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WO2009089072A1 - Stents tressés biodégradables et procédés - Google Patents

Stents tressés biodégradables et procédés Download PDF

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Publication number
WO2009089072A1
WO2009089072A1 PCT/US2009/000187 US2009000187W WO2009089072A1 WO 2009089072 A1 WO2009089072 A1 WO 2009089072A1 US 2009000187 W US2009000187 W US 2009000187W WO 2009089072 A1 WO2009089072 A1 WO 2009089072A1
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WO
WIPO (PCT)
Prior art keywords
stent
polymer
fibers
fiber
anhydride
Prior art date
Application number
PCT/US2009/000187
Other languages
English (en)
Inventor
Olexander Hnojewyj
Patrick Rivelli
Zohar Ophir
Michael Jaffe
Tony B. Shaffer
Phillip M. Leopold
Andrew R. Leopold
David Cheung
Original Assignee
Bioabsorbable Therapeutics, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bioabsorbable Therapeutics, Inc. filed Critical Bioabsorbable Therapeutics, Inc.
Publication of WO2009089072A1 publication Critical patent/WO2009089072A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/148—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • D—TEXTILES; PAPER
    • D04—BRAIDING; LACE-MAKING; KNITTING; TRIMMINGS; NON-WOVEN FABRICS
    • D04C—BRAIDING OR MANUFACTURE OF LACE, INCLUDING BOBBIN-NET OR CARBONISED LACE; BRAIDING MACHINES; BRAID; LACE
    • D04C1/00—Braid or lace, e.g. pillow-lace; Processes for the manufacture thereof
    • D04C1/06—Braid or lace serving particular purposes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/86—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
    • A61F2/90—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/41—Anti-inflammatory agents, e.g. NSAIDs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • A61L2300/414—Growth factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow
    • A61L2300/604—Biodegradation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings
    • D—TEXTILES; PAPER
    • D10—INDEXING SCHEME ASSOCIATED WITH SUBLASSES OF SECTION D, RELATING TO TEXTILES
    • D10B—INDEXING SCHEME ASSOCIATED WITH SUBLASSES OF SECTION D, RELATING TO TEXTILES
    • D10B2509/00—Medical; Hygiene
    • D10B2509/06—Vascular grafts; stents

Definitions

  • compositions, devices, and methods relates to a braided, biodegradable materials and devices, including tubular stents, and methods of making and using the device or material.
  • Biodegradable polymers are being used for many applications in medicine, including as a carrier for controlled-release drug delivery systems, and in biodegradable bone pins, screws, and scaffolds for cells in tissue engineering.
  • a principal advantage of the materials based on biodegradable polymers over existing non-biodegradable polymers or metal-based material is that the products are removed over time by bioerosion, avoiding the need for surgical removal.
  • PLA polymers typically take a few weeks to several months to completely degrade in the body, but the device is typically depleted of drug more rapidly;
  • PLA devices undergo bulk erosion, which leads to a variety of undesirable outcomes, including exposure of unreleased drug to a highly acidic environment;
  • the particularly fine PLA particles needed for intravenous injection or inhalation can agglomerate significantly, making resuspension for injection or aerosolization for inhalation difficult.
  • polyanhydride polymers Because of their more labile polymer bond, polyanhydride polymers have a more rapid degradation rate and tend to exhibit surface, rather than bulk degradation. Because of these advantages, polyanhydrides polymers may be preferred in biological applications where it is critical to achieve a high degradation rate and/or a better controlled rate of erosion from the polymer surface.
  • biodegradable polymer One indication/application for a biodegradable polymer is for making intravascular stents, which are typically delivered on a balloon catheter and deployed at a site of vascular injury by radial expansion.
  • this application requires the polymer to expand significantly, and to hold its shape within a vessel, once expanded.
  • a limitation of polyanhydride polymers is their relatively high stiffness, or high Young's modulus of elasticity, typically in the range of 3-5 GPa, which makes these polymers unsuitable for applications in which expansion or bending is required.
  • biocompatible, biodegradable stent having the requisite deformability and shape-retention, but also capable of biodegrading over a desired "stenting" period and exhibiting surface rather than bulk erosion.
  • a stent composed of a fiber braid whose fibers (a) are monofilament or multifilament fibers formed of a biodegradable polyanhydride polymer composed of biocompatible multimer or polymer blocks that are linked in the polymer by anhydride linkages, and (b) have the thermal characteristics of an at least partially crystalline polymer, as measured by differential scanning calorimetry, and a tensile strength per fiber cross-sectional area, of at least about 0.8 g/mil 2 .
  • the fibers may be monofilaments having cross-sectional areas of between about 1 to 100 mil 2 , and a circular or elliptical cross-section.
  • Monofilament fibers may be characterized by a tensile strength per filament cross-sectional area between 1 and 50 g/mil 2 .
  • the fibers may be characterized by less than 10%, and preferably less than 5% shrinkage in a water bath at 37 0 C.
  • the at least partially crystalline nature of the monofilament fibers may be evidenced by the absence, substantially, of a characteristic glass-transition curve and a characteristic melting endotherm of at least 20 J/g, when measured by differential scanning calorimetry. This melting endotherm value should exclude the cold crystallization exotherm that may develop during the DSC test Itself.
  • a characteristic glass-transition curve and a characteristic melting endotherm of at least 20 J/g
  • the fibers are composed of anhydride-linked multimer blocks of the form: salicylate-linker-salicylate, where the linker is a hydrocarbon linear-chain di-acid containing between 5 and 20 carbon atoms, and the number of anhydride-linked blocks is between about 1 and 10.
  • the filaments are composed of anhydride- linked polyester-based blocks, each block having a molecular weight in the range from about 1 to about 18 kDa, and the number of anhydride-linked blocks is between about 1 and 15. In particular embodiments, each block having a molecular weight in the range from about 10 to about 13 kDa.
  • the polyester chains in the polyester-based blocks are D, L, or D/L polylactide chains having molecular weights in the range from about 1 to about 18 kDa.
  • the anhydride-linked blocks forming one or more of the fiber filaments in the braid contain one or more therapeutic drugs that are linked together in the polymer backbone by the anhydride linkages, such that molecules of the drug are released upon biodegradation of the filaments, and that are selected from a group consisting of salicylic acid, derivatives of salicylic acid, salsalate, diflunisal, ibuprofen, derivatives of ibuprofen, naproxen, ketoprofen, diclofenac, indomethacin, mefenamic acid, ketorolac, and iodinated salicylates.
  • one of more of the fiber filaments in the braid may be coated with therapeutic drug in a drug coating that includes (i) the drug alone, (ii) the drug carried in an excipient, or (iii) the drug carried in a biodegradable polymer coating.
  • a stent composed of a fiber braid whose fibers are prepared by the steps of (a) subjecting extruded fibers of a biodegradable polyanhydride polymer composed of biocompatible multimer or polymer blocks that are linked in the polymer by anhydride linkages to a fiber-drawing process at a selected temperature between the glass-transition and the cold crystallization temperatures of the fibers, as determined by differential scanning calorimetry, (see E. Turi, edit.
  • step (b) repeating step (a) at successively higher temperatures between the glass-transition and crystallization temperatures of the fibers, until the fibers exhibit the thermal characteristics of crystalline polymer, having an edothermic melting peak of at least 20 J/g, as measured by differential scanning calorimetry.
  • the fibers may have the physical characteristics and polymer compositions noted above.
  • an intravascular stent having a radially expandable, tubular body comprised of a fiber braid whose braided fibers are (a) monofilament or multifilament biodegradable polymer fibers characterized by the thermal characteristics of an at least partially crystalline polymer, as measured by differential scanning calorimetry, and a tensile strength per fiber cross-sectional area, of greater than about 0.8 g/mil 2 , and (b) fastened at their free ends at the opposite ends of the stent, to minimize sharp fiber points that could injure the artery wall but still permit the stent body to be stretched in a radial direction with respect to the stent's tubular axis.
  • the fibers can be fastened at braid -filament crossover points to create a tubular structure with greater radial and axial rigidity, while still permitting the stent body to be stretched in a radial direction with respect to the stent's tubular axis.
  • the fibers may have the physical characteristics and polymer compositions noted above.
  • the braid may be flared at the opposite ends of the stent, and the stent braid may have a pick count, designating the number of times the fibers of the braid cross over one another over a one-inch length of stent, of between about 10 and about 85, when constrained on a mandrel having a diameter of about 3 mm.
  • the fibers forming the braid may be fastened at their free ends by one of (i) heat bonding by laser or ultrasonic weld, (ii) solvent or adhesive binding, (iii) crimping, or (iv) attachment to a separate band forming an end of the stent.
  • the braid fibers may be bonded at their internal crossover points, by (i) heat bonding like laser, ultrasonic weld, or other source of heat, and by(ii) solvent or adhesive binding.
  • a method of forming a braided-fiber stent comprising the steps:
  • the fastening step may be carried out by (i) heat bonding by laser or ultrasonic weld, (ii) solvent or adhesive binding, (iii) crimping, or (iv) attachment to a separate band forming an end of the stent.
  • the braid fibers may be bonded at their internal crossover points, by (i) heat bonding by laser or ultrasonic weld and (ii) solvent or adhesive binding.
  • the invention includes deploying an expandable braided stent of the type described above at a selected treatment site in a vessel, to maintain the vessel in an expanded condition.
  • Fig. 1 illustrates steps in the synthesis of an ⁇ - ⁇ ,-dihydroxy polylactide prepolymer having a diethylene glycol core, and the conversion of the dihydroxy prepolymer to a dicarboxylic acid prepolymer;
  • Fig. 2 illustrates steps in the conversion of the dicarboxylic acid prepolymer of Fig. 1 to an ⁇ - ⁇ ,-dianhydride polylactide prepolymer, and its polymerization to yield a polyanhydride polymer;
  • Fig. 3 illustrates steps in the synthesis of a polyethyleneglycol-based polyanhydride;
  • Fig. 4 illustrates steps in the synthesis of a 1 ,3-bis(p- carboxyphenoxy)propane subunit
  • Fig. 5 illustrates steps in the synthesis of a polyanhydride copolymer of polylactide and the 1 ,3-bis(p-carboxyphenoxy)propane subunit of Fig. 4;
  • Fig. 6 is a plot showing the rates of degradation of (i) a PLA polymer, (ii) a PLA polyanhydride polymer constructed in accordance with the invention; and (iii) a conventional polyanhydride polymer;
  • Figs. 7A-7C shows the structures of a D/L PLA polyanhydride polymer (7A); a ansalicylate-adipic-salicylate polyanhydride polymer (7B); and a salicylate-sebacic acid-salicylate polyanhydride polymer (7C);
  • Fig. 8 illustrates steps in the degradation of a PLA polyanhydride polymer.
  • Fig. 9 illustrates steps in the degradation of a salicy late-ad ipic acid-salicylate polyanhydride polymer;
  • Fig. 10 illustrates steps in the degradation of a salicylate-sebacic acid- salicylate polyanydride polymer
  • Fig. 11 shows the results of DSC analysis of raw PLA polyanhydride polymer
  • Fig. 12 shows the results of a tensile strength test performed using as-spun fibers
  • Fig. 13 shows the results of a tensile strength test performed using a first sample of heated and drawn fibers, which did not crystallize sufficiently;
  • Fig. 14 shows the results of a tensile strength test performed using a sample of heated and drawn fibers, which exhibit characteristic crystallinity by DSC;
  • Fig. 15 shows the results of TMA analysis performed using as-spun fibers;
  • Fig. 16 shows the results of TMA analysis performed using heated and drawn fibers;
  • Fig. 17 shows the results of DSC analysis performed using as-spun fibers.
  • Fig. 18 shows the results of DSC analysis performed on fibers, which were subjected to different heating and drawing conditions;
  • Fig. 19 shows the results of DSC analysis performed using fibers from different stages of heating and drawing
  • Fig. 20 shows a comparison of polyanhydride polymer fibers with other materials
  • Fig. 21 shows the behavior of different heated and drawn fibers in a 37 0 C water bath, which were subjected to different heating and drawing conditions
  • Figs. 22A and 22B illustrate a braided stent formed in accordance with the invention (22A) and the deployment of the braided stent of the invention at a site of vascular injury.
  • a "polyanhydride polymer” is a polymer having at least some anhydride linkages between subunits of the polymer chain. More particularly, a polyanhydride polymer as defined herein, includes polyester or polyether subunits or blocks joined by anhydride linkages, and this polymer is also identified herein as a mixed polyester/polyan hydride or polyether/polyanhydride polymer. This polyanhydride polymer may also contain other polymer subunits or blocks, forming block copolymers whose blocks are linked by anhydride linkages. The composition of such polyanhydride co-polymers may be expressed in terms of relative weight percent of the two polymer blocks making up the block co-polymer.
  • a "prepolymer” or “prepolymer component” refers to a polyester, polyether, or other chemical component that can be incorporated directly or modified to be incorporated into a polyanhydride polymer.
  • Prepolymers include drugs and components that contain or include drugs.
  • Prepolymer component are also referred to as blocks or block subunits.
  • the "average number of anhydride linkages" in an anhydride polymer is the average total number of anhydride linkages present connecting one or more polymer subunits in the polyanhydride chains, and may be determined, for example, by determining the average molecular weight of the anhydride polymer, knowing the relative amounts and sizes of the individual polymer blocks making up the polyanhydride polymer.
  • the "average molecular weight of polymer chains" in a polymer composition is the average molecular weight of the chains determined with respect to polylactide standard (from Polymer Source, Inc.) by size exclusion chromatography, according to standards methods (see, e.g., Kowalski, A. et. al. (1998) Macromolecules 31 :2114).
  • the average molecular weight can also be measured by other means, including laser- desorption ionization time-of-fliqht mass spectrometry, as described (e.g., Zhu, H. et al. (1998) Journal of the American Society for Mass Spectrometry 9:275-81 ).
  • the viscosity average molecular weight can be determined by solution viscosity measured in chloroform at 35C using, e.g., a size 4 Ubbelohde viscometer (obtained from Cannon Instruments, Inc. USA).
  • [ ⁇ ] K M ⁇
  • K and ⁇ are parameters related to type of polymer, solvent and temperature.
  • the molecular weight can be calculated from intrinsic viscosity if the other parameters are known.
  • the number of anhydride linkages in a polymer chain can be estimated from the molecular weight of the polyanhydride divided by the molecular weight of the pre polymer.
  • the average number of anhydride linkages can also be determined from Light Scattering detectors attached on line with size exclusion chromatography.
  • the size of the macromolecule is large enough to cause light scattering, which can be used to calculate the molecular weight. Combining size exclusion chromatography (SEC) and light scattering on-line detector gives a rapid, efficient way to determine molecular weight and molecular weight distribution. Unlike pure polylactide, a polylactide anhydride can have difficulty eluting through a column packing material.
  • the SEC columns are disconnected and a known concentration of polyanhydride is directly injected to the Viscotek T60A dual detector (Visco-LS) and the Varian 9040 Rl detector with a guard column between the sample injector and the detectors.
  • Chloroform (dried on CaH 2 ) or THF (dried over a benzophenone/Na complex) is used as the eluent at a flow rate of 1 ml/min.
  • the d ⁇ /dc of the polymer was calculated in CHCI 3 and in THF.
  • the molecular weight, intrinsic viscosity and radius of gyration may be analyzed by the Viscotek TriSEC software.
  • Young's modulus or "Young's modulus of elasticty” is a measure of the stiffness of a given material. This can be experimentally determined from the slope of a stress-strain curve created during tensile tests conducted on a sample of the material, and is usually expressed in GPa, i.e., 1012 N/m 2 .
  • Relatively stiff polymers such as conventional polyanhydrides, polystyrene, and polyimides, have Young's modulus values in the range 3-5.
  • Soft or highly flexible polymers, such as polyethylene, or rubber can have Young's modulus values below 1. Young's modulus measurements can be made, for example, as described in Adams, D. F. et al.
  • a polymer or coating is "biodegradable" when it is capable of being completely or substantially degraded or eroded when exposed to either an in vivo environment or an in vitro environment having physical, chemical, or biological characteristics substantially similar to those of the in vivo environment within a mammal.
  • a polymer or coating is capable of being degraded or eroded when it can be gradually broken-down, resorbed, absorbed and/or eliminated by, for example, hydrolysis, enzymolysis, metabolic processes, bulk or surface erosion, and the like within a mammal. It should be appreciated that traces or residue of polymer may remain on a device following biodegradation.
  • bioabsorbable and “biodegradable” are used interchangeably.
  • Spinning is a manufacturing step involved in making raw fibers.
  • the term originated in the textile industry, where cotton or wool fibers were twisted together to form a yarn.
  • Spinning polymer fibers typically involves heating an extruding the polymer through a spinning head having a spinneret head having one or more extrusion dies.
  • “Drawing” is the process wherein raw fibers are stretched over heated shoes, plates, or rollers in order to improve their mechanical properties. Such manufacturing practices are known to the skilled. See, for example, I. Ward, P. Coats & M. Dumoulin, editors, Solid Phase Properties of Polymers, Published by Carl Hanser Velrag, Kunststoff 2000.
  • Linear weight relates to the thickness of a fiber, and is sometimes easier to measure than fiber cross-section area or diameter.
  • Linear weight may be expressed using the terms denier or tex, which are known in the art. For example, a linear weight of 124 denier means that 9,000 meters of the fiber weight 124 grams.
  • the braided materials may be manufactured from monofilament or multifilament fibers formed of a biodegradable polyanhydride polymer composed of biocompatible multimer or polymer blocks that are linked in the polymer by anhydride linkages. Such polymers may incorporate drugs that are released as the polymer degrades.
  • a variety of biodegradable polyester- or polyether-based polyanhydride polymers can be used to manufacture the present braided materials and devices.
  • Exemplary polyanhydride polymers are polylactide anhydride (PLA) polymers and salicylate-linker-salicylate polymers.
  • Preferred polyanhydride polymers have the thermal characteristics of an at least partially crystalline polymer, which maybe achieved by heating and drawing raw fibers as described, herein.
  • A. Polyanhvdride polymer components and synthesis [0064] Prepolymer components (i.e., blocks or block subunits) for use in preparing polyanhydride polymers are typically provided by synthesis.
  • Prepolymer components can have a molecular weight of from about 1 to about 100 kiloDaltons (kDa), from about 1 to about 50 kDa, from about 1 to about 30 kDa, from about 1 to about 20 kDa, from about 1 to about 18 kDa, from about 1 to about 13 kDa, from about 10 to about 19 kDa, from about 10 to about 13 kDa, or any range therein.
  • kDa kiloDaltons
  • Several polymers can be mixed to produce a mixture of polymers. Different polymers in a mixture can have different elasticity or degradation properties. Copolymer components can be added to modulate elasticity, alter the degradation rate, or otherwise improve performance.
  • the polyanhydride polymer has a desired Young's modular of elasticity in the range of 1.5-3.
  • the oreoolvmer mav have a molecular weight (MW) greater than 5 kiloDaltons (kDa) and less than about 10 kDa, for example, about 6-7 KDa.
  • the polyester-based polymer component can be a monomer, oligomer, polymer, or combinations, thereof.
  • the polyester prepolymer may include a non- polyester core, for example, a dihydric alcohol core. Exemplary dihydric alcohols are ethylene glycol, diethylene glycol, and tri-ethylene glycol.
  • the compounds shown and described in Examples 1 and 2 and with respect to Figs. 1 and 2 include a diethylene glycol core.
  • Preferred polyester polymers include biocompatible and bioerodable polyester polymers, such as poly(lactic acid) (PLA; polylactide), polyglycolic acid (PGA), and poly( ⁇ -caprolactone), which may each contain a dihydric alcohol core.
  • PLA poly(lactic acid)
  • PGA polyglycolic acid
  • ⁇ -caprolactone poly( ⁇ -caprolactone)
  • the polyanhydride polymer may contain other block components including, but not limited to, diphenoxy subunits, such as the 1 ,3-bis(carboxyphenoxy) propane subunit whose synthesis is described in Example 4 with respect to Fig. 4.
  • diphenoxy subunits such as the 1 ,3-bis(carboxyphenoxy) propane subunit whose synthesis is described in Example 4 with respect to Fig. 4.
  • Prepolymer component(s) may be converted to terminal-group dicarboxylic acids, e.g., from ⁇ - ⁇ ,-dihydroxy-terminated polyester prepolymers, to corresponding ⁇ - ⁇ ,-dicarboxylic acid terminated prepolymers.
  • This conversion is typically carried out by reaction of the prepolymer with succinic anhydride. More generally, a reaction of ⁇ - ⁇ ,-dihydroxy terminated polyester (or polyether) polymers with the cyclic anhydride, for example, produces ⁇ - ⁇ ,-dicarboxylic acid terminated polyester (or polyether) prepolymers, according to known methods.
  • Methods for converting polyester or polyether or mixed polyether/polyester polymers to corresponding dicarboxylic acids are well-known in the art. Exemplary methods are described below in Example 2 with respect to reference to Fig. 2.
  • the prepolymer components are polymerized under conditions effective to link the components by anhydride linkages. This may be performed by first reacting the dicarboxvlic acid Drepolymer or block components with acetic anhydride to convert the terminal acid groups to corresponding anhydrides. The prepolymer dianhydrides are then dried to remove unreacted acetic anhydride. In the final polymerization step, the dianhydride block or prepolymer components are mixed in a desired weight proportion.
  • the reaction conditions should be effective to produce a polyanhydride polymer having a selected number of polyanhydride linkages, e.g., 1-30 anhydride linkages, which also determines the number of anhydride linked blocks in the polymer.
  • Each polymer molecule typically contains about 1-30 blocks, 1-20, 1-15 blocks, or even 3-10 blocks.
  • Example 2 An exemplary polymerization method is described in Example 2 with reference to Fig. 2. Briefly, in this method, the dianhydride prepolymer components are added to a metal oxide, such as calcium oxide, and heated in an inert atmosphere until melting, with continued heating under vacuum to remove excess acetic anhydride, and with additional heating, e.g., at a temperature between 180 0 C to 22O 0 C, until a desired degree of polymerization has occurred.
  • a metal oxide such as calcium oxide
  • the degree of polymerization that is, the number of anhydride linkages in the final polymer, can be readily determined by measuring the intrinsic viscosity of the polymer and by light scattering measurement from Viscotek detectors to determine polyanhydride molecular weight, and then dividing by the known molecular weight of the prepolymer.
  • the extent of polymerization depends ondictates the elastic properties and rate of degradation.
  • a polyanhydride with high flexibility can be achieved using polyester prepolymers having an average molecular weight between about 6-15 Kdal.
  • the rate of surface degradation can be controlled by the number of anhydride linkages in the polymer, a relatively high rate of surface degradation being achieved when the polymer is formed with 8-12 anhydride linkages.
  • Numerous different biocompatible, biodegradable polymers with preselected elasticity and surface degradation rate properties can be made by varying (i) the molecular weight of the polyester (or polyether) prepolymer, (ii) the extent of polymerization, and (iii) the presence of block components other polyester prepolymers, and other reaction and component variables.
  • the polyester-based polymer component (blocks) may have the form,
  • E ester link a para ester or a meta or para ether linkage
  • the pre-polymer is an ⁇ - ⁇ ,- dihydroxy terminated polyester or polyether polymer having a molecular weight in a selected range between 1 to 20 kDa, 1 to 19 kDa, 2 to 20 kDa, 2 to 19 kDa, 1 to 18 kDa, 1 to 15 kDa, 1 to 13 kDa, and the like.
  • the x is 80% to 98% of the polymer by weight
  • the y is 20% to 2% of the polymer by weight
  • the n ranges from 2 to 4
  • the m ranges from 2 to 10
  • the average total number of anhydride linkages is a selected number ranging from about 5 to about 30.
  • the polyanhydride polymer may contain other block components including, but not limited to, diphenoxy subunits, such as the 1 ,3-bis(carboxyphenoxy) propane subunit whose synthesis is described in Example 4 with respect to Fig. 4.
  • diphenoxy subunits such as the 1 ,3-bis(carboxyphenoxy) propane subunit whose synthesis is described in Example 4 with respect to Fig. 4.
  • the polyester is preferably present in an amount ranging from about 80%-98 percent by weight of the final polymer, with the other component(s) being present in an amount ranging from about 2-20% by weight of the final polymer.
  • Drugs and drug-containing polymer components can be incorporated into the backbone of the polymer, e.g., by polymerizing a suitable drug or drug-containing polymer component along with a polyester-based polymer component to form drug-containing polyanhydride polymer. Alternatively or additionally, drugs can be blended and/or otherwise combined with the polymers. Drug-containing polyanhydride polymers can provide a therapeutic benefit upon biodegradation in the body.
  • the polyester-based polymer component may have the form:
  • the drug-containing polymer component may have the form
  • X 1 comprises a component selected from a group consisting of a substituted, unsubstituted, hetero-, straight-chained, branched, cyclic, saturated or unsaturated aliphatic radical; a substituted, unsubstituted, or hetero- aromatic radical; a releasable agent; or a combination thereof; such that X 1 has a molecular weight of less than about 2,000 Daltons.
  • X 2 comprises a therapeutic agent and has a molecular weight of less than about 10 KDa, wherein the component of X 1 is the same as, or different than, the releasable agent of X 2 .
  • the k and p are integers selected such that the composition comprised of about 80% to about 98% by weight of the polyester-based polymer component; m is an integer ranging from 1 to 10; and n is an integer selected such that the molecular weight of each polyester-based polymer component ranges from about 2 to about 20 KDa.
  • the rate of release of the drug can be controlled by the design of the polyanhydride polymer and shape of the incorporating material or device, such that the degradation of the matrix and accompanying surface morphology changes dictate diffusion of the drug from the polymer into a body.
  • the type of bond (or absence, thereof) used to combine the drug with the polymeric matrix also affects release rate.
  • an anhydride bond is more labile than an ester bond
  • an ester bond is more labile than an amide bond
  • an amide bond is more labile than an ether bond.
  • the presence of electron donating and withdrawing groups provides additional control over polymer properties.
  • Functional groups/moieties that affect hydrophilicity can also be added to control interactions with water.
  • An example of such a group is poly(ethylene glycol) (PEG), which can be added as a pendant group or in-chain group.
  • the therapeutic drug in the polyanhydride polymer may be selected from a group consisting of salicylic acid, derivatives of salicylic acid, salsalate, diflunisal, ibuprofen, derivatives of ibuprofen, naproxen, ketoprofen, diclofenac, indomethacin, mefenamic acid, ketorolac, and iodinated salicylates.
  • the composition is formed by linking the drug (or a drug-containing polymer component) and the polyester-based polymer component via anhydride.
  • Additional drugs that can be used to form a drug-containing polymer component can also be used, including, salicylic acid, 4-aminosalicylic acid, 5- aminosalicylic acid, 4-(acetylamino)salicylic acid, 5-(acetylamino)salicylic acid, 5- chlorosalicylic acid, salicylsalicylic acid (salsalate), 4-thiosalicylic acid, 5-thiosalicylic acid, 5-(2,4-difluorophenyl)salicylic acid (diflunisal), 4-trifluoromethylsalicylic acid, sulfasalazine, dichlofenac, penicillamine, balsalazide, olsalazine, mefenamic acid, carbidopa, levodopa, etodolac, cefaclor, and captopril.
  • the drug-containing polymer component can be a monomer, oligomer, or polymer.
  • An unprotected salicylate for example, can be directly coupled to a diacyl halide, which acts as a linker to join salicylate units to form a dimer of the salicylate, and the dimer is a polymerizable subunit.
  • Salicylate monomers coupling occurs in the presence of at least about 2 equivalents to about 50 equivalents of an organic base such as, for example, pyridine and the like in a suitable solvent, such as, for example, tetrahydrofuran
  • THF dimethyl formamide
  • DMF dimethyl formamide
  • the process uses solvents such as tetrahydrofuran
  • the dimer of salicylate is a dicarboxylic acid that can be polymerized in the manner discussed herein with respect to the 1 ,3-bis(carboxyphenoxy)propane subunit, to form a drug-containing polymer component of the present invention.
  • the diacyl halide is an example of a linker, and other linkers can be used, as described herein.
  • a multitude of low molecular weight therapeutically drugs can be used in the present invention, such as. for exarriDle. those disclosed in U.S. Pat. No. 6,486,214, which is hereby incorporated herein by reference in its entirety.
  • Drugs which can be linked into degradable co-polymers via the polyanhydrides, often have the following characteristics: a relatively low molecular weight of approximately 1 ,000 Daltons or less, at least one carboxylic acid group, and at least one hydroxy, amine, or thiol group.
  • a combination of drugs can be administered using the methods of the present invention.
  • a second drug for example, can be (i) dispersed in the polymeric matrix and released upon degradation; (ii) appended to a polymer as a sidechain, for example; and/or (iii) incorporate into the backbone of a polymer in the polyester- based polymer component, the drug-containing polymer component, or a linker.
  • additional drugs that can be dispersed, appended, and in some cases incorporated, include antiproliferative agents, antineoplastic agents, antimitotic agents, anti-inflammatory agents, antiplatelet agents, anticoagulant agents, antifebrin agents, antithrombin agents, antibiotics, antiallergic agents, antioxidants, analgesics, anesthetics, antipyretic agents, antiseptics, and antimicrobial agents.
  • Exemplary antiproliferative agents include actinomycin D, actinomycin IV, actinomycin U, actinomycin X 1 , actinomycin C 1 , and dactinomycin (COSMEGEN®, Merck & Co., Inc.).
  • Antineoplastics or antimitotics include, for example, paclitaxel (TAXOL®, Bristol-Myers Squibb Co.), docetaxel (TAXOTERE®, Aventis S.A.), methotrexate, azathioprine, vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (ADRIAMYCIN®, Pfizer, Inc.) and mitomycin (MUTAMYCIN®, Bristol-Myers Squibb Co.), and any prodrugs, metabolites, analogs, homologues, congeners, derivatives, salts and combinations thereof.
  • paclitaxel TAXOL®, Bristol-Myers Squibb Co.
  • TXOTERE® docetaxel
  • methotrexate methotrexate
  • azathioprine vincristine, vinblastine
  • fluorouracil fluorouracil
  • doxorubicin hydrochloride ADRIA
  • Antiplatelets, anticoagulants, antifibrin, and antithrombins include, for example, sodium heparin, low molecular weight heparins, heparinoids, hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclin analogues, dextran, D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole, glycoprotein llb/llla platelet membrane receptor antagonist antibody, recombinant hirudin, and thrombin inhibitors (ANGIOMAX®, Biogen, Inc.), and any prodrugs, metabolites, analogs, homologues, congeners, derivatives, salts and combinations thereof.
  • cytostatic or antiproliferative agents include, for example, angiopeptin, angiotensin converting enzyme inhibitors such as captopril (CAPOTEN® and CAPOZIDE®, Bristol-Myers Squibb Co.), cilazapril or lisinopril (PRINIVIL® and PRINZIDE®, Merck & Co., Inc.); calcium channel blockers such as nifedipine; colchicines; fibroblast growth factor (FGF) antagonists, fish oil (omega 3-fatty acid); histamine antagonists; lovastatin (MEVACOR®, Merck & Co., Inc.); monoclonal antibodies including, antibodies specific for Platelet-Derived Growth Factor (PDGF) receptors; nitroprusside; phosphodiesterase inhibitors; prostaglandin inhibitors; suramin; serotonin blockers; steroids; thioprotease inhibitors; PDGF antagonists including, triazolopyrimidine;
  • drugs/bioactive agents include free radical scavengers; nitric oxide donors; rapamycin; everolimus; tacrolimus; 40-O-(2-hydroxy)ethyl-rapamycin; 40-O- (3-hydroxy)propyl-rapamycin; 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin; tetrazole containing rapamycin analogs such as those described in U.S. Pat. No.
  • 6,329,386 estradiol; clobetasol; idoxifen; tazarotene; alpha-interferon; host cells such as epithelial cells; genetically engineered epithelial cells; dexamethasone; and, any prodrugs, metabolites, analogs, homologues, congeners, derivatives, salts and combinations thereof.
  • Free radical scavengers include, but are not limited to, 2,2',6,6'- tetramethyl-1-piperinyloxy, free radical (TEMPO); 4-amino-2,2',6,6 > -tetramethyl-1- piperinyloxy, free radical (4-amino-TEMPO); 4-hydroxy-2,2',6,6'-tetramethyl- piperidene-1-oxy, free radical (TEMPOL), 2,2',3,4,5,5'-hexamethyl-3-imidazolinium- 1-yloxy methyl sulfate, free radical; 16-doxyl-stearic acid, free radical; superoxide dismutase mimic (SODm) and any analogs, homologues, congeners, derivatives, salts and combinations thereof.
  • TEMPO free radical
  • Nitric oxide donors include, but are not limited to, S- nitrosothiols, nitrites, N-oxo-N-nitrosamines, substrates of nitric oxide synthase, diazenium diolates such as spermine diazenium diolate and any analogs, homologues, congeners, derivatives, salts and combinations thereof.
  • Dosages of the drugs can be determined using techniques well-known to one of skill. For example, one of skill can use in vitro or in vivo activity of a drug in animal models. The extrapolation of effective doses in mice to humans, for example, is a technique that is well-known in the art. See, for example, U.S. Pat. No.
  • Linker units may be included for linking the drug- containing and/or polyester-based polymer components via anhydride linkages.
  • Linker units can be selected to modulate elasticity, change the degradation rate, or otherwise improve performance.
  • Linkers can have an interunit linkage in the form of an ester, an anhydride, an acetal, an amide, a urethane, a urea, a glycoside, a disulfide, and a siloxane linkage.
  • the linkers may be an oligomer of an ether, an amide, an ester, an anhydride, a urethane, a carbamate, a carbonate, a hydroxyalkanoate, or an azo compound. Linkers can also addition therapeutic drugs.
  • the selection of the linker allows for control of the relative strength or stability of the bonds provided by the linker to join the polymer components.
  • a stable linker can be used to maintain the integrity of at least a portion of a polymer. As the polymer biodegrades, physical properties that are provided by the polymer are affected, and a stable linker can help to maintain physical properties.
  • the linker may be a substituted, unsubstituted, hetero-, straight-chained, branched, cyclic, saturated or unsaturated aliphatic radical; and a substituted or unsubstituted aromatic radical.
  • the linker can comprise from about 0 to about 50 carbon atoms, from about 2 to about 40 carbon atoms, from about 3 to about 30 carbon atoms, from about 4 to about 20 carbon atoms, from about 5 to about 20 carbon atoms, from about 5 to about 10 carbon atoms, and any range therein.
  • the linker can alternately comprise a non- carbon species such as, for example, a disulfide.
  • the linker can include substituted or unsubstituted poly(alkylene glycols), which include, but are not limited to, PEG, PEG derivatives such as PPG, poly(tetramethylene glycol), poly(ethylene oxide-co-propylene oxide), or copolymers and combinations thereof.
  • the linker can include amino acids.
  • the amino acids can be therapeutic peptides.
  • the therapeutic peptides can be oligopeptides, polypeptides, or proteins. Examples of amino acids that can be useful in the present invention are chemokines and chemokine analogs, such as interleukins and interferons
  • diacyl halides which can be prepared from dicarboxylic acids, having the general formula: HOOC-(Ch ⁇ ) n -COOH.
  • the polymerization conditions can be varied to produce a selected number of anhydride linkages.
  • the average number of anhydride linkages per molecule is typically between 1-30, 1-15, 5-25, 7- 20, 8-15, and any range therein.
  • Polyanhydride polymers having a greater number of such linkages show more rapid surface degradation but have a lower elasticity.
  • Polyanhydride polymers having a lower number of such linkages show less rapid surface degradation but have a greater elasticity.
  • a high degree of elasticity corresponds to a low Young's modulus.
  • Polymerization conditions may be selected to strike a balance between achieving desired elasticity properties and surface degradation properties.
  • polymerization conditions that yield an average of about 8 to about 12, e.g., about 10 anhydride linkages. If a greater rate of surface degradation is desired, polymerization conditions yielding a greater number of anhydride linkages, e.g., up to about 30, are desirable. As can be seen from Example 2, increasing numbers of anhydride linkages are achieved by carrying out the polymerization reaction for longer periods, e.g., up to 6-12 hours, and optionally, at somewhat higher temperatures, e.g., 17O 0 C, and preferably at 18O 0 C.
  • the degradation properties of polyanhydrides compopsitions can be determined from the degradation plots as exemplified in Fig. 6. This plot compares the rate of degradation of a conventional PLA polymer, a conventional polyanhydride polymer, and a polyanhydride polymer as described herein, having a prepolymer molecular weight of between 6 -7.5 KDa, and an average of about 8-12 anhydride linkages. Degradation rates were measured by weighing, at period intervals, a polymer bar having bar dimensions of 50 microns x 50 microns x 2 mm, incubated in phosphate-buffered saline (PBS) at 37 0 C, for periods of up to 100 days.
  • PBS phosphate-buffered saline
  • the material was also inspected microscooicallv to determine whether degradation was largely occurring at the surface, as evidenced by a relatively smooth-surfaced bar, or by bulk degradation, as evidenced by the presence of pits or cavities within the bar.
  • the PLA polymer showed little degradation after 80 days. Over longer period of time, PLA bar showed signs of bulk degradation.
  • the conventional polyanhydride polymer was about 90% degraded after one day and completely degraded within 10 days. At all times, the bar had a smooth surface indicative of surface degradation.
  • the polyester-based polyanhydride showed a relatively linear degradation rate that was intermediate between the other two polymers, losing about 40% of its weight after about 50 days. Extrapolation of these time points show that complete degradation would occur over a period of about 150 days. Further, inspection of the degrading polymer showed that degradation was occurring by surface, rather than bulk loss.
  • Preferred biodegradable anhydride polymer compositions for use in manufacturing braided materials and devices are characterized by a Young's modulus of from about 1.5 to about 3 GPa as determined by standard methods, such as by the ASTM Standard #E111-4.
  • the fibers should have a tensile strength of at least about 0.8 g/mil 2 cross-sectional area, and preferably about 1-50 g/mil 2 cross- sectional area.
  • the weight ratio of the polyester-based polymer component is between about 80% to about 98%.
  • the rate of surface degradation is effective to fully erode a bar of the polymer having dimensions of about 50 microns x 50 microns x 2 mm, when incubated in phosphate buffered saline at 37 0 C, within a period ranging from about 5 to about 365 days, depending on the indication. Exemplary time periods are 90-180 days and 180-360 days. The use of solvents in the manufacturing and processing of the polymers should be minimized.
  • Exemplary polymers are PLA polymers (Fig. 7A) and salicylate-linker- salicylate polymers (Figs. 7B and 7C).
  • Particular PLA polymers are the D/L and D PLA polymers.
  • Particular salicylate-linker-salicylate polymers are salicylate-adipic acid- salicylate polymers (Fig. 7B) and salicylate-sebacic acid-salicylate polymers (Fig. 7C).
  • the degradation of PLA polymers is shown in Fig. 8.
  • the degredation of salicylate- adipic acid-salicylate polymers is shown in Fig. 9 and the degradation of salicylate- sebacic acid-salicylate polymers is shown in Fig. 10.
  • Preferred polyanhydride polymers have a glass transition (Tg) or softening temperature of from about 40°C to about 70°C, from about 45 0 C to about 65°C, from about 50°C to about 60°C; crystallize in a ⁇ uiescent state above about 80°, above about 90°, above about 100°, or even above about 110 0 C; and complete melting above about 130 0 C 1 above about 150 0 C, or even above about 170 0 C.
  • An exemplified polymer, D/L PLA anhydride has a Tg of about 56°C, crystallizes in a quiescent state above about 100 0 C, and completes melting above about 153°C. Thermal degradation is observed above about 160 0 C.
  • DSC differential scanning calorimetry
  • the raw polyanhydride polymer may be used to manufacture fibers having preselected thermal-mechanical properties.
  • Such fibers are typically made by "melt spinning," which is known in the art. Briefly, pellets or other raw forms of polymer material are dried under vacuum as needed to evolve residual solvents, and then heated to a temperature slightly above their Tg. The molten/melted polymer is then extruded through a spinneret head with one or more extrusion dies to produce one or more individual raw polymer fibers or "threadlines,” which are quenched/cooled using water or air. Typically, individual fibers, or yarns or threads comprising multiple fibers, are then wound onto a spool in preparation for subsequent use or further processing.
  • the drawing of both the fibers was performed in three stages at different temperatures and DR values.
  • the main difference between the processing of the fibers was in the temperature of the third drawing stage, which was 82 0 C for fiber 126-42-1 and 9O 0 C for fiber 126-42-2.
  • the DSC tests provided an explanation for the differences in the fiber properties.
  • the traces of the as-spun fiber (126-41-1) demonstrated that that the processed polymer was mostly amorphous, as evidenced by the characteristic Tg at about 51 0 C and by the cold crystallization and subsequent melting peaks at higher temperatures (Fig. 17).
  • the DSC trace of the as spun fiber was similar to that of the pellet material (Fig. 11).
  • the DSC trace of the first of the drawn fibers (126-42-1) showed similar transitions (Fig. 18; upper trace), which similarly provided evidence of its amorphous state.
  • the DSC trace of the second drawn fiber (126-42-2) demonstrated very different material characteristics (Fig. 18 lower trace).
  • the only significant transition that can be observed on the initial heating trace is a melting peak, which indicated that a very significant portion of the molecules of the fiber had crystallized during its drawing process. At least some portion of the molecules in the fiber was likely to have remained in an amorphous state, as is the case with other semi-crystalline polymers; nonetheless, the fiber structure and properties of the crystalline portion of the molecules appear to predominate.
  • DSC analysis of the same fiber sample at various stages during iterative cycles of heating and stretching is shown in Fig. 19 which illustrates the progression toward crystallinity.
  • the as-spun fiber 126-41-1 is amorphous and its molecules have little, if any, orientation. As a result, the fiber is weak and brittle. Once the temperature exceeds the Tg, this fiber becomes very soft and stretches under very low load.
  • the first drawn fiber sample 126-42-1 has some molecular orientation, which enables the fiber to deform without breaking during the tensile test. However, it appears that the drawing temperature of this fiber was not sufficiently high to developing crystallinity, resulting in a fiber that became soft above its Tg.
  • the second of the drawn fibers (126-42-2) is drawn at a sufficiently high temperature for developing both orientation and crystallinity. This fiber is much stronger than the others, and even retains some strength, above the Tg.
  • Fig. 21 The in-vivo benefits of crystallization are illustrated by the results shown in Fig. 21 , which compared the behavior of the two drawn fiber samples in a water bath.
  • lengths of fibers 126-42-1 and 126-42-2 were maintained in a water bath at body temperature (37 0 C) and the fiber length was measured at different times.
  • the length of fiber 126-42-2 did not change much during the test, while fiber 126-42-1 shrunk about 20% in a few days. It is postulated that in this case, moisture which was absorbed by the fiber, plasticized the polymer and lowered its Tg to the point that the amorphous molecules of the fiber could relax, leading to a significant loss of modulus and causing shrinkage by molecular coiling back into their un-oriented state.
  • an aspect of the present material, devices, and methods is to produce polyanhydride polymer fibers for making braided (or woven) materials by subjecting extruded fibers of a biodegradable polyanhydride polymer composed of biocompatible multimer or polymer blocks linked in the polymer by anhydride linkages to a fiber-drawing process at a selected temperature between the glass- transition and crystallization temperatures of the fibers, as determined by, e.g., differential scanning calorimetry.
  • This drawing step may be repeated at successively higher temperatures between the Tg and crystallization temperatures of the fibers, until the fibers exhibit the thermal characteristics of a semi-crystalline polymer, as evidenced by the substantial absence of a glass-transition curve and a glass- crystallization curve and is a melting endotherm of at least 20 J/g, as measured using DSC.
  • a least one drawing stage is performed at a temperature above 82°C, preferably above 85°C, and preferably about 90°C or greater.
  • the drawn fibers should have a diameter of about 0.001" to 0.010" or a total fiber cross-section area, which is equivalent to fibers with such diameters.
  • Suitable fibers have a tensile strength greater than 250 grams/filament (g/f), greater than 300 g/f, and preferably even greater than 350 g/f, when measured by a tensile test (see for example ASTM C 1557-03).
  • the fibers should be dimensionally stable at physiological temperature (about 37°C), shrinking no more than 10%, preferably less than 7%, in a 37°C water bath.
  • Fiber diameter may be measured using standard methods (e.g., micrometers, vernier calipers, optical measuring devices, and the like). The tensile strength of the fibers can be measured by weight testing. Thermal-mechanical properties of the filaments can be determined using thermal mechanical analysis (TMA), thermal gravimetric analysis (TGA), shrinkage or water absorption at 37°C. Melting temperature an profile can be determined using DSC and melt viscosity can be determined by film molding.
  • TMA thermal mechanical analysis
  • TGA thermal gravimetric analysis
  • Melting temperature an profile can be determined using DSC and melt viscosity can be determined by film molding.
  • the present polyanhvdride polvmers are useful in a number of biomedical applications that exploit their improved elasticity and/or degradation properties of the polymers.
  • Exemplary anhydride polymers for use in medical devices are polylactide anhydride (PLA) polymers and salicylate-linker-salicylate polymers. As described described herein, these polymers have thermal-mechanical properties that make them well-suited for making biodegradable materials and devices.
  • Preferred PLA polymers are the D/L and D PLA polymers.
  • Preferred salicylate-linker-salicylate polymers are salicylate-adipic acid-salicylate polymers and salicylate-sebacic acid-salicylate polymers. The degredation of salicylate-sebacic acid-salicylate polymers, salicylate- adipic acid-salicylate polymers, and D/L PLA polymers.
  • polyanhydride polymers An important application of polyanhydride polymers is in the manufacture of biocompatible, biodegradable intravascular stents.
  • Conventional stents for use at intravascular sites of injury are deployed by radial expansion over a balloon catheter, and thus require the ability to expand significantly and to hold their expanded shape when deployed, properties that led to the widespread use of metals, such as stainless steel, in stent construction.
  • the present expandable, shape-retaining bioerodable stents offers the advantages of temporary physical stenting, but ultimately biodegrade by surface erosion over a preselected stenting period. Degradation of the stent decreases restenosis, which is a chronic and severe complication associated with non-biodegradable stents.
  • Biodegradable stents may be made from braided materials produced from any of the biodegradable polyanhydride polymer materials described herein. Such polymers include biocompatible multimer or polymer blocks that are linked in the polymer by anhydride linkages.
  • the fibers have the thermal characteristics of an at least partially crystalline polymer, having a melting endotherm of at least 20 J/g, as measured by, e.g., DSC.
  • a braided stent is formed by forming a cylindrical braid from the polymer filaments described above.
  • the braided stent may be manufactured using mono-fibers or multi-fiber yarns. Fibers comprising different polymer components can be combined/comingled to in the same braided materials.
  • polymer components can be drugs or drug- containing polymer components.
  • An exemplary braided stent is prepared using 0.175 mm monofilament fibers having an average tensile strength of 0.467 lbs.
  • the Pick-count (number of times fibers cross per 1" -length of material ⁇ of the braided material was 16 ⁇ 2. This material was used to form stents having 24 braid ends, overall diameters of about 6-8 mm, and lengths of 10-20 mm.
  • the Pick count of the material used to make the stent can be varied to modulate the radial strength of the stent.
  • a "tighter" or denser braid pattern i.e., having an increased Pick count) will produce a stent with greater radial strength.
  • the stent has sufficient radial strength to resist compression following delivery via a catheter.
  • a braided-fiber stent is prepared by weaving on a mandrel, biodegradable monofilament or multifilament fibers having the thermal characteristics of an at least partially crystalline polymer, as measured by differential scanning calorimetry, and a tensile strength per fiber cross-sectional area, of greater than about 0.8 g/mil 2 .
  • the diameter of the mandrel on which the stent is woven can range typically between about 1-10 mm, corresponding to diameter of the braided stent in its expanded deployed conditions. That is, the diameter of the braided stent will be the desired diameter of the stent in its expanded, deployed state.
  • the weaving process forms a tubular or cylindrical braid having a pick count, corresponding to the number of times the fibers of the stent cross over one another over a one-inch length of stent, of between about 10 and about 85 when constrained on a 3 mm diameter pin.
  • Such tubular braid structures may then be cut into lengths corresponding to a selected stent length.
  • Braiding machines for producing cylindrical braids are well known, as described for example, in U.S. Patent Nos: 6,997,948, 7,001 ,423, 7,213,495, and 7,311 ,031.
  • the braided tube is cut into desired-length sections, and the free ends of the segments are fastened, woven, or sealed, to prevent the braided material from unraveling.
  • Sealing may be accomplished by, e.g., (i) heat bonding by laser or ultrasonic weld, (ii) solvent or adhesive binding, (iii) crimping, or (iv) attachment to a separate band forming an end of the stent.
  • the ends of a braided stent may also be flared to ensure a smooth transition from the inside surface of the stent to the blood vessel wall, thereby minimizing restriction in the stented vessel.
  • the filaments forming the braided stent are also sealed or bonded by their internal crossover points. This may be done, for example, by infusing an adhesive or polymer solution into the braid, with binding occurring as the infusate dries.
  • the internal filaments may also be bonded by heat treatment, e.g., produced by heating the stent on the mandrel or spot welding the cross-over points with a laser beam. Bondin ⁇ the internal filaments to one another can enhance the radial strength of the stent.
  • the braid would be more rigid radially and axially, while still allowing radial and axial deformation, e.g., when the stent is stretched axially to place it on a catheter. It can be further crimped on the catheter for subsequent expansion into the artery.
  • the stents may be manufactured using fibers of different polyanhydride polymers, to control degradation rates and properties.
  • Fibers for use in stents should have an elliptical (including circular) cross-section of about 1 to about 100 mil 2 , and a tensile strength (per fiber cross-sectional area) of at least about 0.8 g/mil 2 , and preferably about 1 to about 50 g/mil 2 .
  • An exemplary stent is illustrated in Fig. 22A.
  • the fibers may fastened or woven at their free ends (i.e., at the opposite ends of the stent) to prevent unraveling and retain the stent's tubular shape.
  • the fibers may also be fastened or woven at filament cross-over points, to enhance the radial strength of the stent in its expanded condition.
  • the polyanhydride polymer material may comprise drugs incorporated into the polymer, dispersed in the polymers, or coated on the polymer.
  • drugs incorporated into the biodegradable polyanhydride polymers which are released as the polymer degrades in an artery.
  • Exemplary drugs include anti-inflammatory agents, antir-restenotic agents, growth factors, and the like.
  • the stent may be coated on the inside or outside surface with a biodegradable drug-eluting coating, designed to release an anti-restensosis drug, such as taxol or rapamycin, embedded in the coating, over a selected time period.
  • drug-elution is designed to occur over a relatively short period, e.g., 3 days to two weeks post implantation, and therefore the coating can be formed advantageously from a conventional polyanhydride with rapid surface erosion characteristics.
  • a drug-containing polymer may be prepared by known methods, and applied to the stent core by conventional means, such as by dipping or spraying.
  • the coating has a typical thickness between 3-50 microns and thus can be expanded, along with the stent core, even though the coating has a Young's modulus in the range greater than 3 GPa.
  • Coronary artery stents may be about 2.5-4.5 mm in diameter; superficial femoral artery (SFA) stents may be about 5-8 mm in diameter; and carotid artery stents may be about 7-10 mm in diameter.
  • SFA superficial femoral artery
  • carotid artery stents may be about 7-10 mm in diameter.
  • length depends on the indication.
  • the pick count of the stent should be between about 10 and about 85 when constrained on a 3 mm diameter pin. Generally, increasing the pick count increased radial stability.
  • Stents for different indications may include different polymers and/or different drugs. Stents may also be made from different biodegradable polyanhydride polymers, allowing independent control of the release rates of different drugs; sequential or "time-release" dosing of a drug over a preselected time; or other orchestrated dosing schemes.
  • the stent is delivered to the site of vascular injury by a catheter carrying the stent at the catheter's distal end.
  • the expanded diameter of the stent is selected to be slightly greater than that of the vessel which will receive the stent, to ensure that stent remains anchored at the site of deployment.
  • a braided stent having an expanded diameter of about 3.5-4 mm is selected.
  • the stent is typically delivered by way of a guide-wire catheter, with the stent being carried at the distal end of the catheter in a contracted, small-diameter condition, e.g., having a diameter of 20-50% of the expanded stent diameter.
  • the stent may be loaded onto the catheter by stretching it lengthwise over a distal-end delivery wire in the catheter, to produce a proportional reduction in radius, then placing a sleeve over the stent to hold the stent in its contracted state. After an initial balloon angioplasty procedure to open an occluded vessel, the stent-delivery catheter is guided through the vessel to position its distal end at the site of injury.
  • the stent is then pushed out of the delivery catheter and expanded into the vessel by pushing it against an expanded feature placed distally to the site of the injury.
  • the expanded feature is collapsed and the catheter is then withdrawn from the vascular site, leaving the expanded stent in place. Stent placement in a vessel is shown in Fig. 22B
  • the stent acts to maintain the vessel in its opened state, and may also deliver drugs, such as anti-inflammatory and/or anti-restenosis drugs to the surrounding vascular tissue, to reduce the risk of restenosis of the vessel during the period of vessel healing.
  • drugs such as anti-inflammatory and/or anti-restenosis drugs
  • the stent will biodegrade over a period of 2-6 months.
  • the stent may be employed in a variety of vascular settings where a temporary vessel support, with or without the delivery of medication to the site.
  • the braided stent is formed of polymer filaments that can be designed, according to the number of anhydride linkages and the properties of the polymer blocks employed in the polymer, to have desired degradation, flexibility and strength properties.
  • the filaments forming the stent braid may be prepared to include therapeutic compounds, such as anti-inflammatory drugs, that are released during stent degradation, to provide a desired therapeutic result, such as reduced restenosis of the stented vessel.
  • the stents are easily loaded onto the distal end region of a catheter, for deployment at a selected vascular site, and readily assume an expanded stent diameter when deployed.
  • Diethylene glycol is distilled over CaH 2 before use.
  • D/L-lactide was sublimed under vacuum. All the solvents were purified by distillation over proper dehydrating reagent to remove the moisture.
  • 0.0238mole of diethylene glycol, D/L-lactide (12Og) were added to a 1000 ml flask. The mixture was heated to 135 0 C. Once the lactide monomer was melted down, a catalyst of Tin(ll) 2- ethylhexanoate (100mg in 1 ml of toluene) was added by glass syringe. The mixture was heated to 135°C for 25 minutes.
  • the polymer was dissolved in cold dichloromethane . 500ml of water was introduced and the solution was stirred for 1 hour. The water was separated by a globe-shaped separatory funnel. The washing of the polymer solution was carried out three times to remove the unreacted succinic anhydride (by identifying the disappearance of the anhydride peak (1820 cm “1 ) on the FTIR spectrum). The polymer was recovered from precipitation of the polymer in cold diethyl ether. The yield of the polymer was 105g.
  • Example 2 Synthesis of an ⁇ - ⁇ ,- di anhydride polylactide prepolvmer and its polymerization to yield a polvanhvdride based on the polylactide.
  • the steps in this example are described with reference to Fig. 2.
  • the ⁇ - ⁇ ,- dicarboxylic acid polylactide (D/L-lactide) from example 1 was heated with 600 ml acetic anhydride (chemical purity + 99%) to 100°C for 8 hours, then the mixture was applied vacuum to remove the excess of acetic anhydride.
  • the obtained polymer was added to 10 mg of calcium oxide, and under Argon protection, the mixture was cooked at 165°C until melting. The temperature was increased to 180 0 C for 4 hours with vacuum removal of acetic anhydride. Finally, the temperature was maintained at 180 0 C for 8 hours to extend the molecular weight to a maximum.
  • the resulting polyanhydride was pure enough for our applications. The molecular weight was estimated from viscosity measurements to be about 40,000 to 80,000.
  • the polymer has a molecular weight that is high enough to make fibers, which can endure the braiding process (preferably 250 g/f or higher).
  • the washing of the polymer solution was carried out three times to remove the unreacted succinic anhydride (identified by the disappearance of the anhydride peak (1820 cm “1 ) on the FTIR spectrum).
  • the polymer was recovered by precipitating the polymer in cold diethyl ether. The yield of the polymer was 110g.
  • Example 5 Synthesis of a drug-containing polymer component having a linker that forms amide bonds in the drug-containing polymer
  • Amoxicillin has an amine functionality that can be used to form a dimer of amoxicillin using a linker, after protecting groups have been added to the carbolxyl and hydroxyl functionalities of the amoxicillin.
  • An acyl halide can be used as the linker to form amide linkages, which are less labile than the ester linkages that were formed in Example 4.
  • acyl halide linker examples include, but are not limited to, cephalexin, carbidopa, levodopa, and amtenac. Examples of such syntheses are known in the art and can be found, for example, in U.S. Pat. No. 6,486,214, which is hereby incorporated herein by reference in its entirety.

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Abstract

L'invention concerne un stent intravasculaire qui comporte un corps tubulaire expansible radialement qui comprend une tresse de fibres dont les fibres sont des fibres polymères biodégradables, caractérisées par les caractéristiques thermiques d'un polymère au moins partiellement cristallin, telles que mesurées par calorimétrie à balayage différentiel, et par une résistance à la traction, par superficie de la section des fibres, supérieure à environ 0,8 g/mil2. Selon l'invention, les fibres sont attachées ou tissées au niveau de leurs extrémités libres aux extrémités opposées du stent afin de conserver la forme tubulaire du stent. Le corps du stent peut ainsi être étiré dans une direction radiale par rapport à l'axe tubulaire du stent. L'invention concerne également des procédés de formation et d'utilisation du stent.
PCT/US2009/000187 2008-01-11 2009-01-12 Stents tressés biodégradables et procédés WO2009089072A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040015187A1 (en) * 2002-04-18 2004-01-22 Mnemoscience Corporation Biodegradable shape memory polymeric sutures
US20040176565A1 (en) * 2001-11-30 2004-09-09 Lee James Gao Process and apparatus for crystallization of polytrimethylene terephthalate (PTT)
US20070092704A1 (en) * 2005-10-26 2007-04-26 Dow Global Technologies Inc. Multi-Layer, Elastic Articles
US20070135834A1 (en) * 2003-01-30 2007-06-14 Ev3 Inc. Embolic filters with controlled pore size
US20070179590A1 (en) * 2005-12-29 2007-08-02 Wenfeng Lu Hybrid intraluminal device with varying expansion force
US7279005B2 (en) * 1997-08-01 2007-10-09 Boston Scientific Scimed, Inc. Bioabsorbable self-expanding stent
US20070270941A1 (en) * 2006-05-17 2007-11-22 Headley F Anthony Bioabsorbable stents with reinforced filaments

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Publication number Priority date Publication date Assignee Title
US7279005B2 (en) * 1997-08-01 2007-10-09 Boston Scientific Scimed, Inc. Bioabsorbable self-expanding stent
US20040176565A1 (en) * 2001-11-30 2004-09-09 Lee James Gao Process and apparatus for crystallization of polytrimethylene terephthalate (PTT)
US20040015187A1 (en) * 2002-04-18 2004-01-22 Mnemoscience Corporation Biodegradable shape memory polymeric sutures
US20070135834A1 (en) * 2003-01-30 2007-06-14 Ev3 Inc. Embolic filters with controlled pore size
US20070092704A1 (en) * 2005-10-26 2007-04-26 Dow Global Technologies Inc. Multi-Layer, Elastic Articles
US20070179590A1 (en) * 2005-12-29 2007-08-02 Wenfeng Lu Hybrid intraluminal device with varying expansion force
US20070270941A1 (en) * 2006-05-17 2007-11-22 Headley F Anthony Bioabsorbable stents with reinforced filaments

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