WO2006132950A2 - Polymeres therapeutiques et leurs procedes d'utilisation - Google Patents

Polymeres therapeutiques et leurs procedes d'utilisation Download PDF

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WO2006132950A2
WO2006132950A2 PCT/US2006/021395 US2006021395W WO2006132950A2 WO 2006132950 A2 WO2006132950 A2 WO 2006132950A2 US 2006021395 W US2006021395 W US 2006021395W WO 2006132950 A2 WO2006132950 A2 WO 2006132950A2
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Prior art keywords
therapeutic
polymer
composition
diol
acid
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PCT/US2006/021395
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English (en)
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WO2006132950A3 (fr
Inventor
William G. Turnell
Zaza D. Gomurashvili
Ramaz Katsarava
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Medivas, Llc
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Priority to JP2008514885A priority Critical patent/JP2008542393A/ja
Priority to AU2006255262A priority patent/AU2006255262A1/en
Priority to CA002610745A priority patent/CA2610745A1/fr
Priority to EP06760640A priority patent/EP1906976A4/fr
Publication of WO2006132950A2 publication Critical patent/WO2006132950A2/fr
Publication of WO2006132950A3 publication Critical patent/WO2006132950A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/0008—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
    • A61K48/0025—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid
    • A61K48/0041—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid the non-active part being polymeric
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • 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
    • A61K47/58—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 by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
    • 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
    • A61K47/595—Polyamides, e.g. nylon
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G71/00—Macromolecular compounds obtained by reactions forming a ureide or urethane link, otherwise, than from isocyanate radicals in the main chain of the macromolecule
    • C08G71/04—Polyurethanes
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L77/00—Compositions of polyamides obtained by reactions forming a carboxylic amide link in the main chain; Compositions of derivatives of such polymers
    • C08L77/12—Polyester-amides

Definitions

  • the invention relates, in general, to drug delivery systems and, in particular, to polymer delivery compositions that incorporate a therapeutic agent into a biodegradable polymer backbone.
  • the drug is physically matrixed by dissolving or melting with a polymer.
  • Another approach has also been reported in which a drug is chemically attached as a side group to a polymer.
  • compositions represent synthetic polymers that combine therapeutic or palliative bioactivity with desirable mechanical and physical properties, and degrade into useful therapeutic active compounds. In other words, the compositions have the activity of a drug, but have the physical properties of a material.
  • NSAIDs non-steroidal anti- inflammatory drugs
  • hydrogel-type materials can be used to shepherd various medications through the stomach and into the more alkaline intestine.
  • Hydrogels are cross-linked, hydrophilic, three-dimensional polymer networks that are highly permeable to entrap molecules, which can be released in vivo through their weblike surfaces.
  • different internal and external stimuli e.g., changes inpH, application of a magnetic or electric field, variations in temperature, and ultrasound irradiation
  • the rate of entrapped drug release is generally determined by the cross-linking level of the polymer network.
  • the present invention is based on the premise that poly(ester amide) (PEA), poly(ester urethane) (PEUR), and poly(ester urea) (PEU) polymers, can be formulated as polymer delivery compositions that incorporate a therapeutic diol or di-acid into the backbone of the polymer for time release of the therapeutic agent in a consistent and reliable manner by biodegradation of the polymer.
  • the invention provides a biodegradable therapeutic polymer composition in which at least one therapeutic diol or di-acid is incorporated into the backbone of one or more biodegradable polymers.
  • the biodegradable polymer of the composition contains or is a blend of at least one PEA having a structural formula described by structural formula (I),
  • R 1 is independently selected from residues of ⁇ , ⁇ -bis(4-carboxyphenoxy)-(C 1 -C 8 ) alkane, 3,3'-(alkanedioyldioxy)dicinnamic acid or 4,4'-(alkanedioyldioxy)dicinnamic acid, (C 2 - C 20 ) alkylene, (C 2 -C 2 o) alkenylene or saturated or unsaturated residues of therapeutic di-acids;
  • the R 3 S in individual n monomers are independently selected from the group consisting of hydrogen, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -Ci 0 ) aryl (C 1 -C 6 ) alkyl, and -(CEb) 2 S(CH 3 ); and R 4 is independently selected from the group
  • R 1 and R 4 are a therapeutic amount of the residue of a therapeutic di-acid and diol, respectively, [0013] or at least one PEA polymer having a chemical formula described by structural formula IE:
  • R 1 is independently selected from residues of ⁇ , ⁇ -bis(4- carboxyphenoxy ⁇ Q-Cs) alkane, 3,3'-(alkanedioyldioxy)dicinnamic acid or 4,4'- (alkanedioyldioxy)dicinnamic acid, (C 2 - C 20 ) alkylene, (C 2 -C 2 o) alkenylene or a saturated or unsaturated residues of therapeutic di-acids; each R 2 is independently hydrogen, (C 1 - C 12 ) alkyl or (Ce-C 10 ) aryl or a protecting group; the R 3 S in individual m monomers are independently selected from the group consisting of hydrogen, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2
  • R 4 is independently selected from the group consisting Of (C 2 -C 20 ) alkylene, (C 2 -C 20 ) alkenylene, (C 2 -C 8 ) alkyloxy (C 2 -C 20 ) alkylene, bicyclic-fragments of l,4:3,6-dianhydrohexitols of structural formula (II), residues of saturated or unsaturated therapeutic diols and combinations thereof, except that at least one of R 1 and R 4 in at least one of the m monomers is the residue of a therapeutic di-acid or diol, respectively,
  • n ranges from about 5 to about 150; wherein R 3 S in independently selected from the group consisting of hydrogen, (Ci-C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -Ci 0 ) aryl (C 1 -C 6 ) alkyl, and -(CH 2 ) 2 S(CH 3 ) and; R 4 is selected from the group consisting of (C 2 -C 20 ) alkylene, (C 2 -C 20 ) alkenylene or alkyloxy, and bicyclic-fragments of 1,4:3,6- dianhydrohexitols of structural formula (II), or fragments of saturated or unsaturated therapeutic diols; and R 6 is independently selected from (C 2 -C 20 ) alkylene, (C 2 -C 20 ) alkenylene or alkyloxy, bicyclic-fragments of l,4:3,6
  • R 2 is independently selected from hydrogen, (C 6 -C 10 ) aryl (C 1 -C 6 ) alkyl, or a protecting group; the R 3 S in an individual m monomer are independently selected from the group consisting of hydrogen, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -Ci 0 ) ary ⁇ d-Co) alkyl, and -(CHa) 2 S(CH 3 ); R 4 is selected from the group consisting of (C 2 -C 20 ) alkylene, (C 2 -C 20 ) alkenylene or alkyloxy, bicyclic- fragments of l,4:3,6-dianhydrohexitols of structural formula (II) or fragments of saturated
  • n is about 10 to about 150; each R 3 S within an individual n unit are independently selected from hydrogen, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -C 10 ) aryl (Q-C 6 )alkyl, , and -(CH 2 ) 2 S(CH 3 ); R 4 is independently selected from (C 2 -C 20 ) alkylene, (C 2 -C 20 ) alkenylene, (C 2 -C 8 ) alkyloxy (C 2 -C 20 ) alkylene, a residue of a saturated or unsaturated therapeutic diol; or a bicyclic-fragment of a l,4:3,6-dianhydrohexitol of structural formula (II), and combinations thereof, except that the R 4 within at least one of the n units is the residue of a therapeutic diol;
  • each R 2 is independently hydrogen, (C 1 -C 12 ) alkyl or (C 6 -C 10 ) aryl; the R 3 S within an individual m monomer are independently selected from hydrogen, (Ci-C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -C 10 ) aryl (C 1 -C 6 ) alkyl, and -(CH 2 ) 2 S(CH 3 ); each R 4 is independently selected from (C 2 -C 20 ) alkylene, (C 2 -C 20 ) alkenylene, (C 2 -C 8 ) alkyloxy (C 2 - C 20 ) alkylene, a residue of a saturated or unsaturated therapeutic diol; or a bicyclic- fragment of
  • the invention provides methods for administering a therapeutic diol or di-acid to a subject by administering to the subject an invention therapeutic polymer composition containing one or more polymers of formula(s) (I) or (HI)-(VII) in the form of a liquid dispersion, which composition biodegrades by enzymatic action to release the therapeutic diol or di-acid over time.
  • the invention provides a bis-nucleophilic compound wherein the compound is a di(amino acid)-estradiol -3,17- ⁇ -diester, or salt thereof.
  • Fig. 1 is showing a 1 H NMR (500 MHz, DMSO-J 6 ) spectrum of 17 ⁇ -estradiol based monomer (compound 5 of Example 1).
  • Fig. 2 is a trace of differential scanning calorimetry (DSC) of the therapeutic PEA polymer formed in Example 1, showing a first heating curve, with sharp melting endotherm.
  • Fig. 3 is showing a 1 H NMR (500 MHz, DMSO-J 6 ) spectrum of an invention 17 ⁇ -estradiol-based PEA copolymer (scheme 5) formed in Example 1.
  • the invention is based on the discovery that biodegradable poly(ester amide) (PEA), and poly(ester urethane) (PEUR) polymers can be used to create a therapeutic polymer composition for in vivo delivery of at least one therapeutic diol or di-acid contained within a biodegradable polymer backbone.
  • the therapeutic PEA, PEUR and PEU polymer compositions biodegrade in vivo by enzymatic action at the surface so as to release therapeutic diols or di-acids from the polymer backbone in a controlled manner over time.
  • the invention compositions are stable, and can be lyophilized for transportation and storage and can be redispersed for administration.
  • the invention therapeutic polymer compositions provide for high loading of the therapeutic diol or di-acid, as well as optional bioactive agents.
  • a "therapeutic diol or di-acid” means any diol or di-acid molecule, whether synthetically produced, or naturally occurring (e.g., endogenously) that affects a biological process in a mammalian individual, such as a human, in a therapeutic or palliative manner when administered to the mammal.
  • the term "residue of a therapeutic di-acid” means a portion of such a therapeutic di-acid, as described herein, that excludes the two carboxyl groups of the di-acid.
  • the term “residue of a therapeutic diol” means a portion of a therapeutic diol, as described herein, that excludes the two hydroxyl groups of the diol.
  • the corresponding therapeutic di-acid or diol containing the "residue” thereof is used in synthesis of the polymer compositions.
  • the residue of the therapeutic di-acid or diol is reconstituted in vivo (or under similar conditions of pH, aqueous media, and the like) to the corresponding diol or di-acid upon release from the backbone of the polymer by biodegradation in a controlled manner that depends upon the properties of the particular PEA, PEUR or PEU polymer selected to fabricate the composition, which properties are well known in the art and as described herein, for example in the Examples.
  • bioactive agent means a bioactive agent as disclosed herein that is not incorporated into the polymer backbone.
  • bioactive agents may optionally be dispersed in the invention therapeutic polymer compositions.
  • the term “dispersed” is used to refer to bioactive agents (not incorporated into the polymer backbone) and means that the bioactive agent is dispersed, mixed, dissolved, homogenized, and/or covalently bound (“dispersed") in a polymer, for example attached to a functional group in the polymer of the composition or to the surface of a polymer particle, but not incorporated into the backbone of a PEA or PEUR polymer.
  • bioactive agent(s) dispersed therapeutic diols and di-acids
  • bioactive agent(s) may be contained within polymer conjugates or otherwise dispersed in the polymer composition in the same manner as other bioactive agents, as described below.
  • biodegradable as used herein to describe the polymers used in the invention therapeutic polymer compositions means the polymer is capable of being broken down into innocuous and therapeutic products in the normal functioning of the body.
  • the polymers in the invention therapeutic polymer compositions include hydrolyzable ester and enzymatically cleavable amide linkages that provide biodegradability, and are typically chain terminated predominantly with amino groups.
  • the breakdown product delivered is the naturally occurring molecule.
  • these amino termini can be acetylated or otherwise capped by conjugation to any other acid-containing, biocompatible molecule, to include without restriction organic acids, bioinactive biologies, and bioactive agents as described herein.
  • the entire therapeutic polymer composition is biodegradable.
  • the invention therapeutic polymer composition comprises a biodegradable, biocompatible polymer with a residue of at least one therapeutic diol or di- acid incorporated into the backbone of the polymer, hi one embodiment, the invention therapeutic polymer composition comprises at least one PEA having a chemical formula described by structural formula (I),
  • R 1 is independently selected from residues of 3,3'-(alkanedioyldioxy)dicinnamic acid or 4,4'-(alkanedioyldioxy)dicinnamic acid or of ⁇ , ⁇ -bis(4-carboxyphenoxy)-(Ci-C 8 ) alkane, (C 2 - C 20 ) alkylene, (C 2 -C 20 ) alkenylene or residues of saturated or unsaturated therapeutic di-acids;
  • the R 3 S in individual n units are independently selected from the group consisting of hydrogen, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -Ci 0 ) aryl (Ci-C 6 ) alkyl, and -(CH 2 ) 2 S(CH 3 ); and R 4 is independently selected from the group consisting
  • R 1 and R 4 are therapeutic amounts of the residue of a therapeutic di-acid or diol, respectively;
  • n ranges from about 5 to about 150, m ranges about 0.1 to 0.9; p ranges from about 0.9 to 0.1; wherein R 1 is independently selected from residues of ⁇ , ⁇ -bis(4- carboxyphenoxyHQ-Cs) alkane, 3,3'-(alkanedioyldioxy)dicinnamic acid or 4,4'- (alkanedioyldioxy)dicinnamic acid, (C 2 - C 20 ) alkylene, (C 2 -C 20 ) alkenylene or a saturated or unsaturated residues of therapeutic di-acids; each R 2 is independently hydrogen, (Ci- Ci 2 ) alkyl or (C 6 -Ci 0 ) aryl or a protecting group; the R 3 S in individual m monomers are independently selected from the group consisting of hydrogen, (Ci-C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 )
  • n ranges from about 5 to about 150; wherein R 3 S in independently selected from the group consisting of hydrogen, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -C 10 ) 8TyI(C 1 -C 6 ) alkyl, and -(CH 2 ) 2 S(CH 3 ) and; R 4 is selected from the group consisting of (C 2 - C 20 ) alkylene, (C 2 -C 20 ) alkenylene or alkyloxy, and bicyclic-fragments of 1,4:3,6- dianhydrohexitols of structural formula (II), residues of saturated or unsaturated therapeutic diols and combinations thereof; and R 6 is independently selected from (C 2 -C 20 ) alkylene, (C 2 -C 20 ) alkenylene or alkyloxy, bicyclic-fragments of l,4:
  • R 2 is independently selected from hydrogen, (C 6 -C 10 ) aryl (C 1 -C 6 ) alkyl, or a protecting group; the R 3 S in an individual m units are independently selected from the group consisting of hydrogen, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -C 10 ) aryl(CrC 6 ) alkyl, and -(CH 2 ) 2 S (CH 3 ); R 4 is selected from the group consisting of (C 2 -C 20 ) alkylene, (C 2 -C 20 ) alkenylene or alkyloxy, and bicyclic-fragments of l,4:3,6-dianhydrohexitols of structural formula (II
  • n is about 10 to about 150; each R 3 S within an individual n unit are independently selected from hydrogen, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -C 1 O) aryl (C 1 -C 6 )alkyl, and -(CH 2 ) 2 S (CH 3 ); R 4 is independently selected from (C 2 -C 20 ) alkylene, (C 2 -C 20 ) alkenylene, (C 2 -C 8 ) alkyloxy (C 2 -C 2 o) alkylene, a residue of a saturated or unsaturated therapeutic diol; or a bicyclic-fragment of a l,4:3,6-dianhydrohexitol of structural formula (II), and combinations thereof, except that the R 4 within at least one of the n units is the residue of a therapeutic diol;
  • each R 2 is independently hydrogen, (C 1 -C 12 ) alkyl or (C 6 -C 10 ) aryl, or a protecting group; the R 3 s within an individual m unit are independently selected from hydrogen, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 6 -C 10 ) aryl (C 1 -C 6 )alkyl, and -(CH 2 ) 2 S(CH 3 ); each R 4 is independently selected from (C 2 -C 20 ) alkylene, (C 2 -C 20 ) alkenylene, (C 2 -C 8 ) alkyloxy (C 2 -C 20 ) alkylene, a residue of a saturated or unsaturated therapeutic diol; or a bicyclic-frag
  • the bicyclic- fragments of such dianhydrohexitols can be derived from sugar alcohols, such as D-glucitol, D-mannitol and L-iditol.
  • Dianhydrosorbitol is the presently preferred bicyclic fragment of a l,4:3,6-dianhydrohexitol for use in the PEA, PEUR and PEU polymers used in fabrication of the invention therapeutic polymer compositions.
  • the protecting group can be t-butyl or any other protecting group known in the art.
  • the residue of the therapeutic diol or di-acid incorporated into the polymer backbone of the invention therapeutic polymer composition of any one of Formulas (I) and (HI)-(VII) is a therapeutic amount of the therapeutic diol or di-acid so that, upon administration, the composition biodegrades to release a therapeutic amount of the therapeutic diol or di-acid to the subject.
  • the invention therapeutic polymer compositions in which a therapeutic diol and/or di-acid is used in the place of a diol and/or di-acid otherwise useful in making PEA, PEUR, or PEU polymers as described herein, can be formulated into particles to provide a variety of properties.
  • the particles can have a variety of sizes and structures suitable to meet differing therapeutic goals and routes of administration as described in full in co- pending U.S. provisional applications 60/654,715, filed February 17, 2005, 60/684,670, filed May 25, 2005, and 60/737,401, filed November 14, 2005.
  • amino acid and " ⁇ -amino acid” mean a chemical compound containing an amino group, a carboxyl group and a pendent R group, such as the R groups defined herein.
  • biological ⁇ -amino acid means the amino acid(s) used in synthesis are selected from phenylalanine, leucine, glycine, alanine, valine, isoleucine, methionine, or a mixture thereof.
  • a "therapeutic diol” or “therapeutic di-acid” means, respectively, any diol or di-acid molecule, whether synthetically produced, or naturally occurring (e.g., endogenously) that affects a biological process in a mammalian individual, such as a human, in a therapeutic or palliative manner when administered to the mammal.
  • the term "residue of a therapeutic diol” means a portion of a therapeutic diol, as described herein, which portion excludes the two hydroxyl groups of the diol.
  • the term “residue of a therapeutic di-acid” means a portion of a therapeutic di-acid, as described herein, which portion excludes the two carboxyl groups of the di-acid. The corresponding therapeutic diol or di-acid containing the "residue" thereof is used in synthesis of the polymer compositions.
  • the residue of the therapeutic di-acid or diol is reconstituted in vivo (or under similar conditions of pH, aqueous media, and the like) to the corresponding di-acid or diol upon release from the backbone of the polymer by biodegradation in a controlled manner that depends upon the properties of the PEA, PEUR or PEU polymer selected to fabricate the composition, which properties are as known in the art and as described herein.
  • bioactive agent means an active agent that affects a biological process in a mammalian individual, such as a human, in a therapeutic or palliative manner when administered to the mammal and that is not incorporated into the polymer backbone.
  • Bioactive agents may include, without limitation, small molecule drugs, peptides, proteins, DNA, cDNA, RNA, sugars, lipids and whole cells.
  • One or more such bioactive agents may be dispersed in the invention therapeutic polymer compositions.
  • the term "dispersed" as used to refer to bioactive agents means that the bioactive agent is loaded into, mixed, dissolved, homogenized, and/or covalently bound (“dispersed") in a polymer, for example, attached to a functional group in the therapeutic polymer of the composition or to the surface of a polymer particle, but not incorporated into the backbone of a PEA, PEUR, or PEU polymer.
  • bioactive agent(s) dispersed therapeutic diols and di-acids
  • biological agent(s) may be linked to the polymer, contained within polymer conjugates or otherwise dispersed in the invention therapeutic polymer composition the same as other bioactive agents disclosed herein.
  • biodegradable as used herein to describe the invention therapeutic polymer compositions means the polymer used therein is capable of being broken down into innocuous products in the normal functioning of the body. This is particularly true when the amino acids used in fabrication of the therapeutic polymer compositions are biological L- ⁇ -amino acids.
  • the polymers in the invention therapeutic polymer compositions include hydrolyzable ester and enzymatically cleavable amide linkages that provide biodegradability, and are typically chain terminated, predominantly with amino groups.
  • the amino termini of the polymers can be acetylated or otherwise capped by conjugation to any other acid-containing, biocompatible molecule, to include without restriction organic acids, bioinactive biologies, and bioactive agents as described herein.
  • the entire polymer composition, and any particles made thereof, is substantially biodegradable.
  • at least one of the ⁇ -amino acids used in fabrication of the invention polymers is a biological ⁇ -amino acid.
  • the biological ⁇ -amino acid used in synthesis is L-phenylalanine.
  • the polymer contains the biological ⁇ -amino acid, L-leucine.
  • other biological ⁇ -amino acids can also be used, e.g., glycine (when the R 3 S are H), alanine (when the R 3 S are CH 3 ), valine (when the R 3 S are CH(CH 3 ) 2 ), isoleucine (when the R 3 S are CH(CH 3 )-CH 2 -CH 3 ), phenylalanine (when the R 3 S are CH 2 -C 6 H 5 ), or methionine (when the R 3 S are -(CHa) 2 S- CH 3 ), and combinations thereof.
  • all of the various ⁇ -amino acids contained in the polymers used in making the invention therapeutic polymer compositions are biological ⁇ -amino acids, as described herein.
  • the polymer is a PEA, PEUR or PEU of any one of formulas (I) and (HI)-(VII)
  • at least one of the R 3 S further can be -(CH 2 ) 3 -, which cyclizes to form the chemical structure described by structural formula (XIII):
  • the polymer in the invention therapeutic polymer composition plays an active role in the treatment processes at the site of local administration, e.g., by injection, by holding the polymer in an agglomeration or polymer depot at the site of injection for a period of time sufficient to allow the subject's endogenous processes to slowly release particles or polymer molecules from the agglomeration. Meanwhile, the subject's endogenous processes biodegrade the polymer backbone so as to release the incorporated therapeutic diol and/or di-acid therapeutic agents, as well as any bioactive agents dispersed in the polymer. The fragile therapeutic diols and di-acids and optional bioactive agents are protected by the more slowly biodegrading polymer to increase half-life and persistence of the therapeutic diol or di- acid and bioactive agent(s) at the site of local administration.
  • the polymers disclosed herein e.g., those having structural formulas (I) and ( ⁇ i)-(VII)
  • upon enzymatic degradation provide essential amino acids and other breakdown products that can be metabolized using pathways similar to those used in metabolizing fatty acids and sugars.
  • Uptake of the invention therapeutic polymer compositions is safe: studies have shown that the subject can metabolize/clear the polymer degradation products.
  • These polymers and the invention therapeutic polymer compositions are, therefore, substantially non-inflammatory to the subject both at the site of injection and systemically, apart from any trauma caused by injection itself.
  • the PEA, PEUR and PEU polymer molecules may also have the bioactive agent attached thereto, optionally via a linker or incorporated into a crosslinker between molecules.
  • the polymer is contained in a polymer- bioactive agent conjugate having structural formula VIII:
  • R 5 is selected from the group consisting of-
  • R 8 is H or (Q-C ⁇ alkyl; and R 7 is the bioactive agent.
  • two molecules of the polymer of structural formula (IX) can be crosslinked to provide an -R 5 -R 7 -R 5 - conjugate.
  • the bioactive agent is covalently linked to two parts of a single polymer molecule of structural formula (III) through the -R 5 -R 7 -R 5 - conjugate and R 5 is independently selected from the group consisting of-O-, -S-, and - NR 8 -, wherein R 8 is H or (C 1 -C 8 ) alkyl; and R 7 is the bioactive agent.
  • a linker, -X-Y- can be inserted between R and bioactive agent R , in the molecule of structural formula (III), wherein X is selected from the group consisting of (Ci-C 18 ) alkylene, substituted alkylene, (C 3 -C 8 ) cycloalkylene, substituted cycloalkylene, 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group O, N, and S, substituted heterocyclic, (C 2 -C 18 ) alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, C 6 and Ci 0 aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkynyl, substituted arylalkynyl, arylalkenyl, substituted arylalkenyl, aryl
  • two parts of a single macromolecule are covalently linked to the bioactive agent through an -R 5 -R 7 -Y-X- R 5 - bridge (Formula XI):
  • X is selected from the group consisting Of(C 1 -Ci 8 ) alkylene, substituted alkylene, (C 3 -C 8 ) cycloalkylene, substituted cycloalkylene, 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from the group O, N, and S, substituted heterocyclic, (C 2 -Ci 8 ) alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, (C 6 -C 10 ) aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkynyl, substituted arylalkynyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, substituted arylalkynyl, wherein the substituents are selected from the group consisting of H, F, Cl,
  • the polymer particle delivery composition contains four molecules of the polymer, except that only two of the four molecules omit R 7 and are crosslinked to provide a single -R 5 -X-R 5 - conjugate.
  • aryl is used with reference to structural formulae herein to denote a phenyl radical or an ortho-fused bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic. In certain embodiments, one or more of the ring atoms can be substituted with one or more of nitro, cyano, halo, trifluoromethyl, or trifluoromethoxy. Examples of aryl include, but are not limited to, phenyl, naphthyl, and nitrophenyl.
  • alkenylene is used with reference to structural formulae herein to mean a divalent branched or unbranched hydrocarbon chain containing at least one unsaturated bond in the main chain or in a side chain.
  • the molecular weights and polydispersities herein are determined by gel permeation chromatography (GPC) using polystyrene standards. More particularly, number and weight average molecular weights (M n and M w ) are determined, for example, using a Model 510 gel permeation chromatography (Water Associates, Inc., Milford, MA) equipped with a high-pressure liquid chromatographic pump, a Waters 486 UV detector and a Waters 2410 differential refractive index detector. Tetrahydrofuran (THF) or N,N- dimethylacetamide (DMAc) is used as the eluent (1.0 mL/min). Polystyrene or poly(methyl methacrylate) standards having narrow molecular weight distribution were used for calibration.
  • GPC gel permeation chromatography
  • the bis- ⁇ , ⁇ -diamine is entered into a polycondensation reaction with a di-acid such as sebacic acid, or bis-activated esters, or bis-acyl chlorides, to obtain the final polymer having both ester and amide bonds (PEA).
  • a di-acid such as sebacic acid, or bis-activated esters, or bis-acyl chlorides
  • PDA ester and amide bonds
  • an activated di-acid derivative e.g., bis-4-nitrophenyl diester
  • a bis-di-carbonate such as bis(4-nitrophenyl) dicarbonate
  • a final polymer is obtained having both ester and urethane bonds.
  • R 4 in (I) is -C 4 H 8 - or -C 6 H 12 -.
  • R 1 in (I) is -C 4 H 8 - or -C 8 H 16 -.
  • the UPEAs can be prepared by solution polycondensation of either (1) di-4- toluene sulfonic acid salt of bis( ⁇ -amino acid) di-ester of unsaturated diol and di-4- nitrophenyl ester of saturated dicarboxylic acid or (2) di-4-toluene sulfonic acid salt of bis ( ⁇ -amino acid) diester of saturated diol and di-4-nitrophenyl ester of unsaturated dicarboxylic acid or (3) di-4-toluene sulfonic acid salt of bis( ⁇ -amino acid) diester of unsaturated diol and di-4-nitrophenyl ester of unsaturated dicarboxylic acid.
  • Salts of 4-toluene sulfonic acid are known for use in synthesizing polymers containing amino acid residues.
  • the aryl sulfonic acid salts are used instead of the free base because the aryl sulfonic salts of bis ( ⁇ -amino acid) diesters are easily purified through recrystallization and render the amino groups as unreactive ammonium tosylates throughout workup.
  • the nucleophilic amino group is readily revealed through the addition of an organic base, such as triethylamine, so the polymer product is obtained in high yield.
  • the di-4-nitrophenyl esters of unsaturated dicarboxylic acid can be synthesized from 4-nitrophenyl and unsaturated dicarboxylic acid chloride, e.g., by dissolving triethylamine and 4-nitrophenol in acetone and adding unsaturated dicarboxylic acid chloride dropwise with stirring at -78°C and pouring into water to precipitate product.
  • Suitable acid chlorides included fumaric, maleic, mesaconic, citraconic, glutaconic, itaconic, ethenyl-butane dioic and 2-propenyl- butanedioic acid chlorides.
  • each R 5 is independently (C 6 -C 10 ) aryl optionally substituted with one or more nitro, cyano, halo, trifluoromethyl, or trifluoromethoxy; and R 6 is independently (C 2 -C 20 ) alkylene, (C 2 -C 20 ) alkenylene or (C 2 -C 20 ) alkyloxy (C 2 -C 20 ) alkenylene, fragments of l,4:3,6-dianhydrohexitols of general formula (II), or a residue of a saturated or unsaturated therapeutic diol .
  • Suitable therapeutic diol compounds that can be used to prepare bis( ⁇ -amino acid) diesters of therapeutic diol monomers, or bis(carbonate) of therapeutic di-acid monomers, for introduction into the invention therapeutic polymer compositions include naturally occurring therapeutic diols, such as 17- ⁇ -estradiol, a natural and endogenous hormone, useful in preventing restenosis and tumor growth (Yang, N.N., et al. Identification of an estrogen response element activated by metabolites of 17- ⁇ -estradiol and raloxifene.
  • Example 8 Incorporation of a therapeutic diol into the backbone of a PEA, PEUR or PEU polymer is illustrated in this application by Example 8, in which active steroid hormone 17- ⁇ -estradiol containing mixed hydroxyls - secondary and phenolic - is introduced into the backbone of a PEA polymer.
  • active steroid hormone 17- ⁇ -estradiol containing mixed hydroxyls - secondary and phenolic - is introduced into the backbone of a PEA polymer.
  • PTCA percutaneous transluminal coronary angioplasty
  • 17- ⁇ -estradiol is only one example of a diol with therapeutic properties that can be incorporated in the backbone of a PEA, PEUR or PEU polymer in accordance with the invention, hi one aspect, any bioactive steroid-diol containing primary, secondary or phenolic hydroxyls can be used for this purpose.
  • bioactive steroid diols for use in the invention are disclosed in European application EP 0127 829 A2.
  • the amount of the therapeutic diol or di-acid incorporated in the polymer backbone can be controlled by varying the proportions of the building blocks of the polymer. For example, depending on the composition of the PEA, loading of up to 40% w/w of 17- ⁇ -estradiol can be achieved. Two different regular, linear PEAs with various loading ratios of 17- ⁇ -estradiol are illustrated in Scheme 1 below:
  • the loading of the therapeutic diol into PEUR and PEU polymer can be varied by varying the amount of two or more building blocks of the polymer. Synthesis of a PEUR containing 17-beta-estradiol is illustrated in Example 9 below.
  • synthetic steroid based diols based on testosterone or cholesterol such as 4-androstene-3, 17 diol (4-Androstenediol), 5-androstene-3, 17 diol (5- Androstenediol), 19-nor5-androstene-3, 17 diol (19-Norandrostenediol) are suitable for incorporation into the backbone of PEA and PEUR polymers according to this invention.
  • therapeutic diol compounds suitable for use in preparation of the invention therapeutic polymer compositions include, for example, amikacin; amphotericin B; apicycline; apramycin; arbekacin; azidamfenicol; bambermycin(s); butirosin; carbomycin; cefpiramide; chloramphenicol; chlortetracycline; clindamycin; clomocycline; demeclocycline; diathymosulfone; dibekacin, dihydrostreptomycin; dirithromycin; doxycycline; erythromycin; fortimicin(s); gentamycin(s); glucosulfone solasulfone; guamecycline; isepamicin; josamycin; kanamycin(s); leucomycin(s); lincomycin; lucensomycin; lymecycline; meclocycline; methacycline; micronomycin; midecamycin(s);
  • Suitable naturally occurring and synthetic therapeutic di-acids that can be used to prepare an amide linkage in the PEA polymer compositions of the invention include, for example, bambermycin(s); benazepril; carbenicillin; carzinophillin A; cefixime; cefminox cefpimizole; cefodizime; cefonicid; ceforanide; cefotetan; ceftazidime; ceftibuten; cephalosporin C; cilastatin; denopterin; edatrexate; enalapril; lisinopril; methotrexate; moxalactam; nifedipine; olsalazine; penicillin N; ramipril; quinacillin; quinapril; temocillin; ticarcillin; Tomudex® (N-[[5-[[(l,4-Dihydro-2-methyl-4-
  • the di-aryl sulfonic acid salts of diesters of ⁇ -amino acid and unsaturated diol can be prepared by admixing ⁇ -amino acid, e.g., 4-aryl sulfonic acid monohydrate and saturated or unsaturated diol in toluene, heating to reflux temperature, until water evolution is minimal, then cooling.
  • ⁇ -amino acid e.g., 4-aryl sulfonic acid monohydrate
  • saturated or unsaturated diol in toluene
  • the unsaturated diols include, for example, 2-butene- 1,3-diol and l,18-octadec-9-en-diol.
  • Saturated di-4-nitrophenyl esters of dicarboxylic acid and saturated di-4-toluene sulfonic acid salts of bis- ⁇ -amino acid esters can be prepared as described in U.S. Patent No. 6,503,538 Bl.
  • UPEAs unsaturated poly(ester-amide)s
  • UPEAs having the structural formula (I) can be made in similar fashion to the compound (VII) of U. S. Patent No. 6,503,538 Bl, except that R 4 of (III) of 6,503,538 and/or R 1 of (V) of 6,503,538 is (C 2 -C 20 ) alkenylene as described above.
  • the reaction is carried out, for example, by adding dry triethylamine to a mixture of said (III) and (IV) of 6,503,538 and said (V) of 6,503,538 in dry N,N-dimethylacetamide, at room temperature, then increasing the temperature to 60°C and stirring for 16 hours, then cooling the reaction solution to room temperature, diluting with ethanol, pouring into water, separating polymer, washing separated polymer with water, drying to about 3O 0 C under reduced pressure and then purifying up to negative test on p-nitrophenol and p-toluene sulfonate.
  • a preferred reactant (IV) of 6,503,538 is p-toluene sulfonic acid salt of Lysine benzyl ester, the benzyl ester protecting group is preferably removed from (H) to confer biodegradability, but it should not be removed by hydrogenolysis as in Example 22 of U.S. Patent No. 6,503,538 because hydrogenolysis would saturate the desired double bonds; rather the benzyl ester group should be converted to an acid group by a method that would preserve unsaturation.
  • the lysine reactant (IV) of 6,503,538 can be protected by a protecting group different from benzyl that can be readily removed in the finished product while preserving unsaturation, e.g., the lysine reactant can be protected with t-butyl (i.e., the reactant can be t-butyl ester of lysine) and the t-butyl can be converted to H while preserving unsaturation by treatment of the product (II) with acid.
  • t-butyl i.e., the reactant can be t-butyl ester of lysine
  • a working example of the compound having structural formula (I) is provided by substituting p-toluene sulfonic acid salt of bis(L-phenylalanine) 2-butene-l,4-diester for (III) in Example 1 of 6,503,538 or by substituting di-p-nitrophenyl fumarate for (V) in Example 1 of 6,503,538 or by substituting the p-toluene sulfonic acid salt of bis(L- phenylalanine) 2-butene-l,4-diester for III in Example 1 of 6,503,538 and also substituting bis-p-nitrophenyl fumarate for (V) in Example 1 of 6,503,538.
  • an amino substituted aminoxyl (N-oxide) radical bearing group e.g., 4- amino TEMPO
  • carbonyldiimidazol or suitable carbodiimide, as a condensing agent
  • Bioactive agents as described herein, can be attached via the double bond functionality. Hydrophilicity can be imparted by bonding to poly(ethylene glycol) diacrylate.
  • the PEA and PEUR polymers contemplated for use in forming the invention therapeutic polymer compositions include those set forth in U.S. Patent Nos. 5,516, 881; 6,476,204; 6,503,538; and in U.S. Application Nos. 10/096,435; 10/101,408; 10/143,572; and 10/194,965; the entire contents of each of which is incorporated herein by reference.
  • the biodegradable PEA, PEUR and PEU polymers can contain from one to multiple different ⁇ -amino acids per polymer molecule and preferably have weight average molecular weights ranging from 10,000 to 125,000; these polymers and copolymers typically have intrinsic viscosities at 25 0 C, determined by standard viscosimetric methods, ranging from 0.3 to 4.0, for example, ranging from 0.5 to 3.5.
  • PEA and PEUR polymers contemplated for use in the practice of the invention can be synthesized by a variety of methods well known in the art.
  • tributyltin (IV) catalysts are commonly used to form polyesters such as poly( ⁇ -caprolactone), poly(glycolide), poly(lactide), and the like.
  • a wide variety of catalysts can be used to form polymers suitable for use in the practice of the invention.
  • Such poly(caprolactones) contemplated for use have an exemplary structural formula (XIV) as follows:
  • Poly(glycolides) contemplated for use have an exemplary structural formula (XV) as follows:
  • Poly(lactides) contemplated for use have an exemplary structural formula (XVI) as follows:
  • the first step involves the copolymerization of lactide and ⁇ -caprolactone in the presence of benzyl alcohol using stannous octoate as the catalyst to form a polymer of structural formula (XVII).
  • 4-amino-2,2,6,6-tetramethylpiperidine- 1 -oxy can be reacted with the carboxylic end group to covalently attach the aminoxyl moiety to the copolymer via the amide bond which results from the reaction between the 4-amino group and the carboxylic acid end group.
  • the maleic acid capped copolymer can be grafted with polyacrylic acid to provide additional carboxylic acid moieties for subsequent attachment of further aminoxyl groups.
  • the invention bioactive PEA, PEUR and PEU polymer compositions useful in the invention methods biodegrade by enzymatic action at the surface. Therefore, the polymers, for example particles thereof, facilitate in vivo release of a bioactive agent incorporated into the backbone or dispersed in the polymer at a controlled release rate, which is specific and constant over a prolonged period. Additionally, PEA, PEUR and PEU polymers break down in vivo without production of adverse side products, the polymers in the compositions are substantially non-inflammatory.
  • the biodegradable PEA, PEUR and PEU polymers can contain from one to multiple different ⁇ -amino acids per polymer molecule and preferably have weight average molecular weights ranging from 10,000 to 125,000; these polymers and copolymers typically have intrinsic viscosities at 25 0 C, determined by standard viscosimetric methods, ranging from 0.3 to 4.0, for example, ranging from 0.5 to 3.5.
  • the PEU polymers disclosed herein can be fabricated as high molecular weight polymers useful for making the invention therapeutic polymer compositions for delivery to humans and other mammals of a variety of pharmaceutical and biologically active agents.
  • the PEUs incorporate hydrolytically cleavable ester groups and non-toxic, naturally occurring monomers that contain ⁇ -amino acids in the polymer chains.
  • the ultimate biodegradation products of PEUs will be amino acids, diols, and CO 2 .
  • the invention PEUs are crystalline or semi-crystalline and possess advantageous mechanical, chemical and biodegradation properties that allow formulation of completely synthetic, and hence easy to produce, crystalline and semi-crystalline polymer particles, for example nanoparticles.
  • the PEU polymers used in the invention therapeutic polymer compositions have high mechanical strength, and surface erosion of the PEU polymers can be catalyzed by enzymes present in physiological conditions, such as hydrolases.
  • an amino substituted aminoxyl (N-oxide) radical bearing group e.g., 4- amino TEMPO
  • carbonyldiimidazole or suitable carbodiimide, as a condensing agent.
  • Bioactive agents, and the like, as described herein, optionally can be attached via the double bond functionality provided that the therapeutic diol residue in the polymer composition does not contain a double or triple bond.
  • the invention high molecular weight semi-crystalline PEUs having structural formula (VI) can be prepared inter-facially by using phosgene as a bis- electrophilic monomer in a chloroform/water system, as shown in the reaction scheme (2) below:
  • the ⁇ -amino acid can be converted into a bis( ⁇ -amino acid)- ⁇ , ⁇ -diol- diester monomer, for example, by condensing the ⁇ -amino acid with a diol HO-R ⁇ -OH. As a result, ester bonds are formed.
  • acid chloride of carbonic acid (phosgene, diphosgene, triphosgene) is entered into a polycondensation reaction with a di-p- toluenesulfonic acid salt of a bis( ⁇ -amino acid) -alkylene diester to obtain the final polymer having both ester and urea bonds, hi the present invention, at least one therapeutic diol can be used in the polycondensation protocol.
  • the unsaturated PEUs can be prepared by interfacial solution condensation of di-p-toluenesulfonate salts of bis( ⁇ -amino acid)-alkylene diesters, comprising at least one double bond in R 1 .
  • Unsaturated diols useful for this purpose include, for example, 2- butene-l,4-diol and l,18-octadec-9-en-diol.
  • Unsaturated monomer can be dissolved prior to the reaction in alkaline water solution, e.g. sodium hydroxide solution.
  • the water solution can then be agitated intensely, under external cooling, with an organic solvent layer, for example chloroform, which contains an equimolar amount of monomeric, dimeric or trimeric phosgene.
  • an organic solvent layer for example chloroform, which contains an equimolar amount of monomeric, dimeric or trimeric phosgene.
  • An exothermic reaction proceeds rapidly, and yields a polymer that (in most cases) remains dissolved in the organic solvent.
  • the organic layer can be washed several times with water, dried with anhydrous sodium sulfate, filtered, and evaporated. Unsaturated PEUs with a yield of about 75%-85% can be dried in vacuum, for example at about 45°C.
  • L-Leu based PEUs such as l-L-Leu-4 and l-L-Leu-6
  • L-Leu based PEUs can be fabricated using the general procedure described below. Such procedure is less successful in formation of a porous, strong material when applied to L- Phe based PEUs.
  • reaction solution or emulsion (about 100 mL) of PEU in chloroform, as obtained just after interfacial polycondensation, is added dropwise with stirring to 1,000 mL of about 80 0 C -85 0 C water in a glass beaker, preferably a beaker made hydrophobic with dimethyldichlorsilane to reduce the adhesion of PEU to the beaker's walls.
  • the polymer solution is broken in water into small drops and chloroform evaporates rather vigorously. Gradually, as chloroform is evaporated, small drops combine into a compact tar-like mass that is transformed into a sticky rubbery product.
  • This rubbery product is removed from the beaker and put into hydrophobized cylindrical glass-test-tube, which is thermostatically controlled at about 80 0 C for about 24 hours. Then the test-tube is removed from the thermostat, cooled to room temperature, and broken to obtain the polymer. The obtained porous bar is placed into a vacuum drier and dried under reduced pressure at about 80 0 C for about 24 hours.
  • any procedure known in the art for obtaining porous polymeric materials can also be used.
  • a glass transition temperature in the range from about 30 C° to about 90 C°, for example, in the range from about 35 C 0 to about 70 C°;
  • a film of the polymer with average thickness of about 1.6 cm will have tensile stress at yield of about 20 Mpa to about 150 Mpa, for example, about 25 Mpa to about 60 Mpa;
  • a film of the polymer with average thickness of about 1.6 cm will have a percent elongation of about 10 % to about 200%, for example about 50 % to about 150%; and [0101] 4.
  • a film of the polymer with average thickness of about 1.6 cm will have a Young's modulus in the range from about 500 MPa to about 2000 MPa. Table 2 below summarizes the properties of exemplary PEUs of this type.
  • the PEA, PEUR and PEU polymers described herein can be fabricated in a variety of molecular weights and a variety of w/w% concentrations of the therapeutic diol or di-acid in the backbone of the polymer.
  • the appropriate molecular weight for use with a given concentration of bioactive agent is readily determined by one of skill in the art.
  • a suitable molecular weight will be on the order of about 5,000 to about 300,000, for example about 5,000 to about 250,000, or about 75,000 to about 200,000, or about 100,000 to about 150,000 and a suitable w/w% concentration of a residue of a bioactive agent incorporated into the backbone of the polymer will be on the order of about 5 w/w% to about 70 w/w%, for example about 10 w/w% to about 40 w/w%, or about 20 w/w% to about 40 w/w%.
  • the amount of bioactive agent incorporated into the backbone of the polymer will be highest in the case of a homopolymer (e.g., containing no Lysine-based monomer) that incorporates both a therapeutic diol and a therapeutic di-acid.
  • a homopolymer e.g., containing no Lysine-based monomer
  • the molecular weights and polydispersities herein are determined by gel permeation chromatography (GPC) using polystyrene standards. More particularly, number and weight average molecular weights (M n and M w ) are determined, for example, using a Model 510 gel permeation chromatography (Water Associates, Inc., Milford, MA) equipped with a high-pressure liquid chromatographic pump, a Waters 486 UV detector and a Waters 2410 differential refractive index detector. Tetrahydrofuran (THF) or N,N- dimethylacetamide (DMAc) is used as the eluent (1.0 niL/min).
  • GPC gel permeation chromatography
  • bioactive agent(s) can be dispersed within the polymer matrix without chemical linkage to the polymer carrier, it is also contemplated that one or more bioactive agents or covering molecules can be covalently bound to the biodegradable polymers via a wide variety of suitable functional groups.
  • a free carboxyl group can be used to react with a complimentary moiety on a bioactive agent or covering molecule, such as an hydroxy, amino, or thio group, and the like.
  • suitable reagents and reaction conditions are disclosed, e.g., in March's Advanced Organic Chemistry, Reactions, Mechanisms, and Structure, Fifth Edition, (2001); and Comprehensive Organic Transformations, Second Edition, Larock (1999).
  • one or more bioactive agent can be linked to any of the polymers of structures (I) and (III- VII) through an amide, ester, ether, amino, ketone, thioether, sulfmyl, sulfonyl, or disulfide linkage.
  • a linkage can be formed from suitably functionalized starting materials using synthetic procedures that are known in the art.
  • a polymer can be linked to a bioactive agent via a free carboxyl group (e.g., COOH) of the polymer.
  • a compound of structures (I) and (111) can react with an amino functional group or a hydroxyl functional group of a bioactive agent to provide a biodegradable polymer having the bioactive agent attached via an amide linkage or ester linkage, respectively.
  • the carboxyl group of the polymer can be benzylated or transformed into an acyl halide, acyl anhydride/"mixed" anhydride, or active ester.
  • the free -NH 2 ends of the polymer molecule can be acylated to assure that the bioactive agent will attach only via a carboxyl group of the polymer and not to the free ends of the polymer.
  • Water soluble covering molecule(s) such as polyethylene glycol) (PEG); phosphatidylcholine (PC); glycosaminoglycans including heparin; polysaccharides including chitosan, alginates and polysialic acid; ⁇ oly(ionizable or polar amino acids) including polyserine, polyglutamic acid, polyaspartic acid, polylysine and polyarginine; as described herein, and targeting molecules, such as antibodies, antigens and ligands, are bioactive agents that can also be conjugated to the polymer on the exterior of particles formed from the therapeutic polymer composition after production of the particles to block active sites not occupied by a bioactive agent or to target delivery of the particles to a specific body site as is known
  • a bioactive agent or covering molecule can be attached to the polymer via a linker molecule or by cross-linking two or more molecules of the polymer as described herein.
  • a linker may be utilized to indirectly attach a bioactive agent to the biodegradable polymer, hi certain embodiments, the linker compounds include poly(ethylene glycol) having a molecular weight (MW) of about 44 to about 10,000, preferably 44 to 2000; amino acids, such as serine; polypeptides with repeat number from 1 to 100; and any other suitable low molecular weight polymers.
  • the linker typically separates the bioactive agent from the polymer by about 5 angstroms up to about 200 angstroms.
  • alkyl refers to a straight or branched chain hydrocarbon group including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, and the like.
  • alkenyl refers to straight or branched chain hydrocarbyl groups having one or more carbon-carbon double bonds.
  • alkynyl refers to straight or branched chain hydrocarbyl groups having at least one carbon-carbon triple bond.
  • aryl refers to aromatic groups having in the range of 6 up to 14 carbon atoms.
  • the linker may be a polypeptide having from about 2 up to about 25 amino acids.
  • Suitable peptides contemplated for use include poly-L-glycine, poly-L-lysine, poly-L-glutamic acid, poly-L-aspartic acid, poly-L-histidine, poly-L- ornithine, poly-L-serine, poly-L-threonine, poly-L-tyrosine, poly-L-leucine, poly-L-lysine- L-phenylalanine, poly-L-arginine, poly-L-lysine-L-tyrosine, and the like.
  • a bioactive agent can covalently crosslink the polymer, i.e. the bioactive agent is bound to more than one polymer molecule, to form an intermolecular bridge.
  • This covalent crosslinking can be done with or without a linker containing a bioactive agent.
  • a bioactive agent molecule can also be incorporated into an intramolecular bridge by covalent attachment between two sites on the same polymer molecule.
  • a linear polymer polypeptide conjugate is made by protecting the potential nucleophiles on the polypeptide backbone and leaving only one reactive group to be bound to the polymer or polymer linker construct. Deprotection is performed according to methods well known in the art for deprotection of peptides (Boc and Fmoc chemistry for example).
  • a bioactive agent is a polypeptide presented as a retro-inverso or partial retro-inverso peptide.
  • a bioactive agent may be mixed with a photocrosslmkable version of the polymer in a matrix, and, after crosslmking, the material is dispersed (ground) to form particles having an average diameter in the range from about 0.1 to about lO ⁇ m.
  • the linker can be attached first to the polymer or to the bioactive agent or covering molecule.
  • the linker can be either in unprotected form or protected from, using a variety of protecting groups well known to those skilled in the art.
  • the unprotected end of the linker can first be attached to the polymer or the bioactive agent or covering molecule.
  • the protecting group can then be de-protected using PdZH 2 hydrogenation for saturated polymer backbones, mild acid or base hydrolysis for unsaturated polymers, or any other common de-protection method that is known in the art.
  • the de-protected linker can then be attached to the bioactive agent or covering molecule, or to the polymer
  • a biodegradable polymer herein can be reacted with an aminoxyl radical containing compound, e.g., 4-amino- 2,2,6,6-tetramethylpiperidine-l-oxy, in the presence of N,N'-carbonyl diimidazole or suitable carbodiimide, to replace the hydroxyl moiety in the carboxyl group, either on the pendant carboxylic acids of the PEAs, PEURs or PEUs, or at the chain end of a polyester as described, with an amide linkage to the aminoxyl (N-oxide) radical containing group.
  • an aminoxyl radical containing compound e.g., 4-amino- 2,2,6,6-tetramethylpiperidine-l-oxy
  • the amino moiety covalently bonds to the carbon of the carbonyl residue such that an amide bond is formed.
  • the N,N'-carbonyldiimidazole or suitable carbodiimide converts the hydroxyl moiety in the carboxyl group at the chain end of the polyester into an intermediate activated moiety which will react with the amino group of the aminoxyl (N oxide) radical compound, e.g., the amine at position 4 of 4-amino-2,2,6,6- tetramethylpiperidine-1-oxy.
  • the aminoxyl reactant is typically used in a mole ratio of reactant to polyester ranging from 1 : 1 to 100: 1.
  • the mole ratio of N 3 N'- carbonyldiimidazole or carbodiimide to aminoxyl is preferably about 1:1.
  • a typical reaction is as follows.
  • a polyester is dissolved in a reaction solvent and reaction is readily carried out at the temperature utilized for the dissolving.
  • the reaction solvent may be any in which the polyester will dissolve; this information is normally available from the manufacturer of the polyester.
  • the polyester is a polyglycolic acid or a poly(glycolide-L-lactide) (having a monomer mole ratio of glycolic acid to L-lactic acid greater than 50:50), highly refined (99.9+% pure) dimethyl sulfoxide at 115 0 C to 130 0 C or DMSO at room temperature suitably dissolves the polyester.
  • polyester is a poly-L-lactic acid
  • a poly-DL-lactic acid or a poly(glycolide-L-lactide) having a monomer mole ratio of glycolic acid to L-lactic acid 50:50 or less than 50:50
  • tetrahydrofuran tetrahydrofuran
  • dichloromethane DCM
  • chloroform at room temperature to 40 -50 0 C suitably dissolve the polyester.
  • the product may be precipitated from the reaction mixture by adding cold non- solvent for the product.
  • cold non- solvent for the product aminoxyl-containing polyglycolic acid and aminoxyl-containing poly(glycolide-L-lactide) formed from glycolic acid-rich monomer mixture are readily precipitated from hot dimethylsulfoxide by adding cold methanol or cold acetone/methanol mixture and then recovered, e.g., by filtering.
  • the product and solvent may be separated by using vacuum techniques.
  • aminoxyl-containing poly-L-lactic acid is advantageously separated from solvent in this way.
  • the recovered product is readily further purified by washing away water and by-products (e.g.
  • urea with a solvent which does not dissolve the product, e.g., methanol in the case of the modified polyglycolic acid, polylactic acid and poly(glycolide-L-lactide) products herein. Residual solvent from such washing may be removed using vacuum drying.
  • a solvent which does not dissolve the product e.g., methanol in the case of the modified polyglycolic acid, polylactic acid and poly(glycolide-L-lactide) products herein. Residual solvent from such washing may be removed using vacuum drying.
  • the polymers used to make the invention therapeutic polymer compositions as described herein have one or more bioactive agent directly linked to the polymer.
  • the residues of the polymer can be linked to the residues of the one or more bioactive agents.
  • one residue of the polymer can be directly linked to one residue of a bioactive agent.
  • the polymer and the bioactive agent can each have one open valence.
  • more than one bioactive agent, multiple bioactive agents, or a mixture of bioactive agents having different therapeutic or palliative activity can be directly linked to the polymer.
  • the residue of each bioactive agent can be linked to a corresponding residue of the polymer
  • the number of residues of the one or more bioactive agents can correspond to the number of open valences on the residue of the polymer having at least one diol or di-acid bioactive agent incorporated into the backbone of the polymer.
  • a "residue of a polymer” refers to a radical of a polymer having one or more open valences. Any synthetically feasible atom, atoms, or functional group of the polymer (e.g., on the polymer backbone or pendant group) is substantially retained when the radical is attached to a residue of a bioactive agent. Additionally, any synthetically feasible functional group (e.g., carboxyl) can be created on the polymer (e.g., on the polymer backbone as a pendant group or as chain termini) to provide the open valence, provided bioactivity of the backbone therapeutic agent is substantially retained when the radical is attached to a residue of a bioactive agent. Based on the linkage that is desired, those skilled in the art can select suitably functionalized starting materials that can be used to derivatize the PEA and PEUR polymers used in the present invention using procedures that are known in the art.
  • a "residue of a compound of structural formula (*)” refers to a radical of a compound of polymer formulas (I), (III)-(VII) as described herein having one or more open valences. Any synthetically feasible atom, atoms, or functional group of the compound (e.g., on the polymer backbone, pendant or end group) can be removed to provide the open valence, provided bioactivity of the backbone therapeutic agent is substantially retained when the radical is attached.
  • any synthetically feasible functional group e.g., carboxyl
  • any synthetically feasible functional group can be created on the compound of formulas (I), (HI)- (VII) (e.g., on the polymer backbone or pendant group) to provide the open valence, provided bioactivity of the backbone therapeutic agent is substantially retained when the radical is attached to a residue of a bioactive agent.
  • suitably functionalized starting materials that can be used to derivatize the compound of formulas (I), (IH)-(VII) using procedures that are known in the art.
  • Such a linkage can be formed from suitably functionalized starting materials using synthetic procedures that are known in the art. Based on the linkage that is desired, those skilled in the art can select suitably functional starting material to derivatize any residue of a compound of structural formula (I) or (III) - (VII) and thereby conjugate a given residue of a bioactive agent using procedures that are known in the art.
  • the residue of the optional bioactive agent can be linked to any synthetically feasible position on the residue of a compound of structural formula (I) or (III) - (VII). Additionally, the invention also provides compounds having more than one residue of abioactive agent directly linked to a compound of structural formula (I), (11I)- (VII).
  • the number of bioactive agents that can be linked to the polymer molecule can typically depend upon the molecular weight of the polymer and the number of backbone therapeutic agents incorporated into the polymer. For example, for a compound of structural formula (I), wherein n is about 5 to about 150, preferably about 5 to about 70, up to about 150 bioactive agent molecules (i.e., residues thereof) can be directly linked to the polymer (i.e., residue thereof) by reacting the bioactive agent with backbone, pendant or terminal groups of the polymer. The number of sites for linkage of a bioactive agent in the invention therapeutic polymer compositions is accordingly reduced by the number of backbone therapeutic diol or di-acids incorporated into the polymer.
  • bioactive agents can also be reacted with double (or triple) bonds in the polymer, provided that the therapeutic diol or di-acid residues incorporated into the polymer backbone do not contain any double (or triple) bonds themselves.
  • linkage of a bioactive agent at a double bond in the polymer composition would not be recommended, to prevent bonding of the bioactive agent to a double bond in the backbone diol or di-acid residue (i.e., the estradiol) in a reaction.
  • a bioactive agent in the therapeutic polymer composition, either in the form of particles or not, can be covalently attached directly to the polymer, rather than being dispersed by "loading" into the polymer without chemical attachment, using any of several methods well known in the art and as described hereinbelow.
  • the amount of bioactive agent is generally approximately 0.1% to about 60% (w/w) bioactive agent to polymer composition, more preferably about 1% to about 25% (w/w) bioactive agent, and even more preferably about 2% to about 20% (w/w) bioactive agent.
  • the percentage of bioactive agent will depend on the desired dose and the condition being treated, as discussed in more detail below.
  • the invention therapeutic polymer compositions can be used in the fabrication of polymer coatings for various types of surgical devices.
  • the polymer coating on the surgical device is effective for controlled delivery to surrounding tissue of the therapeutic diol or di-acid as well as any bioactive agents dispersed in the polymer or covalently attached to the surface of a particle thereof.
  • the invention therapeutic polymer composition can be fabricated in the form of a pad, sheet or wrap of any desired surface area.
  • the polymer can be woven or formed as a thin sheet of randomly oriented fibers.
  • Such pads, sheets and wraps can be used in a number of types of wound dressings for treatment of a variety of conditions, for example by promoting endogenous healing processes at a wound site.
  • the polymer compositions in the wound dressing biodegrade over time, releasing the therapeutic diol or di-acid to be absorbed into a target cell in a wound site where it acts intracellularly, either within the cytosol, the nucleus, or both, or the bioactive agent can bind to a cell surface receptor molecule to elicit a cellular response without entering the cell.
  • the therapeutic diol or di-acid released from the polymer composition for example when used as the covering for a bioactive stent, promotes endogenous healing processes at the wound site by contact with the surroundings into which the wound dressing or implant is placed.
  • a detailed description of methods of making polymer particles using PEA and PEUR polymers may be found in co-pending U.S. provisional applications 60/654,715, filed February 17, 2005, and 60/674,670, May 25, 2005, each of which is incorporated herein in its entirety.
  • Bioactive agents contemplated for dispersion within the polymers used in the invention therapeutic polymer compositions include anti-proliferants, rapamycin and any of its analogs or derivatives, paclitaxel or any of its taxene analogs or derivatives, everolimus, sirolimus, tacrolimus, or any of its -limus named family of drugs, and statins such as simvastatin, atorvastatin, fluvastatin, pravastatin, lovastatin, rosuvastatin, geldanamycins, such as 17AAG (17-allylamino-17-demethoxygeldanamycin); Epothilone D and other epothilones, ⁇ -dimethylaminoethylamino- ⁇ -demethoxy-geldanamycin and other polyketide inhibitors of heat shock protein 90 (Hsp90), cilostazol, and the like.
  • statins such as simvastatin, atorvastatin, fluva
  • Suitable bioactive agents for dispersion in the invention therapeutic polymer compositions and particles made therefrom also can be selected from those that promote endogenous production of a therapeutic natural wound healing agent, such as nitric oxide, which is endogenously produced by endothelial cells.
  • a therapeutic natural wound healing agent such as nitric oxide
  • the bioactive agents released from the polymers during degradation may be directly active in promoting natural wound healing processes by endothelial cells.
  • These bioactive agents can be any agent that donates, transfers, or releases nitric oxide, elevates endogenous levels of nitric oxide, stimulates endogenous synthesis of nitric oxide, or serves as a substrate for nitric oxide synthase or that inhibits proliferation of smooth muscle cells.
  • Such agents include, for example, aminoxyls, furoxans, nitrosothiols, nitrates and anthocyanins; nucleosides such as adenosine and nucleotides such as adenosine diphosphate (ADP) and adenosine triphosphate (ATP); neurotransmitter/neuromodulators such as acetylcholine and 5- hydroxytryptamine (serotonin/5-HT); histamine and catecholamines such as adrenalin and noradrenalin; lipid molecules such as sphingosine-1 -phosphate and lysophosphatidic acid; amino acids such as arginine and lysine; peptides such as the bradykinins, substance P and calcium gene-related peptide (CGRP), and proteins such as insulin, vascular endothelial growth factor (VEGF), and thrombin.
  • nucleosides such as adenosine and nucleo
  • bioactive agents such as targeting antibodies, polypeptides (e.g., antigens) and drugs can be covalently conjugated to the surface of the polymer coatings or particles.
  • bioactive agents such as targeting antibodies, polypeptides (e.g., antigens) and drugs can be covalently conjugated to the surface of the polymer coatings or particles.
  • coating molecules such as polyethylene glycol (PEG) as a ligand for attachment of antibodies or polypeptides or phosphatidylcholine (PC) as a means of blocking attachment sites on the surface of the particles, can be surface-conjugated to the particles to prevent the particles from sticking to non-target biological molecules and surfaces in a subject to which the particles are administered.
  • PEG polyethylene glycol
  • PC phosphatidylcholine
  • small proteinaceous motifs such as the B domain of bacterial Protein A and the functionally equivalent region of Protein G are known to bind to, and thereby capture, antibody molecules by the Fc region.
  • proteinaceous motifs can be attached as bioactive agents to the invention therapeutic polymer compositions, especially to the surface of the polymer particles described herein.
  • Such molecules will act, for example, as ligands to attach antibodies for use as targeting ligands or to capture antibodies to hold precursor cells or capture cells out of the blood stream. Therefore, the antibody types that can be attached to polymer coatings using a Protein A or Protein G functional region are those that contain an Fc region.
  • the capture antibodies will in turn bind to and hold precursor cells, such as progenitor cells, near the polymer surface while the precursor cells, which are preferably bathed in a growth medium within the polymer, secrete various factors and interact with other cells of the subject.
  • precursor cells such as progenitor cells
  • one or more bioactive agents dispersed in the polymer particles such as the bradykinins, may activate the precursor cells.
  • bioactive agents for attaching precursor cells or for capturing progenitor endothelial cells (PECs) from a blood stream in a subject to which the polymer compositions are administered are monoclonal antibodies directed against a known precursor cell surface marker.
  • CDs complementary determinants
  • These cell surface markers can be of varying specificity and the degree of specificity for a particular cell/developmental type/stage is in many cases not fully characterized, hi addition, these cell marker molecules against which antibodies have been raised will overlap (in terms of antibody recognition) especially with CDs on cells of the same lineage: monocytes in the case of endothelial cells.
  • Circulating endothelial progenitor cells are some way along the developmental pathway from (bone marrow) monocytes to mature endothelial cells.
  • CDs 106, 142 and 144 have been reported to mark mature endothelial cells with some specificity.
  • CD34 is presently known to be specific for progenitor endothelial cells and therefore is currently preferred for capturing progenitor endothelial cells out of blood in the site into which the polymer particles are implanted for local delivery of the active agents.
  • antibodies include single-chain antibodies, chimeric antibodies, monoclonal antibodies, polyclonal antibodies, antibody fragments, Fab fragments, IgA, IgG, IgM, IgD, IgE and humanized antibodies, and active fragments thereof.
  • bioactive agents and small molecule drugs will be particularly effective for dispersion within the invention therapeutic polymer compositions, whether sized to form a time release biodegradable polymer depot for local delivery of the bioactive agents, or sized for entry into systemic circulation, as described herein.
  • the bioactive agents that are dispersed in the invention therapeutic polymer compositions and methods of use will be selected for their suitable therapeutic or palliative effect in treatment of a disease of interest, or symptoms thereof, or in experiments designed for in vitro testing of such effects in cells or tissue culture, or in vivo.
  • the suitable bioactive agents are not limited to, but include, various classes of compounds that facilitate or contribute to wound healing when presented in a time-release fashion.
  • bioactive agents include wound-healing cells, including certain precursor cells, which can be protected and delivered by the biodegradable polymer in the invention compositions.
  • wound healing cells include, for example, pericytes and endothelial cells, as well as inflammatory healing cells.
  • the invention therapeutic polymer compositions and particles thereof used in the invention and methods of use can include ligands for such cells, such as antibodies and smaller molecule ligands, that specifically bind to "cellular adhesion molecules" (CAMs).
  • CAMs cellular adhesion molecules
  • Exemplary ligands for wound healing cells include those that specifically bind to Intercellular adhesion molecules (ICAMs), such as ICAM-I (CD54 antigen); ICAM-2 (CD102 antigen); ICAM-3 (CD50 antigen); ICAM-4 (CD242 antigen); and ICAM-5; Vascular cell adhesion molecules (VCAMs), such as VCAM-I (CD106 antigen); Neural cell adhesion molecules (NCAMs), such as NCAM-I (CD56 antigen); or NCAM-2; Platelet endothelial cell adhesion molecules PECAMs, such as PECAM-I (CD31 antigen); Leukocyte-endothelial cell adhesion molecules (ELAMs), such as LECAM-I; or LECAM-2 (CD62E antigen), and the like.
  • ICAMs Intercellular adhesion molecules
  • VCAMs Vascular cell adhesion molecules
  • VCAMs such as VCAM-I (CD106 antigen)
  • NCAMs Neural cell adhesion molecules
  • ELAMs Le
  • the suitable bioactive agents include extra cellular matrix proteins, macromolecules that can be dispersed into the polymer particles used in the invention therapeutic polymer compositions, e.g., attached either covalently or non- covalently.
  • useful extra-cellular matrix proteins include, for example, glycosaminoglycans, usually linked to proteins (proteoglycans), and fibrous proteins (e.g., collagen; elastin; fibronectins and laminin).
  • Bio-mimics of extra-cellular proteins can also be used. These are usually non-human, but biocompatible, glycoproteins, such as alginates and chitin derivatives. Wound healing peptides that are specific fragments of such extra-cellular matrix proteins and/or their bio-mimics can also be used.
  • Proteinaceous growth factors are another category of bioactive agents suitable for dispersion in the invention therapeutic polymer compositions and methods of use described herein. Such bioactive agents are effective in promoting wound healing and other disease states as is known in the art, for example, Platelet Derived Growth Factor- BB (PDGF-BB), Tumor Necrosis Factor- ⁇ (TNF- ⁇ ), Epidermal Growth Factor (EGF), Keratinocyte Growth Factor (KGF), Thymosin B4; and, various angiogenic factors such as vascular Endothelial Growth Factors (VEGFs), Fibroblast Growth Factors (FGFs), Tumor Necrosis Factor-beta (TNF -beta), and Insulin-like Growth Factor-1 (IGF-I). Many of these proteinaceous growth factors are available commercially or can be produced recombinantly using techniques well known in the art.
  • VEGFs vascular Endothelial Growth Factors
  • FGFs Fibroblast Growth Factors
  • expression systems comprising vectors, particularly adenovirus vectors, incorporating genes encoding a variety of biomolecules can be dispersed in the invention therapeutic polymer compositions and particles thereof for timed release delivery.
  • Methods of preparing such expression systems and vectors are well known in the art.
  • proteinaceous growth factors can be dispersed into the invention therapeutic polymer compositions for administration of the growth factors either to a desired body site for local delivery, by selection of particles sized to form a polymer depot, or systemically, by selection of particles of a size that will enter the circulation.
  • Growth factors such as VEGFs, PDGFs, FGF, NGF, and evolutionary and functionally related biologies, and angiogenic enzymes, such as thrombin, may also be used as bioactive agents in the invention compositions.
  • Small molecule drugs are yet another category of bioactive agents suitable for dispersion in the invention therapeutic polymer compositions and methods of use described herein.
  • Such drugs include, for example, antimicrobials and anti-inflammatory agents as well as certain healing promoters, such as, for example, vitamin A and synthetic inhibitors of lipid peroxidation.
  • antibiotics can be dispersed as bioactive agents in the invention therapeutic polymer compositions to indirectly promote natural healing processes by preventing or controlling infection.
  • Suitable antibiotics include many classes, such as aminoglycoside antibiotics or quinolones or beta-lactams, such as cefalosporins, e.g., ciprofloxacin, gentamycin, tobramycin, erythromycin, vancomycin, oxacillin, cloxacillin, methicillin, lincomycin, ampicillin, and colistin.
  • cefalosporins e.g., ciprofloxacin, gentamycin, tobramycin, erythromycin, vancomycin, oxacillin, cloxacillin, methicillin, lincomycin, ampicillin, and colistin.
  • Suitable antibiotics have been described in the literature.
  • Suitable antimicrobials include, for example, Adriamycin PFS/RDF® (Pharmacia and Upjohn), Blenoxane® (Bristol-Myers Squibb Oncology/Immunology), Cerubidine® (Bedford), Cosmegen® (Merck), DaunoXome® (NeXstar), Doxil® (Sequus), Doxorubicin Hydrochloride® (Astra), Idamycin® PFS (Pharmacia and Upjohn), Mithracin® (Bayer), Mitamycin® (Bristol-Myers Squibb Oncology/Immunology), Nipen® (SuperGen), Novantrone® (Immunex) and Rubex® (Bristol-Myers Squibb Oncology/Immunology).
  • the peptide can be a glycopeptide.
  • glycopeptide refers to oligopeptide (e.g. heptapeptide) antibiotics, characterized by a multi-ring peptide core optionally substituted with saccharide groups, such as vancomycin.
  • glycopeptides included in this category of antimicrobials may be found in "Glycopeptides Classification, Occurrence, and Discovery," by Raymond C. Rao and Louise W. Crandall, ("Bioactive agents and the Pharmaceutical Sciences” Volume 63, edited by Ramakrishnan Nagarajan, published by Marcal Dekker, Inc.). Additional examples of glycopeptides are disclosed in U.S. Patent Nos.
  • glycopeptides include those identified as A477, A35512, A40926, A41030, A42867, A47934, A80407, A82846, A83850, A84575, AB-65, Actaplanin, Actinoidin, Ardacin, Avoparcin, Azureomycin, Balhimyein, Chloroorientiein, Chloropolysporin, Decaplanin, - demethylvancomycin, Eremomycin, Galacardin, Helvecardin, Izupeptin, Kibdelin, LL-AM374, Mannopeptin, MM45289, MM47756, MM47761, MM49721, MM47766, MM55260, MM55266, MM55270, MM56597, MM56598, OA-7653, Orenticin, Parvodicin, Ristocetin, Ristomycin, Synmonicin, Teicoplanin, UK-68597, UD-69542, UK-720
  • glycopeptide or "glycopeptide antibiotic” as used herein is also intended to include the general class of glycopeptides disclosed above on which the sugar moiety is absent, i.e. the aglycone series of glycopeptides. For example, removal of the disaccharide moiety appended to the phenol on vancomycin by mild hydrolysis gives vancomycin aglycone.
  • glycopeptide antibiotics synthetic derivatives of the general class of glycopeptides disclosed above, including alkylated and acylated derivatives. Additionally, within the scope of this term are glycopeptides that have been further appended with additional saccharide residues, especially aminoglycosides, in a manner similar to vancosamine.
  • lipidated glycopeptide refers specifically to those glycopeptide antibiotics that have been synthetically modified to contain a lipid substituent.
  • lipid substituent refers to any substituent contains 5 or more carbon atoms, preferably, 10 to 40 carbon atoms.
  • the lipid substituent may optionally contain from 1 to 6 heteroatoms selected from halo, oxygen, nitrogen, sulfur, and phosphorous. Lipidated glycopeptide antibiotics are well known in the art. See, for example, in U.S. Patent Nos.
  • Anti-inflammatory bioactive agents are also useful for dispersion in invention therapeutic polymer compositions. Depending on the body site and disease to be treated, such anti-inflammatory bioactive agents include, e.g.
  • analgesics e.g., NSAIDS and salicyclates
  • steroids e.g., antirheumatic agents
  • gastrointestinal agents e.g., gout preparations, hormones (glucocorticoids), nasal preparations, ophthalmic preparations, otic preparations (e.g., antibiotic and steroid combinations), respiratory agents, and skin & mucous membrane agents.
  • the antiinflammatory agent can include dexamethasone, which is chemically designated as (1 l ⁇ , 16I)-9-fluro- 11 , 17,21 -trihydroxy- 16-methylpregna- 1 ,4-diene-3 ,20-dione.
  • the anti-inflammatory bioactive agent can be or include sirolimus (rapamycin), which is a triene macrolide antibiotic isolated from Streptomyces hygroscopicus.
  • polypeptide bioactive agents included in the invention compositions and methods can also include "peptide mimetics.”
  • Such peptide analogs referred to herein as “peptide mimetics” or “peptidomimetics,” are commonly used in the pharmaceutical industry with properties analogous to those of the template peptide (Fauchere, J. (1986) Adv. Bioactive agent Res., 15:29; Veber and Freidinger (1985) TINS, p. 392; and Evans et al. (1987; J. Med. Chem., 30:1229) and are usually developed with the aid of computerized molecular modeling.
  • Such peptide mimetics may have significant advantages over natural polypeptide embodiments, including, for example: more economical production, greater chemical stability, enhanced pharmacological properties (half-life, absorption, potency, efficacy, etc.), altered specificity (e.g., a broad-spectrum of biological activities), reduced antigenicity, and others.
  • substitution of one or more amino acids within a peptide may be used to generate more stable peptides and peptides resistant to endogenous peptidases.
  • the synthetic polypeptides covalently bound to the biodegradable polymer can also be prepared from D-amino acids, referred to as inverso peptides. When a peptide is assembled in the opposite direction of the native peptide sequence, it is referred to as a retro peptide.
  • polypeptides prepared from D-amino acids are very stable to enzymatic hydrolysis.
  • compositions and polymer particles thereof can be lyophilized and the dried composition suspended in an appropriate media prior to administration.
  • any suitable and effective amount of the at least one bioactive agent can be released with time from the therapeutic polymer composition, including those in a polymer coating on a medical device, such as a stent or a depot formed from particles thereof introduced in vivo.
  • the suitable and effective amount of the bioactive agent will typically depend, e.g., on the specific PEA or PEUR polymer and concentration of therapeutic backbone diol or di-acid incorporated therein, type of particle or polymer/bioactive agent linkage, if present.
  • up to about 100% of the backbone diol(s) or di-acid(s) and optional bioactive agent(s) can be released from polymer particles sized to avoid circulation as described herein that form a polymer depot in vivo.
  • up to about 90%, up to 75%, up to 50%, or up to 25% thereof can be released from the polymer depot.
  • Factors that typically affect the release rate from the polymer depot are the nature and amount of the polymer/backbone therapeutic agent, the types of polymer/bioactive agent linkage, and the nature and amount of additional substances present in the formulation.
  • compositions are formulated for subsequent intrapulmonary, gastroenteral, subcutaneous, intramuscular, into the central nervous system, inrraperitoneum or intraorgan delivery.
  • the compositions will generally include one or more "pharmaceutically acceptable excipients or vehicles" appropriate for oral, mucosal or subcutaneous delivery, such as water, saline, glycerol, polyethylene glycol, hyaluronic acid, ethanol, etc.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering substances, flavorings, and the like, may be present in such vehicles.
  • intranasal and pulmonary formulations will usually include vehicles that neither cause irritation to the nasal mucosa nor significantly disturb ciliary function.
  • Diluents such as water, aqueous saline or other known substances can be employed with the subject invention.
  • the intrapulmonary formulations may also contain preservatives such as, but not limited to, chlorobutanol and benzalkonium chloride.
  • a surfactant may be present to enhance absorption by the nasal mucosa.
  • the vehicle composition will include traditional binders and carriers, such as, cocoa butter (theobroma oil) or other triglycerides, vegetable oils modified by esterification, hydrogenation and/or fractionation, glycerinated gelatin, polyalkaline glycols, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • traditional binders and carriers such as, cocoa butter (theobroma oil) or other triglycerides, vegetable oils modified by esterification, hydrogenation and/or fractionation, glycerinated gelatin, polyalkaline glycols, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • the invention therapeutic polymer compositions can be formulated in pessary bases, such as those including mixtures of polyethylene triglycerides, or suspended in oils such as corn oil or sesame oil, optionally containing colloidal silica. See, e.g., Richardson et al., hit. J. Pharm. (1995) 115:9-15.
  • the invention therapeutic polymer compositions are also intended as delivery vehicles for use in veterinary administration of bioactive agents to a variety of mammalian patients, such as pets (for example, cats, dogs, rabbits, and ferrets), farm animals (for example, swine, horses, mules, dairy and meat cattle) and race horses.
  • pets for example, cats, dogs, rabbits, and ferrets
  • farm animals for example, swine, horses, mules, dairy and meat cattle
  • the therapeutic polymer compositions used in the invention methods of administration or delivery will comprise an "effective amount" of one or more backbone therapeutic diol or di-acid(s) and optional bioactive agents of interest. That is, an amount of a backbone diol or di-acid will be incorporated into the composition that will produce a sufficient therapeutic or palliative response in order to prevent, reduce or eliminate symptoms.
  • the exact amount necessary will vary, depending on the subject to which the composition is being administered; the age and general condition of the subject; the capacity of the subject's immune system, the degree of therapeutic or palliative response desired; the severity of the condition being treated or investigated; the particular therapeutic diol or di-acid selected and mode of administration of the composition, among other factors.
  • an effective amount can be readily determined by one of skill in the art. Thus, an "effective amount" will fall in a relatively broad range that can be determined through routine trials. For example, for purposes of the present invention, an effective amount will typically range from about 1 ⁇ g to about 100 mg, for example from about 5 ⁇ g to about 1 mg, or about 10 ⁇ g to about 500 ⁇ g of the active agent delivered per dose.
  • the invention therapeutic polymer compositions are administered orally, mucosally, or by subcutaneously or intramuscular injection, and the like, using standard techniques. See, e.g., Remington: The Science and Practice of Pharmacy, Mack Publishing Company, Easton, Pa., 19th edition, 1995, for mucosal delivery techniques, including intranasal, pulmonary, vaginal and rectal techniques, as well as European Publication No. 517,565 and Ilium et al., J. Controlled ReI. (1994) 29:133-141, for techniques of intranasal administration.
  • Dosage treatment may be a single dose of the invention therapeutic polymer composition, or a multiple dose schedule as is known in the art.
  • the dosage regimen at least in part, will also be determined by the need of the subject and be dependent on the judgment of the practitioner.
  • the therapeutic polymer composition in the form of particles, or not
  • the therapeutic polymer compositions are generally administered subsequent to primary disease manifestation.
  • the formulations can be tested in vivo in a number of animal models developed for the study of oral subcutaneous or mucosal delivery.
  • the conscious sheep model is an art-recognized model for testing nasal delivery of substances See, e.g., Longenecker et al, J. Pharm. Sci. (1987) 76:351-355 and Ilium et al., J. Controlled ReI. (1994) 29:133-141.
  • the therapeutic polymer composition generally in powdered, lyophilized form, is blown into the nasal cavity. Blood samples can be assayed for active agent using standard techniques, as known in the art.
  • Di-p-toluenesulfonic acid salt of L-lysine benzyl ester (2) was prepared as described earlier (US 6,503,538) by refluxing of benzyl alcohol, toluenesulfonic acid monohydrate and L-lysine monohydro-chloride in toluene, applying azeotropic removal of generated water (scheme 5).
  • a di-TFA salt of bis-L-leucine- ⁇ -estradiol-diester (compound 5) was prepared by a two step reaction. 17- ⁇ -Estradiol was first reacted with Boc-protected L-Leucine, applying carbodiimide mediated esterification, to form compound 4. In a second step, Boc groups were deprotected using TFA, converting at the same time into a di-TFA salt of di- amino monomer (compound 5) (see Scheme 7).
  • Triethylamine 1.46 mL (10.47 mmol) was added at once to the mixture of monomers (compound 1) (4.986 mmol), (compound 2) (1.246 mmol), (compound 3) (1.869 mmol), (compound 5) (1.869 mmol) in 3 mL of dry DMF and the solution was heated to 6O 0 C while stirring. The reaction vial was kept at the same temperature for 16h.
  • Mw and Mn The number and weight average molecular weights (Mw and Mn) and molecular weight distribution of synthesized polymer was determined by Model 515 gel permeation chromatography (Waters Associates Inc. Milford, MA) equipped with a high pressure liquid chromatographic pump, a Waters 2414 refractory index detector. 0.1% of LiCl solution in N,N-dimethylacetamide (DMAc) was used as eluent (1.0 mL/min). Two Styragel® HR 5E DMF type columns (Waters) were connected and calibrated with polystyrene standards.
  • DMAc N,N-dimethylacetamide
  • a PEA polymer containing a residue of ⁇ -Estradiol in the main polymer backbone was prepared, where both hydroxyls of the diol steroid were incorporated into monomer via ester bonds using a carbodiimide technique.
  • the final monomer introduced into the polymerization reaction was a TFA salt.
  • a high molecular weight copolymer was obtained.
  • the product copolymer was partially soluble in ethanol (when dry), well soluble in chloroform, chloroform:ethanol 1:1 mixture, dichloromethane, and in polar aprotic organic solvents: DMF, DMSO, DMAc.
  • the therapeutic polymer formed a tough film when cast from chloroform solution. Tensile characterization yielded the following results: Stress at break 28.1 MPa, Elongation 173%, Young's Modulus 715 MPa.
  • a therapeutic PEUR polymer composition (structural formula IV) containing a therapeutic diol in the polymer backbone is illustrated in this example.
  • a first monomer used in the synthesis is a di-carbonate of a therapeutic diol with a general formula III.
  • R 5 " 6" 5 chemical structure illustrated by formula R -O-C-O-R -O-C-O-R i s formed using a known procedure (compound (X) as described in U.S. Patent 6,503,538) wherein R 5 is independently (Cg-C 10 ) aryl (e.g. 4-nitrophenol, in this example), optionally substituted with one or more nitro, cyano, halo, trifluoromethyl or trifluoromethoxy; and at least some of p-nitrophenol. At least some of R 6 is a residue of a therapeutic diol as described herein, depending upon the desired drug load.
  • each diol would first be prepared and purified as a separate monomer.
  • di-p-nitrophenyl-3,17- ⁇ -estradiol-dicarbonate (compound 6) can be prepared by the method of Scheme 9 below:

Abstract

La présente invention concerne des compositions polymères thérapeutiques biodégradables à base de polyesteramide, de polyesteruréthane et de polyestère-urée utiles dans l'administration in vivo d'au moins un diol ou un diacide thérapeutique incorporé dans le squelette du polymère biodégradable. Les compositions polymères thérapeutiques se biodégradent in vivo par action enzymatique pour libérer des diols ou des diacides thérapeutiques du squelette polymère de manière régulée dans le temps. Les compositions de l'invention sont stables, peuvent être lyophilisées pour leur transport et leur stockage, et peuvent être redispersées pour être administrées. Du fait des propriétés structurales des polymères de polyesteramide et de polyesteruréthane utilisés, les compositions polymères thérapeutiques de l'invention fournissent un niveau élevé en diol ou diacides thérapeutiques, et également en agents bioactifs optionnels.
PCT/US2006/021395 2005-06-03 2006-06-02 Polymeres therapeutiques et leurs procedes d'utilisation WO2006132950A2 (fr)

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JP2008514885A JP2008542393A (ja) 2005-06-03 2006-06-02 治療用ポリマーおよび使用方法
AU2006255262A AU2006255262A1 (en) 2005-06-03 2006-06-02 Therapeutic polymers and methods of use
CA002610745A CA2610745A1 (fr) 2005-06-03 2006-06-02 Polymeres therapeutiques et leurs procedes d'utilisation
EP06760640A EP1906976A4 (fr) 2005-06-03 2006-06-02 Polymeres therapeutiques et leurs procedes d'utilisation

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008103264A2 (fr) * 2007-02-16 2008-08-28 Abbott Cardiovascular Systems Inc. Particules polymères
EP2227223A2 (fr) * 2007-12-06 2010-09-15 Medivas, LLC Compositions polymères à base d'oligo-éthylène glycol et procédé d'utilisation
US8152758B2 (en) 2003-12-31 2012-04-10 Advanced Cardiovascular Systems, Inc. Needle catheter
US9873765B2 (en) 2011-06-23 2018-01-23 Dsm Ip Assets, B.V. Biodegradable polyesteramide copolymers for drug delivery
US9873764B2 (en) 2011-06-23 2018-01-23 Dsm Ip Assets, B.V. Particles comprising polyesteramide copolymers for drug delivery
US10434071B2 (en) 2014-12-18 2019-10-08 Dsm Ip Assets, B.V. Drug delivery system for delivery of acid sensitivity drugs
WO2021088723A1 (fr) * 2019-11-08 2021-05-14 中国科学院理化技术研究所 Dérivé ou copolymère antimicrobien de poly(acide aminé) ayant une structure alternée et son procédé de préparation

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060177416A1 (en) 2003-10-14 2006-08-10 Medivas, Llc Polymer particle delivery compositions and methods of use
WO2007035938A2 (fr) 2005-09-22 2007-03-29 Medivas, Llc FORMULES DE POLY(ESTER AMIDE) ET DE POLY(ESTER URÉTHANE) CONTENANT DES DIESTERS DE BIS-(α-AMINO)-DIOL ET MÉTHODES D'EMPLOI
JP2009530484A (ja) * 2006-03-24 2009-08-27 メディバス エルエルシー アルキレン−ジカルボキシラート含有の生分解性ポリ（エステル−アミド）および使用法
EP2021141A4 (fr) * 2006-05-09 2013-07-03 Medivas Llc Polymères hydrosolubles biodégradables
WO2016207725A1 (fr) * 2015-06-23 2016-12-29 Phagelux (Canada), Inc. Composition comprenant des polymères d'acide aminé et un agent bioactif et procédé de préparation associé

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1250050B1 (fr) * 2000-01-11 2004-10-27 Intralytix Inc. Procedes et dispositifs pour l'assainissement par bacteriophages
US6703040B2 (en) * 2000-01-11 2004-03-09 Intralytix, Inc. Polymer blends as biodegradable matrices for preparing biocomposites
WO2002009768A2 (fr) * 2000-07-27 2002-02-07 Rutgers, The State University Polyesters et polyamides therapeutiques
US6503538B1 (en) * 2000-08-30 2003-01-07 Cornell Research Foundation, Inc. Elastomeric functional biodegradable copolyester amides and copolyester urethanes
MXPA05003238A (es) * 2002-09-26 2005-09-12 Endovascular Devices Inc Aparato y metodo para administrar mitomicina a traves de un dispositivo medico implantable biocompatible de elucion.
CA2666866A1 (fr) * 2005-10-21 2007-05-03 Medivas, Llc Polymeres de poly(ester-uree) et leurs procedes d'utilisation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of EP1906976A4 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8152758B2 (en) 2003-12-31 2012-04-10 Advanced Cardiovascular Systems, Inc. Needle catheter
WO2008103264A2 (fr) * 2007-02-16 2008-08-28 Abbott Cardiovascular Systems Inc. Particules polymères
WO2008103264A3 (fr) * 2007-02-16 2008-10-09 Abbott Cardiovascular Systems Particules polymères
EP2227223A2 (fr) * 2007-12-06 2010-09-15 Medivas, LLC Compositions polymères à base d'oligo-éthylène glycol et procédé d'utilisation
EP2227223A4 (fr) * 2007-12-06 2013-11-27 Medivas Llc Compositions polymères à base d'oligo-éthylène glycol et procédé d'utilisation
US9873764B2 (en) 2011-06-23 2018-01-23 Dsm Ip Assets, B.V. Particles comprising polyesteramide copolymers for drug delivery
US9873765B2 (en) 2011-06-23 2018-01-23 Dsm Ip Assets, B.V. Biodegradable polyesteramide copolymers for drug delivery
US9896544B2 (en) 2011-06-23 2018-02-20 Dsm Ip Assets, B.V. Biodegradable polyesteramide copolymers for drug delivery
US9963549B2 (en) 2011-06-23 2018-05-08 Dsm Ip Assets, B.V. Biodegradable polyesteramide copolymers for drug delivery
US10434071B2 (en) 2014-12-18 2019-10-08 Dsm Ip Assets, B.V. Drug delivery system for delivery of acid sensitivity drugs
US10888531B2 (en) 2014-12-18 2021-01-12 Dsm Ip Assets B.V. Drug delivery system for delivery of acid sensitivity drugs
US11202762B2 (en) 2014-12-18 2021-12-21 Dsm Ip Assets B.V. Drug delivery system for delivery of acid sensitivity drugs
WO2021088723A1 (fr) * 2019-11-08 2021-05-14 中国科学院理化技术研究所 Dérivé ou copolymère antimicrobien de poly(acide aminé) ayant une structure alternée et son procédé de préparation

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JP2008542393A (ja) 2008-11-27
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EP1906976A2 (fr) 2008-04-09
WO2006132950A3 (fr) 2007-06-14

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