester is activated with oxalyl chloride as above and reacted with 2'-O-(2-napthylmethyl) to give compound 4, 2-carboxy-glutaric acid di-(2-(2-napthylmethyl)-paclitaxel ester)-mono-(2'-acetyl- paclitaxel ester) with each paclitaxel acylated on its free 7-hydroxyl group by one of the three 2-carboxy-glutaric acid carboxyl groups. It is understood that different isomers of compound 4 can be present.
  • the product 4 is isolated by column chromatography on silica gel.
  • One cycle is one generation.
  • the process of adding a short oligomer of PLGA to these hydroxyl groups followed by the tri-paclitaxel linker can be repeated to give the second generation, drug-bearing star polymer (compound 8) containing pendant paclitaxel and paclitaxel within the polymer chain. This process can be repeated as many times as desired to give additional generations of drug-bearing star polymer.
  • the pendant paclitaxels (with the exception of the polymer chain "terminal" paclitaxels, if the growth is stopped at this stage) have their 2'-hydroxyl groups protected by the labile acetyl ester group. This will likely be the first ester bond to hydrolyze in the final star polymer because of the small size of the acetyl group and its pendant position, ultimately releasing free paclitaxel.
  • Scheme 2 Compound 1 is the first generation star core with 8 hydroxyl groups.
  • Compound 2 is the second generation star core with 16 free hydroxyl groups with only one of the 4 branches (each bearing 4 hydroxyl groups) shown.
  • Compound 3 shows a PLGA pentamer polymerized onto one of the 16 hydroxyl groups of compound 2, i.e., one arm of the 16 arm star polymer.
  • Compound 5 is the tri-paclitaxel linker with two free hydroxyl groups.
  • Compound 6 shows the chlorosebacoyl linker attached to the PLGA pentamer of compound 3.
  • Compound 7 shows one of the 16 arms of the first generation, drug-bearing polymer with paclitaxels pendant and within the polymer backbone.
  • Compound 8 shows one arm of the second generation, drug-bearing polymer with paclitaxels pendant and within the polymer backbone.
  • This Example describes the preparation of a star polymer with 16 arms of poly-L-glutamic acid with paclitaxel pendant and in the polymer backbone (second generation star polymer compound 15).
  • Scheme 3 shows compounds of Example 11.
  • the second generation star core with 16 hydroxyl groups at the ends of its branches (compound 2) is prepared as described in Example 10.
  • An excess of the ⁇ -thtyl ester of glutamic acid N-carboxyanhydhde is reacted with compound 2 in dry dichloromethane/tetrahydrofuran until the 16 hydroxyl groups are each reacted with a single ⁇ -trityl-glutamic acid.
  • a drop of water is added to facilitate removal of the carbon dioxide from the amino groups of each of the single glutamic acids attached to each of the 16 hydroxyl groups and to allow growth of the ⁇ -trityl-glutamic acid oligomer to 5-10 monomers in length on each arm to give compound 9.
  • Compound 9 is reacted with sebacic acid dichloride to give compound 10 with a chlorosebacoyl group on the end of each arm.
  • Compound 10 is reacted with an excess of unsubstituted paclitaxel in the presence of dimethylaminopyridine to give the first generation protected polymer (compound 11) with one paclitaxel at the end of each of the 16 arms, each paclitaxel bearing a free hydroxyl group.
  • a short oligomer of poly-L- ⁇ -trityl-glutamic acid is formed as above on each of the free hydroxyl groups followed by reaction with sebacic acid dichloride to give compound 12 with a chlorosebacoyl group at the end of each arm.
  • Compound 12 is reacted with an excess of paclitaxel to give the second generation protected star polymer with drug only in the polymer backbone, compound 13.
  • Compound 13 is treated with 0.5 % thfluoroacetic acid in dichloromethane to remove the trityl protecting groups from all the glutamic acid ⁇ -carboxyl groups to give compound 14.
  • Reaction of compound 14 dissolved in tetrahydrofuran/dimethylformamide with dicyclohexyl carbodiimide and excess paclitaxel in the presence of dimethylaminopyridine gives the second generation star polymer compound 15 with paclitaxel both pendant and incorporated into the polymer backbone.
  • the amount of pendant paclitaxel can be adjusted by regulating the amount of dicyclohexylcarbodimide and paclitaxel in the reaction. Partial or full substitution of the side chain carboxyl groups may give the more desirable release and degradation properties.
  • Additional generation polymers can be prepared by further cycles of adding ⁇ -trityl glutamic acid oligomers, paclitaxel, and sebacic acid dichloride onto the backbone of compound 13, deprotecting the trityl ester groups and coupling the paclitaxels to the pendant carboxyl groups.
  • the protected glutamic acids are abbreviated here rather than drawing each structure as in compound 10.
  • Compound 12 shows compound 11 after reaction with additional ⁇ - trityl-glutamic acid N-carboxyanhydhde followed by reaction with sebacic acid dichloride.
  • Compound 13 shows the reaction product of compound 12 with paclitaxel.
  • Compound 13 has two short protected glutamic acid oligomers and two paclitaxels in the growing polymer chain and is the protected, second generation star polymer with paclitaxel in the backbone only.
  • Compound 14 is the deprotected, second generation star polymer with paclitaxel only in the polymer backbone.
  • the deprotected glutamic acid structures are drawn for one oligomer for clarity.
  • Compound 15 is the second generation star polymer with paclitaxel both pendant and in the polymer backbone. Again the glutamic acid structure is drawn once for clarity and then abbreviated.
  • the second generation star core with 16 hydroxyl groups at the ends of its branches is prepared as described in Example 10.
  • 3-O-Trityl-D- glycehc acid is cyclized to its reactive lactone dimer (compound 16).
  • Compound 2 is reacted with excess compound 16 in the presence of dimethylaminopyhdine to give short chains (5-10 monomers) of 3-O-trityl-D-glyceric acid oligomers attached to each of its 16 hydroxyl groups (compound 17).
  • Compound 17 is reacted with sebacic acid dichloride and then with an excess of unsubstituted paclitaxel in the presence of dimethylaminopyridine to give compound 18 with one paclitaxel at the end of each of the 16 arms, each paclitaxel bearing a free hydroxyl group.
  • a short oligomer of 3-O-trityl-D-glyceric acid is formed on each of the 16 free hydroxyl groups as above, followed by reaction with sebacic acid dichloride and then with additional paclitaxel to give the protected second generation star polymer with backbone drug only, compound 19.
  • Compound 19 is treated with 0.5 % trifluoroacetic acid in dichloromethane to remove the trityl protecting groups from all the glyceric acid 3-hydroxyl groups to give compound 20.
  • Reaction of compound 20 dissolved in tetrahydrofuran/dimethylformamide with sebacic acid dichloride and then paclitaxel in the presence of dimethylaminopyridine gives the second generation star polymer (compound 21) with paclitaxel both pendant and incorporated into the polymer backbone.
  • the amount of pendant paclitaxel can be adjusted by regulating the amount of dicyclohexylcarbodimide and paclitaxel in the reaction. Partial or full substitution of the side chain hydroxyl groups may give the more desirable release and degradation properties.
  • Additional generation polymers can be prepared by further cycles of adding 3-O-trityl-D-glyceric acid oligomers, sebacic acid dichloride and paclitaxel onto the backbone of compound 19, deprotecting the trityl ether groups and coupling the pendant paclitaxels to these side chain hydroxyl groups via sebacic acid dichloride.
  • Scheme 4 Compound 2 is the second generation star core with 16 free hydroxyl groups with only one of the 4 branches (each bearing 4 hydroxyl groups) shown.
  • Compound 17 shows a 3-O-trityl-glyceric acid pentamer polymerized onto each of the 16 hydroxyl groups of compound 2, i.e., one arm of the 16 arm star polymer.
  • Compound 18 shows the growing arm with sebacic acid linking paclitaxel into the polymer backbone.
  • Compound 19 shows the growing arm with the second 3-O-trityl-glyceric acid oligomer, the second sebacic acid linker and the second backbone paclitaxel attached, the protected, second generation star polymer with only backbone paclitaxels.
  • Compound 20 shows the deprotected, second generation star polymer with only backbone paclitaxels.
  • Compound 21 shows compound 20 reacted with sebacic acid dichlohde and then with paclitaxel to give drug-bearing polymer with paclitaxels pendant and within the polymer backbone.
  • This Example describes the preparation of star polymer with 16 arms of D-lactic acid/glycolic acid/D-glyceric acid polymer with paclitaxel pendant and in the polymer chain backbone (second generation star polymer compound 26).
  • Scheme 5 shows compounds of Example 13.
  • the second generation star core with 16 hydroxyl groups at the ends of its branches is prepared as described in Example 10.
  • 3-O-Trityl-D- glycehc acid is cyclized to its reactive lactone dimer (compound 16).
  • the reactive dimers of lactic acid, glycolic acid and compound 16 in a ratio of 2:2:1 are reacted with excess compound 2 in the presence of dimethylaminopyridine to give short chains (5-10 monomers) of lactic acid/glycolic acid/3-O-thtyl-D-glycehc acid oligomers attached to each of its 16 hydroxyl groups (compound 22). It is understood that the ratio and sequence of the hydroxy acids in 22 can be other than what is shown in Scheme 5.
  • Compound 22 is reacted with excess sebacic acid dichlohde, the excess is removed by precipitation and washing, and the chlorosebacoyl product is then reacted with an excess of unsubstituted paclitaxel in the presence of dimethylaminopyridine to give compound 23 with one paclitaxel at the end of each of the 16 arms, each paclitaxel bearing a free hydroxyl group.
  • a short oligomer of lactic acid/glycolic acid/3-O-trityl-D-glycehc acid is formed on each of the 16 free paclitaxel hydroxyl groups as above to give compound 24.
  • the amount of pendant paclitaxel can be adjusted by regulating the amount of dicyclohexylcarbodimide and paclitaxel in the reaction. Partial or full substitution of the side chain hydroxyl groups may give the more desirable release and degradation properties.
  • Additional generation polymers can be prepared by further cycles of adding 3-O-thtyl-D-glycehc acid oligomers, sebacic acid dichloride and paclitaxel onto the terminal hydroxyl groups of compound 24, deprotecting the trityl ether groups and coupling the paclitaxels to the hydroxyl groups via sebacic acid dichloride.
  • Compound 2 is the second generation star core with 16 free hydroxyl groups with only one of the 4 branches (each bearing 4 hydroxyl groups) shown.
  • Compound 22 shows a lactic acid/glycolic acid/3-O-trityl-glyceric acid (ratio 2:2:1 ) pentamer polymerized onto one of the 16 hydroxyl groups of compound 2, i.e., one arm of the 16 arm star polymer.
  • Compound 23 shows the growing arm with sebacic acid linking paclitaxel into the polymer backbone.
  • Compound 24 shows the growing arm with the second pentamer chain attached (only the 3-O-thtyl-glycehc acid portion of the second pentamer is drawn, not the lactic or glycolic acids).
  • Compound 25 shows deprotected second generation star polymer before addition of the terminal and pendant paclitaxels.
  • Compound 26 shows the drug-bearing, second generation star polymer with pendant and terminal paclitaxels attached via sebacic acid linkers.
  • Ethylene glycol is reacted with a quantity of a mixture of the lactone dimers of lactic acid and glycolic acid sufficient to give short oligomers (5-10 monomers) of PLGA (poly-lactic/glycolic acid) on each of its 2 hydroxyl groups, compound 27.
  • Compound 27 has one new hydroxyl group at each end.
  • Paclitaxel is protected on its 2' hydroxyl group with 2-napthylmethyl, leaving its 7-hydroxyl group free.
  • a second batch of paclitaxel is protected on its 2'-hydroxyl with acetyl, leaving its 7-hydroxyl free.
  • Cis-aconitic acid anhydride is catalytically reduced with hydrogen to give the corresponding anhydride of 2-carboxy-glutahc acid.
  • the anhydride of 2- carboxy-glutaric acid is activated on its free carboxylic acid group by stirring with one equivalent of oxalyl chloride in dichloromethane.
  • the anhydride/acid chloride solution is treated with an excess of a dichloromethane solution of the 2'-O-acetyl and 2'-O-(2-napthylmethyl) paclitaxels in a ratio of 1 :1 (acetyl to 2-napthylmethyl) in the presence of dimethylaminopyridine until all the activated glutaric anhydride is converted to a dipaclitaxel diester.
  • the remaining carboxylic acid group of the diester is activated with oxalyl chloride as above and reacted with 2'-O-2- naopthylmethy-lpaclitaxel to give compound 28, 2-carboxy-glutaric acid di-(2'-O-(2- napthylmethyl)-paclitaxel ester)-mono-(2'-O-acetyl-paclitaxel ester) with each paclitaxel acylated on its free 7-hydroxyl group by one of the three 2-carboxy-glutaric acid carboxyl groups.
  • the product 28 is isolated by column chromatography on silica gel.
  • First generation, drug-bearing linear polymer is meant to indicate how many cycles of PLGA and th-paclitaxel linker (compound 29,) have been added to the ethylene glycol starting compound. One cycle is one generation.
  • the process of adding a short oligomer of PLGA to these hydroxyl groups followed by succinic anhydride and the tri-paclitaxel linker can be repeated to give the second generation, drug-bearing linear polymer (compound 32) containing pendant paclitaxel and paclitaxel within the polymer chain. This process can be repeated as many times as desired to give additional generations of drug-bearing linear polymer.
  • the ratio of lactic and glycolic acid can be adjusted to give the desired release and degradation properties.
  • the pendant paclitaxels (with the exception of the polymer chain "terminal" paclitaxels, if the growth is stopped at this stage) have their 2'-hydroxyl groups protected by the labile acetyl ester group. This will likely be the first ester bond to hydrolyze in the final linear polymer because of the small size of the acetyl group and its pendant position, ultimately releasing free paclitaxel.
  • This Example describes the preparation of a linear polymer with poly-L- glutamic acid/L-alanine with paclitaxel pendant and in the polymer backbone (second generation linear polymer compound 39).
  • Scheme 7 shows compounds of Example 15.
  • An excess of a mixture of the ⁇ -trityl ester of glutamic acid N- carboxyanhydride and L-alanine N-carboxy anhydride in a ratio of 2:3 is reacted with ethylene diamine in dry dichloromethane/tetrahydrofuran until the 2 amino groups are each reacted with a single ⁇ -trityl-glutamic acid or alanine.
  • a drop of water is added to facilitate removal of the carbon dioxide from the amino groups of each of the single amino acids attached to each of the 2 amino groups and to allow growth of the ⁇ -trityl-glutamic acid/alanine oligomer to 5-10 monomers in length on each chain to give compound 33.
  • the amino acid sequence of 33 will be more or less random and not necessarily exactly as drawn in Scheme 7.
  • Compound 33 is reacted with succinic anhydride to give compound 34 with a succinic acid group on the end of each polymer chain.
  • Compound 34 is reacted with an excess of unsubstituted paclitaxel in the presence of carbonyldiimidazole and dimethylaminopyridine to give the first generation protected linear polymer (compound 35) with one paclitaxel at the end of each of the 2 chains, each paclitaxel bearing a free hydroxyl group.
  • Excess paclitaxel is removed and a short oligomer of poly-L- ⁇ -thtyl-glutamic acid-L-alanine is formed as above on each of the 2 hydroxyl groups followed by reaction with succinic anhydride to give compound 36 with a succinoyl group at the end of each chain.
  • Compound 36 is reacted with an excess of paclitaxel in the presence of carbonyldiimidazole and dimethylaminopyridine to give the second generation protected linear polymer with drug only in the polymer backbone, compound 37.
  • Compound 37 is treated with 0.5 % thfluoroacetic acid in dichloromethane to remove the trityl protecting groups from all the glutamic acid ⁇ - carboxyl groups to give compound 38.
  • Reaction of compound 38 dissolved in tetrahydrofuran/dimethylformamide with carbonyldiimidazole and excess paclitaxel in the presence of dimethylaminopyridine gives the second generation linear polymer compound 39 with paclitaxel both pendant and incorporated into the polymer backbone.
  • the amount of pendant paclitaxel can be adjusted by regulating the amount of carbonyldiimidazole and paclitaxel in the reaction and the ratio of glutamate to alanine in the polymer chains. Partial or full substitution of the side chain carboxyl groups and particular ratios may give the more desirable release and degradation properties.
  • Additional generation polymers can be prepared by further cycles of adding ⁇ -trityl glutamic acid-alanine oligomers, paclitaxel, and sebacic acid dichloride onto the backbone of compound 37, deprotecting the trityl ester groups and coupling paclitaxel to the pendant side chain carboxyl groups.
  • Scheme 7 Compound 33 shows ethylene diamine with a pentamer of ⁇ -thtyl-glutamic acid/alanine attached to each amino group.
  • Compound 34 shows the result of succinylation of the free amino group of each of the pentamers.
  • Compound 35 shows a paclitaxel with a free hydroxyl group attached to each free succinoyl carboxyl group, the first generation linear polymer with drug in the backbone only.
  • Compound 37 shows the second generation linear polymer with drug only in the polymer backbone.
  • Compound 39 shows the second generation linear polymer with drug both pendant and in the polymer backbone.
  • the glutamic acid abbreviation GIu and the alanine abbreviation Ala indicate their carboxyl groups on the left and their amino groups on the right, the reverse of the usual convention. Starting with compound 37 all amino acids are abbreviated instead of writing out their structures.
  • Compound 41 is reacted with succinic anhydride and then with an excess of unsubstituted paclitaxel in the presence of carbonyldiimidazole and dimethylaminopyridine to give compound 42 with one paclitaxel at the end of each of the 2 chains, each paclitaxel bearing a free hydroxyl group.
  • Compound 42 is the first generation linear polymer with drug in the backbone only. Only 1 of the 2 chains is shown in Scheme 8.
  • a short oligomer of 3-O-thtyl-D-glyceric acid is formed on each of the 2 free hydroxyl groups as above, followed by reaction with succinyl chloride (or with succinic anhydride followed by activation) and then with additional excess paclitaxel to give the protected second generation linear polymer with backbone drug only, compound 43.
  • Compound 43 is treated with 0.5 % thfluoroacetic acid in dichloromethane to remove the trityl protecting groups from all the glyceric acid 3- hydroxyl groups to give compound 44.
  • Additional generations of linear polymers can be prepared by further cycles of adding 3-O-trityl-D-glyceric acid oligomers, succinic anhydride or succinyl dichloride, and paclitaxel onto the backbone of compound 43, deprotecting the trityl ether groups and coupling the pendant paclitaxels to these side chain hydroxyl groups via succinic anhydride or succinyl dichloride.
  • Scheme 8 Compound 40 is the reactive cyclic 3-O-trityl-D-glyceric acid.
  • Compound 41 shows a 3-O-thtyl-glycehc acid pentamer polymerized onto each of the 2 hydroxyl groups of ethylene glycol.
  • Compound 42 shows one of the two chains reacted with succinic anhydride and then paclitaxel, the protected, first generation linear polymer with drug only in the backbone.
  • Compound 43 shows the growing chain with the second 3-O-thtyl-glycehc acid oligomer, the second succinic linker and the second backbone paclitaxel attached.
  • Compound 43 is the protected, second generation linear polymer with only backbone paclitaxels.
  • Compound 44 shows the deprotected, second generation linear polymer with only backbone paclitaxels.
  • Compound 45 shows compound 44 reacted with succinic anhydride and then with paclitaxel to give second generation, drug-bearing linear polymer with paclitaxels pendant and within the polymer backbone.
  • This Example describes the preparation of a linear polymer with D- lactic acid/glycolic acid/D-glyceric acid with paclitaxel pendant and in the polymer chain (second generation linear polymer compound 50).
  • Scheme 9 shows compounds of Example 17.
  • 3-O-Thtyl-D-glyceric acid is cyclized to its reactive lactone dimer (compound 40).
  • the reactive dimers of lactic acid, glycolic acid and compound 40 in a ratio of 2:2:1 are reacted with excess ethylene glycol in the presence of dimethylaminopyridine to give short chains (5-10 monomers) of lactic acid/glycolic acid/3-O-thtyl-D-glyceric acid oligomers attached to each of its 2 hydroxyl groups (compound 46). It is understood that the ratio and sequence of the hydroxyacids in 46 can be other than as shown in Scheme 9.
  • Compound 46 is reacted with excess succinic anhydride, the excess is removed by precipitation and washing, and the di- succinoyl product is then reacted with an excess of unsubstituted paclitaxel in the presence of carbonyldiimidazole and dimethylaminopyridine to give compound 47 with one paclitaxel at the end of each of the 2 chains, each paclitaxel bearing a free hydroxyl group. Only one of the two chains of compound 47 is shown. A short oligomer of lactic acid/glycolic acid/3-O-trityl-D-glycehc acid is formed on each of the 2 free paclitaxel hydroxyl groups as above to give compound 48.
  • Compound 48 is treated with 0.5 % thfluoroacetic acid in dichloromethane to remove the trityl protecting groups from all the glyceric acid 3-hydroxyl groups to give compound 49.
  • Additional generations of linear polymers can be prepared by further cycles of adding 3-O-trityl-D-glyceric acid oligomers, succinic anhydride and paclitaxel onto the terminal hydroxyl groups of compound 48, deprotecting the trityl ether groups and coupling the paclitaxels to the hydroxyl groups via succinic anhydride
  • Scheme 9 Compound 40 shows the reactive cyclic 3-0-trity I -g lyceric acid.
  • Compound 46 shows a lactic acid/glycolic acid/3-O-thtyl-glycehc acid (ratio 2:2:1 ) pentamer polymerized onto each of the 2 hydroxyl groups of ethylene glycol.
  • Compound 47 shows 1 of the growing chains with succinic acid linking paclitaxel into the polymer backbone.
  • Compound 48 shows the growing chain with the second pentamer chain attached (only the 3-O-thtyl-glycehc acid portion of the second pentamer is shown, not the lactic or glycolic acids).
  • Compound 49 shows the deprotected, second generation linear polymer before addition of the terminal and pendant paclitaxels.
  • Compound 50 shows the drug-bearing, second generation linear polymer with pendant and terminal paclitaxels attached via succinic acid linkers.
  • Compound 51 is reacted with di-hydroxy-polyethylene glycol (average molecular weight 200 (about 5 monomers), Sigma Chemical Company number P3015-5G) to give a linear polymer with paclitaxel both pendant and in the polymer backbone, the terminal paclitaxel bearing a chlorosuccinoyl group, compound 52.
  • Compound 52 is treated with water to hydrolyze the acid chloride groups to carboxylic acid groups, giving the linear polymer compound 53.
  • the length of the polymer can be varied by adjusting the reaction time, temperature and concentrations of the two reacting components.
  • Procedure B Alternatively, a mixture of 1 equivalent each of compound 29 and the dihydroxy-polyethylene glycol can be treated with 2 equivalents of succinyl di-chlohde in the presence of dimethylaminopyhdine and then quenched with water to give compound 53.
  • the pendant paclitaxels have their 2'-hydroxyl groups protected by the labile acetyl ester group.
  • the terminal paclitaxel has its 2'-hydroxyl groups protected by the succinoyl ester group.
  • the acetyl and succinyl groups will likely be the first ester bonds to hydrolyze in the final linear polymer because of the small size of the groups and their pendant (terminal) positions, ultimately releasing free paclitaxel.
  • Compound 29 is the tri-paclitaxel linker.
  • Compound 51 is the tri-paclitaxel linker activated on the two unprotected paclitaxels with succinyl chloride.
  • Compound 52 is the linear polymer with polyethylene glycol containing paclitaxel both pendant and in the polymer backbone, the terminal paclitaxel protected with a chloro-succinoyl group.
  • Compound 53 is the linear polymer with polyethylene glycol containing paclitaxel both pendant and in the polymer backbone, the terminal paclitaxel protected with a succinoyl group. Both the succinoyl group and the acetyl group are readily biodegradable.
  • This Example describes the preparation of a linear polymer of polyethylene glycol with paclitaxel pendant and in the polymer chain (second generation linear polymer compound 57).
  • Figure 12 shows compounds of Example 10.
  • Compound 54 is reacted with 2 equivalents of compound 29 (the mono-(acetyl-paclitaxel ester)-di-(paclitaxel ester) of 2-carboxy-glutahc acid, the tri-paclitaxel linker of Example 18) in the presence of carbonyldiimidazole and dimethylaminopyridine to give the first generation linear polymer with paclitaxel both pendant and in the polymer backbone, compound 55.
  • Compound 55 is reacted with sufficient ethylene oxide to add a short oligomer (5-10 monomers) of polyethylene glycol on the free hydroxyl group of the each of the two terminal paclitaxels.
  • Additional generation linear polymers can be prepared by further cycles of adding polyethylene glycol oligomers, succinic anhydride and tri-paclitaxel linker onto the terminal hydroxyl groups of compound 57.
  • the acetyl group on the pendant paclitaxels will likely be the first ester bonds to hydrolyze in the final linear polymer because of the small size of the groups and their pendant (terminal) positions, ultimately releasing free paclitaxel.
  • This Example describes the preparation of a poly-L-lactic acid-glycolic acid dendrimer with paclitaxel pendant and in the polymer backbone (second generation dendrimer, compound 65).
  • Compound 60 is reacted with an excess of the tri-paclitaxel linker of Example 19 (compound 29) in the presence of carbonyldiimidazole and dimethylaminopyridine to give the first generation dendrimer with paclitaxel both pendant and in the polymer backbone, compound 61.
  • first generation means that the first set of paclitaxels have been incorporated into branches both as pendant and backbone molecules. Only one end of compound 61 (2 of the 4 branches) is shown.
  • Compound 61 is reacted with a sufficient quantity of a mixture of cyclic L-lactic acid dimer and cyclic glycolic acid dimer to give an oligomer of about 5-10 monomers on each of its four free paclitaxel hydroxyl groups, then with 4 moles of the reactive cyclic dimer of 3-O-thtyl-D-glyceric acid (compound 40 of Example 19) to give compound 62.
  • Compound 62 is deprotected with 0.5 % trifluoroacetic acid in dichloromethane to give compound 63 with 8 deprotected hydroxyl groups. Only one of the 4 branches of compound 63 is shown.
  • Compound 65 can be extended for additional generations by repeating the process described above.
  • the release kinetics of drug can be adjusted by varying the length and composition of the lactate/glycolate oligomer.
  • the acetyl groups on the pendant paclitaxels will likely be the first ester groups of the dendrimer to hydrolyze due to the small size of acetyl and their pendant positions, ultimately releasing free paclitaxel.
  • Scheme 12 Compound 40 is the reactive dimer of 3-O-trityl-D- glycehc acid.
  • Compound 59 is polyethylene glycol of about 5 monomers reacted with the dimer and deprotected with 0.5 % thfluoroacetic acid in dichloromethane.
  • Compound 29 is the tri-paclitaxel linker.
  • Compound 61 shows one end of compound 59 after reaction with succinic anhydride and the tri-paclitaxel linker. Only 2 of the 4 branches of compound 61 are shown.
  • Compound 61 is the first generation dendrimer with paclitaxel both pendant and in the polymer backbone.
  • Compound 63 shows one of the 4 branches of compound 61 to which has been added a short oligomer of poly-lactic acid/glycolic acid and then a single glyceric acid.
  • Compound 65 shows the two terminal branches of the second generation dendrimer with paclitaxel both pendant and in the polymer backbone.
  • Compound 65 has a total of 8 branches as shown in the schematic structure at the bottom of Scheme 12.
  • the long connecting lines are the polylactate/glycolate oligomers and the short lines are the glyceric acid and succinic acid linkers.
  • This Example describes the preparation of a poly-L-alanine dendrimer with paclitaxel pendant and in the polymer backbone (second generation dendrimer, compound 71 ).
  • Scheme 13 shows compounds of Example 21.
  • first generation means that the first set of paclitaxels have been incorporated into branches both as pendant and backbone molecules.
  • Compound 67 is reacted with N ⁇ -Bpoc-L-alanine in the presence of carbonyldiimidazole and deprotected with 0.1 % trifluoroacetic acid in dichloromethane to give compound 68 with a single L- alanine containing a single amino group at the end of each of the 4 growing branches.
  • Compound 68 is reacted with Bpoc-L-alanine and deprotected as above for four more cycles to give a penta-alanine oligomer with a free amino group at the end of each of the 4 growing chains, compound 69.
  • Compound 69 is reacted with 4 equivalents of N ⁇ -N ⁇ -di-Bpoc-L-lysine in the presence of dicyclohexylcarbodiimide and then treated with 0.1 % trifluoroacetic acid in dichloromethane to give compound 70 with 8 amino groups.
  • Compound 70 is reacted with an excess of succinic anhydride and then reacted with an excess of the tri-paclitaxel linker (compound 29) in the presence of carbonyldiimidazole and dimethylaminopyridine to give the second generation dendrimer with paclitaxel both pendant and in the polymer backbone, compound 71.
  • Compound 71 can be further reacted as above to give additional generations of dendrimers.
  • the acetyl groups on the pendant paclitaxels will likely be the first ester groups of the dendrimer to hydrolyze due to the small size of acetyl and their pendant positions, ultimately releasing free paclitaxel.
  • This Example describes the preparation of a star polymer with 16 arms of polyethylene glycol with paclitaxel pendant and in the backbone (second phase star polymer compound 76).
  • Scheme 14 shows compounds of Example 22.
  • the pendant paclitaxels (with the exception of the polymer chain "terminal" paclitaxels, if the growth is stopped at this stage) have their 2'-hydroxyl groups protected by the labile acetyl ester group. This will likely be the first ester bond to hydrolyze in the final star polymer because of the small size of the acetyl group and its pendant position, ultimately releasing free paclitaxel.
  • Scheme 14 Compound 2 is the second generation star core with 16 free hydroxyl groups with only 1 of the initial 4 arms (each bearing 4 hydroxyl groups) shown.
  • Compound 72 shows a polyethylene glycol pentamer polymerized onto 1 of the 16 hydroxyl groups of compound 2, i.e., one arm of the 16 arm star polymer.
  • Compound 29 is the tri-paclitaxel linker with two free hydroxyl groups.
  • Compound 74 shows the reaction of compound 73 with succinic anhydride followed by reaction with the tri-paclitaxel linker in the presence of carbonyldiimidazole and dimethylaminopyridine.
  • Compound 74 is the first generation, polyethylene glycol star polymer with paclitaxel both pendant and within the polymer backbone.
  • 76 shows one of the 16 arms of the second generation, drug-bearing polymer with paclitaxels pendant and within the polymer backbone.
  • Compound 59 is reacted with excess succinic anhydride to succinylate all 4 hydroxyl groups giving compound 60 of Example 20.
  • Compound 60 is reacted with an excess of 2-O- napthylmethyl-paclitaxel in the presence of carbonyldiimidazole and dimethylaminopyridine and deprotected with 1 ,2-dichloro-4,5-dicyanoquinone to give a first generation dendrimer with 4 branches and paclitaxel only in the polymer backbone, compound 78. Only one end of compound 78 (2 of the 4 branches) is shown.
  • Compound 78 is reacted with 2-O-napthylmethyl-glycolic acid (compound 79) in the presence of carbonyldiimidazole and dimethylaminopyridine and deprotected with 1 ,2-dichloro-4,5-dicyanoquinone to give compound 80.
  • Compound 80 is reacted with sufficient ethylene oxide to give short oligomers (5-10 monomers) on each of its 4 terminal hydroxyl groups to give compound 81.
  • Compound 81 is reacted with 4 equivalents (1 for each free hydroxyl group) of the reactive cyclic dimer of 3-O-thtyl-D-glyceric acid (compound 40 of Example 20 and Scheme 15) and then with sufficient ethylene oxide to give compound 82.
  • Compound 84 is reacted with 4 equivalents of the cyclic lactone dimer of 3-O-napthylmethyl-D-glyceric acid and the naphthylmethyl groups removed by treatment with 1 ,2-dichloro-4,5-dicyanoquinone to give compound 85.
  • Compound 85 is reacted with ethylene oxide and then the cyclic lactone dimer of 3-O-thtyl-D- glyceric acid to give compound 86.
  • Compound 86 is reacted with ethylene oxide and all the trityl groups are removed with 0.5 % trifluoroacetic acid in dichloromethane to give compound 87.
  • Compound 87 is reacted with excess succinic anhydride and then excess paclitaxel in the presence of carbonyldiimidazole and dimethylaminopyridine to give compound 88, a second generation dendritic polymer with 8 terminal branches containing 2 backbone paclitaxels and 1 pendant paclitaxel in each terminal branch.
  • the 4 branches of the first generation dendhmer each have 1 backbone and 1 pendant paclitaxel in addition to the ones in the 8 terminal branches.
  • Scheme 15 Compound 40 is the reactive lactone dimer of 3-O-trityl- D-glyceric acid.
  • Compound 59 is polyethylene glycol of about 5 monomers reacted with the dimer and deprotected with 0.5 % thfluoroacetic acid in dichloromethane.
  • Compound 77 is the reactive lactone dimer of 3-O-napthylmethyl-D-glyceric acid.
  • Compound 78 shows one end of compound 59 after reaction with succinic anhydride, 2-O-napthylmethyl-paclitaxel, and deprotection with 1 ,2-dichloro-4,5- dicyanoquinone. Only 2 of the 4 branches of compound 78 are shown.
  • Compound 78 is a first generation dendrimer with 4 branches containing paclitaxel only in the polymer backbone.
  • Compound 80 shows compound 78 after reaction with 2-O- napthylmethyl-glycolic acid (compound 79) and removal of the naphthylmethyl group.
  • Compound 82 shows compound 80 extended with ethylene oxide, the cyclic lactone dimer of 3-O-thtyl-D-glyceric acid, and then ethylene oxide again.
  • Compound 83 shows compound 82 after reaction with the reactive lactone dimer of 3-O- napthylmethyl-D-glyceric acid, then deprotection with 1 ,2-dichloro-4,5- dicyanoquinone to give a first generation dendrimer with 4 branches and paclitaxel only in the polymer backbone.
  • the terminal glyceric acids are the branch points to construct the 8 branch dendrimer. Only 1 of the 4 branches of compound 83 is shown.
  • Compound 84 shows compound 83 after reaction with succinic anhydride, 2- O-napthylmethyl-paclitaxel, and deprotection. Only one of the 8 terminal branches of 84 is shown.
  • Compound 86 shows compound 84 after reaction with 2-O- napthylmethyl-glycolic acid, deprotection, reaction with ethylene oxide and then reaction with the cyclic lactone dimer of 3-O-thtyl-D-glyceric acid. Only 1 of the 8 terminal branches of compound 86 is shown.
  • Compound 87 shows compound 86 after reaction with ethylene oxide and removal of all trityl groups with 0.5 % trifluoroacetic acid in dichloromethane.
  • Compound 88 shows compound 87 after reaction with succinic anhydride and excess paclitaxel.
  • compound 40 compound 59 compound 77 compound 79
  • This Example describes the preparation of a star polymer with 16 arms of poly-L-aspartic acid with paclitaxel pendant and in the polymer backbone (second generation star polymer compound 89).
  • Scheme 16 shows the star polymer of Example 24.
  • This Example describes the preparation of a linear polymer with poly-L- aspartic acid/L-alanine with paclitaxel pendant and in the polymer backbone (second generation linear polymer compound 90).
  • Scheme 17 shows the linear polymer of Example 25.
  • This Example describes the preparation of a poly-L-aspartic acid/L- alanine dendrimer with paclitaxel pendant and in the polymer backbone (second generation dendrimer, compound 96).
  • Scheme 18 shows compounds of Example 26.
  • Compound 92 is reacted with N ⁇ -N ⁇ -di-Fmoc-L-lysine in the presence of diclyclohexylcarbodiimide, and deprotected with dry piperidine in dimethylformamide to give compound 93.
  • Compound 93 is extended with a pentamer of 4 alanines and 1 ⁇ -thtyl-L-aspartic acid to give compound 94, a dendrimer with 8 terminal branches.
  • Compound 94 is deprotected with 0.5 % trifluoroacetic acid in dichloromethane, removing all the trityl groups, to give compound 95.
  • Compound 95 is reacted with an excess of succinic anhydride and then with an excess of paclitaxel in the presence of carbonyldiimidazole and dimethylaminopyridine to give compound 96, the second generation dendrimer with 8 branches with both pendant and terminal paclitaxels.
  • Scheme 18 Compound 66 is 1 ,6-hexanediamine after reaction with 2 equivalents of N ⁇ -N ⁇ -di-Bpoc-L-lysine and deprotection.
  • Compound 91 shows the addition of a pentapeptide of alanine and ⁇ -O-thtyl-aspartic acid to compound 66. Only 2 of the 4 branches of compound 91 are shown.
  • Compound 92 shows the result of the reaction of compound 91 with succinic anhydride and then 2-O- napthylmethyl-paclitaxel followed by deprotection of the paclitaxel 2-hydroxyl group.
  • Compound 92 is the first generation dendrimer (4 branches) with paclitaxel only in the polymer backbone. Only 1 of the 4 branches of compound 92 is shown. Reaction of compound 92 with N ⁇ -N ⁇ -di-Fmoc-L-lysine, deprotection of the lysine amino groups and addition of a pentapeptide of alanine and ⁇ -O-trityl-aspartic acid gives compound 94. Compound 94 contains the 8 growing branches of the second generation dendrimer. Compound 95 shows the result of deprotection of all the aspartic acid ⁇ -carboxyl groups.
  • Compound 96 shows the result of succinylation of the free amino groups followed by reaction with an excess of paclitaxel in the presence of carbonyldiimidazole and dimethylaminopyhdine.
  • Compound 96 is the second generation dendrimer with paclitaxel both pendant and in the polymer backbone.
  • Examples 27-29 Star, linear and dendritic polymers with polv-L-serine (pendant OH) , poly-L-cysteine (pendant SH), and poly-L lysine (pendant NH 2 ).
  • This Example describes the preparation of a star polymer with 16 arms of poly-L-serine with paclitaxel pendant and in the polymer backbone (second generation star polymer compound 97).
  • Scheme 19 shows compound 97.
  • This Example describes the preparation of a linear polymer with poly-L- cysteine/L-alanine with paclitaxel pendant and in the polymer backbone (compound 102).
  • Scheme 20 shows compounds of Example 28.
  • N ⁇ -Bpoc-L-cysteine is reacted with excess sebacic acid mono-acid chloride mono-t-butylester to give N ⁇ -Bpoc-S-(O-t-butyl-sebacoyl)-L-cysteine shown in Scheme 20.
  • Hexanediamine is reacted with N ⁇ -Bpoc-L-alanine in the presence of dicyclohexylcarbodiimide and the Bpoc group removed with 0.1 % thfluoroacetic acid in dichloromethane.
  • reaction and deprotection is repeated once with N ⁇ -Bpoc-L- alanine, once with N ⁇ -Bpoc-S-(O-t-butyl-sebacoyl)-L-cysteine, and twice with N ⁇ - Bpoc-L-alanine to give diaminohexane acylated on each amino group with a pentamer containing one S-(O-t-butyl-sebacoyl)-L-cysteine, compound 98.
  • Compound 98 is reacted with an excess of succinic anhydride and then with 2-O- napthylmethyl-paclitaxel in the presence of carbonyldiimidazole and dimethylaminopyridine and deprotected with 1 ,2-dichloro-4,5-dicyanoquinone to give compound 99.
  • Compound 99 with two free paclitaxel hydroxyl groups is reacted with the same sequence of protected cysteine and alanine followed by amino group deprotection and succinylation, as above, to give compound 100.
  • Compound 100 is deprotected with 25 % trifluoroacetic acid in dichloromethane to give compound 101 with both terminal and pendant carboxylic acid groups.
  • Compound 101 is reacted with excess paclitaxel in the presence of cabonyldiimidazole and dimethylaminopyridine to give a linear polymer with paclitaxel both pendant and in the polymer backbone, compound 102.
  • the linear polymer 100 can be extended to any length by further cycles of reactions as described above.
  • Compound 99 shows compound 98 after reaction with succinic anhydride and 2-O-napthylmethyl-paclitaxel followed by removal of the O- naphthylmethyl group.
  • Compound 100 shows compound 99 after addition of a second pentapeptide and succinylation.
  • Compound 101 shows compound 100 after removal of the t-butyl groups.
  • Compound 102 shows compound 101 after addition of paclitaxel.
  • 105 is extended with 8 pentapeptides to give compound 106 as described above.
  • Compound 106 is deprotected with 0.1 % trifluoroacetic acid in dichloromethane to give compound 107 with a total of 24 pendant and terminal amino groups.
  • Compound 107 is reacted with succinic anhydride and then with excess paclitaxel in the presence of carbonyldiimidazole and dimethlaminopyhdine to give the second generation dendrimer 108 which contains paclitaxel both pendant and in the backbone.
  • the dendrimer 106 can be extended to any length and number of branches by further cycles of reactions as described above.
  • Scheme 21 Compound 66 shows the result of reacting of N ⁇ -N ⁇ -di- Bpoc-L-lysine with hexanediamine and deprotecting with 0.1 % trifluoroacetic acid in dichloromethane.
  • Compound 103 shows the result of adding a pentapeptide containing N ⁇ -Bpoc-L-lysine to compound 66. Only 2 of the 4 branches of compound 103 are shown.
  • Compound 104 shows the result of adding succinic anhydride and then paclitaxel to compound 103.
  • Compound 104 has paclitaxel only in the backbone of its 4 branches. Only 1of the 4 branches is shown.
  • Compound 105 shows the result of reacting compound 104 with N ⁇ -N ⁇ -di-Fmoc-L-lysine followed by deprotection. The added lysine forms the branch points for the 8 new branches.
  • Compound 106 shows the results of adding a pentapeptide containing N ⁇ -Bpoc-L- lysine to the amino groups of compound 105.
  • Compound 107 shows the result of deprotection of all N ⁇ -amino groups of compound 106.
  • Compound 108 shows the result of succinylation of all amino groups of compound 107 followed by addition of paclitaxel.
  • Compound 108 is a second generation dendrimer with 8 branches, each branch containing paclitaxel both pendant and in the polymer backbone.

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Abstract

Disclosed herein are polymers comprising a chemical moiety linked through a covalent bond, where the chemical moiety forms a pharmaceutically active agent upon degradation of the covalent bond. The polymers can be chosen from star polymers, dendrimers, and hyperbranched polymers. Also disclosed are coatings for implantable medical device comprising such polymers.

Description

POLYMERIC THERAPEUTICS
RELATED APPLICATIONS
[01] This application claims the benefit of priority under 35 U. S. C. § 119(e) to U.S. Prov. App. No. 60/885,097, filed January 16, 2007, U.S. Prov. App. No. 60/885,105, filed January 16, 2007, U.S. Prov. App. No. 60/885,109, filed January 16, 2007, U.S. Prov. App. No. 60/885,112, filed January 16, 2007, U.S. Prov. App. No. 60/942,301 , filed June 6, 2007, and U.S. Prov. App. No. 60/942,309, filed June 6, 2007, and U.S. Prov. App. No.60/943,077, filed June 11 , 2007, the disclosures of which are incorporated herein by reference.
FIELD OF THE INVENTION
[02] The present invention relates to biodegradable polymers covalently bonded to one or more pharmaceutically active agents typically for use as coatings on medical devices that are inserted within the body and subject to internal body, organ or blood conditions.
BACKGROUND OF THE INVENTION
[03] Restenosis, thrombosis and other intravascular conditions are complex diseases that can be treated by drug eluting stents (DES), catheters, guidewires and the like. Currently, commercially available DES comprise a coated device where the coating includes a single drug eluted from a polymeric carrier.
[04] For DES treatments, sustained delivery of the drug is generally desired. With a coating comprising a nonbiodegradable polymeric carrier, the mechanism for drug release into the bloodstream is diffusion of the drug through the polymer. Biodegradable polymers have been developed in stent coatings that ideally should reduce the dependency on diffusion and allow sustained drug delivery due to degradation of the polymer in vivo. However, in practice, even systems employing biodegradable polymers ultimately rely mainly on the diffusion mechanism as the polymer degradation rate is too slow for delivering an effective amount of drug to the bloodstream over the required time period. [05] Accordingly, there remains a need to develop new coatings for implantable medical devices that allow sustained drug release.
SUMMARY OF THE INVENTION
[06] One embodiment provides a polymer comprising a chemical moiety covalently linked to at least one branch of the polymer, the chemical moiety being linked through a covalent bond, wherein the chemical moiety forms a pharmaceutically active agent upon degradation of the covalent bond, and wherein the polymer is chosen from star polymers, dendrimers, and hyperbranched polymers.
[07] In one embodiment, the polymer is less soluble in an aqueous medium, e.g., a physiological medium, than is the free form of the pharmaceutically active agent.
[08] In one embodiment, the polymer has a Tg greater than 37°C. In one embodiment, the polymer has a Tg greater than 400C, e.g., a Tg greater than 500C, or greater than 60°C.
[09] Another embodiment provides a star polymer comprising a chemical moiety covalently linked to at least one branch of the polymer, the chemical moiety being linked through a covalent bond, wherein the chemical moiety forms a pharmaceutically active agent upon degradation of the covalent bond.
[10] In one embodiment, the chemical moiety is incorporated in the main chain (backbone) of the at least one branch of the star polymer.
[11] In one embodiment, the chemical moiety is a pendant (side chain and/or terminus) group of the at least one branch of the star polymer.
[12] In one embodiment, the chemical moiety is linked to the terminus of the at least one branch of the star polymer.
[13] In one embodiment, each branch of the star polymer have substantially the same molecular weight and length.
[14] In one embodiment, branches of the star polymer have different molecular weights and different lengths. [15] In one embodiment, the star polymer comprises branches of substantially the same molecular weight and length and one branch of substantially higher molecular weight and length.
[16] In one embodiment, the molecular weight of one or more branches of the star polymer ranges from 10,000 Da to 100,000 Da.
[17] In one embodiment, the covalent bond is hydrolytically degradable.
[18] In one embodiment, the covalent link between the star polymer and the pharmaceutically active agent is selected from anhydride, ester, carbonate, amide, and thioester linkages.
[19] In one embodiment, the chemical moiety is linked to the star polymer via a linking group.
[20] In one embodiment, the linking group is selected from aliphatic C4-C2o chains, polylactide, poly(lactide-co-galactide), polyethylene glycol, polycaprolactone, polyethyleneimine, polycaprolactone/polyethyleneimine, and phospholipids.
[21] In one embodiment, the linking group is biodegradable.
[22] In one embodiment, at least one branch contains a stimuli-responsive linking group.
[23] In one embodiment, the stimuli-responsive linking group is selected from temperature responsive polymers and pH responsive polymers.
[24] In one embodiment, the temperature responsive polymers are selected from poly(N-isopropylacrylamide).
[25] In one embodiment, the pH responsive polymers are selected from polypropyl acrylic acid.
[26] In one embodiment, the star polymer comprises a monomer selected from ethylenimine, ethylene glycol, amphiphilic scorpion-like macromolecules, phosphazenes, amidoamines, and propyleneimine.
[27] In one embodiment, the star polymer comprises a polymer selected from polyethyleneimine, polyethylene glycol, polyethyleneimine/polyethylene glycol, amphiphilic scorpion-like macromolecules, polyphosphazenes, polyamidoamines, and polypropyleneimine, and the chemical moiety is covalently linked as a pendant group (e.g., a side chain) or terminus group.
[28] In one embodiment, the star polymer is biodegradable. [29] In one embodiment, the pharmaceutically active agent is selected from taxanes, limus derivatives, and non-steroidal anti-inflammatory agents.
[30] In one embodiment, the pharmaceutically active agent is selected from paclitaxel, sirolimus, everolimus, biolimus, zotarolimus, and AP23573.
[31] In one embodiment, the star polymer is less soluble in an aqueous medium than is the free form of the pharmaceutically active agent.
[32] In one embodiment, the pharmaceutically active agent is hydrophobic.
[33] In one embodiment, the pharmaceutically active agent is present in a dose density ranging from 0.05 to 10 μg/mm2.
[34] In one embodiment, the star polymer has a Tg greater than 37°C. In one embodiment, the compound has a Tg greater than 400C. In one embodiment, the compound has a Tg greater than 500C, or greater than 60°C.
[35] In one embodiment, at least one branch of the star polymer comprises two or more different chemical moieties that form pharmaceutically active agents.
[36] In one embodiment, at least one branch of the star polymer comprises at least three different chemical moieties that form pharmaceutically active agents. In one embodiment, the at least three chemical moieties comprises a first chemical moiety that forms an antiproliferative pharmaceutically active agent, at second chemical moiety forms an anti-inflammatory agent, and a third chemical moiety that forms a healing promoter.
[37] In one embodiment, at least one branch of the star polymer comprises a first chemical moiety, and at least one branch of the star polymer comprises a second chemical moiety.
[38] In one embodiment, at least one branch of the star polymer comprises a first chemical moiety, at least one branch of the star polymer comprises a second chemical moiety, and at least one branch of the star polymer comprises a third chemical moiety.
[39] In one embodiment, the first chemical moiety forms an antiproliferative pharmaceutically active agent, the second chemical moiety forms an antiinflammatory agent, and the third chemical moiety forms a healing promoter.
[40] A polymer comprising at least two covalently linked star polymers. [41] Another embodiment provides an implantable medical device having at least one coating covering at least a portion of the device, the at least one coating comprising a polymer selected from star polymers, dendhmers, and hyperbranched polymers as disclosed herein.
[42] In one embodiment, the device is implantable into a mammalian lumen. In one embodiment, the device is a stent. In one embodiment, the stent is either balloon expandable or self-expanding.
[43] In one embodiment, the composition is coated on the stent to form a conformal coating around all surfaces of the stent.
[44] In one embodiment, the composition is coated only on the abluminal surface of the stent. In one embodiment, the composition is coated only on the abluminal surface of the stent and the composition resides partially or completely within micro-reservoirs or pores in the stent surface.
[45] In one embodiment, the device is selected from pacemaker leads, valve replacement and repair devices, vena cava filters, and embolic coils and beads.
[46] In one embodiment, the device is an angioplasty balloon having coated thereon the coating comprising the composition, wherein the balloon is used to deliver the composition to an endoluminal surface.
[47] In one embodiment, the at least one coating comprises at least two coatings to provide a multi-layered structure.
[48] In one embodiment, the at least one coating comprises at least three coatings.
[49] In one embodiment, each of the at least three coatings provides a different chemical moiety that forms a different pharmaceutically active agent.
[50] In one embodiment, the composition in one of the at least three coatings comprises a chemical moiety that forms an antiproliferative pharmaceutically active agent.
[51] In one embodiment, the composition in one of the at least three coatings comprises a chemical moiety that forms an anti-inflammatory agent.
[52] In one embodiment, the composition in one of the at least three coatings comprises a chemical moiety that forms a healing promoter. [53] In one embodiment, wherein the at least one coating directly contacts the device.
[54] In one embodiment, the device further comprises an inner coating free of a pharmaceutically active agent that directly contacts the device, wherein the inner coating also directly contacts the at least one coating.
[55] Another embodiment provides a polymer comprising: one or more of a star polymer, a dendrimer polymer and a hyperbranched polymer having a plurality of branches, one more of the branches comprising a biodegradable polymer comprising a chemical moiety bonded to a linker group; wherein the chemical moiety is bonded to the linker group via a linkage that is naturally hydrolysable in an in vivo environment, the polymer being less soluble in vivo than the free form of the pharmaceutically active agent is soluble in vivo.
[56] In one embodiment, the pharmaceutically active agent is incorporated into a backbone of one or more of the branches.
[57] In one embodiment, the pharmaceutically active agent is bonded in pendant relationship to one or more of the branches.
[58] In one embodiment, the hydrolysable linkage is preselected to produce a selected concentration of the pharmaceutically active moieties over a selected period of time in an in vivo environment.
[59] In one embodiment, one or more of the number and length of the one or more branches is preselected to produce a selected concentration of the pharmaceutically active moieties over a selected period of time in an in vivo environment.
[60] In one embodiment, the linker group comprises one or more of an aliphatic chain of 2-20 carbon atoms, a lactide, a glycolide, a glycol, a caprolactide, an alkylene oxide and co-monomers and copolymers of all of the foregoing.
[61] One embodiment provides a composition comprising a biocompatible polymer, the polymer being linked to a chemical moiety through a covalent bond, wherein, the chemical moiety forms a pharmaceutically active agent upon degradation of the covalent bond, the chemical moiety is linked to a polysaccharide or phospholipid.
[62] In one embodiment, the polymer has a Tg greater than 37°C, e.g., greater than 400C, greater than 500C, or greater than 60°C.
[63] In one embodiment, the chemical moiety is incorporated into the backbone of the polymer.
[64] In one embodiment, the covalent bond is hydrolytically degradable or biodegradable.
[65] In one embodiment, the covalent bond comprises an ester, amide, carbonate, anhydride or thioester linkage.
[66] In one embodiment, the composition is used for at least one coating for an implantable medical device, the at least one coating covering at least a portion of the device.
[67] In one embodiment, the biodegradable polymer further comprises a linker group linking the polysaccharide or phospholipid to the chemical moiety, the linker group being linked to the polysaccharide or phospholipid via an ester, amide, carbonate, anhydride or thioester linkage and to the chemical moiety via an ester, amide, carbonate, anhydride or thioester linkage.
[68] In one embodiment, the polysaccharide includes a plurality of hydroxyl groups, a selected number of such plurality of hydroxyl groups being reacted with a second chemical moiety to form a second biodegradable linkage, the second chemical moiety forming a second pharmaceutically active agent on degradation of the second biodegradable linkage.
[69] In one embodiment, the pharmaceutically active agent is selected from taxanes, limus derivatives, and non-steroidal anti-inflammatory agents.
[70] In one embodiment, the pharmaceutically active agent is selected from paclitaxel, rapamycin and their analogs and derivatives.
[71] In one embodiment, the biodegradable polymer is present in an amount ranging from 40% to 95% by weight relative to the total weight of the composition. [72] In one embodiment, the pharmaceutically active agent is present in a dose density ranging from 0.05 to 10 μg/mm2.
[73] In one embodiment, the number average molecular weight of the polymer is between about 10,000 daltons and about 100,000 daltons.
[74] In one embodiment, the structure and molecular weight of the polysaccharide is pre-selected to impart a pre-selected degree of hydrophilicity to the polymer.
[75] In one embodiment the polysaccharide is pre-selected to impart or possess a predetermined bioactivity on degradation of the covalent bond.
[76] In one embodiment, the structure and molecular weight of the phospholipid is pre-selected to impart a pre-selected degree of hydrophobicity to the polymer.
[77] In one embodiment the phospholipid is pre-selected to impart or possess a predetermined bioactivity on degradation of the covalent bond.
[78] In one embodiment, polymer comprises both a phospholipid and a polysaccharide, each linked to the same or different chemical moieties, the chemical moieties forming a pharmaceutically active agent upon degradation of the covalent bond. In such an embodiment the structure, molecular weight and relative amounts of the polysaccharide and phospholipid are pre-selected to impart a pre-selected degree of hydrophilicity or hydrophobicity to the polymer.
[79] Another embodiment provides a method of making a polymer having therapeutic properties, the method comprising: selecting a first chemical moiety having a selected pharmaceutical activity; covalently bonding a first reactive site on the first chemical moiety to a first reactive site on a selected polysaccharide or phospholipid; and, covalently bonding a second reactive site on the first chemical moiety to a second reactive site on the selected polysaccharide or phospholipid to form a polymer of alternating sequence of the first chemical moiety and the selected polysaccharide or phospholipid.
[80] In another embodiment, a method of making a polymer having therapeutic properties is provided, the method comprising: selecting a first chemical moiety having a selected pharmaceutical activity; selecting a polysaccharide or a phospholipid having multiple reactive sites capable of linking to the first chemical moiety; protecting all but two of the reactive sites of the selected polysaccharide or phospholipid; and linking the first chemical moiety to at least one of the two unprotected sites of the selected polysaccharide or phospholipid.
[81] In one embodiment, the selected polysaccharide or phospholipid is polymerized in alternating sequence with the first chemical moiety alone or together with a second chemical moiety having a second selected pharmaceutical activity. The selected polysaccharide or phospholipid can be copolymehzed together with the first and second selected chemical moieties to form a straight or branched chain polymer of the first and/or second chemical moieties in alternating sequence with one or both of the polysaccharide and/or phospholipid.
[82] In one embodiment, the first and/or second selected chemical moieties have at least two reactive sites for forming covalent linkages to the selected polysaccharide and/or phopholipid. Such linkages can be selected from direct ester, amide, carbonate, anhydride and/or thioester linkages. Alternatively, the linkages between the one or more selected chemical moieties and the polysaccharide or phospholipid can be created via a linker having two reactive groups capable of forming an ester, amide, carbonate, anhydride or thioester linkage with a corresponding reactive group of the selected chemical moiety(ies) and the selected polysaccharide and/or phospholipid.
[83] In one embodiment, the structure and molecular weight of the polysaccharide or phospholipid is selected to impart a pre-selected degree of hydrophilicity and/or hydrophobicity to the polymer so formed.
[84] In one embodiment, the polysaccharide and/or phospholipid has a preselected biologic therapeutic activity such as an anti-restenotic, anti-inflammatory or anti-thrombotic activity. [85] Another embodiment provides an implantable medical device having at least one coating covering at least a portion of the device, the at least one coating comprising a compound according to any of the above described polymers..
[86] In one embodiment, the at least one coating comprises at least two coatings to provide a multi-layered structure.
[87] In one embodiment, the at least one coating comprises at least three coatings.
[88] In one embodiment, each of the at least two or three coatings provides a different chemical moiety that forms a different pharmaceutically active agent. In one embodiment, the composition in one of the at least two or three coatings comprises a chemical moiety that forms an antiproliferative pharmaceutically active agent. In one embodiment, the composition in one of the at least two or three coatings comprises a chemical moiety that forms an anti-inflammatory agent.
[89] In one embodiment, the at least one coating directly contacts the device.
[90] In one embodiment, an inner coating free of a pharmaceutically active agent that directly contacts the device, wherein the inner coating also directly contacts the at least one coating.
[91] In one embodiment, the device is implantable into a mammalian lumen. In one embodiment, the device is a stent. In one embodiment, the stent is either balloon expandable or self-expanding.
[92] In one embodiment, the composition is coated on the stent to form a conformal coating around all surfaces of the stent.
[93] In one embodiment, the composition is coated only on the abluminal surface of the stent. In one embodiment, the composition is coated only on the abluminal surface of the stent and the composition resides partially or completely within micro-reservoirs or pores in the stent surface.
[94] In one embodiment, the device is selected from pacemaker leads, valve replacement and repair devices, vena cava filters, and embolic coils and beads. [95] In one embodiment, the device is an angioplasty balloon having coated thereon the coating comprising the composition, wherein the balloon is used to deliver the composition to an endoluminal surface.
[96] Another embodiment provides a polymer comprising the repeat unit:
-[D1-L1-D2-L2]- wherein:
L1 and L2 are the same or different, and each are linking groups selected from the group of polysaccharides and phospholipids and are covalently linked to D1 and D2 via one or more of an amide, ester, anhydride, carbonate and thioester linkage;
D1 and D2 are the same or different and are a chemical moiety that upon degradation of a linkage to the linking groups form a pharmaceutically active agent.
[97] Another embodiment provides a polymer comprising the repeat unit:
-[D1-L3-L1-L4-D2-L5-L2-L6] wherein:
L1 and L2 are the same or different, and each are linking groups selected from the group of polysaccharides and phospholipids and are covalently linked to D1 and D2 via one or more of an amide, ester, anhydride, carbonate and thioester linkage;
L3, L4, L5 and L6 can be the same or different, and each are one or the other of an amide, ester, anhydride, carbonate and thioester linkage or are a linking group that are linked to an adjacent group via one or the other of an amide, ester, anhydride, carbonate and thioester linkage; and
D1 and D2 are the same or different and are a chemical moiety that upon degradation of a linkage to the linking groups form a pharmaceutically active agent.
[98] Another embodiment provides a polymer comprising the repeat unit:
-[D1-L1-D2-L2-D3-L3] wherein:
L1 and L2 and L3 are the same or different, and each are linking groups selected from the group of polysaccharides and phospholipids and are covalently linked to D1 and D2 via one or more of an amide, ester, anhydride, carbonate and thioester linkage;
Di and D2 and D3 are the same or different and are a chemical moiety that upon degradation of a linkage to the linking groups form a pharmaceutically active agent.
[99] Another embodiment provides a polymer comprising the repeat unit:
-[Dr L4-LrL5-D2-L6-L2- L7-D3-L8-L3-L9] wherein:
Li and L2 and L3 are the same or different, and each are linking groups selected from the group of polysaccharides and phospholipids
L4, L5, L6, L7, L8 and L9 can be the same or different, and each are one or the other of an amide, ester, anhydride, carbonate and thioester linkage or are a linking group that are linked to an adjacent group via one or the other of an amide, ester, anhydride, carbonate and thioester linkage;
Di and D2 and D3 are the same or different and are a chemical moiety that upon degradation of a linkage to the linking groups form a pharmaceutically active agent.
[100] In one embodiment, Di and D2 and D3 are each selected from taxanes, limus derivatives, and non-steroidal anti-inflammatory agents.
[101] In one embodiment, D1 and D2 and D3 are each selected from paclitaxel, rapamycin and their analogs and derivatives.
[102] In one embodiment, D1 and D2 and D3 are each selected from taxanes, limus derivatives, non-steroidal anti-inflammatory agents and healing promoters.
[103] In one embodiment, there is provided a composition comprising the above described polymer, the polymer being present in an amount ranging from 40% to 95% by weight relative to the total weight of the composition. In one embodiment, the pharmaceutically active agent is present in a dose density ranging from 0.05 to 10 μg/mm2.
[104] In one embodiment, the number average molecular weight of the polymer is between about 10,000 daltons and about 100,000 daltons. [105] In one embodiment, the structure and molecular weight of the polysaccharide is pre-selected to impart a pre-selected degree of hydrophilicity to the polymer.
[106] In one embodiment the polysaccharide is pre-selected to impart or possess a predetermined bioactivity on degradation of the covalent bond.
[107] In one embodiment, the structure and molecular weight of the phospholipid is pre-selected to impart a pre-selected degree of hydrophobicity to the polymer.
[108] In one embodiment the phospholipid is pre-selected to impart or possess a predetermined bioactivity on degradation of the covalent bond.
[109] In one embodiment, the relative molar or weight ratios of the polysaccharide and phospholipid contained within the polymer are pre-selected to impart a preselected degree of hydrophilicity or hydrophobicity to the polymer.
[110] One embodiment provides a composition comprising a biodegradable polymer, the polymer comprising: a backbone having a first chemical moiety incorporated into the backbone of the polymer via one or more biodegradable covalent linkages, a pendant arm (side chain and/or terminus group) linked to the backbone via a biodegradable linkage, the pendant arm having a second chemical moiety bonded to the pendant arm via a single biodegradable covalent linkage, wherein the first and second chemical moieties are the same or different and each forms a pharmaceutically active agent upon degradation of their biodegradable linkages. In one embodiment, the pendant arm is linked to the backbone via an ester, amide, carbonate, anhydride or thioester linkage.
[111] In one embodiment, the backbone of the biodegradable polymer further comprises one or more of an aliphatic chain of 4 to 20 carbon atoms, a polylactide, a polyether, a polyglycolide, a polyethyleneimine, a polycaprolactone, a polysaccharide, a polyphospholipid or a polyamino acid linked to the first chemical moiety via one or more of an ester, amide, carbonate, anhydride or thioester linkage.
[112] In one embodiment, the polylactide, polyether, polyglycolide, polyethyleneimine, polycaprolactone, polysaccharide or polyphospholipid is incorporated into the backbone via a linker group, the linker group being linked to both the first chemical moiety and to the polylactide, polyether, polyglycolide, polysaccharide and/or polyphospholipid via an ester, amide, carbonate, anhydride or thioester linkage. Such a linker group typically comprises an aliphatic chain of 4 to 20 carbon atoms.
[113] In one embodiment, the pendant arm comprises one or more of an aliphatic chain of 4 to 20 carbon atoms, a polylactide, a polyether, a polyglycolide, a polyethyleneimine, a polycaprolactone, a polysaccharide, a polyphospholipid or a polyamino acid linked to the second chemical moiety via one or more of an ester, amide, carbonate, anhydride or thioester linkage.
[114] In one embodiment, the polymer has a Tg greater than 37°C, e.g., a Tg greater than 400C, greater than 500C, or even greater than 60°C.
[115] In one embodiment, the covalent bond is hydrolytically degradable or biodegradable.
[116] In one embodiment, the covalent comprises an ester, amide, carbonate, anhydride or thioester linkage.
[117] In one embodiment, the composition is used for at least one coating for an implantable medical device, the at least one coating covering at least a portion of the device.
[118] In one embodiment, the pharmaceutically active agent is selected from taxanes, limus derivatives, and non-steroidal anti-inflammatory agents.
[119] In one embodiment, the pharmaceutically active agent is selected from paclitaxel, rapamycin and their analogs and derivatives.
[120] In one embodiment, the biodegradable polymer is present in an amount ranging from 40% to 95% by weight relative to the total weight of the composition.
[121] In one embodiment, the pharmaceutically active agent is present in a dose density ranging from 0.05 to 10 μg/mm2.
[122] In one embodiment, the number average molecular weight of the polymer is between about 5,000 daltons and about 100,000 daltons.
[123] In one embodiment, the structure and molecular weight of the aliphatic chain of 4 to 20 carbon atoms, a polylactide, a polyether, a polyglycolide, a polyethyleneimine, a polycaprolactone, a polysaccharide, a polyphospholipid or a polyamino acid is pre-selected to impart a pre-selected degree of hydrophilicity, hydrophobicity or rate of degradation to the polymer.
[124] In one embodiment the aliphatic chain of 4 to 20 carbon atoms, a polylactide, a polyether, a polyglycolide, a polyethyleneimine, a polycaprolactone, a polysaccharide, a polyphospholipid or a polyamino acid is pre-selected to impart or possess a predetermined bioactivity on degradation of the covalent linkages.
[125] In one embodiment, the polymer comprises two or more of an aliphatic chain of 4 to 20 carbon atoms, a polylactide, a polyether, a polyglycolide, a polyethyleneimine, a polycaprolactone, a polysaccharide, a polyphospholipid or a polyamino acid, each linked to the same or different first chemical moieties, the first chemical moieties forming a pharmaceutically active agent upon degradation of the covalent bond. In such an embodiment the structure, molecular weight and relative amounts of the two or more of an aliphatic chain of 4 to 20 carbon atoms, a polylactide, a polyether, a polyglycolide, a polyethyleneimine, a polycaprolactone, a polysaccharide, a polyphospholipid or a polyamino acid are pre-selected to impart a pre-selected degree of hydrophilicity, hydrophobicity or rate of degradation to the polymer.
[126] In another aspect of the invention, a method of making a polymer having therapeutic properties is provided, the method comprising: selecting a first chemical moiety having a selected pharmaceutical activity; covalently bonding a first reactive site on the first chemical moiety via a first biodegradable linkage to a selected aliphatic chain of 4 to 20 carbon atoms, a polylactide, a polyether, a polyglycolide, a polyethyleneimine, a polycaprolactone, a polysaccharide, a polyphospholipid or a polyamino acid; and, covalently bonding a second reactive site on the first chemical moiety via a second biodegradable linkage to the selected aliphatic chain of 4 to 20 carbon atoms, polylactide, polyether, polyglycolide, polyethyleneimine, polycaprolactone, polysaccharide, polyphospholipid or polyamino acid to form a polymer of alternating sequence of the first chemical moiety and the selected polylactide, polyether, polyglycolide, polyethyleneimine, polycaprolactone, polysaccharide, polyphospholipid or polyamino acid. [127] In another embodiment, a method of making a polymer having therapeutic properties is provided, the method comprising: selecting a second chemical moiety having a selected pharmaceutical activity; selecting a pendant arm comprising one or more of an aliphatic chain of 4 to 20 carbon atoms, a polylactide, a polyether, a polyglycolide, a polyethyleneimine, a polycaprolactone, a polysaccharide, a polyphospholipid or a polyamino acid; linking the second chemical moiety via a single biodegradable linkage to the pendant arm via one or more of an ester, amide, carbonate, anhydride or thioester linkage; linking the pendant arm to the backbone of the polymer via an ester, amide, carbonate, anhydride or thioester linkage.
[128] In such methods the selected aliphatic chain of 4 to 20 carbon atoms, polylactide, polyether, polyglycolide, polyethyleneimine, polycaprolactone, polysaccharide, polyphospholipid or polyamino acid can be polymerized in alternating sequence with the first chemical moiety alone or together with a third chemical moiety having a third selected pharmaceutical activity. The selected aliphatic chain of 4 to 20 carbon atoms, polylactide, polyether, polyglycolide, polyethyleneimine, polycaprolactone, polysaccharide, polyphospholipid or polyamino acid can be copolymehzed together with each other and with the first and third selected chemical moieties.
[129] In such methods the aliphatic chains of 4 to 20 carbon atoms, polylactide, polyether, polyglycolide, polyethyleneimine, polycaprolactone, polysaccharide, polyphospholipid or polyamino acid can be pre-selected to impart or possess a predetermined temperature or pH responsive property.
[130] Further in such methods, the first, second, and/or third selected chemical moieties have at least two reactive sites for forming covalent linkages to the selected aliphatic chain of 4 to 20 carbon atoms, polylactide, polyether, polyglycolide, polyethyleneimine, polycaprolactone, polysaccharide, polyphospholipid or polyamino acid. Such linkages can be direct ester, amide, carbonate, anhydride and/or thioester linkages. The linkages between the one or more selected first, second, and/or third chemical moieties and the polylactide, polyether, polyglycolide, polyethyleneimine, polycaprolactone, polysaccharide, polyphospholipid or polyamino acid can be created via a linker having two reactive groups each capable of forming an ester, amide, carbonate, anhydride or thioester linkage with a corresponding reactive group of the selected chemical moiety(ies) as well as with a corresponding next one of the poly moieties in the chain.
[131] In another aspect of the invention, the structure and molecular weight of the aliphatic chain of 4 to 20 carbon atoms, polylactide, polyether, polyglycolide, polyethyleneimine, polycaprolactone, polysaccharide, polyphospholipid or polyamino acid is selected to impart a pre-selected degree of hydrophilicity and/or hydrophobicity to the polymer so formed.
[132] In another aspect of the invention, the polylactide, polyether, polyglycolide, polyethyleneimine, polycaprolactone, polysaccharide, polyphospholipid or polyamino acid has a pre-selected rate of biodegradability.
[133] Another embodiment provides an implantable medical device having at least one coating covering at least a portion of the device, the at least one coating comprising a compound according to any of the above described polymers.
[134] In one embodiment, the at least one coating comprises at least two coatings to provide a multi-layered structure.
[135] In one embodiment, the at least one coating comprises at least three coatings.
[136] In one embodiment, each of the at least two or three coatings provides a different chemical moiety that forms a different pharmaceutically active agent. In one embodiment, the composition in one of the at least two or three coatings comprises a chemical moiety that forms an antiproliferative pharmaceutically active agent. In one embodiment, the composition in one of the at least two or three coatings comprises a chemical moiety that forms an anti-inflammatory agent.
[137] In one embodiment, the at least one coating directly contacts the device.
[138] In one embodiment, an inner coating free of a pharmaceutically active agent that directly contacts the device, wherein the inner coating also directly contacts the at least one coating. [139] In one embodiment, the device is implantable into a mammalian lumen. In one embodiment, the device is a stent. In one embodiment, the stent is either balloon expandable or self-expanding.
[140] In one embodiment, the composition is coated on the stent to form a conformal coating around all surfaces of the stent.
[141] In one embodiment, the composition is coated only on the abluminal surface of the stent. In one embodiment, the composition is coated only on the abluminal surface of the stent and the composition resides partially or completely within micro-reservoirs or pores in the stent surface.
[142] In one embodiment, the device is selected from pacemaker leads, valve replacement and repair devices, vena cava filters, and embolic coils and beads.
[143] In one embodiment, the device is an angioplasty balloon having coated thereon the coating comprising the composition, wherein the balloon is used to deliver the composition to an endoluminal surface.
[144] Another embodiment provides a polymer comprising the repeat unit:
-[D1-L1-D2-L2]- I
L3 I
D3 wherein:
L1, L2 and L3 are the same or different, and each are linking groups selected from the group of aliphatic chains of 4 to 20 carbon atoms, polysaccharide, polyphospholipid or polyamino acid and are covalently linked to D1, D2 and D3 via one or more of an amide, ester, anhydride, carbonate and thioester linkage;
D1, D2 and D3 are the same or different and are a chemical moiety that upon degradation of a linkage to the linking groups form a pharmaceutically active agent. L3 can be linked to L1 via a biodegradable linkage such as an amide, ester, anhydride, carbonate and thioester linkage.
[145] In one embodiment, a "polymer comprising the repeat unit" can have additional linking groups and repeat units other than the repeat unit listed herein. [146] Another embodiment provides a polymer comprising the repeat unit:
-[D1-L3-L1-L4-D2-L5-L2-L6] I
L7 I
D3 wherein:
L1, L2 and L7 are the same or different, and each are linking groups selected from the group of aliphatic chains of 4 to 20 carbon atoms, polylactide, polyether, polyglycolide, polyethyleneimine, polycaprolactone, polysaccharide, polyphospholipid or polyamino acid and are covalently linked to D1, D2 and D3 via one or more of an amide, ester, anhydride, carbonate and thioester linkage;
L3, L4, L5 and L6 are the same or different, and each are one or the other of an amide, ester, anhydride, carbonate and thioester linkage or are a linking group that are linked to an adjacent group via one or the other of an amide, ester, anhydride, carbonate and thioester linkage;
D1, D2 and D3 are the same or different and are a chemical moiety that upon degradation of a linkage to the linking groups form a pharmaceutically active agent. L7 can be linked to L1 via a biodegradable linkage such as an amide, ester, anhydride, carbonate and thioester linkage.
[147] Another embodiment provides a polymer comprising the repeat unit:
-[D1-L1-D2-L2-D3-L3] I
L7 I
D4 wherein:
L1 and L2 and L3 and L7 are the same or different, and each are linking groups selected from the group of aliphatic chains of 4 to 20 carbon atoms, polysaccharide, polyphospholipid or polyamino acid and are covalently linked to D1 and D2 and D3 and D4 via one or more of an amide, ester, anhydride, carbonate and thioester linkage; D1 and D2 and D3 and D4 are the same or different and are a chemical moiety that upon degradation of a linkage to the linking groups form a pharmaceutically active agent. L7 can be linked to Li via a biodegradable linkage such as an amide, ester, anhydride, carbonate and thioester linkage.
[148] Another embodiment provides a polymer comprising the repeat unit: -[Di- L4-Li- L5-D2- L6-L2- L7-D3- L8-L3-L9] I
Lio I
D4 wherein:
L1 and L2 and L10 are the same or different, and each are linking groups selected from the group of aliphatic chains of 4 to 20 carbon atoms, polylactide, polyether, polyglycolide, polyethyleneimine, polycaprolactone, polysaccharide, polyphospholipid or polyamino acid;
L4, L5, L6, L7, L8 and L9 can be the same or different, and each are one or the other of an amide, ester, anhydride, carbonate and thioester linkage or are a linking group that are linked to an adjacent group via one or the other of an amide, ester, anhydride, carbonate and thioester linkage;
Di and D2 and D3 are the same or different and are a chemical moiety that upon degradation of a linkage to the linking groups form a pharmaceutically active agent. Li0 can be linked to Li via a biodegradable linkage such as an amide, ester, anhydride, carbonate and thioester linkage.
[149] In one embodiment, D1 and D2 and D3 are each selected from taxanes, limus derivatives, and non-steroidal anti-inflammatory agents.
[150] In one embodiment, D1 and D2 and D3 are each selected from paclitaxel, rapamycin and their analogs and derivatives.
[151] In one embodiment, D1 and D2 and D3 are each selected from taxanes, limus derivatives, non-steroidal anti-inflammatory agents and healing promoters. [152] In one embodiment, there is provided a composition comprising the above described polymer, the polymer being present in an amount ranging from 40% to 95% by weight relative to the total weight of the composition. In one embodiment, the pharmaceutically active agent is present in a dose density ranging from 0.05 to 10 μg/mm2.
[153] In one embodiment, the number average molecular weight of the polymer is between about 10,000 daltons and about 100,000 daltons.
[154] In one embodiment, the polymer is a linear, star or hyperbranched or dendrimer polymer in structure.
[155] In one embodiment the aliphatic chain of 4 to 20 carbon atoms, polylactide, polyether, polyglycolide, polyethyleneimine, polycaprolactone, polysaccharide, polyphospholipid or polyamino acid is pre-selected to impart or possess a predetermined temperature or pH response property.
[156] In one embodiment, the relative molar or weight ratios of the aliphatic chains of 4 to 20 carbon atoms, polylactide, polyether, polyglycolide, polyethyleneimine, polycaprolactone, polysaccharide, polyphospholipid or polyamino acid contained within the polymer are pre-selected to impart a preselected degree of hydrophilicity or hydrophobicity or glass transition temperature to the polymer.
BRIEF DESCRIPTION OF THE DRAWINGS
[157] Various embodiments of the invention will be understood from the following description, the appended claims and the accompanying drawings, in which:
[158] FIG. 1 is a schematic showing a paclitaxel polymer via a covalent linking group; and
[159] FIG. 2 is a schematic of a multi-layered coating containing different pharmaceutically active agents;
[160] FIG. 3 is a schematic showing a star polymer containing pharmaceutically active agents incorporated in the main chain (backbone) of the branches;
[161] FIG. 4 is a schematic showing pharmaceutically active agents as pendant groups (side chain and terminal groups) covalently bonded to a star polymer;
[162] FIG. 5 is a schematic showing a pharmaceutically active agents covalently bonded to the end of branches (terminus) of a star polymer; [163] FIG. 6 is a schematic showing a pharmaceutically active agents covalently bonded to the end of branches (terminus) of a star polymer, where the branches have varying lengths; and
[164] FIG. 7 is a schematic showing star polymers of FIGs. 3-5 and including an additional branch having a high molecular weight.
DETAILED DESCRIPTION
[165] One embodiment provides a prodrug for at least one coating covering all or a portion of an implantable medical device. The at least one coating comprises a composition comprising a biodegradable polymer. The biodegradable polymer comprises one or more moieties covalently linked in a polymeric chain. Upon degradation of the covalent linkage, the chemical moiety forms a pharmaceutically active agent. The polymeric chain can be straight or branched, or can be a star polymer, a dendrimer, or a hyperbranched polymer. In another alternative, the chemical moiety is linked to a polysaccharide or phospholipid. The chemical moiety can be present in a pendant arm (side chain and/or terminus group) or in the polymer backbone.
[166] In one embodiment, the biodegradable polymer is linked to the chemical moiety. In one embodiment, the biodegradable polymer is linked to a pendant chemical moiety. In another embodiment, a "biodegradable polymer linked to a chemical moiety" refers to a chemical moiety incorporated in the backbone of the biodegradable polymer.
[167] In one embodiment, the degradation of the covalent bond occurs via hydrolysis. The hydrolysis can involve a direct reaction with an aqueous medium, or can be catalyzed chemically or enzymatically. "Aqueous medium" refers to water, aqueous solutions, physiological media or biological fluids (e.g., body fluids), and other pharmaceutically acceptable media. Suitable hydrolysable covalent bonds include those forming esters, amides, urethanes, carbamates, carbonates, azo linkages, anhydrides, thioesters, and combinations thereof.
[168] In one embodiment, an ester linkage has the formula -OC(=O)-. In one embodiment, a thioester linkage has the formula -SC(=O)-. In one embodiment, an amide linkage has the formula -N(R)C(=O)-, wherein R is a suitable organic radical, such as, for example, hydrogen, (Ci-C6)alkyl, (C3-C6)cycloalkyl, (C3 - C6)cycloalkyl(Ci-C6)alkyl, aryl, heteroaryl, aryl(Ci-C6)alkyl, or heteroaryl(Ci -C6)alkyl. In one embodiment, a carbamate linkage has the formula -OC(=O)N(R)-, wherein each R is a suitable organic radical as described above. In one embodiment, a "carbonate" linkage has the formula -OC(=O)O-. In one embodiment, an anhydride linkage has the formula -C(=O)-O-C(=O)-. In one embodiment, an azo linkage has the formula -N=N-.
[169] In one embodiment, the hydrolysis rate can be controlled by choice of linker chemistry (as discussed below). Additional control of active agent release can be obtained by variables that are unique to these polymer structures, e.g., density and length of polymer branches, the hydrophobicity/hydrophilicity profile of the polymer branches, combination of polymer branches of various lengths, and stimuli responsiveness of the polymer branches (such as stimuli-responsiveness to pH, temperature, light, ultrasound etc.). Examples of stimuli-responsive polymeric linker segments include those composed of temperature responsive polymers like poly(N- isopropylacrylamide) (poly-NIPAAM) or pH responsive polymers like polypropyl acrylic acid (PPAc).
[170] In one embodiment, the polymer is less soluble in an aqueous medium, e.g., a physiological medium, than is the free form of the pharmaceutically active agent. The "free form" of the pharmaceutically active agent can refer to the neutral compound, or salts thereof, e.g., the isolable or stable form of the agent. In one embodiment, the compositions (comprising the chemical moiety) have a lower solubility in aqueous media (or in physiological media) than the free form of the pharmaceutically active agent. Often during treatment of a disease or condition with a medical device having a coating comprising a drug, the drug is washed away when or after being inserted into a mammal prior to its reaching the target site. In one embodiment, a coating comprising a drug in a form affording it reduced solubility can provide a lesser probability of the drug being inadvertently eliminated by dissolution (or partial dissolution) prior to its reaching the target site.
[171] In another embodiment, by tailoring the structure of the polymer, the polymer is more soluble in an aqueous medium, e.g., a physiological medium, than is the free form of the pharmaceutically active agent. [172] In one embodiment, a product of the degradation or hydrolysis is the pharmaceutically active agent, e.g., the free form of the agent. In another embodiment, the pharmaceutically active agent has a different structure than the free form of the pharmaceutically active agent but is the true active species that treats the disease or condition, e.g., the form of the agent in vivo.
[173] In one embodiment, the polymer comprises a monomer selected from ethylenimine, ethylene glycol, amphiphilic scorpion-like macromolecules, phosphazenes, amidoamines, and propyleneimine. In one embodiment, where the polymer links the chemical moiety as a pendant group, the polymer is selected from polyethyleneimine (PEI), polyethylene glycol (PEG), polyethyleneimine/polyethylene glycol, amphiphilic scorpion-like macromolecules (AScMs), polyphosphazenes, polyamidoamines (PAMAM), and polypropyleneimine (PPI).
[174] In one embodiment, the polymer (i.e., the polymer containing the covalently linked chemical moiety) is biodegradable. "Biodegradable polymer," as used herein, refers to a polymer capable of hydrolyzing or otherwise degrading in an aqueous medium, as opposed to being soluble in an aqueous medium without degradation. In one embodiment, the resulting product(s) of biodegradation is soluble in the resulting body fluid or, if insoluble, can be suspended in a body fluid and transported away from the implantation site without clogging the flow of the body fluid. The body fluid can be any fluid in the body of a mammal including, but not limited to, blood, serum, urine, saliva, lymph, plasma, gastric, biliary, or intestinal fluids, seminal fluids, and mucosal fluids, humors, and extracellular fluids. In one embodiment, the biodegradable polymer is soluble, degradable as defined above, or is an aggregate of soluble and/or degradable matehal(s) with insoluble matehal(s) such that, with the resorption of the soluble and/or degradable materials, the residual insoluble materials are of sufficiently fine size such that they can be suspended in a body fluid and transported away from the implantation site without clogging the flow of the body fluid. Ultimately, the degraded compounds can be eliminated from the body either by excretion in perspiration, urine or feces, or dissolved, degraded, corroded or otherwise metabolized into soluble components that are then excreted from the body. [175] In one embodiment, the biodegradable polymers are degraded through cleavage of functional groups such as esters, anhydrides, carbonates, thioesters, orthoesters, glycosidic bonds, phosphate esters, and amides. Suitable biodegradable polymers include those in the FDA GRAS (Generally Regarded As Safe) list, the disclosure of which is incorporated herein by reference.
[176] In one embodiment, the biodegradable polymer comprises one or more monomers that form the following biodegradable polymers: polyglycolides, polylactides (e.g., poly-l-lactide (PLLA)), polycaprolactones, polydioxanones, poly(lactide-co-glycolide) (PLGA), polyhydroxybutyrate, polyhydroxyvalerate, polyphosphoesters, polyphosphoester-urethane, polyamino acids, polycyanoacrylates, poly(trimethylene carbonate), biomolecules such as fibrin, fibrinogen, cellulose, starch, collagen, and blends and copolymers thereof.
[177] In one embodiment, the "chemical moiety" is a fragment of a pharmaceutically active agent. For example, upon reacting the pharmaceutically active agent with another species (e.g., a polymer or linker), the portion of the agent that is covalently bonded is the chemical moiety of the agent. In one embodiment, the polymer "linked to a chemical moiety through a covalent bond" can refer to one or more covalent bonds. Accordingly, in one embodiment, the chemical moiety is linked directly to the polymer (or monomers) via one or more covalent bonds. "Linked directly" as used herein refers to the product of a reaction between the polymer (or monomer unit) and the pharmaceutically active agent, where the linking atom originates from the starting materials. In another embodiment, the chemical moiety is linked to the polymer or monomer through covalent bond(s) to a linking group (comprising one or more molecules) or spacer that is covalently bonded to the polymer or monomer unit. Here, the linking group comes from an external reagent and does not originate from either the polymer (or monomer unit) or the pharmaceutically active agent. Suitable linking groups bind the biodegradable polymer to the chemical moiety through covalent bonds, such as those covalent linkages described herein, e.g., ester, amide, carbamate, carbonate, azo, anhydride, and thioester linkages. [178] FIG. 1 shows a schematic of a chemical moiety covalently linked to a biodegradable polymer. The chemical moiety of FIG. 1 is paclitaxel (PAC), shown below:
Figure imgf000027_0001
paclitaxel (PAC)
[179] In FIG. 1 , a linking group containing two carbonyl chloride functional groups (acyl chlorides if L is, e.g., an alkyl group), is reacted with a hydroxyl group of paclitaxel in the presence of triethylamine (TEA). The resulting -[C(=O)-L-C(=O)-O-PAC-O]- unit can be covalently bonded to a second such unit, and/or can be covalently bonded to another species, such as a polymer (e.g., a biodegradable polymer) via its residual carbonyl chloride group or via a subsequently introduced second linker group. In another embodiment, the L is a biodegradable polymer, resulting in the paclitaxel being directly bonded to the polymer. In either embodiment, the paclitaxel is bonded to the polymer via a series of carbonate/ester linkages, and other linkages such as anhydride, carbamate, etc., depending on the linking group and polymers.
[180] In one embodiment, the linking group can impart mechanical properties and release kinetics for the selected therapeutic application. In one embodiment, the linking group is a divalent organic radical having a molecular weight ranging from 25 daltons to 400 daltons, e.g., a molecular weight ranging from 40 daltons to 200 daltons. [181] In one embodiment, the linking group has a length ranging from 5 angstroms to 100 angstroms using standard bond lengths and angles, e.g., a length ranging from 10 angstroms to 50 angstroms.
[182] The linking group may be biologically inactive, or may itself possess biological activity. The linking group can also comprise other functional groups (including hydroxy groups, mercapto groups, amine groups, carboxylic acids, as well as others) that can be used to modify the properties of the polymer (e.g. for branching, for cross linking, for appending other molecules (e.g. another biologically active compound) to the polymer, for reducing the solubility of the polymer, or for effecting the biodisthbution of the polymer).
[183] In one embodiment, the linking group is selected from aliphatic C4-C2o chains, such as C4-C2o chains, polylactide, poly(lactide-co-galactide), polyethylene glycol, polycaprolactone, polyethyleneimine, polycaprolactone/polyethyleneimine, and phospholipids.
[184] Examples of polylactides or lactides usable as linkers include PLLA, PLGA, PDLA and PDLLA and co-polymers and mixtures of all of the foregoing with each other and with caprolactone, etheyleneimine, thmethylenecarbonate, amino acids, and the like. Other linkers include phospholipids and polysaccharides, as described herein.
[185] Examples of polycaprolactones usable as linkers include polycaprolactone, polydiaxonone and copolymers and mixtures of all of the foregoing with lactides, ethyleneimine, glycolides, thmethylenecarbonate, amino acids and the like.
[186] Examples of polyethylenimines usable as linkers include polyethyleneimine and copolymers and mixtures of all of the foregoing with lactides, caprolactones, glycolides, trimethylenecarbonate, amino acids and the like.
[187] Examples of polyglycolides usable as linkers include PLGA, polyglyconate and copolymers and mixtures of glycolides with lactides, caprolactones, ethyleneimine, trimethylenecarbonate, amino acids and the like.
[188] In one embodiment, the linking group is: a (Ci -Cβjalkyl, e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, 3-pentyl, or hexyl; (C3 - C6)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (C3 - C6)cycloalkyl(Ci -C6)alkyl can be cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2- cyclopentylethyl, or 2-cyclohexylethyl; (Ci -C6)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy; (Ci -C6)alkanoyl can be acetyl, propanoyl or butanoyl; (Ci - Cβjalkoxycarbonyl can be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, or hexyloxycarbonyl; (Ci - Cβjalkylthio can be methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, pentylthio, or hexylthio; (C2 -C6)alkanoyloxy can be acetoxy, propanoyloxy, butanoyloxy, isobutanoyloxy, pentanoyloxy, or hexanoyloxy; aryl can be phenyl, indenyl, or naphthyl; and heteroaryl can be furyl, imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (or its N-oxide), thienyl, pyrimidinyl (or its N-oxide), indolyl, isoquinolyl (or its N-oxide) or quinolyl (or its N-oxide).
[189] In one embodiment, the linking group is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 1 to 20 carbon atoms, wherein the chain is optionally substituted on carbon with one or more (e.g. 1 , 2, 3, or 4) substituents selected from (Ci -C6)alkoxy, (C3 -C6)cycloalkyl, (Ci - C6)alkanoyl, (Ci -C6)alkanoyloxy, (Ci -C6)alkoxycarbonyl, (Ci -C6)alkylthio, azido, cyano, nitro, halo, hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl, and heteroaryloxy.
[190] In another embodiment, the linking group is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 1 to 20 carbon atoms, wherein one or more (e.g. 1 , 2, 3, or 4) of the carbon atoms is optionally replaced by (-O-) or (-NR-).
[191] In another embodiment, the linking group is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 3 to 15 carbon atoms, wherein one or more (e.g. 1 , 2, 3, or 4) of the carbon atoms is optionally replaced by (-O-) or NR-), and wherein the chain is optionally substituted on carbon with one or more (e.g. 1 , 2, 3, or 4) substituents selected from the group consisting of (Ci -C6)alkoxy, (C3 -C6)cycloalkyl, (C1 -C6)alkanoyl, (Ci - Cβjalkanoyloxy, (Ci -Cβjalkoxycarbonyl, (Ci -Cβjalkylthio, azido, cyano, nitro, halo, hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl, and heteroaryloxy. [192] In another embodiment, the linking group is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 3 to 15 carbon atoms, wherein one or more (e.g. 1 , 2, 3, or 4) of the carbon atoms is optionally replaced by (-O-) or (-NR-).
[193] Other linking groups are disclosed in U.S. Patent Nos. 6,613,807, and 6,685,928, and U.S. Patent Publication Nos. 20060188546 and 20050031577, the disclosures of which are incorporated herein by reference.
[194] In another embodiment, the linking group is selected from amino acids and peptides.
[195] In one embodiment, the linking group is present in an amount ranging from 5% to 50% by weight relative to the total weight of the composition.
[196] In one embodiment, the biodegradable polymers are degraded through cleavage of the linkages between the linker groups and the bioactive chemical moieties, the linkages including functional groups such as esters, anhydrides, carbonates, thioesters, and amides.
[197] In one embodiment, the polymers containing the chemical moieties can be linked with other such polymers.
[198] In one embodiment, more than one pharmaceutically active agents other than the agent covalently bonded can be incorporated in the polymer. The additional agents can be either covalently bonded to the polymer or even admixed with the polymer, so long as at least one agent is covalently bonded to the polymer.
[199] In one embodiment, the number average molecular weight of the polymer is 20,000 Da or less, such as a number average molecular weight of 10,000 Da or less, or 5,000 Da or less. In one embodiment, the number average molecular weight of the polymer ranges from 5,000 daltons to 100,000 daltons. In another embodiment, the number average molecular weight of the polymer is 25,000 Da or less. In yet another embodiment, the number average molecular weight of the polymer ranges from 25,000 daltons to 100,000 daltons.
Star Polymers, Dendrimers, and Hyperbranched Polymers
[200] One embodiment of the at least one coating comprises a polymer comprising a chemical moiety covalently linked to at least one branch of the polymer, where the polymer is chosen from star polymers, dendrimers, and hyperbranched polymers. The chemical moiety is linked through a covalent bond, wherein the chemical moiety forms a pharmaceutically active agent upon degradation of the covalent bond.
[201] Star polymers have a three-dimensional structure of linear arms extending from a central core. The linear arms can be of the same or different molecular weight. Dendrimers also have a three-dimensional structure where a repetitive series of branched units emanate from an extended core. Each new branch unit is termed a "generation." Hyperbranched polymers have a less regular three-dimensional structure than either dendrimers or star polymers, and have been characterized as having a combination of the two polymer types. Like dendrimers, hyperbranched polymers can have generations; however, each successive "generation" can have varying molecular weights, branching or nonbranching groups, and different chemical functional groups. A description of hyperbranched polymers is provided in Gao et al., "Hyperbranched polymers: from synthesis to applications," Prog. Polym. Sci., pp. 183-275 (2004), the disclosure of which is incorporated herein by reference. A review of the different polymer types and methods for covalently incorporating pharmaceuticals are provided in Qiu et al., "Polymer Architecture and Drug Delivery," Pharmaceutical Research, Vol. 23, No. 1 , pp. 1 -30 (2006), the disclosure of which is incorporated herein by reference.
[202] In one embodiment, the chemical moiety is incorporated in the main chain (backbone) of the at least one branch of the polymer. As shown schematically in FIG. 3, all branches of an exemplary star polymer incorporate the chemical moiety in the main chain. In another embodiment, the chemical moiety ("D") is a pendant group of the at least one branch of the polymer, as shown schematically in FIG. 4 for a star polymer. In another embodiment, the chemical moiety is linked to the terminus of the at least one branch, as shown schematically in FIG. 5 for a star polymer. One of ordinary skill in the art can readily appreciate that these linking modes can also be provided in dendrimers or hyperbranched polymers
[203] As an improvement over conventional linear biodegradable systems, these star, dendrimers, or hyperbranched polymer systems can offer the prospect of high drug loading at the same time as achieving appropriate duration and profile of drug-delivery. High polymer drug-loading may allow a minimal coat-weight to achieve delivery of appropriate levels of drug. If biodegradable, the biodegradation can eliminate the polymer after the drug-delivery and revert back to the bare-metal stent surface, which is desirable for healing.
[204] In one embodiment, structures with therapeutic agent(s) attached as pendant groups offer the prospect of minimal perturbation to the drug molecule(s). Pendant attachment of the drug molecules to the star polymer branches may allow for chemically reacting with only one site on the molecule. Being able to minimize perturbation of the drug molecules in this manner may result in better drug activity upon release. For example, with paclitaxel, the site of reaction could be the 2'-OH group or a 7'-OH group, each offering unique kinetics of drug-release.
[205] In one embodiment, the molecular weight of the one or more branches of the polymer ranges from 10,000 Da to 100,000 Da.
[206] In one embodiment, the polymer is a star polymer. Each branch of the star polymer can have substantially the same molecular weight and length. Alternatively, branches of the star polymer have different molecular weights and different lengths, as shown schematically in FIG. 6. Although FIG. 6 depicts different size branches having a terminal chemical moiety, it is understood that the chemical moiety can be linked to the star polymer having varying branch sizes as pendant groups, or incorporated in the backbone of the branch.
[207] In another embodiment, the star polymer comprises branches of substantially the same molecular weight and length and one branch of substantially higher molecular weight and length, as shown in FIG. 7. This structure may allow mutual entanglement of the star polymer structures and facilitate forming of polymer films, thus, potentially providing an additional variable for tuning the physical properties of the polymer. In one embodiment, the branch of substantially higher molecular weight and length has at least a 25% greater molecular weight or length, such as at least a 50% greater molecular weight or length compared to the other branches of substantially the same molecular weight and length.
[208] Star polymers can be prepared by a "core first" method or an "arm-first" method." In a core-first method, the arms are propagated by polymerizing from a reactive core. An arm-first method comprises joining the already polymerized arms to a core. A core first method is typically used when a more homogeneous structure is desired, e.g., where each branch has substantially the same chemical structure. An arm first method can be used to prepare a polymer of varying sized branches and/or chemistries.
[209] In one embodiment, hyperbranched polymer systems include the chemistry and molecular architecture represented by PEI / PEI-PEG systems, AScMs, and polyphosphazenes. In one embodiment, dendhmehc polymer structures include the chemistry and polymer architecture represented by PAMAM, PPI, and/or PEG systems (via multifunctional linkers if necessary).
[210] In one embodiment, at least one branch of the polymer comprises two or more different chemical moieties that form pharmaceutically active agents. In another embodiment, at least one branch of the polymer comprises at least three different chemical moieties that form pharmaceutically active agents. For example, the at least three chemical moieties comprises a first chemical moiety that forms an antiproliferative pharmaceutically active agent, at second chemical moiety forms an anti-inflammatory agent, and a third chemical moiety that forms a healing promoter.
[211] In one embodiment, at least one branch of the star polymer comprises a first chemical moiety, and at least one branch of the star polymer comprises a second chemical moiety. In another embodiment, at least one branch of the star polymer comprises a first chemical moiety, at least one branch of the star polymer comprises a second chemical moiety, and at least one branch of the star polymer comprises a third chemical moiety. The first chemical moiety can form an antiproliferative pharmaceutically active agent, the second chemical moiety can form an anti-inflammatory agent, and the third chemical moiety can form a healing promoter.
[212] In one embodiment, these polymers (star polymers, dendhmers, or hyperbranched polymers) can offer several variables for controlling the release of the pharmaceutically active agent, such as: (a) choice and combinations of linker/conjugation chemistry; (b) lengths of the polymer branches; (c) hydrophobicity/hydrophilicity of the polymer branches; (d) density of polymer branches; and (e) stimuli responsiveness of the polymer branches. These polymers may offer one or more of greater control over the release profile of the therapeutic agent, better processability and physical characteristics of the polymer, and the prospect of eliminating the polymer after drug delivery, if biodegradable.
[213] In one embodiment, the chemical moiety is positioned in the backbone of the polymer. In one embodiment, the composition comprises a polymer selected from star polymers, dendrimers, and hyperbranched polymers in which at least one arm of the polymer comprises the repeat unit:
-[D-L]-
(a) wherein,
L is a linker derived from one or more molecules selected from diacids, diols, diamines, hydroxyacids, amino acids, and other difunctional molecules that can be bonded to D; and
D is a chemical moiety that releases a pharmaceutically active agent upon degradation of the covalent bond, e.g., upon hydrolysis of covalent bonds binding it to L.
[214] In one embodiment L is derived from one or more molecules selected from carbonic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, pimelic acid, adipic acid or sebacic acid. In one embodiment, D is a chemical moiety that releases rapamycin and/or paclitaxel.
[215] In one embodiment, the chemical moiety is in a side chain. In one embodiment, the composition comprises a polymer selected from star polymers, dendrimers, and hyperbranched polymers in which at least one arm of the polymer comprises the repeat unit:
-[L]- I
D (b) wherein:
L is a linker derived from one or more molecules selected from dihydroxyacids, amino diacids, diamino acids, and other thfunctional molecules that can be bonded to each other and to D; and D is a chemical moiety that releases a pharmaceutically active agent upon degradation of the covalent bond, e.g., upon hydrolysis of covalent bonds binding it to L.
[216] In one embodiment L is derived from glutamic and/or aspartic acid. In one embodiment, D is a chemical moiety that releases rapamycin and/or paclitaxel.
[217] Alternatively, using similar chemistry, the chemical moiety can be positioned in a side chain and terminal group, as shown in the structure below:
D D I I
-L-L-L-L-D I I D D where L is a linker as defined in (b) above. In one embodiment L is derived from glutamic and/or aspartic acid and D is a chemical moiety that releases rapamycin and/or paclitaxel.
[218] In one embodiment, a linker may be used to bind the terminal group that is different from the linker used to bind the side chain, as shown in the structure below:
D D I I
-L1-L1-L1-L1-L2-D I I D D wherein L1 is a linker as in (b) above and L2 is a linker as in (a) above. In one embodiment L1 is derived from glutamic and/or aspartic acid, L2 is derived from at least one linker selected from carbonic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, pimelic acid, adipic acid, and sebacic acid, and D is a chemical moiety that releases rapamycin and/or paclitaxel.
[219] The chemical moiety can be positioned in both the backbone and side chain. In one embodiment, the composition comprises a polymer selected from star polymers, dendhmers, and hyperbranched polymers in which at least one arm of the polymer comprises the repeat unit: D I -[D-L]- wherein:
L is a linker derived from one or more molecules selected from dihydroxyacids, amino diacids, diamino acids, and other thfunctional molecules that can be bonded to each other and to D; and
D is a chemical moiety that releases a pharmaceutically active agent upon degradation of the covalent bond, e.g., upon hydrolysis of covalent bonds binding it to L.
[220] In one embodiment, L is derived from 2-carboxyglutaric acid and D is a chemical moiety that releases rapamycin and/or paclitaxel.
[221] Optionally, the same chemistry can be used to position the chemical moiety in a terminal group. In another alternative, two different linkers can be used to position the chemical moiety in the backbone, side chain and terminal groups, as shown in the structure below:
-(L1 )H-L2-D-(L1)H-L2-D I I
D D wherein L1 is a linker as in (b) above, L2 is a linker as in (a) above, n is either 1 , 2, 1 -5, 1 -20, 1 -50, 1 -100 or 1 -500. In one embodiment, L1 is derived from glutamic and/or aspartic acid, L2 is a diacid, and D is a chemical moiety that releases rapamycin and/or paclitaxel. In another embodiment, L1 is derived from glutamic and/or aspartic acid, L2 is derived from at least one molecule selected from carbonic acid, oxalic acid, malonic acid, succinic acid, glutahc acid, pimelic acid, adipic acid, and sebacic acid, and D is a chemical moiety that releases rapamycin and/or paclitaxel.
[222] In another alternative, a linker can be used to link the chemical moiety in the side chain, as shown in the structure below: -(L1)H-L2-D-(L1)H-L2-D I I
L2 L2
I I
D D wherein L1 is a linker as in (b) above, L2 is a linker as in (a) above, and n is either 1 , 2, 1 -5, 1 -20, 1 -50, 1 -100 or 1 -500. For example, L1 is derived from glyceric acid, L2 is derived from a diacid, and D is a chemical moiety that releases rapamycin and/or paclitaxel. In another embodiment L1 is derived from at least one molecule selected from glyceric acid, lysine, serine, threonine, tyrosine, cysteine, and ornithine, L2 is derived from at least one molecule selected from carbonic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, pimelic acid, adipic acid, and sebacic acid, and D is a chemical moiety that releases rapamycin or paclitaxel.
[223] In another alternative, D is positioned in the terminal groups and side chains only, as shown in the structure below:
-L2-L1-L2-L1-L2-D- I I
L3 L3
I I
D D wherein L1 is a linker as in defined (b) above, L2 is a biodegradable polymer, L3 is a linker as defined in (a) above, and D is a chemical moiety that releases rapamycin and/or paclitaxel. In one embodiment L2 is derived from at least one biodegradable polymer selected from PLLA, PDLA, PDLLA, PGA, PLGA, polycaprolactone, polydioxinone, poly amino acids prepared from at least one monomer selected from glycine, alanine, leucine, isoleucine, norleucine, valine, norvaline, methionine, phenylalanine, and tryptophan, L1 is derived from at least one molecule selected from glyceric acid, lysine, serine, threonine, tyrosine, cysteine, and ornithine, L3 is derived from at least one molecule selected from carbonic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, pimelic acid, adipic acid, and sebacic acid, and D is a chemical moiety which releases rapamycin or paclitaxel. Polysaccharides and Phospholipids
[224] In one embodiment, the biodegradable polymer comprises one or more moieties covalently linked in a chain, straight or branched, to one or the other or both of a polysaccharide or phospholipid linker group, e.g., via one or the other of an ester, amide, carbonate, anhydride or thioester. In one embodiment, the polymer has a Tg greater than 37°C, such as a Tg greater than 400C, a Tg greater than 500C, or a Tg greater than 60°C.
[225] One embodiment provides a composition comprising a biocompatible polymer, the polymer being linked to a chemical moiety through a covalent bond, wherein, the chemical moiety forms a pharmaceutically active agent upon degradation of the covalent bond, the chemical moiety is linked to a polysaccharide or phospholipid.
[226] In one embodiment, the molar or weight ratio of polysaccharide and/or phospholipid to each other and/or to the chemical moiety contained within the polymer are preselected to impart a predetermined hydrophilicity and/or hydrophobicity to the polymer.
[227] Examples of polysaccharides usable as linkers in the invention include hyaluronic acid, chitosan, cellulose, alginate, cyclodextrin, GAGs (GAG: glycosaminoglycan) and the like. Examples of phospholipids usable as linkers in the invention include phosphatylcholine / phosphatidylcholine (Lecithin), phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, phosphatidylethanolamine etc.
[228] Further examples of phospholipids and their analogs usable as linkers in the invention are disclosed in Wieder et al. Mechanisms of action of phospholipid analogs as anticancer compounds. Prog Lipid Res. 1999 May;38(3):249-59 and in Morris-Natschke et al. Phospholipid analogs against HIV-1 infection and disease. Curr Pharm Des. 2003;9(18):1441 -51 as well as U.S. patent nos. 6,127,349; 5,830,432; 4,534,899. The disclosures of all of the foregoing articles and patents are incorporated herein by reference as if fully set out herein.
[229] Further examples of polysaccharides and their analogs usable in the invention are disclosed in Cascone et al. Bioartificial polymeric materials based on polysaccharides. J Biomater Sci Polym Ed. 2001 ;12(3):267-81 and also in U.S. patent nos. 6,534,481 ; 6,528,497; 4,603,006. The disclosures of all of the foregoing articles and patents are incorporated herein by reference as if fully set out herein. [230] Examples of structures of known polysaccharides and phospholipids appear below. The following examples illustrate that such linkers have several functional groups (e.g. hydroxyl, amine, carboxyl and the like) contained within the backbone of their structure available for polymerization reactions (either directly or after dehvatization).
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[231] In one embodiment the invention provides a polymer comprising the repeat unit:
-[D1-L1-D2-L2]- wherein:
L1 and L2 are the same or different, and each are linking groups selected from the group of polysaccharides and phospholipids and are covalently linked to of D1 and D2 via one or more of an amide, ester, anhydride, carbonate and thioester linkage;
D1 and D2 are the same or different and are a chemical moiety that upon degradation of a linkage to the linking groups form a pharmaceutically active agent.
[232] As noted above the invention also provides a polymer comprising the repeat unit:
-[D1-L3-L1-L4-D2-L5-L2-L6] wherein: L3, L4, L5 and L6 can be the same or different, and each are one or the other of an amide, ester, anhydride, carbonate and thioester linkage or are a linking group that are linked to an adjacent group via one or the other of an amide, ester, anhydride, carbonate and thioester linkage.
[233] In this example, the linker groups L3, L4 L5 or L6 are typically an aliphatic moiety having at least two reactive groups capable of forming one or the other of an ester, amide, carbonate, anhydride or thioester linkage with an adjacent drug, polysaccharide or phospholipid group.
[234] Also as noted above, the invention provides a polymer comprising the repeat unit:
-[Di- L4-Li- L5-D2- L6-L2- L7-D3- L8-L3-L9] wherein
L4, L5, L6, L7, L8 and L9 can be the same or different, and each are one or the other of an amide, ester, anhydride, carbonate and thioester linkage or are a linking group that are linked to an adjacent group via one or the other of an amide, ester, anhydride, carbonate and thioester linkage
[235] Similarly in this example the linker groups L4, L5, L6, L7, L8 and L9 are typically an aliphatic moiety having at least two reactive groups capable of forming one or the other of an ester, amide, carbonate, anhydride or thioester linkage with an adjacent drug, polysaccharide or phospholipid group.
[236] Examples of such aliphatic linker groups are disclosed in the following patents and/or applications nos. US 6,468,519; US 6,486,214; US 6,602,915; US 6,613,807; US 6,685,928; US 6,689,350; US 2003/0035787; US 2003/0059469; US 2004/0038948; US 2004/0044125; US 2004/0096476; US 2004/0228832; US 2005/0031577; US 2005/0048121 ; US 2005/0053577; US 2005/0089506; US 2005/0100526; US 2005/0131199; US 2005/0249697; WO 1999/12990 ; US 6,300,424; US 2003/0170202; US 2005/0089504; US 2004/0198641 ; US 2006/0039964; PCT/US04/17916): US 2006/0188546. The disclosures of all of the foregoing are incorporated herein by reference as if fully set out herein. For example such linking groups are: a (Ci -C6)alkyl, e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, 3-pentyl, or hexyl; (C3 -C6)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (C3 -C6)cycloalkyl(Ci -C6)alkyl can be cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2- cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, or 2-cyclohexylethyl; (Ci - C6)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec- butoxy, pentoxy, 3-pentoxy, or hexyloxy; (Ci -C6)alkanoyl can be acetyl, propanoyl or butanoyl; (Ci -C6)alkoxycarbonyl can be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, or hexyloxycarbonyl; (Ci -Cβjalkylthio can be methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, pentylthio, or hexylthio; (C2 -Cβjalkanoyloxy can be acetoxy, propanoyloxy, butanoyloxy, isobutanoyloxy, pentanoyloxy, or hexanoyloxy; aryl can be phenyl, indenyl, or naphthyl; and heteroaryl can be furyl, imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (or its N-oxide), thienyl, pyrimidinyl (or its N- oxide), indolyl, isoquinolyl (or its N-oxide) or quinolyl (or its N-oxide).
[237] In one embodiment, such aliphatic linking groups are a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 1 to 20 carbon atoms, wherein the chain is optionally substituted on carbon with one or more (e.g. 1 , 2, 3, or 4) substituents selected from (Ci -Cβjalkoxy, (C3 - C6)cycloalkyl, (Ci -C6)alkanoyl, (Ci -C6)alkanoyloxy, (Ci -C6)alkoxycarbonyl, (Ci - C6)alkylthio, azido, cyano, nitro, halo, hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl, and heteroaryloxy.
[238] In another embodiment, such aliphatic linking groups are a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 1 to 20 carbon atoms, wherein one or more (e.g. 1 , 2, 3, or 4) of the carbon atoms is optionally replaced by (-O-) or (-NR-).
[239] In another embodiment, such aliphatic linking groups are a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 3 to 15 carbon atoms, wherein one or more (e.g. 1 , 2, 3, or 4) of the carbon atoms is optionally replaced by (-O-) or NR-), and wherein the chain is optionally substituted on carbon with one or more (e.g. 1 , 2, 3, or 4) substituents selected from (Cr C6)alkoxy, (C3-C6)cycloalkyl, (Ci -C6)alkanoyl, (Ci -C6)alkanoyloxy, (Cr Cβjalkoxycarbonyl, (Ci -Cβjalkylthio, azido, cyano, nitro, halo, hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl, and heteroaryloxy. [240] In another embodiment, such aliphatic linking groups are a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 3 or 4 to 15 carbon atoms, wherein one or more (e.g. 1 , 2, 3, or 4) of the carbon atoms is optionally replaced by (-O-) or (-NR-).
[241] Polysaccharides usually have more than the two functional groups required for synthesis of a polymer of the form ...-drug-linker-drug-linker-... For example chitosan depicted above has three functional groups per monosaccharide monomer plus an extra group (total of 4) on each end monomer. In synthetic chemistry, usually all functional groups of a molecule except the one which is being reacted are blocked by protecting groups which are removed when the reaction is complete. The following examples are given without using these protection- deprotection reactions so the resulting polymers may be complex mixtures, highly branched or crosslinked with multiple types of linkages due to the many functional groups available. Carbonate, amide and ester linkage examples are set forth below. In order to made acid anhydrides alginic acid could be used as the polysaccharide but all OH groups would have to be protected to derivatize its carboxylic acid groups into anhydrides.
[242] Similar considerations apply to di-acyl phospholipids such as a trifunctional phosphatidylglycerol. Even with only two reactive functional groups (phosphatidic acid and phosphatidyl ethanolamine), synthetic reactions would usually be performed by protecting all groups except the one being reacted. Many of the exemplified compositions do not use protection-deprotection reactions so the end products may comprise complex polymers rather than an overall linear polymer of the general formula ...-drug-linker-drug-linker -.
[243] In one embodiment, the chemical moiety that forms an active pharmaceutical agent on degradation is incorporated into the backbone of the polymer and is linked directly via one or more covalent bonds. "Linked directly" as used herein refers to the product of a reaction between the polysaccharide, phospholipid or other linking groups disclosed herein and the pharmaceutically active agent. Methods for covalently incorporating pharmaceuticals are provided in Qiu et al., "Polymer Architecture and Drug Delivery," Pharmaceutical Research, Vol. 23, No. 1 , pp. 1 -30 (2006), the disclosure of which is incorporated herein by reference. [244] For purposes of illustration of the formation of an ester linkage to a paclitaxel molecule, there is shown in FIG. 1 , an aliphatic linking group containing two carbonyl chloride functional groups (e.g. acyl chlorides if L is, e.g., an alkyl group or a polysaccharide or phospholipid having a carbonyl group) can be reacted with a hydroxyl group of paclitaxel in the presence of triethylamine (TEA) to form an alternating aliphatic linking group-paclitaxel polymer. Alternatively, the resulting -[C(=O)-L-C(=O)-O-PAC-O]- unit can be covalently bonded to another linking group such as a polysaccharide or phospholipid linker group via its residual carbonyl chloride group or through another subsequently introduced second linker group.
[245] The linking groups may be biologically inactive, or may themselves possess biological activity. For example, High-Molecular-Weight-Hyaluronic-Acid (a natural polysaccharide) has anti-inflammatory activity and phosphatidylcholine (a natural phospholipid) has anti-thrombotic activity.
[246] In another embodiment, pharmaceutically active agents in addition to Di, D2, and D3 can also be present in the composition, e.g., any other agents useful for treating vascular injury, e.g., restenosis. Alternatively, pharmaceutically active agents in addition to D1, D2, and D3 can be incorporated in the polymer, e.g., either covalently linked to the polymer or admixed with the polymer.
[247] In one embodiment, two or more coatings (e.g., layers) are applied to the device where each coating contains a different pharmaceutically active agent. In one embodiment, each layer contains a unique agent, e.g., D1, D2, and D3 as described herein, or any other agents useful for treating vascular injury, e.g., restenosis. Alternatively, pharmaceutically active agents in addition to D1, D2, and D3 can be incorporated in the polymer, e.g., either covalently linked to the polymer or admixed with the polymer.
[248] In addition to polysaccharides and phospholipids, several of the advantages offered by polysaccharides and phospholipids as linkers are also offered by other natural molecules such as structural natural polymers (e.g. collagen, keratin); amino-acids etc. and analogs thereof.
Pendant Arms
[249] One embodiment provides a composition comprising a biodegradable polymer, the polymer comprising: a backbone having a first chemical moiety incorporated into the backbone of the polymer via one or more biodegradable covalent linkages, a pendant arm linked to the backbone via a biodegradable linkage, the pendant arm having a second chemical moiety bonded to the pendant arm via a single biodegradable covalent linkage, wherein the first and second chemical moieties are the same or different and each forms a pharmaceutically active agent upon degradation of their biodegradable linkages. The pendant arm is typically linked to the backbone via an ester, amide, carbonate, anhydride or thioester linkage.
[250] In one embodiment the invention provides a polymer comprising any one or the other of the following repeat units:
-[D1-L1-D2-L2]- I
L3
I
D3
-[D1-L1-D2-L2-D3-L3]
I
L7
I
D4
[251] Another embodiment includes polymers having one or the other of the following structures:
-[D1-L3-L1-L4-D2-L5-L2-L6] I
L7 I D3
-[D1- L4-L1- L5-D2- L6-L2- L7-D3- L8-L3-L9] I
-10
I D4 [252] In these embodiments the l_i, L2, L3, L7, Li0 chains can have two functional groups that are capable of forming a direct amide, ester, anhydride, carbonate or thioester linkage with an adjacent group. Such chains can comprise for example a C4-C20 aliphatic chain as described above. Alternatively, Li, L2, L3, L7, L10 can comprise a chain that is linked to the drug molecules via an intermediate linker group L3, L4, L5, L6, L7, L8 or L9 as shown in the above structures. The linkages between the chains Li, L2, L3, L7, Li0 and the linker groups are via an amide, ester, anhydride, carbonate or thioester linkage. Typical examples of such chains that are linked to the drugs via intermediate linker groups are polylactide, polyether, polyglycolide, polyethyleneimine, polycaprolactone, polysaccharide and polyphospholipid chains. The linkages between such intermediate linker groups and a drug molecule may be an amide, ester, anhydride, carbonate or thioester linkage. Intermediate linker groups such as L3, L4, L5, L6, L7, L8 or L9 above typically comprise chains of 1 -20 carbon atoms.
[253] In another embodiment, pharmaceutically active agents in addition to Di, D2, D3 and D4 can also be present in the composition, e.g., any other agents useful for treating vascular injury, e.g., restenosis. Alternatively, pharmaceutically active agents in addition to Di, D2, D3 and D4 can be incorporated in the polymer, e.g., either covalently linked to the polymer or admixed with the polymer.
[254] In each of the embodiments above, the polymer chains have drug molecules, i.e. moieties that are pharmaceutically active on hydrolysis of the amide, ester, anhydride, carbonate or thioester linkage, incorporated by two linkages into a backbone portion of the polymers and also have a pendant group having a drug molecule having a single linkage to the pendant group.
[255] In these examples L1 and L2 and L3 and L7 are chains that have two functional groups that are capable of forming a direct amide, ester, anhydride, carbonate or thioester linkage with an adjacent group. Examples of such linker chains or moieties are aliphatic linker groups, such as any of the aliphatic linker groups disclosed herein.
[256] For purposes of illustration of the formation of an ester linkage to a paclitaxel molecule, there is shown in FIG. 1 , an aliphatic linking group containing two carbonyl chloride functional groups (e.g. acyl chlorides if L is, e.g., an alkyl group or a polysaccharide or phospholipid having a carbonyl group) can be reacted with a hydroxyl group of paclitaxel in the presence of triethylamine (TEA) to form an alternating aliphatic linking group-paclitaxel polymer. Alternatively, the resulting -[C(=O)-L-C(=O)-O-PAC-O]- unit can be covalently bonded to another linking group such as a polysaccharide or phospholipid linker group via its residual carbonyl chloride group or through another subsequently introduced second linker group.
[257] Other chemical moieties positioned in pendant groups can be attached as described in the section relating to star polymers, hyperbranched polymers, and dendrimers, above.
Devices
[258] In one embodiment, the polymers disclosed herein can be used to form a coating for an implantable medical device. In device applications, the polymers can offer one or more of: (a) tunable and controllable release profile for therapeutic agent(s) for optimal therapeutic effect; (b) polymer physical properties amenable to polymer-processing leading to a viable stent coating for optimal coating viability and performance; and (c) biodegradation along with high drug-loading to be able to deliver the therapeutic agent(s) over a long period of avoiding polymer-mediated negative effects (e.g. thrombosis).
[259] In one embodiment, the device treats narrowing or obstruction of a body passageway in a subject in need thereof. In another embodiment, the method comprises inserting the device into the passageway, the device comprising a generally tubular structure, the surface of the structure being coated with a composition disclosed herein, such that the passageway is expanded. In the method, the body passageway may be selected from arteries, veins, lacrimal ducts, trachea, bronchi, bronchiole, nasal passages, sinuses, eustachian tubes, the external auditory canal, oral cavities, the esophagus, the stomach, the duodenum, the small intestine, the large intestine, biliary tracts, the ureter, the bladder, the urethra, the fallopian tubes, uterus, vagina, the vasdeferens, and the ventricular system.
[260] Exemplary devices include sutures, staples, anastomosis devices, vertebral disks, bone pins, suture anchors, hemostatic barriers, clamps, screws, plates, clips, vascular implants, urological implants, tissue adhesives and sealants, tissue scaffolds, bone substitutes, intraluminal devices, and vascular supports. For example, the device can be a cardiovascular device, such as venous catheters, venous ports, tunneled venous catheters, chronic infusion lines or ports, including hepatic artery infusion catheters, pacemakers and pace maker leads, and implantable defibrillators. Alternatively, the device can be a neurologic/neurosurgical device such as ventricular peritoneal shunts, ventricular atrial shunts, nerve stimulator devices, dural patches and implants to prevent epidural fibrosis post- laminectomy, and devices for continuous subarachnoid infusions. The device can be a gastrointestinal device, such as chronic indwelling catheters, feeding tubes, portosystemic shunts, shunts for ascites, peritoneal implants for drug delivery, peritoneal dialysis catheters, and suspensions or solid implants to prevent surgical adhesions. In another example, the device can be a genitourinary device, such as uterine implants, including intrauterine devices (IUDs) and devices to prevent endometrial hyperplasia, fallopian tubal implants, including reversible sterilization devices, fallopian tubal stents, artificial sphincters and periurethral implants for incontinence, ureteric stents, chronic indwelling catheters, bladder augmentations, or wraps or splints for vasovasostomy, central venous catheters.
[261] In one embodiment, the device is selected from pacemaker leads, valve replacement and repair devices, vena cava filters, and embolic coils and beads.
[262] Other exemplary devices include prosthetic heart valves, vascular grafts ophthalmologic implants (e.g., multino implants and other implants for neovascular glaucoma, drug eluting contact lenses for pterygiums, splints for failed dacrocystalrhinostomy, drug eluting contact lenses for corneal neovascularity, implants for diabetic retinopathy, drug eluting contact lenses for high risk corneal transplants), otolaryngology devices (e.g., ossicular implants, Eustachian tube splints or stents for glue ear or chronic otitis as an alternative to transtempanic drains), plastic surgery implants (e.g., breast implants or chin implants), and catheter cuffs and orthopedic implants (e.g., cemented orthopedic prostheses).
[263] Another exemplary device according to the invention is a stent, such as a stent comprising a generally tubular structure. A stent is commonly used as a tubular structure disposed inside the lumen of a duct to relieve an obstruction. In one embodiment, the stent is either balloon expandable or self-expanding. Commonly, stents are inserted into the lumen in a non-expanded form and are then expanded autonomously, or with the aid of a second device in situ. A typical method of expansion occurs through the use of a catheter-mounted angioplasty balloon which is inflated within the stenosed vessel or body passageway in order to shear and disrupt the obstructions associated with the wall components of the vessel and to obtain an enlarged lumen.
[264] An exemplary stent is a stent for treating narrowing or obstruction of a body passageway in a human or animal in need thereof. "Body passageway" as used herein refers to any of number of passageways, tubes, pipes, tracts, canals, sinuses or conduits which have an inner lumen and allow the flow of materials within the body. Representative examples of body passageways include arteries and veins, lacrimal ducts, the trachea, bronchi, bronchiole, nasal passages (including the sinuses) and other airways, eustachian tubes, the external auditory canal, oral cavities, the esophagus, the stomach, the duodenum, the small intestine, the large intestine, biliary tracts, the ureter, the bladder, the urethra, the fallopian tubes, uterus, vagina and other passageways of the female reproductive tract, the vasdeferens and other passageways of the male reproductive tract, and the ventricular system (cerebrospinal fluid) of the brain and the spinal cord. Exemplary devices of the invention are for these above-mentioned body passageways, such as stents, e.g., vascular stents. There is a multiplicity of different vascular stents known in the art that may be utilized following percutaneous transluminal coronary angioplasty.
[265] Any number of stents may be utilized in accordance with the present invention and the invention is not limited to the specific stents that are described in exemplary embodiments of the present invention. The skilled artisan will recognize that any number of stents may be utilized in connection with the present invention. In addition, as stated above, other medical devices may be utilized, such as e.g., orthopedic implants.
[266] In one embodiment, the composition is coated on the stent to form a conformal coating around all surfaces of the stent. In another embodiment, the composition is coated only on the abluminal surface of the stent. In one embodiment, the composition resides partially or completely within micro-reservoirs or pores in the stent surface.
[267] In one embodiment, the device is an angioplasty balloon having coated thereon the coating comprising the composition, wherein the balloon is used to deliver the composition to an endoluminal surface.
[268] The devices of the invention may be coated partially or wholly with the above defined compositions in any manner known in the art, e.g., dipping, spraying, rolling, brushing, electrostatic plating or spinning, vapor deposition (e.g., physical or chemical), air spraying including atomized spray coating, and spray coating using an ultrasonic nozzle. The compositions can be applied by these methods either as a solid (e.g., film or particles), a suspension, a solution, or as a vapor. Alternatively, the device can be coated with a first substance (such as a hydrogel) that is capable of absorbing the composition. In another embodiment, the device can be constructed from a material comprising a polymer/drug composition.
[269] In another embodiment, the device comprises at least two coatings to provide a multi-layered structure. In another embodiment, the device has at least three coatings. Each of the at least three coatings can provide a different chemical moiety that forms a different pharmaceutically active agent. For example, one of the at least three coatings comprises a chemical moiety that forms an antiproliferative pharmaceutically active agent, a second of the three coatings comprises a chemical moiety that forms an anti-inflammatory agent, and a third of the at least three coatings comprises a chemical moiety that forms a healing promoter.
[270] In one embodiment, two or more coatings (e.g., layers) are applied to the device where each coating contains a different pharmaceutically active agent. FIG. 2 is a schematic showing a multi-layered coating arrangement, where each of layers 1 , 2, and 3 contain either a unique pharmaceutically active agent, or if two or more layers contain the same agent, the agent is linked to the polymer via a different linking chemistry. This arrangement allows control of the release profile of the agents and can provide control of the sequence of release of different pharmaceutically active agents. In one embodiment, each layer can be individually customized by choice of agents, linking chemistry, polymer structure, thickness, etc. for controlling the release profile and kinetics. [271] In one embodiment, each layer contains a unique agent, or any other agents useful for treating vascular injury, e.g., restenosis.
Methods of Treatment
[272] In one embodiment, the method is used for treating at least one disease or condition associated with vascular injury or angioplasty, e.g., one or more of atherosclerosis, restenosis, neointima, neointimal hyperplasia and thrombosis.
[273] In one embodiment, the implantable devices disclosed herein are implanted in a subject in need thereof to achieve a therapeutic effect, e.g., therapeutic treatment and/or prophylactic/preventative measures. Those in need of treatment may include individuals already having a particular medical disease as well as those at risk for the disease (e.g., those who are likely to ultimately acquire the disorder). A therapeutic method can also result in the prevention or amelioration of symptoms, or an otherwise desired biological outcome, and may be evaluated by improved clinical signs, delayed onset of disease, reduced/elevated levels of lymphocytes and/or antibodies.
[274] Exemplary pharmaceutically active agents include antiproliferative agents (e.g., those active against smooth muscle cells), anti-inflammatory agents, and healing promoters. Exemplary antiproliferative agents include paclitaxel, sirolimus, everolimus, biolimus, zotarolimus, AP23573 (a sirolimus analog), and other limus derivatives. Exemplary anti-inflammatory agents include non-steroidal agents (e.g., 3-amino-4-hydroxybutyric acid, aceclofenac, alminoprofen, bromfenac, bumadizon, carprofen, diclofenac, diflunisal, enfenamic acid, etodolac, fendosal, flufenamic acid, gentisic acid, meclofenamic acid, mefenamic acid, mesalamine, niflumic acid, olsalazine oxaceprol, S-adenosylmethionine, salicylic acid, salsalate, sulfasalazine, tolfenamic acid). Exemplary healing promoters include nitric oxide donors such as halofuganone, S-nitrosothiols, and glyceryl thnitrite 1 -[N-(3- aminopropyl)-N-(3-ammoniopropyl]diazen-1 -ium-1 ,2-diolate, 1 -[N-(2-aminoethyl)-N- (2-ammonioethyl)amino]diazen-1 -ium-1 ,2-diolate, as well as epidermal growth factor and other growth factors.
[275] Other exemplary pharmaceutically active agents include analgesics, anesthetics, anti acne agents, antibiotics, synthetic antibacterial agents, anticholinergics, anticoagulants, antidyskinetics, antifibrotics, antifungal agents, antiglaucoma agents, anti-inflammatory agents, antineoplastics, antiosteoporotics, antipagetics, anti-Parkinson's agents, antisporatics, antipyretics, antiseptics/disinfectants, antithrombotics, bone resorption inhibitors, calcium regulators, keratolytics, sclerosing agents and ultraviolet screening agents. Exemplary antithrombotics and anticoagulants include aspirin and plavix.
[276] In one embodiment, the pharmaceutically active agent is a drug useful for treating diseases and conditions associated with restenosis, e.g., antithrombotics, anticoagulants, antiplatelet agents, thrombolytics, antiproliferatives, antiinflammatories, antimitotic, antimicrobial, agents that inhibit restenosis, smooth muscle cell inhibitors, antibiotics, fibrinolytic, immunosuppressive, and anti-antigenic agents.
[277] Examples of anti-bacterial compounds suitable for use in the present invention include, but are not limited to, 4-sulfanilamidosalicylic acid, acediasulfone, amfenac, amoxicillin, ampicillin, apalcillin, apicycline, aspoxicillin, aztreonam, bambermycin(s), biapenem, carbenicillin, carumonam, cefadroxil, cefamandole, cefatrizine, cefbuperazone, cefclidin, cefdinir, cefditoren, cefepime, cefetamet, cefixime, cefinenoxime, cefminox, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotetan, cefotiam, cefozopran, cefpimizole, cefpiramide, cefpirome, cefprozil, cefroxadine, ceftazidime, cefteram, ceftibuten, ceftriaxone, cefuzonam, cephalexin, cephaloglycin, cephalosporin C, cephradine, ciprofloxacin, clinafloxacin, cyclacillin, enoxacin, epicillin, flomoxef, grepafloxacin, hetacillin, imipenem, lomefloxacin, lymecycline, meropenem, moxalactam, mupirocin, nadifloxacin, norfloxacin, panipenem, pazufloxacin, penicillin N, pipemidic acid, quinacillin, ritipenem, salazosulfadimidine, sparfloxacin, succisulfone, sulfachrysoidine, sulfaloxic acid, teicoplanin, temafloxacin, temocillin, ticarcillin, tigemonam, tosufloxacin, trovafloxacin, and vancomycin.
[278] Examples of anti-fungal compounds suitable for use in the present invention include, but are not limited to amphotericin B, azasehne, candicidin(s), lucensomycin, natamycin, and nystatin.
[279] Examples of anti-neoplastic compounds suitable for use in the present invention include, but are not limited to 6-diazo-5-oxo-L-norleucine, azaserine, carzinophillin A, denoptehn, edatrexate, eflomithine, melphalan, methotrexate, mycophenolic acid, podophyllinic acid 2-ethylhydrazide, pteropterin, streptonigrin, Tomudex.RTM. (N-((5-(((1 ,4-Dihydro-2-methyl-4-oxo-6- quinazolinyl)methyl)nnethylannino)-2- thienyl)carbonyl)-L-glutamic acid), and ubenimex.
[280] Examples of anti-thrombotic compounds for use in the present invention include, but are not limited to, argatroban, iloprost, lamifiban, taprostene, and tirofiban.
[281] Examples of immunosuppressive compounds suitable for use in the present invention include, but are not limited to bucillamine, mycophenolic acid, procodazole, romurtide, and ubenimex.
[282] Dosages of the pharmaceutically active agent may be determined by means known in the art. Typically, the dosage is dependent upon the particular drug employed and medical condition being treated to achieve a therapeutic result. In one embodiment, the amount of drug represents about 0.001 percent to about seventy percent of the total coating weight, or about 0.01 percent to about sixty percent of the total coating weight. In one embodiment, the weight percent of the therapeutic agents in the carrier or polymer coating is 1 % to 50%, 2% to 45%, 5% to 40%, or 10% to 25% by weight relative to the total coating weight. In another embodiment, it is possible that the drug may represent as little as 0.0001 percent to the total coating weight. In another embodiment, the dosage is determined per coated surface area of the device. For example, the dose density may range from 0.05 to 10 μg/mm2, such as a dose-density ranging from 0.05 to 1.0 μg/mm2, or ranging from 0.1 to 4 μg/mm2, or ranging from 0.2 to 4 μg/mm2.
[283] In one embodiment, the device delivers the agent over a selected period of time, such as days, weeks or months, e.g., such as a period of at least one week, at least two weeks, at least one month, at least six months, or at least one year.
[284] In one embodiment, the biodegradable polymer functions to reduce the solubility of the pharmaceutically active agent in an aqueous medium. In this embodiment, the polymer covalently linked to the chemical moiety is less soluble in an aqueous medium than the free form of the agent. [285] In one embodiment, the at least one pharmaceutically active agent is hydrophobic or amphipathic (e.g., paclitaxel). Although hydrophobic agents may have some solubility in water, generally a hydrophobic agent generally dissolves more readily in oils or non-polar solvents than in water or polar solvents. In one embodiment, the agent is hydrophilic, e.g., dissolves more readily in water or polar solvents than in oils or non-polar solvents.
[286] In one embodiment, two or more different chemical moieties are incorporated in the polymer to impart different therapeutic effects based on the resulting drug. The choice of drug, and the monomer(s) can allow control of release profile and kinetics of pharmaceutically active agents from the medical device. For example, the release profile and kinetics can be controlled by the hydrolysis rates and chemistry of the various hydrolytic linkages. The period of time of drug delivery and drug dosage can be controlled to substantially prevent undesirable burst release. Moreover, the linking groups and biodegradable polymer can be chosen to provide desirable mechanical properties.
EXAMPLES
[287] Examples of routines for synthesis of polymers using aliphatic linker groups as intermediate spacers or links between polysaccharide or phospholipid and pharmaceutically active moieties are as follows.
Example 1. Polymer with activated carboxyl terminated cellulose and paclitaxel
[288] One example of a method of preparation of such a polymer is one that uses enzyme-catalyzed synthesis and protection-deprotection of the polysaccharide hydroxyl groups and does not employ any linkers between the polysaccharide and drug. The polysaccharide is coupled only on its terminal ends to the drug via biodegradable carboxylic ester bonds. In particular, the polymer prepared is a cellulose-paclitaxel-cellulose-paclitaxel... polymer. Cellulose is a linear un-branched polymer of β-D-glucose with a reducing and a non-reducing end. Reaction of cellulose with galactose catalyzed by milk galactosyl transferase adds a galactose to the non-reducing end in glycosidic linkage. Treatment with galactose oxidase oxidizes the terminal 6-hydroxyl group of the galactose to an aldehyde. The result is cellulose with two reducing ends (an aldehyde at each end). Mild oxidation with peracetic converts both aldehyde groups to carboxylic acid groups. Reaction of this product with an excess of 2- naphthylmethyl bromide in dimethylformamide in the presence of a base protects all of the hydroxyl groups as naphthylmethyl ethers and both carboxyl groups as naphthylmethyl esters. Mild base hydrolysis regenerates the two carboxyl groups. The hydroxyl-protected, cellulose dicarboxylic acid dissolved in dichloromethane or dimethylformamide is now activated by reacting the two carboxylic acid groups with an equimolar amount of dicyclohexylcarbodiimide. Paclitaxel is dissolved in dichloromethane with a catalytic amount of 4- dimethylaminopyhdine and added to the protected, cellulose dicarboxylic acid solution. The mixture is stirred at room temperature until unreacted paclitaxel is almost consumed. Addition of water precipitates the polymer which is washed carefully with dichloromethane to remove the unreacted paclitaxel. The polymer is dissolved in dichloromethane/methanol or another suitable solvent and stirred at room temperature with an excess of 1 ,2-dichloro-4,5-dicyanoquinone to remove all the naphthylmethyl protecting groups. When the reaction is judged complete by thin layer chromatography or high performance liquid chromatography the precipitate (in case of dichloromethane-methanol solvent) was isolated by vacuum filtration, washed with dichloromethane-methanol and dried to give the biodegradable polymer ...cellulose-paclitaxel-cellulose-paclitaxel ....
Example 2. Polymer with activated paclitaxel and chitosan (amide (urethane) and carbonate-type bonds using triphosqene)
[289] One equivalent of paclitaxel is reacted with 2/3 equivalent of triphosgene in a minimum amount of chloroform at 00C in the presence of 2 equivalents of triethylamine to give paclitaxel activated with one chloro-carbonyl group on each of its reactive hydroxyl groups (2' and 7). (One mole of triphosgene contains 3 equivalents of phosgene.) Chitosan (1 equivalent) dissolved in a minimum amount of dimethylformamide and an excess of triethylamine is added dropwise at 00C with stirring to the activated paclitaxel solution. The solution is stirred overnight at room temperature, rotary evaporated to dryness, dissolved in water, adjusted to pH 5 and extracted 3 times with chloroform to remove excess paclitaxel. The aqueous phase is lyophilized to give a polymer with mixed ester and amide bonds joining paclitaxel to chitosan, of the form ...-paclitaxel-chitosan- paclitaxel-chitosan-... along with more complex polymers, i.e. branched/hyperbranched .
Example 3. Polymer with activated rapamycin and dextran (ester bonds using sebacic acid dichloride)
[290] One equivalent of rapamycin is derivatized with two equivalents of sebacic acid dichloride similar to Example 3 to give rapamycin activated on each of its two reactive hydroxyl groups with a chlorosebacoyl group. Dextran is dissolved in dimethylformamide and reacted with the activated rapamycin similarly to Example 2. The solution is rotary evaporated to dryness, dissolved in water and extracted with chloroform to remove excess rapamycin. The aqueous phase is lyophilized to yield a polymer with ester bonds joining rapamycin to dextran, of the form ...-rapamycin- dextran-rapamycin-dextran-... along with more complex polymers.
Example 4. Polymer with paclitaxel and activated chitosan (amide (urethane) and carbonate-type bonds using triphosgene)
[291] One equivalent of chitosan is dissolved in pyridine and reacted with 2/3 equivalent of triphosgene at 00C to give, on average, activated chitosan with two chlorocarbonyl groups per chitosan molecule. Paclitaxel dissolved in dimethylformamide is added dropwise at 00C with stirring. The mixture is stirred overnight and worked up as in Example 2 to yield a polymer with mixed ester and amide bonds joining paclitaxel to chitosan, of the form ...-paclitaxel-chitosan- paclitaxel-chitosan-... along with more complex polymers.
Example 5. Polymer with activated paclitaxel and di-acyl phosphatidylethanolamine (mixed carboxylic-phosphoric anhydride and amide (urethane)-type bonds using triphosgene)
[292] One equivalent of paclitaxel is reacted with 2/3 equivalent of triphosgene in a minimum amount of chloroform at 0 0C in the presence of 2 equivalents of triethylamine to yield paclitaxel activated with one chloro-carbonyl group on each of its two reactive hydroxyl groups (2' and 7). Phosphatidylethanoamine (1 equivalent) dissolved in a minimum amount of dimethylformamide with 2 equivalents of triethylamine is added dropwise at 0 0C with stirring to the activated paclitaxel solution. The solution is stirred overnight at room temperature and rotary evaporated to dryness to yield a polymer with mixed anhydride, ester and amide (urethane) bonds joining paclitaxel to phosphatidylethanolamine, of the form ...-paclitaxel-phosphatidylethanolamine- paclitaxel-phosphatidyl ethanolamine -....
Example 6. Polymer with activated paclitaxel and di-acyl phosphatidylethanolamine (mixed carboxylic-phosphoric anhydride, ester and amide (urethane)-type bonds using sebacic acid dichloride
[293] Paclitaxel is reacted with 2 equivalents of sebacic acid dichloride in a minimum amount of chloroform at 00C in the presence of 2 equivalents of triethylamine to yield paclitaxel activated with one chlorosebacoyl group on each of its two reactive hydroxyl groups (2' and 7). Phosphatidylethanoamine (1 equivalent) dissolved in a minimum amount of dimethylformamide with 2 equivalents of triethylamine is added dropwise at 00C with stirring to the activated paclitaxel solution. The solution is stirred overnight at room temperature and rotary evaporated to dryness to yield a polymer with mixed anhydride and amide (urethane) bonds joining paclitaxel to phosphatidylethanolamine, of the form ...-paclitaxel- phosphatidylethanolamine-paclitaxel-phosphatidylthanolamine -....
Example 7. Polymer with activated phosphatidylethanolamine dimer and paclitaxel (phosphoric anhydride and amide (urethane) and carbonate bonds) using triphosqene
[294] One equivalent of phosphatidyl ethanolamine is dissolved in sodium hydroxide solution at 00C and pH 12 and shaken with one equivalent of liquid benzyl chloroformate until all the latter dissolves. The mixture is extracted with chloroform to remove the remaining chloroformate and acidified to pH 2. The mixture is extracted with chloroform and the chloroform layer dried and rotary evaporated to dryness to give N-carbobenzoxy phosphatidylethanolamine. Two equivalents of N- carbobenzoxy phosphatidylethanolamine are dissolved in tetrahydrofuran/dimethylformamide, cooled to 00C and reacted with 1 equivalent of dicyclohexyl carbodiimide, then stirred overnight at room temperature. The solid dicyclohexyl urea is removed by filtration and the solvent evaporated to dryness to give the pyrophosphate (phosphoric anhydride) dimer of N-carbobenzoxy phosphatidylethanolamine. The carbobenzoxy groups are removed by hydrogenolysis in tetrahydrofuran over a palladium on carbon catalyst to yield the pyrophosphate dimer of phosphatidylethanolamine.
[295] One equivalent of paclitaxel is reacted with 2/3 equivalent of triphosgene in a minimum amount of chloroform at 0 0C in the presence of 2 equivalents of triethylamine to give paclitaxel activated with one chloro-carbonyl group on each of its two reactive hydroxyl groups (2' and 7). One equivalent of the dimer of phosphatidylethanolamine is dissolved in tetrahydrofuran/dimethylformamide with two equivalents of triethylamine and added dropwise to the solution of paclitaxel at 0 0C. The mixture is stirred overnight at room temperature, rotary evaporated to dryness, and the residue triturated with ether to remove excess paclitaxel. The product is a polymer of the form ...paclitaxel- phosphatidylethanolamine dimer-paclitaxel-phosphatidylethanolamine dimer-....
Example 8. Polymer with activated paclitaxel and phosphatidylqlvcerol (ester- tvpe bonds using sebacic acid dichloride
[296] Paclitaxel is reacted with 2 equivalents of sebacic acid dichloride in a minimum amount of chloroform at 0 0C in the presence of 2 equivalents of triethylamine to give paclitaxel activated with one chlorosebacoyl group on each of its two reactive hydroxyl groups (2' and 7). Phosphatidylglycerol (1 equivalent) dissolved in a minimum amount of pyridine is added dropwise at 0 0C with stirring to the activated paclitaxel solution. The solution is stirred overnight at room temperature and rotary evaporated to dryness to give a polymer with ester bonds joining paclitaxel to phosphatidylglycerol, of the form ...-paclitaxel- phosphatidylglycerol-paclitaxel-phosphatidylglycerol-... along with more complex polymers.
Example 9. Polymer with rapamvcin and dextran (ester bonds using sebacic acid dichloride)
[297] One equivalent of rapamycin and one equivalent of dextran is dissolved in tetrahydrofuran/dimethylformamide with two equivalents triethylamine. One equivalent of sebacic acid dichloride is added at O0C. The mixture is stirred at room temperature overnight. The solution is rotary evaporated to dryness, dissolved in water and extracted with chloroform to remove excess rapamycin. The aqueous phase is lyophilized to give a polymer with ester bonds joining rapamycin to dextran, of the form ...-rapamycin-dextran-rapamycin-dextran-...along with more complex polymers.
Examples 10-13: Star Polymers
[298] The general structure of the star polymers of the invention are shown in Scheme 1 below. Star polymers branch only at the central star core and have linear arms in contrast to dendrimers which continue branching and thus have branched arms. P represents paclitaxel or any of the therapeutic agents of the invention. The 16 arm star polymer has a central core of pentaerythritol with 4 hydroxyl groups. This central core is extended with 2,2-(dihydroxymethyl)propanoic acid for two generations to give a star core with 16 hydroxy groups. One arm of the star polymer is attached to each of the 16 hydroxyl groups via a short oligomer and linkers. Either the linker or the oligomer has pendant functional side chains to which the pendant therapeutic agent is attached. Therapeutic agent is also incorporated into the polymer backbone via linkers. Scheme 1 shows a second generation, drug-bearing star polymer with therapeutic agent both pendant and within the polymer backbone. The second generation star polymer can be extended for additional generations by addition of oligomers, linkers and therapeutic agent to each of the 16 arms. Drug- bearing star polymers with more than 16 arms can be prepared by adding additional generations of 2,2-(dihydroxymethyl)propanoic acid to the star core before chain extension.
Scheme 1
Figure imgf000060_0001
Example 10
[299] This Example describes the synthesis of a star polymer with 16 arms of PLGA polymer with paclitaxel pendant and in the polymer backbone (second phase star polymer compound 8). Scheme 2 below shows compounds of Example 10.
[300] The tetrahydroxyl core molecule pentaerythritol is reacted with an excess of the anhydride of 2,2-dihydroxymethyl-propanoic acid dimethylacetal in the presence of dimethylaminopyridine to give pentaerythritol substituted with 2,2- dihydroxymethyl-propanoic acid dimethylacetal on each of its 4 hydroxyl groups. Treatment of this product with dilute sulfuric acid in methanol deprotects the 8 new hydroxyl groups to give O1,O2,O3,O4-tetra-(2,2-dihydroxymethyl-propanoyl)- pentaerythritol, the first generation star core (compound 1). Treatment of this first generation core with an excess of the anhydride of 2,2-dihydroxymethyl-propanoic acid dimethylacetal in the presence of dimethylaminopyridine and deprotection with dilute sulfuric acid in methanol gives the second generation star core (compound 2) with 16 hydroxyl groups at the ends of its branches. Compound 2 is reacted with a quantity of the cyclic lactone dimers of lactic acid and glycolic acid sufficient to give a short oligomer (5-10 monomers) of PLGA (poly-lactic/glycolic acid) on each of its 16 hydroxyl groups, compound 3. Compound 3 has 16 new hydroxyl groups. The ratio of lactic and glycolic acid can be adjusted to give the desired release and degradation properties. It is understood that the sequence and ratio of lactic/glycolic acid can be other than what is shown in Scheme 2.
[301] Paclitaxel is protected on its 2' hydroxyl group with 2-napthylmethyl, leaving its 7-hydroxyl group free. A second batch of paclitaxel is protected on its 2'- hydroxyl with acetyl, leaving its 7-hydroxyl free. Cis-aconitic acid anhydride is catalytically reduced with hydrogen to give the corresponding anhydride of 2- carboxy-glutaric acid. The anhydride of 2-carboxy-glutaric acid is activated on its free carboxylic acid group by stirring with one equivalent of oxalyl chloride in dichloromethane. The anhydride/acid chloride solution is treated with an excess of a dichloromethane solution of 2'-O-(2-napthylmethyl) and 2'-O-acetyl- paclitaxels (molar ratio 1 :1 ) in the presence of dimethylaminopyridine until all the activated glutaric anhydride is converted to a dipaclitaxel diester. The diester is activated with oxalyl chloride as above and reacted with 2'-O-(2-napthylmethyl) to give compound 4, 2-carboxy-glutaric acid di-(2-(2-napthylmethyl)-paclitaxel ester)-mono-(2'-acetyl- paclitaxel ester) with each paclitaxel acylated on its free 7-hydroxyl group by one of the three 2-carboxy-glutaric acid carboxyl groups. It is understood that different isomers of compound 4 can be present. The product 4 is isolated by column chromatography on silica gel. Treatment of 4 in dichloromethane at room temperature with an excess of 1 ,2-dichloro-4,5-dicyanoquinone removes both 2- napthylmethyl protecting groups to give compound 5, the mono-(acetyl-paclitaxel ester)-di-(paclitaxel ester) of 2-carboxy-glutaric acid, the tri-paclitaxel linker. It is understood that the acetyl paclitaxel will likely be distributed between the 3 carboxyl groups of the 2-carboxy-glutaric acid.
[302] Compound 3 is dissolved in dichloromethane/tetrahydrofuran and its 16 hydroxyl groups are reacted with an excess of sebacic acid dichloride to give compound 3 with 16 chlorosebacoyl groups attached, compound 6. The product 6 is evaporated to dryness and the residue washed exhaustively with diethyl ether/hexane to remove excess sebacoyl dichloride. An excess of the tri-paclitaxel linker (compound 5) is dissolved in dichloromethane and reacted with compound 6 in the presence of dimethylaminopyridine to give the first generation star polymer containing pendant paclitaxel and paclitaxel within the polymer chain, compound 7, with 16 free paclitaxel 7-hydroxyl groups. (First generation, drug-bearing star polymer is meant to indicate how many cycles of PLGA and tri-paclitaxel linker (compound 5,) have been added to the star core. One cycle is one generation.) The process of adding a short oligomer of PLGA to these hydroxyl groups followed by the tri-paclitaxel linker can be repeated to give the second generation, drug-bearing star polymer (compound 8) containing pendant paclitaxel and paclitaxel within the polymer chain. This process can be repeated as many times as desired to give additional generations of drug-bearing star polymer.
[303] The pendant paclitaxels (with the exception of the polymer chain "terminal" paclitaxels, if the growth is stopped at this stage) have their 2'-hydroxyl groups protected by the labile acetyl ester group. This will likely be the first ester bond to hydrolyze in the final star polymer because of the small size of the acetyl group and its pendant position, ultimately releasing free paclitaxel.
[304] Scheme 2: Compound 1 is the first generation star core with 8 hydroxyl groups. Compound 2 is the second generation star core with 16 free hydroxyl groups with only one of the 4 branches (each bearing 4 hydroxyl groups) shown. Compound 3 shows a PLGA pentamer polymerized onto one of the 16 hydroxyl groups of compound 2, i.e., one arm of the 16 arm star polymer. Compound 5 is the tri-paclitaxel linker with two free hydroxyl groups. Compound 6 shows the chlorosebacoyl linker attached to the PLGA pentamer of compound 3. Compound 7 shows one of the 16 arms of the first generation, drug-bearing polymer with paclitaxels pendant and within the polymer backbone. Compound 8 shows one arm of the second generation, drug-bearing polymer with paclitaxels pendant and within the polymer backbone.
Figure imgf000063_0001
compound 1 compound 2
Figure imgf000063_0002
compound 5 compound 6
Figure imgf000063_0003
compound 7
Figure imgf000063_0004
Example 11
[305] This Example describes the preparation of a star polymer with 16 arms of poly-L-glutamic acid with paclitaxel pendant and in the polymer backbone (second generation star polymer compound 15). Scheme 3 shows compounds of Example 11.
[306] The second generation star core with 16 hydroxyl groups at the ends of its branches (compound 2) is prepared as described in Example 10. An excess of the γ-thtyl ester of glutamic acid N-carboxyanhydhde is reacted with compound 2 in dry dichloromethane/tetrahydrofuran until the 16 hydroxyl groups are each reacted with a single γ-trityl-glutamic acid. A drop of water is added to facilitate removal of the carbon dioxide from the amino groups of each of the single glutamic acids attached to each of the 16 hydroxyl groups and to allow growth of the γ-trityl-glutamic acid oligomer to 5-10 monomers in length on each arm to give compound 9. Compound 9 is reacted with sebacic acid dichloride to give compound 10 with a chlorosebacoyl group on the end of each arm. Compound 10 is reacted with an excess of unsubstituted paclitaxel in the presence of dimethylaminopyridine to give the first generation protected polymer (compound 11) with one paclitaxel at the end of each of the 16 arms, each paclitaxel bearing a free hydroxyl group. A short oligomer of poly-L-γ-trityl-glutamic acid is formed as above on each of the free hydroxyl groups followed by reaction with sebacic acid dichloride to give compound 12 with a chlorosebacoyl group at the end of each arm. Compound 12 is reacted with an excess of paclitaxel to give the second generation protected star polymer with drug only in the polymer backbone, compound 13. Compound 13 is treated with 0.5 % thfluoroacetic acid in dichloromethane to remove the trityl protecting groups from all the glutamic acid γ-carboxyl groups to give compound 14. Reaction of compound 14 dissolved in tetrahydrofuran/dimethylformamide with dicyclohexyl carbodiimide and excess paclitaxel in the presence of dimethylaminopyridine gives the second generation star polymer compound 15 with paclitaxel both pendant and incorporated into the polymer backbone. The amount of pendant paclitaxel can be adjusted by regulating the amount of dicyclohexylcarbodimide and paclitaxel in the reaction. Partial or full substitution of the side chain carboxyl groups may give the more desirable release and degradation properties.
[307] Additional generation polymers can be prepared by further cycles of adding γ-trityl glutamic acid oligomers, paclitaxel, and sebacic acid dichloride onto the backbone of compound 13, deprotecting the trityl ester groups and coupling the paclitaxels to the pendant carboxyl groups.
[308] Scheme 3: Compound 2 is the second generation star core with 16 free hydroxyl groups with only one of the 4 branches (each bearing 4 hydroxyl groups) shown. Compound 9 shows one of the 16 arms of the star polymer with a pentaglutamic acid with trityl protected γ-carboxyl groups polymerized onto one of the 16 hydroxyl groups of compound 2. Compound 10 shows the chlorosebacoyl derivative of compound 9. Compound 11 shows the growing arm with one paclitaxel at the end of the polymer backbone. In compound 10 and the following compounds, the glutamic acid abbreviation GIu indicates its carboxyl group on the left and its amino group on the right, the reverse of the usual convention. The protected glutamic acids are abbreviated here rather than drawing each structure as in compound 10. Compound 12 shows compound 11 after reaction with additional γ- trityl-glutamic acid N-carboxyanhydhde followed by reaction with sebacic acid dichloride. Compound 13 shows the reaction product of compound 12 with paclitaxel. Compound 13 has two short protected glutamic acid oligomers and two paclitaxels in the growing polymer chain and is the protected, second generation star polymer with paclitaxel in the backbone only. Compound 14 is the deprotected, second generation star polymer with paclitaxel only in the polymer backbone. The deprotected glutamic acid structures are drawn for one oligomer for clarity. Compound 15 is the second generation star polymer with paclitaxel both pendant and in the polymer backbone. Again the glutamic acid structure is drawn once for clarity and then abbreviated.
Figure imgf000066_0001
compound 2
Figure imgf000066_0002
compound 10
Figure imgf000066_0003
compound 12
Figure imgf000066_0004
compound 13
Figure imgf000066_0005
compound 14
Figure imgf000066_0006
Example 12
[309] This Example describes the preparation of star polymer with 16 arms of D-glyceric acid polymer with paclitaxel pendant and in the polymer chain (second generation star polymer compound 21). Scheme 4 shows compounds of Example 12.
[310] The second generation star core with 16 hydroxyl groups at the ends of its branches (compound 2) is prepared as described in Example 10. 3-O-Trityl-D- glycehc acid is cyclized to its reactive lactone dimer (compound 16). Compound 2 is reacted with excess compound 16 in the presence of dimethylaminopyhdine to give short chains (5-10 monomers) of 3-O-trityl-D-glyceric acid oligomers attached to each of its 16 hydroxyl groups (compound 17). Compound 17 is reacted with sebacic acid dichloride and then with an excess of unsubstituted paclitaxel in the presence of dimethylaminopyridine to give compound 18 with one paclitaxel at the end of each of the 16 arms, each paclitaxel bearing a free hydroxyl group. A short oligomer of 3-O-trityl-D-glyceric acid is formed on each of the 16 free hydroxyl groups as above, followed by reaction with sebacic acid dichloride and then with additional paclitaxel to give the protected second generation star polymer with backbone drug only, compound 19. Compound 19 is treated with 0.5 % trifluoroacetic acid in dichloromethane to remove the trityl protecting groups from all the glyceric acid 3-hydroxyl groups to give compound 20. Reaction of compound 20 dissolved in tetrahydrofuran/dimethylformamide with sebacic acid dichloride and then paclitaxel in the presence of dimethylaminopyridine gives the second generation star polymer (compound 21) with paclitaxel both pendant and incorporated into the polymer backbone. The amount of pendant paclitaxel can be adjusted by regulating the amount of dicyclohexylcarbodimide and paclitaxel in the reaction. Partial or full substitution of the side chain hydroxyl groups may give the more desirable release and degradation properties.
[311] Additional generation polymers can be prepared by further cycles of adding 3-O-trityl-D-glyceric acid oligomers, sebacic acid dichloride and paclitaxel onto the backbone of compound 19, deprotecting the trityl ether groups and coupling the pendant paclitaxels to these side chain hydroxyl groups via sebacic acid dichloride. [312] Scheme 4: Compound 2 is the second generation star core with 16 free hydroxyl groups with only one of the 4 branches (each bearing 4 hydroxyl groups) shown. Compound 17 shows a 3-O-trityl-glyceric acid pentamer polymerized onto each of the 16 hydroxyl groups of compound 2, i.e., one arm of the 16 arm star polymer. Compound 18 shows the growing arm with sebacic acid linking paclitaxel into the polymer backbone. Compound 19 shows the growing arm with the second 3-O-trityl-glyceric acid oligomer, the second sebacic acid linker and the second backbone paclitaxel attached, the protected, second generation star polymer with only backbone paclitaxels. Compound 20 shows the deprotected, second generation star polymer with only backbone paclitaxels. Compound 21 shows compound 20 reacted with sebacic acid dichlohde and then with paclitaxel to give drug-bearing polymer with paclitaxels pendant and within the polymer backbone.
Figure imgf000069_0001
compound 2
Figure imgf000069_0002
compound 18
Figure imgf000069_0003
compound 19
Figure imgf000069_0004
compound 20
Figure imgf000069_0005
compound 21 Example 13
[313] This Example describes the preparation of star polymer with 16 arms of D-lactic acid/glycolic acid/D-glyceric acid polymer with paclitaxel pendant and in the polymer chain backbone (second generation star polymer compound 26). Scheme 5 shows compounds of Example 13.
[314] The second generation star core with 16 hydroxyl groups at the ends of its branches (compound 2) is prepared as described in Example 10. 3-O-Trityl-D- glycehc acid is cyclized to its reactive lactone dimer (compound 16). The reactive dimers of lactic acid, glycolic acid and compound 16 in a ratio of 2:2:1 are reacted with excess compound 2 in the presence of dimethylaminopyridine to give short chains (5-10 monomers) of lactic acid/glycolic acid/3-O-thtyl-D-glycehc acid oligomers attached to each of its 16 hydroxyl groups (compound 22). It is understood that the ratio and sequence of the hydroxy acids in 22 can be other than what is shown in Scheme 5. Compound 22 is reacted with excess sebacic acid dichlohde, the excess is removed by precipitation and washing, and the chlorosebacoyl product is then reacted with an excess of unsubstituted paclitaxel in the presence of dimethylaminopyridine to give compound 23 with one paclitaxel at the end of each of the 16 arms, each paclitaxel bearing a free hydroxyl group. A short oligomer of lactic acid/glycolic acid/3-O-trityl-D-glycehc acid is formed on each of the 16 free paclitaxel hydroxyl groups as above to give compound 24. Only the 3- O-trityl-glyceric portion of the second pentamer chain is shown here, not the lactic or glycolic acids. Compound 24 is treated with 0.5 % trifluoroacetic acid in dichloromethane to remove the trityl protecting groups from the glyceric acid 3- hydroxyl groups to give compound 25. Reaction of compound 25 dissolved in tetrahydrofuran/pyhdine with excess sebacic acid dichlohde, removal of the excess by precipitation and washing, and then reaction with excess paclitaxel in the presence of dimethylaminopyridine gives the second generation star polymer (compound 26) with paclitaxel both pendant and incorporated into the polymer backbone. The amount of pendant paclitaxel can be adjusted by regulating the amount of dicyclohexylcarbodimide and paclitaxel in the reaction. Partial or full substitution of the side chain hydroxyl groups may give the more desirable release and degradation properties. [315] Additional generation polymers can be prepared by further cycles of adding 3-O-thtyl-D-glycehc acid oligomers, sebacic acid dichloride and paclitaxel onto the terminal hydroxyl groups of compound 24, deprotecting the trityl ether groups and coupling the paclitaxels to the hydroxyl groups via sebacic acid dichloride.
[316] Scheme 5: Compound 2 is the second generation star core with 16 free hydroxyl groups with only one of the 4 branches (each bearing 4 hydroxyl groups) shown. Compound 22 shows a lactic acid/glycolic acid/3-O-trityl-glyceric acid (ratio 2:2:1 ) pentamer polymerized onto one of the 16 hydroxyl groups of compound 2, i.e., one arm of the 16 arm star polymer. Compound 23 shows the growing arm with sebacic acid linking paclitaxel into the polymer backbone. Compound 24 shows the growing arm with the second pentamer chain attached (only the 3-O-thtyl-glycehc acid portion of the second pentamer is drawn, not the lactic or glycolic acids). Compound 25 shows deprotected second generation star polymer before addition of the terminal and pendant paclitaxels. Compound 26 shows the drug-bearing, second generation star polymer with pendant and terminal paclitaxels attached via sebacic acid linkers.
Figure imgf000072_0001
compound 2
Figure imgf000072_0002
compound 23
Figure imgf000072_0003
Figure imgf000072_0004
compound 25
Figure imgf000072_0005
compound 26 Examples 14-19: Linear Polymers
Example 14
[317] This Example describes the preparation of linear lactic acid/glycolic acid polymer with paclitaxel pendant and in the polymer backbone (second generation linear polymer compound 32). Scheme 6 shows compounds of Example 14.
[318] Ethylene glycol is reacted with a quantity of a mixture of the lactone dimers of lactic acid and glycolic acid sufficient to give short oligomers (5-10 monomers) of PLGA (poly-lactic/glycolic acid) on each of its 2 hydroxyl groups, compound 27. Compound 27 has one new hydroxyl group at each end. Paclitaxel is protected on its 2' hydroxyl group with 2-napthylmethyl, leaving its 7-hydroxyl group free. A second batch of paclitaxel is protected on its 2'-hydroxyl with acetyl, leaving its 7-hydroxyl free. Cis-aconitic acid anhydride is catalytically reduced with hydrogen to give the corresponding anhydride of 2-carboxy-glutahc acid. The anhydride of 2- carboxy-glutaric acid is activated on its free carboxylic acid group by stirring with one equivalent of oxalyl chloride in dichloromethane. The anhydride/acid chloride solution is treated with an excess of a dichloromethane solution of the 2'-O-acetyl and 2'-O-(2-napthylmethyl) paclitaxels in a ratio of 1 :1 (acetyl to 2-napthylmethyl) in the presence of dimethylaminopyridine until all the activated glutaric anhydride is converted to a dipaclitaxel diester. The remaining carboxylic acid group of the diester is activated with oxalyl chloride as above and reacted with 2'-O-2- naopthylmethy-lpaclitaxel to give compound 28, 2-carboxy-glutaric acid di-(2'-O-(2- napthylmethyl)-paclitaxel ester)-mono-(2'-O-acetyl-paclitaxel ester) with each paclitaxel acylated on its free 7-hydroxyl group by one of the three 2-carboxy-glutaric acid carboxyl groups. The product 28 is isolated by column chromatography on silica gel. Treatment of 28 in dichloromethane at room temperature with an excess of 1 ,2-dichloro-4,5-dicyanoquinone removes both 2-napthylmethyl protecting groups to give compound 29, the mono-(acetyl-paclitaxel ester)-di-(paclitaxel ester) of 2- carboxy-glutaric acid, the tri-paclitaxel linker (compound 5 of Example 10).
[319] Compound 27 is dissolved in dichloromethane/tetrahydrofuran and its 2 hydroxyl groups are reacted with an excess of succinic anhydride to give compound 30 with 1 succinoyl group attached to each end. An excess of the th-paclitaxel linker (compound 29) is dissolved in dichloromethane and reacted with compound 30 in the presence dicyclohexylcarbodiimide and dimethylaminopyridine to give the first generation linear polymer containing pendant paclitaxel and paclitaxel within the polymer chain, compound 31 , with 2 free paclitaxel 7-hydroxyl groups. (First generation, drug-bearing linear polymer is meant to indicate how many cycles of PLGA and th-paclitaxel linker (compound 29,) have been added to the ethylene glycol starting compound. One cycle is one generation.) The process of adding a short oligomer of PLGA to these hydroxyl groups followed by succinic anhydride and the tri-paclitaxel linker can be repeated to give the second generation, drug-bearing linear polymer (compound 32) containing pendant paclitaxel and paclitaxel within the polymer chain. This process can be repeated as many times as desired to give additional generations of drug-bearing linear polymer. The ratio of lactic and glycolic acid can be adjusted to give the desired release and degradation properties.
[320] The pendant paclitaxels (with the exception of the polymer chain "terminal" paclitaxels, if the growth is stopped at this stage) have their 2'-hydroxyl groups protected by the labile acetyl ester group. This will likely be the first ester bond to hydrolyze in the final linear polymer because of the small size of the acetyl group and its pendant position, ultimately releasing free paclitaxel.
[321] Scheme 6: Compound 27 shows the product of the reaction of the cyclic dimers of lactic acid and glycolic acid with ethylene glycol to give di-pentamer dehvatized ethylene glycol. Compound 29 shows the tri-paclitaxel linker with 2 free hydroxyl groups. Compound 30 shows compound 29 reacted with one succinic anhydride on each of its 2 hydroxyl groups. Compound 31 shows compound 30 reacted with two molecules of tri-paclitaxel linker. Compound 32 shows compound
31 reacted with the cyclic dimers of lactic and glycolic acids, followed by with succinic anhydride, then with the tri-paclitaxel linker to give the second generation linear polymer with paclitaxel both pendant and in the polymer backbone. Compound 32 shows only one chain of the two-chain linear polymer backbone.
Figure imgf000075_0001
ethylene glycol compound 27
Figure imgf000075_0002
compound 30
Figure imgf000075_0003
Figure imgf000075_0004
Example 15
[322] This Example describes the preparation of a linear polymer with poly-L- glutamic acid/L-alanine with paclitaxel pendant and in the polymer backbone (second generation linear polymer compound 39). Scheme 7 shows compounds of Example 15. [323] An excess of a mixture of the γ-trityl ester of glutamic acid N- carboxyanhydride and L-alanine N-carboxy anhydride in a ratio of 2:3 is reacted with ethylene diamine in dry dichloromethane/tetrahydrofuran until the 2 amino groups are each reacted with a single γ-trityl-glutamic acid or alanine. A drop of water is added to facilitate removal of the carbon dioxide from the amino groups of each of the single amino acids attached to each of the 2 amino groups and to allow growth of the γ-trityl-glutamic acid/alanine oligomer to 5-10 monomers in length on each chain to give compound 33. It is understood that the amino acid sequence of 33 will be more or less random and not necessarily exactly as drawn in Scheme 7. Compound 33 is reacted with succinic anhydride to give compound 34 with a succinic acid group on the end of each polymer chain. Compound 34 is reacted with an excess of unsubstituted paclitaxel in the presence of carbonyldiimidazole and dimethylaminopyridine to give the first generation protected linear polymer (compound 35) with one paclitaxel at the end of each of the 2 chains, each paclitaxel bearing a free hydroxyl group. Excess paclitaxel is removed and a short oligomer of poly-L-γ-thtyl-glutamic acid-L-alanine is formed as above on each of the 2 hydroxyl groups followed by reaction with succinic anhydride to give compound 36 with a succinoyl group at the end of each chain. Compound 36 is reacted with an excess of paclitaxel in the presence of carbonyldiimidazole and dimethylaminopyridine to give the second generation protected linear polymer with drug only in the polymer backbone, compound 37. Compound 37 is treated with 0.5 % thfluoroacetic acid in dichloromethane to remove the trityl protecting groups from all the glutamic acid γ- carboxyl groups to give compound 38. Reaction of compound 38 dissolved in tetrahydrofuran/dimethylformamide with carbonyldiimidazole and excess paclitaxel in the presence of dimethylaminopyridine gives the second generation linear polymer compound 39 with paclitaxel both pendant and incorporated into the polymer backbone. The amount of pendant paclitaxel can be adjusted by regulating the amount of carbonyldiimidazole and paclitaxel in the reaction and the ratio of glutamate to alanine in the polymer chains. Partial or full substitution of the side chain carboxyl groups and particular ratios may give the more desirable release and degradation properties. [324] Additional generation polymers can be prepared by further cycles of adding γ-trityl glutamic acid-alanine oligomers, paclitaxel, and sebacic acid dichloride onto the backbone of compound 37, deprotecting the trityl ester groups and coupling paclitaxel to the pendant side chain carboxyl groups.
[325] Scheme 7: Compound 33 shows ethylene diamine with a pentamer of γ-thtyl-glutamic acid/alanine attached to each amino group. Compound 34 shows the result of succinylation of the free amino group of each of the pentamers. Compound 35 shows a paclitaxel with a free hydroxyl group attached to each free succinoyl carboxyl group, the first generation linear polymer with drug in the backbone only. Compound 37 shows the second generation linear polymer with drug only in the polymer backbone. Compound 39 shows the second generation linear polymer with drug both pendant and in the polymer backbone. In compound 33 and the following compounds, the glutamic acid abbreviation GIu and the alanine abbreviation Ala indicate their carboxyl groups on the left and their amino groups on the right, the reverse of the usual convention. Starting with compound 37 all amino acids are abbreviated instead of writing out their structures.
Figure imgf000078_0001
compound 37
Figure imgf000078_0002
compound 39 Example 16
[326] This Example describes the preparation of a linear polymer of D- glycehc acid with paclitaxel pendant and in the polymer chain (second generation linear polymer compound 45). Scheme 8 shows compounds of Example 16.
[327] 3-O-Thtyl-D-glyceric acid is cyclized to its reactive lactone dimer (compound 40). Ethylene glycol is reacted with excess compound 40 in the presence of dimethylaminopyridine to give short chains (5-10 monomers) of 3-O- trityl-D-glycehc acid oligomers attached to each of its 2 hydroxyl groups (compound 41). Compound 41 is reacted with succinic anhydride and then with an excess of unsubstituted paclitaxel in the presence of carbonyldiimidazole and dimethylaminopyridine to give compound 42 with one paclitaxel at the end of each of the 2 chains, each paclitaxel bearing a free hydroxyl group. Compound 42 is the first generation linear polymer with drug in the backbone only. Only 1 of the 2 chains is shown in Scheme 8. A short oligomer of 3-O-thtyl-D-glyceric acid is formed on each of the 2 free hydroxyl groups as above, followed by reaction with succinyl chloride (or with succinic anhydride followed by activation) and then with additional excess paclitaxel to give the protected second generation linear polymer with backbone drug only, compound 43. Compound 43 is treated with 0.5 % thfluoroacetic acid in dichloromethane to remove the trityl protecting groups from all the glyceric acid 3- hydroxyl groups to give compound 44. Reaction of compound 44 dissolved in tetrahydrofuran/dimethylformamide with succinic anhydride and then excess paclitaxel in the presence of carbonyldiimidazole and dimethylaminopyridine gives the second generation linear polymer (compound 45) with paclitaxel both pendant and incorporated into the polymer backbone. The amount of pendant paclitaxel can be adjusted by regulating the amount of carbonyldiimidazole and paclitaxel in the reaction. Partial or full substitution of the side chain hydroxyl groups may give the more desirable release and degradation properties.
[328] Additional generations of linear polymers can be prepared by further cycles of adding 3-O-trityl-D-glyceric acid oligomers, succinic anhydride or succinyl dichloride, and paclitaxel onto the backbone of compound 43, deprotecting the trityl ether groups and coupling the pendant paclitaxels to these side chain hydroxyl groups via succinic anhydride or succinyl dichloride. [329] Scheme 8: Compound 40 is the reactive cyclic 3-O-trityl-D-glyceric acid. Compound 41 shows a 3-O-thtyl-glycehc acid pentamer polymerized onto each of the 2 hydroxyl groups of ethylene glycol. Compound 42 shows one of the two chains reacted with succinic anhydride and then paclitaxel, the protected, first generation linear polymer with drug only in the backbone. Compound 43 shows the growing chain with the second 3-O-thtyl-glycehc acid oligomer, the second succinic linker and the second backbone paclitaxel attached. Compound 43 is the protected, second generation linear polymer with only backbone paclitaxels. Compound 44 shows the deprotected, second generation linear polymer with only backbone paclitaxels. Compound 45 shows compound 44 reacted with succinic anhydride and then with paclitaxel to give second generation, drug-bearing linear polymer with paclitaxels pendant and within the polymer backbone.
Figure imgf000081_0001
compound 43
Figure imgf000081_0002
compound 44
Figure imgf000081_0003
compound 45 Example 17
[330] This Example describes the preparation of a linear polymer with D- lactic acid/glycolic acid/D-glyceric acid with paclitaxel pendant and in the polymer chain (second generation linear polymer compound 50). Scheme 9 shows compounds of Example 17.
[331] 3-O-Thtyl-D-glyceric acid is cyclized to its reactive lactone dimer (compound 40). The reactive dimers of lactic acid, glycolic acid and compound 40 in a ratio of 2:2:1 are reacted with excess ethylene glycol in the presence of dimethylaminopyridine to give short chains (5-10 monomers) of lactic acid/glycolic acid/3-O-thtyl-D-glyceric acid oligomers attached to each of its 2 hydroxyl groups (compound 46). It is understood that the ratio and sequence of the hydroxyacids in 46 can be other than as shown in Scheme 9. Compound 46 is reacted with excess succinic anhydride, the excess is removed by precipitation and washing, and the di- succinoyl product is then reacted with an excess of unsubstituted paclitaxel in the presence of carbonyldiimidazole and dimethylaminopyridine to give compound 47 with one paclitaxel at the end of each of the 2 chains, each paclitaxel bearing a free hydroxyl group. Only one of the two chains of compound 47 is shown. A short oligomer of lactic acid/glycolic acid/3-O-trityl-D-glycehc acid is formed on each of the 2 free paclitaxel hydroxyl groups as above to give compound 48. Only the 3-O-trityl- glycehc portion of the second pentamer chain is shown here, not the lactic or glycolic acids. Compound 48 is treated with 0.5 % thfluoroacetic acid in dichloromethane to remove the trityl protecting groups from all the glyceric acid 3-hydroxyl groups to give compound 49. Reaction of compound 49 dissolved in tetrahydrofuran/pyridine with excess succinic anhydride in the presence of dimethylaminopyridine, removal of the excess by precipitation and washing, and then reaction with excess paclitaxel in the presence of carbonyldiimidazole and dimethylaminopyridine gives the second generation linear polymer (compound 50) with paclitaxel both pendant and incorporated into the polymer backbone. The amount of pendant paclitaxel can be adjusted by regulating the amount of carbonyldiimidazole and paclitaxel in the reaction or the ratio of tri- to mono-functional monomers. Partial or full substitution of the side chain hydroxyl groups may give the more desirable release and degradation properties. [332] Additional generations of linear polymers can be prepared by further cycles of adding 3-O-trityl-D-glyceric acid oligomers, succinic anhydride and paclitaxel onto the terminal hydroxyl groups of compound 48, deprotecting the trityl ether groups and coupling the paclitaxels to the hydroxyl groups via succinic anhydride
[333] Scheme 9: Compound 40 shows the reactive cyclic 3-0-trity I -g lyceric acid. Compound 46 shows a lactic acid/glycolic acid/3-O-thtyl-glycehc acid (ratio 2:2:1 ) pentamer polymerized onto each of the 2 hydroxyl groups of ethylene glycol. Compound 47 shows 1 of the growing chains with succinic acid linking paclitaxel into the polymer backbone. Compound 48 shows the growing chain with the second pentamer chain attached (only the 3-O-thtyl-glycehc acid portion of the second pentamer is shown, not the lactic or glycolic acids). Compound 49 shows the deprotected, second generation linear polymer before addition of the terminal and pendant paclitaxels. Compound 50 shows the drug-bearing, second generation linear polymer with pendant and terminal paclitaxels attached via succinic acid linkers.
Figure imgf000084_0001
compound 47
Figure imgf000084_0002
compound 50 Example 18
[334] This Example describes the synthesis of a linear polymer of polyethylene glycol with paclitaxel pendant and in the polymer chain (linear polymer compound 53). Scheme 10 shows compounds of Example 18.
[335] Procedure A. Compound 29, the mono-(acetyl-paclitaxel ester)-di- (paclitaxel ester) of 2-carboxy-glutahc acid, the tri-paclitaxel linker of Example 5, is reacted with an excess of succinyl dichloride, the product precipitated and the excess acid chloride removed by washing to give compound 51 , the activated tri- paclitaxel linker. Compound 51 is reacted with di-hydroxy-polyethylene glycol (average molecular weight 200 (about 5 monomers), Sigma Chemical Company number P3015-5G) to give a linear polymer with paclitaxel both pendant and in the polymer backbone, the terminal paclitaxel bearing a chlorosuccinoyl group, compound 52. Compound 52 is treated with water to hydrolyze the acid chloride groups to carboxylic acid groups, giving the linear polymer compound 53. The length of the polymer can be varied by adjusting the reaction time, temperature and concentrations of the two reacting components.
[336] Procedure B. Alternatively, a mixture of 1 equivalent each of compound 29 and the dihydroxy-polyethylene glycol can be treated with 2 equivalents of succinyl di-chlohde in the presence of dimethylaminopyhdine and then quenched with water to give compound 53.
[337] The pendant paclitaxels have their 2'-hydroxyl groups protected by the labile acetyl ester group. The terminal paclitaxel has its 2'-hydroxyl groups protected by the succinoyl ester group. The acetyl and succinyl groups will likely be the first ester bonds to hydrolyze in the final linear polymer because of the small size of the groups and their pendant (terminal) positions, ultimately releasing free paclitaxel.
[338] Scheme 10: Compound 29 is the tri-paclitaxel linker. Compound 51 is the tri-paclitaxel linker activated on the two unprotected paclitaxels with succinyl chloride. Compound 52 is the linear polymer with polyethylene glycol containing paclitaxel both pendant and in the polymer backbone, the terminal paclitaxel protected with a chloro-succinoyl group. Compound 53 is the linear polymer with polyethylene glycol containing paclitaxel both pendant and in the polymer backbone, the terminal paclitaxel protected with a succinoyl group. Both the succinoyl group and the acetyl group are readily biodegradable.
Figure imgf000086_0002
compound 29
Figure imgf000086_0001
Figure imgf000086_0003
Figure imgf000086_0004
Example 19
[339] This Example describes the preparation of a linear polymer of polyethylene glycol with paclitaxel pendant and in the polymer chain (second generation linear polymer compound 57). Figure 12 shows compounds of Example 10.
[340] Di-hydroxy-polyethylene glycol (average molecular weight 200 (about 5 monomers), Sigma Chemical Company number P3015-5G) is reacted with succinic anhydride in the presence of dimethylaminopyridine to give di-succinoyl-polyethylene glycol, compound 54. Compound 54 is reacted with 2 equivalents of compound 29 (the mono-(acetyl-paclitaxel ester)-di-(paclitaxel ester) of 2-carboxy-glutahc acid, the tri-paclitaxel linker of Example 18) in the presence of carbonyldiimidazole and dimethylaminopyridine to give the first generation linear polymer with paclitaxel both pendant and in the polymer backbone, compound 55. Compound 55 is reacted with sufficient ethylene oxide to add a short oligomer (5-10 monomers) of polyethylene glycol on the free hydroxyl group of the each of the two terminal paclitaxels. The 1 free hydroxyl group of each of the 2 new oligomers is reacted with succinic anhydride the presence of dimethylaminopyridine to give the di-succinoyl compound 56. Compound 56 is reacted with the tri-paclitaxel linker (compound 29) in the presence of carbonyldiimidazole and dimethylaminopyridine to give the second generation linear polymer with paclitaxel both pendant and within the polymer backbone, compound 57. Only one chain of the second generation linear polymer is shown in Scheme 11 for compound 57.
[341] Additional generation linear polymers can be prepared by further cycles of adding polyethylene glycol oligomers, succinic anhydride and tri-paclitaxel linker onto the terminal hydroxyl groups of compound 57. The acetyl group on the pendant paclitaxels will likely be the first ester bonds to hydrolyze in the final linear polymer because of the small size of the groups and their pendant (terminal) positions, ultimately releasing free paclitaxel.
[342] Scheme 11 : Compound 54 shows di-succinoyl polyethylene glycol. Compound 29 is the tri-paclitaxel linker of Example 18. Compound 55 shows the first generation linear polymer with paclitaxel both pendant and within the polymer backbone. Compound 57 shows the drug-bearing, second generation, linear polymer with pendant and terminal paclitaxels attached via succinic acid linkers.
Figure imgf000088_0001
compound 29
Figure imgf000088_0002
Figure imgf000088_0003
Examples 20 and 21 : Dendritic Polymers
Example 20
[343] This Example describes the preparation of a poly-L-lactic acid-glycolic acid dendrimer with paclitaxel pendant and in the polymer backbone (second generation dendrimer, compound 65).
[344] Di-hydroxy-polyethylene glycol of molecular weight 200 (about 5 monomers, Sigma Chemical Company #P3015-5G) is reacted with 2 moles of the reactive cyclic dimer of 3-O-thtyl-D-glyceric acid (compound 40 of Example 19) to give compound 58 with two hydroxyl groups at each end, one of which at each end is protected by the trityl group. Compound 58 is deprotected with 0.5 % trifluoroacetic acid in dichloromethane to give compound 59 with two deprotected hydroxyl groups at each end. Compound 59 is reacted with excess succinic anhydride to succinylate all 4 hydroxyl groups giving compound 60. Compound 60 is reacted with an excess of the tri-paclitaxel linker of Example 19 (compound 29) in the presence of carbonyldiimidazole and dimethylaminopyridine to give the first generation dendrimer with paclitaxel both pendant and in the polymer backbone, compound 61. Here first generation means that the first set of paclitaxels have been incorporated into branches both as pendant and backbone molecules. Only one end of compound 61 (2 of the 4 branches) is shown. Compound 61 is reacted with a sufficient quantity of a mixture of cyclic L-lactic acid dimer and cyclic glycolic acid dimer to give an oligomer of about 5-10 monomers on each of its four free paclitaxel hydroxyl groups, then with 4 moles of the reactive cyclic dimer of 3-O-thtyl-D-glyceric acid (compound 40 of Example 19) to give compound 62. Compound 62 is deprotected with 0.5 % trifluoroacetic acid in dichloromethane to give compound 63 with 8 deprotected hydroxyl groups. Only one of the 4 branches of compound 63 is shown. It is understood that the sequence and ratio of the lactic/glycolic acids in 63 may be different than that shown in Scheme 12. Compound 63 is reacted with excess succinic anhydride to succinylate all 8 hydroxyl groups giving compound 64. Compound 64 is reacted with an excess of the tri-paclitaxel linker of Example 19 (compound 29) in the presence of carbonyldiimidazole and dimethylaminopyridine to give the second generation dendrimer with paclitaxel both pendant and in the polymer backbone, compound 65. Only 2 of the 8 terminal branches of compound 65 are shown. The schematic structure of compound 65 at the bottom of Scheme 12 shows all 8 terminal branches.
[345] Compound 65 can be extended for additional generations by repeating the process described above. The release kinetics of drug can be adjusted by varying the length and composition of the lactate/glycolate oligomer. The acetyl groups on the pendant paclitaxels will likely be the first ester groups of the dendrimer to hydrolyze due to the small size of acetyl and their pendant positions, ultimately releasing free paclitaxel.
[346] Scheme 12: Compound 40 is the reactive dimer of 3-O-trityl-D- glycehc acid. Compound 59 is polyethylene glycol of about 5 monomers reacted with the dimer and deprotected with 0.5 % thfluoroacetic acid in dichloromethane. Compound 29 is the tri-paclitaxel linker. Compound 61 shows one end of compound 59 after reaction with succinic anhydride and the tri-paclitaxel linker. Only 2 of the 4 branches of compound 61 are shown. Compound 61 is the first generation dendrimer with paclitaxel both pendant and in the polymer backbone. Compound 63 shows one of the 4 branches of compound 61 to which has been added a short oligomer of poly-lactic acid/glycolic acid and then a single glyceric acid. Compound 65 shows the two terminal branches of the second generation dendrimer with paclitaxel both pendant and in the polymer backbone. Compound 65 has a total of 8 branches as shown in the schematic structure at the bottom of Scheme 12. In the compound 65 schematic structure the long connecting lines are the polylactate/glycolate oligomers and the short lines are the glyceric acid and succinic acid linkers.
Figure imgf000091_0001
compound 40 compound 59 compound 29 compou
Figure imgf000091_0002
Figure imgf000091_0003
compound 65 schematic structure Example 21
[347] This Example describes the preparation of a poly-L-alanine dendrimer with paclitaxel pendant and in the polymer backbone (second generation dendrimer, compound 71 ). Scheme 13 shows compounds of Example 21.
[348] 1 ,6-Hexanediamine is reacted with 2 equivalents of Nα-Nε -di-Bpoc L- lysine in the presence of dicyclohexylcarbodiimide and then treated with 0.1 % trifluoroacetic acid in dichloromethane to give compound 66 with 4 amino groups. Compound 66 is reacted with an excess of succinic anhydride and then with an excess of the th-paclitaxel linker (compound 29 of Example 19) in the presence of carbonyldiimidazole and dimethylaminopyridine to give compound 67, the first generation dendrimer with paclitaxel both pendant and in the polymer backbone. Here first generation means that the first set of paclitaxels have been incorporated into branches both as pendant and backbone molecules. Compound 67 is reacted with Nα-Bpoc-L-alanine in the presence of carbonyldiimidazole and deprotected with 0.1 % trifluoroacetic acid in dichloromethane to give compound 68 with a single L- alanine containing a single amino group at the end of each of the 4 growing branches. Compound 68 is reacted with Bpoc-L-alanine and deprotected as above for four more cycles to give a penta-alanine oligomer with a free amino group at the end of each of the 4 growing chains, compound 69. Compound 69 is reacted with 4 equivalents of Nα-Nε -di-Bpoc-L-lysine in the presence of dicyclohexylcarbodiimide and then treated with 0.1 % trifluoroacetic acid in dichloromethane to give compound 70 with 8 amino groups. Compound 70 is reacted with an excess of succinic anhydride and then reacted with an excess of the tri-paclitaxel linker (compound 29) in the presence of carbonyldiimidazole and dimethylaminopyridine to give the second generation dendrimer with paclitaxel both pendant and in the polymer backbone, compound 71.
[349] Compound 71 can be further reacted as above to give additional generations of dendrimers. The acetyl groups on the pendant paclitaxels will likely be the first ester groups of the dendrimer to hydrolyze due to the small size of acetyl and their pendant positions, ultimately releasing free paclitaxel.
[350] Scheme 13: Compound 66 is 1 ,6-hexanediamine after reaction with 2 equivalents of Nα-Nε -di-Bpoc-L-lysine and deprotection. Compound 29 is the tri- paclitaxel linker of Example 10. Compound 67 shows the reaction of compound 66 with excess succinic anhydride followed by reaction with 4 equivalents of compound 29, to give the first generation dendhmer (4 branches) with paclitaxel both pendant and in the polymer backbone. Compound 71 shows the second generation dendrimer with paclitaxel both pendant and in the polymer backbone. Only 1of the 4 branches of compound 71 is shown. Compound 71 has 4-poly-alanine chains and 8 terminal paclitaxels. The schematic structure of compound 71 is shown at the bottom of Scheme 13.
Figure imgf000094_0001
compound 71 schematic structure Examples 22 and 23: Star and dendritic polymers with polyethylene glycol.
Example 22
[351] This Example describes the preparation of a star polymer with 16 arms of polyethylene glycol with paclitaxel pendant and in the backbone (second phase star polymer compound 76). Scheme 14 shows compounds of Example 22.
[352] The tetrahydroxyl core molecule pentaerythritol is reacted with an excess of the anhydride of 2,2-dihydroxymethyl-propanoic acid dimethylacetal in the presence of dimethylaminopyridine to give pentaerythritol substituted with 2,2- dihydroxymethyl-propanoic acid dimethylacetal on each of its 4 hydroxyl groups. Treatment of this product with dilute sulfuric acid in methanol deprotects the 8 new hydroxyl groups to give O1,O2,O3,O4-tetra-(2,2-dihydroxymethyl-propanoyl)- pentaerythritol, the first generation star core (compound 1 of Example 10). Treatment of this first generation core with an excess of the anhydride of 2,2- dihydroxymethyl-propanoic acid dimethylacetal in the presence of dimethylaminopyridine and deprotection with dilute sulfuric acid in methanol gives the second generation star core (compound 2 of Example 10, shown in Scheme 14) with 1 hydroxyl group at the end of each of its 16 arms.
[353] Compound 2 is reacted with sufficient ethylene oxide to add a short oligomer (5-10 monomers) of polyethylene glycol to each of its 16 hydroxyl groups giving compound 72. The free hydroxyl group of each of the 16 new oligomers is reacted with succinic anhydride in the presence of dimethylaminopyridine to give the succinoyl compound 73. Compound 73 is reacted with the tri-paclitaxel linker (compound 29 of Example 21 ) in the presence of carbonyldiimidazole and dimethylaminopyridine to give the first generation star polymer with paclitaxel both pendant and within the polymer backbone, compound 74. Only one chain of the first generation star polymer (compound 74) is shown in Scheme 14. Compound 74 is reacted with 16 equivalents of the cyclic lactone of glycolic acid (one for each arm) to give compound 75. Compound 75 is reacted with ethylene oxide, succinic anhydride and the tri-paclitaxel linker as above to give the second generation star polymer containing paclitaxel both pendant and within the polymer backbone, compound 76. [354] Additional generation linear polymers can be prepared by further cycles of adding glycolic acid, polyethylene glycol oligomers, succinic anhydride and tri- paclitaxel linker onto the terminal hydroxyl groups of compound 74. The pendant paclitaxels (with the exception of the polymer chain "terminal" paclitaxels, if the growth is stopped at this stage) have their 2'-hydroxyl groups protected by the labile acetyl ester group. This will likely be the first ester bond to hydrolyze in the final star polymer because of the small size of the acetyl group and its pendant position, ultimately releasing free paclitaxel.
[355] Scheme 14: Compound 2 is the second generation star core with 16 free hydroxyl groups with only 1 of the initial 4 arms (each bearing 4 hydroxyl groups) shown. Compound 72 shows a polyethylene glycol pentamer polymerized onto 1 of the 16 hydroxyl groups of compound 2, i.e., one arm of the 16 arm star polymer. Compound 29 is the tri-paclitaxel linker with two free hydroxyl groups. Compound 74 shows the reaction of compound 73 with succinic anhydride followed by reaction with the tri-paclitaxel linker in the presence of carbonyldiimidazole and dimethylaminopyridine. Compound 74 is the first generation, polyethylene glycol star polymer with paclitaxel both pendant and within the polymer backbone. Compound
75 shows compound 74 reacted with the cyclic lactone of glycolic acid. Compound
76 shows one of the 16 arms of the second generation, drug-bearing polymer with paclitaxels pendant and within the polymer backbone.
Figure imgf000097_0001
compound 2 compound 72 compound 73
Figure imgf000097_0002
compound 29
Figure imgf000097_0003
Figure imgf000097_0004
Figure imgf000097_0005
Example 23
[356] Poly-L-lactic acid-glycolic acid dendrimer with paclitaxel pendant and in the polymer backbone (second generation dendrimer, compound 88). Scheme 15 shows compounds of Example 23.
[357] In this dendrimer the backbone and pendant paclitaxels are incorporated at different sites separated by short polyethylene glycol oligomers. New protected linkers and protected paclitaxel are also employed.
[358] Di-hydroxy-polyethylene glycol of molecular weight 200 (about 5 monomers, Sigma Chemical Company #P3015-5G) is reacted with 2 moles of the reactive cyclic dimer of 3-O-thtyl-D-glyceric acid (compound 40 of Example 20) to give compound 58 of Example 20 with two hydroxyl groups at each end, one of which at each end is protected by the trityl group. Compound 58 is deprotected with 0.5 % trifluoroacetic acid in dichloromethane to give compound 59 of Example 20 (and Scheme 15) with two deprotected hydroxyl groups at each end. Compound 59 is reacted with excess succinic anhydride to succinylate all 4 hydroxyl groups giving compound 60 of Example 20. Compound 60 is reacted with an excess of 2-O- napthylmethyl-paclitaxel in the presence of carbonyldiimidazole and dimethylaminopyridine and deprotected with 1 ,2-dichloro-4,5-dicyanoquinone to give a first generation dendrimer with 4 branches and paclitaxel only in the polymer backbone, compound 78. Only one end of compound 78 (2 of the 4 branches) is shown. Compound 78 is reacted with 2-O-napthylmethyl-glycolic acid (compound 79) in the presence of carbonyldiimidazole and dimethylaminopyridine and deprotected with 1 ,2-dichloro-4,5-dicyanoquinone to give compound 80. Compound 80 is reacted with sufficient ethylene oxide to give short oligomers (5-10 monomers) on each of its 4 terminal hydroxyl groups to give compound 81. Compound 81 is reacted with 4 equivalents (1 for each free hydroxyl group) of the reactive cyclic dimer of 3-O-thtyl-D-glyceric acid (compound 40 of Example 20 and Scheme 15) and then with sufficient ethylene oxide to give compound 82.
[359] Compound 82 is reacted with 2-O-napthylmethyl-D-glycehc acid and deprotected with 1 ,2-dichloro-4,5-dicyanoquinone to give compound 83. Compound 83 is reacted with an excess of succinic anhydride and then with an excess of 2-O- napthylmethyl-paclitaxel in the presence of carbonyldiimidazole and dimethylaminopyridine, and deprotected with 1 ,2-dichloro-4,5-dicyanoquinone (of Example 10) to give compound 84, a dendrimer with 8 terminal branches and 2 paclitaxels in each branch only in the backbone. Only 1 of the 8 terminal branches of compound 84 is shown in Scheme 15.
[360] Compound 84 is reacted with 4 equivalents of the cyclic lactone dimer of 3-O-napthylmethyl-D-glyceric acid and the naphthylmethyl groups removed by treatment with 1 ,2-dichloro-4,5-dicyanoquinone to give compound 85. Compound 85 is reacted with ethylene oxide and then the cyclic lactone dimer of 3-O-thtyl-D- glyceric acid to give compound 86. Compound 86 is reacted with ethylene oxide and all the trityl groups are removed with 0.5 % trifluoroacetic acid in dichloromethane to give compound 87. Compound 87 is reacted with excess succinic anhydride and then excess paclitaxel in the presence of carbonyldiimidazole and dimethylaminopyridine to give compound 88, a second generation dendritic polymer with 8 terminal branches containing 2 backbone paclitaxels and 1 pendant paclitaxel in each terminal branch. The 4 branches of the first generation dendhmer each have 1 backbone and 1 pendant paclitaxel in addition to the ones in the 8 terminal branches.
[361] Scheme 15: Compound 40 is the reactive lactone dimer of 3-O-trityl- D-glyceric acid. Compound 59 is polyethylene glycol of about 5 monomers reacted with the dimer and deprotected with 0.5 % thfluoroacetic acid in dichloromethane. Compound 77 is the reactive lactone dimer of 3-O-napthylmethyl-D-glyceric acid. Compound 78 shows one end of compound 59 after reaction with succinic anhydride, 2-O-napthylmethyl-paclitaxel, and deprotection with 1 ,2-dichloro-4,5- dicyanoquinone. Only 2 of the 4 branches of compound 78 are shown. Compound 78 is a first generation dendrimer with 4 branches containing paclitaxel only in the polymer backbone. Compound 80 shows compound 78 after reaction with 2-O- napthylmethyl-glycolic acid (compound 79) and removal of the naphthylmethyl group. Compound 82 shows compound 80 extended with ethylene oxide, the cyclic lactone dimer of 3-O-thtyl-D-glyceric acid, and then ethylene oxide again. Compound 83 shows compound 82 after reaction with the reactive lactone dimer of 3-O- napthylmethyl-D-glyceric acid, then deprotection with 1 ,2-dichloro-4,5- dicyanoquinone to give a first generation dendrimer with 4 branches and paclitaxel only in the polymer backbone. The terminal glyceric acids are the branch points to construct the 8 branch dendrimer. Only 1 of the 4 branches of compound 83 is shown. Compound 84 shows compound 83 after reaction with succinic anhydride, 2- O-napthylmethyl-paclitaxel, and deprotection. Only one of the 8 terminal branches of 84 is shown. Compound 86 shows compound 84 after reaction with 2-O- napthylmethyl-glycolic acid, deprotection, reaction with ethylene oxide and then reaction with the cyclic lactone dimer of 3-O-thtyl-D-glyceric acid. Only 1 of the 8 terminal branches of compound 86 is shown. Compound 87 shows compound 86 after reaction with ethylene oxide and removal of all trityl groups with 0.5 % trifluoroacetic acid in dichloromethane. Compound 88 shows compound 87 after reaction with succinic anhydride and excess paclitaxel.
Figure imgf000100_0001
compound 40 compound 59 compound 77 compound 79
Figure imgf000100_0002
compound 84 compoun
Figure imgf000101_0001
Figure imgf000101_0002
Examples 24-26: Star, linear and dendritic polymers with polv-L-aspartic acid
Example 24
[362] This Example describes the preparation of a star polymer with 16 arms of poly-L-aspartic acid with paclitaxel pendant and in the polymer backbone (second generation star polymer compound 89). Scheme 16 shows the star polymer of Example 24.
[363] Substituting the β-trityl ester of L-aspartic acid N-carboxyanhydride for the γ-thtyl ester of L-glutamic acid N-carboxy anhydride in Example 11 gives a star polymer with 16 arms of poly-L-aspartic acid with paclitaxel pendant and in the polymer backbone (second generation star polymer compound 89). [364] Scheme 16: Only 1 arm of the 16-arm star polymer is shown.
Figure imgf000102_0001
Example 25
[365] This Example describes the preparation of a linear polymer with poly-L- aspartic acid/L-alanine with paclitaxel pendant and in the polymer backbone (second generation linear polymer compound 90). Scheme 17 shows the linear polymer of Example 25.
[366] Substituting the β-trityl ester of L-aspartic acid N-carboxyanhydride for the γ-thtyl ester of L-glutamic acid N-carboxy anhydride in Example 15 gives a linear polymer of poly-L-aspartic acid/L-alanine with paclitaxel pendant and in the polymer backbone (second generation linear polymer compound 90).
[367] Scheme 17: The linear polymer of Example 25, compound 90.
Figure imgf000102_0002
compound 90
Example 26
[368] This Example describes the preparation of a poly-L-aspartic acid/L- alanine dendrimer with paclitaxel pendant and in the polymer backbone (second generation dendrimer, compound 96). Scheme 18 shows compounds of Example 26.
[369] 1 ,6-Hexanediamine is reacted with 2 equivalents of Nα-Nε -di-Bpoc L- lysine in the presence of dicyclohexylcarbodiimide and then treated with 0.1 % trifluoroacetic acid in dichloromethane to give compound 66 with 4 amino groups. Compound 66 is reacted with Nα-Bpoc-L-alanine in the presence of dicyclohexylcarbodiimide and then deprotected with 0.1 % trifluoroacetic acid in dichloromethane. This reaction is repeated and the product reacted with Nα-Fmoc-β- trityl-L-aspartic acid and the Fmoc group removed with dry piperidine in dimethylformamide. Two more L-alanines are added and deprotected as above to give compound 91 with 4 penta-amino acid branches terminating in amino groups. Only 2 of the 4 branches of compound 91 are shown in Scheme 18. Compound 91 is reacted with an excess of succinic anhydride, then with 2-O-napthylmethyl- paclitaxel in the presence of carbonyldiimidazole and dimethylaminopyhdine and then deprotected with 1 ,2-dichloro-4,5-dicyanoquinone to give compound 92, the first generation dendrimer with paclitaxel only in the backbone of each of the 4 branches. Only 1 branch of compound 92 is shown in Scheme 18. Compound 92 is reacted with Nα-Nε -di-Fmoc-L-lysine in the presence of diclyclohexylcarbodiimide, and deprotected with dry piperidine in dimethylformamide to give compound 93. Compound 93 is extended with a pentamer of 4 alanines and 1 β-thtyl-L-aspartic acid to give compound 94, a dendrimer with 8 terminal branches. Compound 94 is deprotected with 0.5 % trifluoroacetic acid in dichloromethane, removing all the trityl groups, to give compound 95. Compound 95 is reacted with an excess of succinic anhydride and then with an excess of paclitaxel in the presence of carbonyldiimidazole and dimethylaminopyridine to give compound 96, the second generation dendrimer with 8 branches with both pendant and terminal paclitaxels.
[370] Compound 94 can be further reacted as above to give additional generations of dendrimers.
[371] Scheme 18: Compound 66 is 1 ,6-hexanediamine after reaction with 2 equivalents of Nα-Nε -di-Bpoc-L-lysine and deprotection. Compound 91 shows the addition of a pentapeptide of alanine and β-O-thtyl-aspartic acid to compound 66. Only 2 of the 4 branches of compound 91 are shown. Compound 92 shows the result of the reaction of compound 91 with succinic anhydride and then 2-O- napthylmethyl-paclitaxel followed by deprotection of the paclitaxel 2-hydroxyl group. Compound 92 is the first generation dendrimer (4 branches) with paclitaxel only in the polymer backbone. Only 1 of the 4 branches of compound 92 is shown. Reaction of compound 92 with Nα-Nε -di-Fmoc-L-lysine, deprotection of the lysine amino groups and addition of a pentapeptide of alanine and β-O-trityl-aspartic acid gives compound 94. Compound 94 contains the 8 growing branches of the second generation dendrimer. Compound 95 shows the result of deprotection of all the aspartic acid β-carboxyl groups. Compound 96 shows the result of succinylation of the free amino groups followed by reaction with an excess of paclitaxel in the presence of carbonyldiimidazole and dimethylaminopyhdine. Compound 96 is the second generation dendrimer with paclitaxel both pendant and in the polymer backbone.
Figure imgf000105_0001
compound 92
Figure imgf000105_0002
Figure imgf000105_0003
compound 95
Figure imgf000105_0004
Examples 27-29: Star, linear and dendritic polymers with polv-L-serine (pendant OH) , poly-L-cysteine (pendant SH), and poly-L lysine (pendant NH2).
Example 27
[372] This Example describes the preparation of a star polymer with 16 arms of poly-L-serine with paclitaxel pendant and in the polymer backbone (second generation star polymer compound 97). Scheme 19 shows compound 97.
[373] Substituting 2-O-trityl-L-sehne N-carboxyanhydride for the β-trityl-L- aspartic acid N-carboxyanhydride in Example 24 and reacting the deprotected serine hydroxyl groups with succinyl dichloride and then with paclitaxel gives a star polymer with 16 arms of poly-L-serine with paclitaxel pendant and in the polymer backbone (second generation star polymer compound 97). Scheme 19 shows 1 of the 16 arms of the star polymer 97 of Example 27.
[374] Scheme 19: The star polymer of Example 18, compound 97.
Figure imgf000106_0001
compound 97
Figure imgf000106_0002
Example 28
[375] This Example describes the preparation of a linear polymer with poly-L- cysteine/L-alanine with paclitaxel pendant and in the polymer backbone (compound 102). Scheme 20 shows compounds of Example 28.
[376] Nα-Bpoc-L-cysteine is reacted with excess sebacic acid mono-acid chloride mono-t-butylester to give Nα-Bpoc-S-(O-t-butyl-sebacoyl)-L-cysteine shown in Scheme 20. Hexanediamine is reacted with Nα-Bpoc-L-alanine in the presence of dicyclohexylcarbodiimide and the Bpoc group removed with 0.1 % thfluoroacetic acid in dichloromethane. The reaction and deprotection is repeated once with Nα-Bpoc-L- alanine, once with Nα-Bpoc-S-(O-t-butyl-sebacoyl)-L-cysteine, and twice with Nα- Bpoc-L-alanine to give diaminohexane acylated on each amino group with a pentamer containing one S-(O-t-butyl-sebacoyl)-L-cysteine, compound 98. Compound 98 is reacted with an excess of succinic anhydride and then with 2-O- napthylmethyl-paclitaxel in the presence of carbonyldiimidazole and dimethylaminopyridine and deprotected with 1 ,2-dichloro-4,5-dicyanoquinone to give compound 99. Compound 99 with two free paclitaxel hydroxyl groups is reacted with the same sequence of protected cysteine and alanine followed by amino group deprotection and succinylation, as above, to give compound 100. Compound 100 is deprotected with 25 % trifluoroacetic acid in dichloromethane to give compound 101 with both terminal and pendant carboxylic acid groups. Compound 101 is reacted with excess paclitaxel in the presence of cabonyldiimidazole and dimethylaminopyridine to give a linear polymer with paclitaxel both pendant and in the polymer backbone, compound 102.
[377] The linear polymer 100 can be extended to any length by further cycles of reactions as described above.
[378] Scheme 20: Cys(Seb-O-tBu) is S-(O-t-butyl-sebacoyl)-L-cysteine. Cys(Seb-OH) is S-sebacoyl-L-cysteine. Compound 98 shows a pentapeptide containing one protected S-sebacoyl-cysteine added to each amino group of diaminohexane. One peptide chain structure is fully drawn, one is shown with abbreviations for the amino acids. The amino acid abbreviations are written with their carboxyl groups on the left and amino groups on the right, in contrast to the normal convention. Compound 99 shows compound 98 after reaction with succinic anhydride and 2-O-napthylmethyl-paclitaxel followed by removal of the O- naphthylmethyl group. Compound 100 shows compound 99 after addition of a second pentapeptide and succinylation. Compound 101 shows compound 100 after removal of the t-butyl groups. Compound 102 shows compound 101 after addition of paclitaxel.
Figure imgf000108_0001
hexane diamine N-Bpoc-S-fO-t-butyl-sebacoylJ-L-cysteine
Figure imgf000108_0002
compound 101
Figure imgf000108_0003
compound 102
Figure imgf000108_0004
Example 29
[379] This Example describes the preparation of a dendrimer of poly-L- Lysine/L-alanine with paclitaxel pendant and in the polymer backbone (compound 108). Scheme 21 shows compounds of Example 29.
[380] Hexanediamine is reacted with Nα-Nε-di-Bpoc-L-lysine in the presence of dicyclohexylcarbodiimide and deprotected with 0.1 % trifluoroacetic acid in dichloromethane to give compound 66 of Example 21. Compound 66 is reacted with Nα-Fmoc-L-alanine in the presence of dicyclohexylcarbodiimide and deprotected with dry piperidine in dimethylformamide. The reaction and deprotection is repeated once with Nα-Fmoc-L-alanine, once with Nα-Fmoc-Nε-Bpoc-L-lysine, and twice with Nα- Fmoc-L-alanine to give compound 103 with 4 pentapeptide branches. Only 2 of the 4 branches are shown in Scheme 21. Compound 103 is reacted with excess succinic anhydride and then with 2-O-napthylmethyl-paclitaxel and deprotected with 1 ,2-dichloro-4,5-dicyanoquinone to give compound 104 with paclitaxel in the backbone only of each of the 4 branches. Only 1 of the 4 branches of compound
104 is shown in Scheme 21. Compound 104 is reacted with Nα-Nε-di-Fmoc-L-lysine and deprotected with dry piperidine in dimethylformamide to give compound 105 with the added lysine providing the branch points for the 8 new branches. Compound
105 is extended with 8 pentapeptides to give compound 106 as described above. Compound 106 is deprotected with 0.1 % trifluoroacetic acid in dichloromethane to give compound 107 with a total of 24 pendant and terminal amino groups. Compound 107 is reacted with succinic anhydride and then with excess paclitaxel in the presence of carbonyldiimidazole and dimethlaminopyhdine to give the second generation dendrimer 108 which contains paclitaxel both pendant and in the backbone.
[381] The dendrimer 106 can be extended to any length and number of branches by further cycles of reactions as described above.
[382] Scheme 21 : Compound 66 shows the result of reacting of Nα-Nε-di- Bpoc-L-lysine with hexanediamine and deprotecting with 0.1 % trifluoroacetic acid in dichloromethane. Compound 103 shows the result of adding a pentapeptide containing Nε-Bpoc-L-lysine to compound 66. Only 2 of the 4 branches of compound 103 are shown. Compound 104 shows the result of adding succinic anhydride and then paclitaxel to compound 103. Compound 104 has paclitaxel only in the backbone of its 4 branches. Only 1of the 4 branches is shown. Compound 105 shows the result of reacting compound 104 with Nα-Nε-di-Fmoc-L-lysine followed by deprotection. The added lysine forms the branch points for the 8 new branches. Compound 106 shows the results of adding a pentapeptide containing Nε-Bpoc-L- lysine to the amino groups of compound 105. Compound 107 shows the result of deprotection of all Nε-amino groups of compound 106. Compound 108 shows the result of succinylation of all amino groups of compound 107 followed by addition of paclitaxel. Compound 108 is a second generation dendrimer with 8 branches, each branch containing paclitaxel both pendant and in the polymer backbone.
Figure imgf000111_0001
compound 105
Figure imgf000111_0002

Claims

1. A composition comprising a polymer selected from star polymers, dendrimers, and hyperbranched polymers, the polymer comprising a chemical moiety covalently linked to at least one branch of the polymer, the chemical moiety being linked through at least one covalent bond, wherein the chemical moiety forms a pharmaceutically active agent upon degradation of the at least one covalent bond, wherein the chemical moiety is present in one or both of a backbone and a side chain of the polymer; and wherein the polymer is less soluble in an aqueous medium than is the free form of the pharmaceutically active agent.
2. The composition of claim 1 , wherein the at least one covalent bond is selected from ester, anhydride, amide, carbonate, and thioester bonds.
3. The composition of claim 1 , wherein the chemical moiety is incorporated in the backbone of the polymer.
4. The composition of claim 1 , wherein the chemical moiety is present in the side chain of the polymer.
5. The composition of claim 1 , wherein the at least one covalent bond is hydrolytically degradable.
6. The composition of claim 1 , wherein the chemical moiety is covalently linked via at least one linking group.
7. The composition of claim 6, wherein the at least one linking group is selected from aliphatic C4-C2O chains, polylactide, poly(lactide-co-galactide), polyethylene glycol, polycaprolactone, polyethyleneimine, polycaprolactone/polyethyleneimine, and phospholipids.
8. The composition of claim 6, wherein the linking group is biodegradable.
9. The composition of claim 1 , wherein the polymer is biodegradable.
10. The composition of claim 1 , wherein the pharmaceutically active agent released is selected from taxanes, limus derivatives, and non-steroidal antiinflammatory agents.
11. The composition of claim 1 , wherein the pharmaceutically active agent released is selected from paclitaxel, sirolimus, everolimus, biolimus, zotarolimus, and AP23573.
12. The composition of claim 1 , wherein the pharmaceutically active agent is hydrophobic.
13. The composition of claim 1 , wherein the polymer has a Tg greater than 500C.
14. The composition of claim 1 , wherein the number average molecular weight of the polymer is 25,000 Da or less.
15. The composition of claim 1 , wherein the number average molecular weight of the polymer ranges from 25,000 Da to 100,000 Da.
16. The composition of claim 1 , wherein the polymer is present in an amount ranging from 40% to 95% by weight relative to the total weight of the composition.
17. The composition of claim 1 , wherein the polymer is a star polymer and each branch of the star polymer has substantially the same molecular weight and length.
18. The composition of claim 1 , wherein the polymer is a star polymer and branches of the star polymer have different molecular weights and different lengths.
19. The composition of claim 1 , wherein the polymer is a star polymer comprising a plurality of branches of substantially the same molecular weight and length and one branch of substantially higher molecular weight and length.
20. The composition of claim 1 , wherein the polymer is a star polymer the molecular weight of one or more branches of the star polymer ranges from 10,000 Da to 100,000 Da.
21. The composition of claim 1 , wherein the polymer comprises two or more different chemical moieties that form pharmaceutically active agents.
22. The composition of claim 21 , wherein one of the chemical moieties comprises a first chemical moiety that forms an antiproliferative pharmaceutically active agent, and a second chemical moiety that forms an anti-inflammatory agent.
23. The composition of claim 22, further comprising a third chemical moiety that forms a healing promoter.
24. The composition of claim 1 , wherein the biodegradable polymer is present in an amount ranging from 40% to 95% by weight relative to the total weight of the composition.
25. An implantable medical device having at least one coating covering at least a portion of the device, the at least one coating comprising the composition of claim 1.
26. The device of claim 25, wherein the chemical moiety is present in a dose density ranging from 0.05 to 10 μg/mm2.
27. The device of claim 25, wherein the device is implantable into a mammalian lumen.
28. The device of claim 26, wherein the device is a stent.
29. The device of claim 28, wherein the coating forms a conformal coating around all surfaces of the stent.
30. The device of claim 25, wherein the at least one coating comprises at least two coatings to provide a multi-layered structure.
31. The device of claim 30, wherein each of the at least two coatings provides a different chemical moiety that forms a different pharmaceutically active agent.
32. The device of claim 31 , wherein at least one chemical moiety forms an antiproliferative pharmaceutically active agent.
33. The device of claim 31 , wherein at least one chemical moiety forms an anti-inflammatory pharmaceutically active agent.
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