WO2007076370A2 - Block copolymer particles - Google Patents

Block copolymer particles Download PDF

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Publication number
WO2007076370A2
WO2007076370A2 PCT/US2006/062323 US2006062323W WO2007076370A2 WO 2007076370 A2 WO2007076370 A2 WO 2007076370A2 US 2006062323 W US2006062323 W US 2006062323W WO 2007076370 A2 WO2007076370 A2 WO 2007076370A2
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WO
WIPO (PCT)
Prior art keywords
microns
particle
block
particles
diameter
Prior art date
Application number
PCT/US2006/062323
Other languages
French (fr)
Other versions
WO2007076370A3 (en
Inventor
Young-Ho Song
Eric D. Welch
Scott D. Bluni
Original Assignee
Boston Scientific Scimed, 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
Priority claimed from US11/314,557 external-priority patent/US7501179B2/en
Priority claimed from US11/314,056 external-priority patent/US20070142560A1/en
Application filed by Boston Scientific Scimed, Inc. filed Critical Boston Scientific Scimed, Inc.
Publication of WO2007076370A2 publication Critical patent/WO2007076370A2/en
Publication of WO2007076370A3 publication Critical patent/WO2007076370A3/en

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    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08FMACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F297/00Macromolecular compounds obtained by successively polymerising different monomer systems using a catalyst of the ionic or coordination type without deactivating the intermediate polymer
    • C08F297/02Macromolecular compounds obtained by successively polymerising different monomer systems using a catalyst of the ionic or coordination type without deactivating the intermediate polymer using a catalyst of the anionic type
    • C08F297/04Macromolecular compounds obtained by successively polymerising different monomer systems using a catalyst of the ionic or coordination type without deactivating the intermediate polymer using a catalyst of the anionic type polymerising vinyl aromatic monomers and conjugated dienes
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08FMACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F293/00Macromolecular compounds obtained by polymerisation on to a macromolecule having groups capable of inducing the formation of new polymer chains bound exclusively at one or both ends of the starting macromolecule
    • C08F293/005Macromolecular compounds obtained by polymerisation on to a macromolecule having groups capable of inducing the formation of new polymer chains bound exclusively at one or both ends of the starting macromolecule using free radical "living" or "controlled" polymerisation, e.g. using a complexing agent
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08FMACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F297/00Macromolecular compounds obtained by successively polymerising different monomer systems using a catalyst of the ionic or coordination type without deactivating the intermediate polymer
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08FMACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F297/00Macromolecular compounds obtained by successively polymerising different monomer systems using a catalyst of the ionic or coordination type without deactivating the intermediate polymer
    • C08F297/02Macromolecular compounds obtained by successively polymerising different monomer systems using a catalyst of the ionic or coordination type without deactivating the intermediate polymer using a catalyst of the anionic type
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08LCOMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L53/00Compositions of block copolymers containing at least one sequence of a polymer obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08LCOMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L53/00Compositions of block copolymers containing at least one sequence of a polymer obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers
    • C08L53/02Compositions of block copolymers containing at least one sequence of a polymer obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers of vinyl-aromatic monomers and conjugated dienes
    • CCHEMISTRY; METALLURGY
    • C09DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09DCOATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D153/00Coating compositions based on block copolymers containing at least one sequence of a polymer obtained by reactions only involving carbon-to-carbon unsaturated bonds; Coating compositions based on derivatives of such polymers
    • CCHEMISTRY; METALLURGY
    • C09DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09DCOATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D153/00Coating compositions based on block copolymers containing at least one sequence of a polymer obtained by reactions only involving carbon-to-carbon unsaturated bonds; Coating compositions based on derivatives of such polymers
    • C09D153/02Vinyl aromatic monomers and conjugated dienes
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00Stock material or miscellaneous articles
    • Y10T428/29Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2982Particulate matter [e.g., sphere, flake, etc.]
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00Stock material or miscellaneous articles
    • Y10T428/29Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2982Particulate matter [e.g., sphere, flake, etc.]
    • Y10T428/2991Coated
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00Stock material or miscellaneous articles
    • Y10T428/29Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2982Particulate matter [e.g., sphere, flake, etc.]
    • Y10T428/2991Coated
    • Y10T428/2993Silicic or refractory material containing [e.g., tungsten oxide, glass, cement, etc.]
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00Stock material or miscellaneous articles
    • Y10T428/29Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2982Particulate matter [e.g., sphere, flake, etc.]
    • Y10T428/2991Coated
    • Y10T428/2993Silicic or refractory material containing [e.g., tungsten oxide, glass, cement, etc.]
    • Y10T428/2995Silane, siloxane or silicone coating
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00Stock material or miscellaneous articles
    • Y10T428/29Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2982Particulate matter [e.g., sphere, flake, etc.]
    • Y10T428/2991Coated
    • Y10T428/2993Silicic or refractory material containing [e.g., tungsten oxide, glass, cement, etc.]
    • Y10T428/2996Glass particles or spheres
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00Stock material or miscellaneous articles
    • Y10T428/29Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2982Particulate matter [e.g., sphere, flake, etc.]
    • Y10T428/2991Coated
    • Y10T428/2998Coated including synthetic resin or polymer

Definitions

  • the invention relates to block copolymer particles, and to related compositions and methods.
  • Agents such as therapeutic agents, can be delivered systemically, for example, by injection through the vascular system or oral ingestion, or they can be applied directly to a sue where treatment is desired. In some eases, particles are used to deliver a therapeutic agent to a target Site. In the case of delivery of a therapeutic agent, it is oflen desirable that the therapeutic agent be delivered ai desired dosages for an extended period of time.
  • the invention features a particle that includes a biocompatible block copolymer with at least one block having a glass transition temperature of at most 37 '-'C and at least one block having a glass transition temperature of greater than 37°C.
  • the pariide has a diameter ofless than about 100 microns, from about 300 microtis to about 500 microns, from about 700 microns to about 900 microns, or from about 1 ,CM)O microns to about 1 ,200 microns.
  • the invention features a particle that includes a biocompatible block copolymer with at least one block having a glass transition temperature of at most 37 ''1 C and at least one block having a glass transition temperature of greater than 37°C.
  • the particle has a diameter of about 1 ,050 microns or more (e.g., about i ,060 microns or more, about 1 ,070 microns or more, about 1 ,080 microns or more, about 1 ,090 microns or more, about 1 , 100 microns or more).
  • the invention features a particle that includes a block copolymer with the formula X-(AB) fls in which A is a block having a glass transition temperature of at most 37 0 C, B is a block having a glass transition temperature of greater than 37'"Cl ⁇ is a positive whole number, and X is an initiator.
  • the particle has a diameter of less than about 100 microns, from about 300 microns to about 500 microns, from about 700 microns to about 900 microns, or from about 1, 000 microns io about !,2(K) microns.
  • the invention features a particle that includes a block. copolymer having the formula X-(AB) n , m which A is a block having a glass transition, temperature of at most 37°C, B is a block having a glass transition temperature of greater than 37 C 5 n is a positive whole number, and X is an initiator.
  • T lie parlieic has a diameter of about 1 ,050 microns or more (e.g., about 1,060 microns or more, about 1,070 microns or more, about KOSO microns or more, about 1 ,090 microns or more, about 1 , 100 microns or more).
  • the invention features a particle that has a matrix including a biocompatible block copolymer including at least one block having a glass transition temperature of at most 37" ' C and at least one block having a glass transition temperature of greater than 37 0 C.
  • the particle also includes at least one sub-particle (eg., a plurality of sub-particles) that is at least partially disposed within the matrix.
  • the particle has a diameter of about 3,000 microns or less (e.g., fro.ni about two microns to about 3,00O microns, less than about 100 microtis, from about 300 microns to about 500 microns, .from about 700 microns to about 900 microns, from about 1 ,000 microns to about 1 ,200 microns).
  • the invention features a particle that includes a matrix including a biocompatible block copolymer having at least one block with a glass transition temperature of at most 37 Q C and at least one block with a glass transition temperature of greater than TPC.
  • the particle also includes at least, one sub-particle that is at least partially disposed within the matrix.
  • the particle has a diameter of about 1,050 microns or more.
  • the invention features a particle that has a matrix including a biocompatible block copolymer having the formula X-(AB) 1x , in which A is a block having a glass transition temperature of at most 37 '" C, 8 is a block having a glass transition temperature of greater than 37°C, n is a positive whole number, and X is an initiator,
  • the particle also includes at least one sub-particle that is at least partially disposed within the matrix.
  • the particle has a diameter of about 3,000 microns or less (e.g., from about two microns to about 3,(K)O microns, less than about 100 microns, from about 300 microns to about 500 microns, from about 700 microns to about 900 microns, from about 1 ,000 microns to about 1 ,200 microns).
  • the invention features a particle thai includes a matrix. including a biocompatible block copolymer having the formula X-(AB) 1 ,, and at least one sub-parUd ⁇ that is at least partially disposed within the matrix.
  • the particle has a diameter of about 1,050 microns or more, and A is a block having a glass transition temperature of at most 37° €, B is a block having a glass transition temperature of greater ⁇ h&n 37 13 C. n is a positive whole number, and X is an initiator.
  • the invention features a composition including a plurality of particles, at least some of the particles having a diameter of less than about H)O microns, from about 300 microns to about 500 microns, from about 700 microns to about 900 microns, or from about 1 ,000 microns to about 1 ,200 microns.
  • At least some of the particles having a diameter of at less than about 100 microns, rrom about 300 microns to about 500 microns, from about 700 microns to about 900 microns, or irom about 1,000 microns to about 1 ,200 microns include a biocompatible block copolymer including at least one block having a glass transition temperature of at most 37 0 C and at least one block having a glass transition temperature of greater than 37 C €.
  • the composition also includes a carrier fluid, the plurality of particles being in the carrier fluid.
  • the invention features a composition including a plurality of particles, at least some of the particles having a diameter of about 1 ,050 microns or more (e.g.. about i ,060 microns or more, about 1,070 microns or more, about 1,080 microns or more, about 1 ,090 microns or more, about L! 00 microns or more).
  • At least some of the panicles having a diameter of about 1 ,050 microns or more include a biocompatible block copolymer including at least one block having a glass transition temperature of at most 37 Q C and at least one block having a glass transition temperature of greater than 37 0 C.
  • the composition also includes a carrier fluid, the plurality of particles being in the carrier fluid.
  • the invention features a composition including a plurality of ⁇ artieles, at least some of the plurality of particles having a diameter of less than about 100 microns, from about 300 microns to about 500 microns, from about 700 microns to about 900 microns, or from about KOOO microns to about 1 ,200 microns.
  • At least soTTic of the particles having a diameter of less than about 100 microns, from •shout 300 microns to about 50C) microns, from about 700 microns to about 900 microns, or frora about IJ)OO microns to about 1,200 microns include a block copolymer.
  • the block copolymer has the formula X-(AB) n , in which.
  • A is a block having a glass transition temperature of at most 37 0 C
  • B is a block having a glass transition temperature of greater than 37"C
  • n is a positive whole number
  • X is an initiator.
  • the composition also includes a carrier fluid, the plurality of particles being in the carrier fluid.
  • the invention features a composition including a plurality of particles, at least some of the plurality of particles having a diameter of about 1 ,050 microns or more (e.g., about 1 ,060 microns or more, about !schreib070 microns or more, about 1,080 microns or more, about 1 ,090 microns or more, about 1 ,100 microns or more). At least some of the particles having a diameter of about 1,050 microns or .more include a block copolymer.
  • the block copolymer has the formula X- (AB) n , in which A is a block having a glass transition temperature of at most 37 ' "C, B is a block having a glass transition temperature of greater than 3 " ⁇ i C, n is a positive whole number, and X is an initiator.
  • the composition also includes a earner -fluid, the plurality of particles being in the carrier fluid,
  • the invention features a method of making particles.
  • the method includes contacting an aqueous first solution with a second solution while the aqueous first solution is being mixed (e.g., homogenized), to form a mixture.
  • the second solution includes a solvent, and a biocompatible block copolymer having at least on c block with a glass transition temperature of at most 37° € and at least one block with a glass transition temperature of greater than 37 0 C, At least .some of the particles have a diameter of about 3,000 microns or less, in another aspect, the invention features a method of making particles.
  • the method includes contacting an aqueous first solution with a second solution while the aqueous first solution is being mixed (e.g., homogenized), to form s mixture.
  • the second solution includes a solvent and a biocompatible block copolymer.
  • the biocompatible block copolymer has the formula X-(AB) n , in which A is a block having a glass transition temperature of at most 37 0 C, B is a block having, a glass transition temperature of greater than 37°C, n is a positive whole number, and X is an initiator. At least some of the particles have a diameter of about 3,000 microns or less.
  • the invention features a method of making particles.
  • the method includes contacting an aqueous first solution with a second solution including a solvent and a biocompatible block copolymer to form a mixture.
  • the biocompatible block copolymer has at least one block with a glass transition temperature of at most 37 0 C and at least one block with a glass transition temperature of greater than 37°C.
  • the method also includes mixing (e.g., homogenizing) the mixture, At least some of die particles have a diameter of about 3,000 microns or less.
  • the invention features a method of making particles.
  • the method includes contacting an aqueous first solution with a second solution including a solvent, and a biocompatible block copolymer, to form a mixture.
  • the method also includes mixing (e.g., homogenizing) the mixture.
  • the biocompatible block copolymer has the formula X-(AB) n , in which A is a block having a glass transition temperature of at most 3?°C, B is a block having a glass transition, temperature of greater than 37°C, ft is a positive whole number, and X is an initiator. At leasi some of the panicles have a diameter of about 3,000 microns or icss.
  • the invention features a method of making particles.
  • the method includes contacting an aqueous first solution with a second solution including a solvent and a biocompatible block copolymer, to form a mixture.
  • the biocompatible block copolymer has at least one block with a glass transition temperature of at most 3 " 1 0 C and at least one block with a glass transition temperature of greater than 37 0 C.
  • At least some of the particles include a first therapeutic agent that is dispersed throughout the particles, and at least some of the particles have a diameter of about 3,000 microns or less.
  • the invention features a method of making particles.
  • the method includes contacting an aqueous first solution with a second solution including a solvent and a biocompatible block copolymer, to form a mixture.
  • the biocompatible Mock copolymer has the formula X-(AB) n , in which A is a block having a glass transition temperature of at most 37"C 5 B is a block having a glass transition temperature of greater than 3?°C, n is a positive whole number, and X is an initiator.
  • Al. least, some of the particles include a first therapeutic agent that is dispersed throughout the particles, and at least some of the particles have & diameter of about 3,000 microns or less.
  • the invention features a method including administering to a patient a therapeutically effective amount of a composition including particles. At least some of the particles have a diameter of leas than about K)O microns, rrom about 30(J microns to about 500 microns, from about 700 microns to about 900 microns, or From about i ,000 microns to about 1 ,200 microns.
  • At least some of the particles having a diameter of less than about 100 microns, from about 300 microns to about 500 microns, from about 700 microns to about 90?) microns, or from about 1 ,000 microns to about 1 ,200 microns include a block copolymer having at least one block with a glass transition temperature of at most 37° € and at least one block with a glass transition temperature of greater than 37 1 Xl
  • the invention features a method including administering to a patiem a therapeutically effective amount of a composition including particles, Ai least, some of the particles have a diameter of about ! ,050 microns or more (e.g. , about 1,060 microns or .more, about 1 ,070 microns or more, about 1,080 microns or more, about 1.090 microns or .more, about LlOO microns or more). At least some of the particles having a diameter of about 1 ,050 microns or more include a block copolymer having at least one block with a glass transition temperature of at most 37°C and at least one block with a glass transition temperature of greater than 37"C.
  • the invention features a method including administering to a patient a therapeutically effective amount of a composition including particles. At least some ofthe particles have a diameter of less than about 100 microns, irora about 300 miercms to about 500 microns, from about 700 microns to about 900 microns, or from about 1 ,000 microns to about 1 ,200 microns.
  • At least some of the particles having a diameter of less than about 100 microns, from about 300 microns to about SCO microns, from about 700 microns to about 900 microns, or from about 1 ,000 microns to about 1 ,200 microns include a block copolymer having the fbrmuk X- (AB) !f , hi which A is a block having a glass transition temperature of at most 37 0 C, B is a block having a glass transition temperature of greater than 37°C. rs is a positive whole number, and X is an ini ⁇ aior.
  • the invention features a method Including administering to ⁇ patient a therapeutically effective amount of a composition including particles. At least some of the particles ' have a diameter of about 1 ,050 microns or more (e.g., about 1 ,060 microns or more, about 1,070 microns or more, about 1 ,0B0 microns or more, about ⁇ ,090 microns or more, about 1 ,100 microns or more).
  • At least some of the particles having a diameter of about 1,050 microtis or more include a block copolymer having the formula X-(AB) n , in which A is a block having a glass transition temperature of at most 37°C, B is a block having a glass transition temperature of greater than 37 0 C. n is a positive whole number, and X is an initiator.
  • Embodiments can also include one or more of the following.
  • the block copolymer can be biocompatible.
  • n block having a glass transition temperature of at most 37"-"C cars be a polyolefm block, hi sonic embodiments, a block having a glass transition temperature of at most 37 0 C can include at least one isob ⁇ tyleae monomer, In certain embodiments, a block having a glass transition temperature of greater than 3? ' 'C can be a vinyl aromatic block or a methaerykte block. In some embodiments, a block having a glass transition temperature of greater than 37"C can include ⁇ least one monomer selected from styrene, u-methylsiyrene, ami combinations thereof.
  • the block copolymer can have the formula X-(AB) 11 , in which n is a positive number and X is an initiator, hi some embodiments, A can be a block having a glass transition temperature of at most 37 0 C, and/or can be a polyolefm block, hi certain embodiments, B can be a block having a glass transition temperature of greater than 3?° €, and/or can be a vinyl aromatic block or a methacrvlaie block. In .some embodiments, the block copolymer can have the formula BAB or ABA, in which A is a block having a glass transition temperature of at most 37 C C and B is a block having a glass transition temperature of greater than 37*C.
  • the block copolymer can have the formula has the formula B(AB), or A(BA X-., in which A is a block having a glass transition temperature of at most 37°C. B is a block having a glass transition temperature of greater than 37 0 C 5 and n is a positive whole number.
  • A can be a polyoiefin block (e.g., a polyoleiki block ⁇ hat includes at least one isobutylene monomer),
  • B can be a vinyl aromatic block or a methacrylaie block, hi certain embodiments, B can include at least one monomer selected from methylmethacrylate, ethylm ⁇ ihaerylate, hydroxyelhyl methacrylate, and combinations thereof.
  • the polyolefjH block can include at least one isobutylene monomer and/or the vinyl aromatic block can include at least, one monomer selected from siyrene.
  • A can have the formula (CRR' -CHb) 5 * > in which R and R' are linear or branched aliphatic groups or cyclic aliphatic groups, and B can be a nielhacrylate block or a vinyl aromatic block.
  • the block copolymer can include from about 45 mol percent to about 95 mol percent of p ⁇ lyo ) efm blocks,
  • the block copolymer can have a molecular weight of more ihan about 40,000 Da ⁇ tons (e.g., from about 80,000 Daltons to about 300,OtM ) Dslions).
  • the block copolymer can include poiyolefi ⁇ blocks having a molecular weight (e.g., a combined molecular weight) of from about 60,000 Daltons to about 200.000 Daltons and vinyl aromatic blocks having a molecular weight (e.g., a combined .molecular weigh!) of from about 20,000 Daltons to about 100,0(K) Daltons.
  • the particle can have a diameter of less than about KM) microns. In some embodiments, the particle can have a diameter of from about 300 microns to about 500 microns, from about 700 microns to about 900 microns, or irom about KOOO .microns to about 1,200 microns. In certain embodiments, the particle can have a diameter of about K050 microns or more (e,g, ? ! ,060 nneroriS or more, 1 ,070 microns or more, 1 t 0S0 microns or more, 1 ,090 microns or more, ! , 1 ( K ) microns or more, ! ,150 microns or more), hi some embodiments, the particle can have a diameter of about 3,000 microns or less (e.g., from about two microns to about 3.000 microns).
  • the particle (e.g., the block copolymer) can include a therapeutic agent (e.g., from about 0.1 weight percent to about 70 weight percent of a therapeutic agent).
  • the therapeutic agent can be dispersed throughout the particle, ia some embodiments, the particle can include at least two therapeutic agents that are different from each other.
  • the particle can further include at least one other polymer (e.g., in a blend with the block copolymer).
  • the other polymer can also be a copolymer (e.g., a block copolymer), or can be a homopolymer.
  • the other polymer can he a polyvinyl alcohol, a polyaerylic acid, a poiymeth&crykc acid, a poly vinyl sulfonate, a carboxymeihyl cellulose, a hydroxyethyl cellulose, a substituted cellulose, a polyacrylamidc, a polyethylene glycol, a poh-arr ⁇ de, a poly urea, a polyurethane, a polyester, a polyeslter, a polystyrene, a polysaccharide, a polylactic acid, a polyethylene, a polymethylmethacrylate, a polycaprolactone, a poSyglycolic acid, & pofyflaetic-co- glycolic) acid, or a styrenc maleic anhydride copolymer, hi certain embodiments, combinations of two or more of these polymers can be used, hi some embodiments, the particle can further include a
  • the hydrogel may be cross-linked or may not be cross-linked, hi some such embodiments, the block copolymer can form a coating over the hydrogel, and/or the hydrogel can form a coating over the block copolymer. In some embodiments, the block, copolymer can form a coating on the particle.
  • the carrier fluid can include a saline solution and/or a contrast agent.
  • the method can include forming a suspension from the mixture ami contacting the suspension with an aqueous third solution hi certain embodiments, the aqueous first solution cars be mixed at a speed of d • l most about 10,000 revolutions per minute (e.g., at most about 5,000 revolutions per minute, at most about 1 ,500 revolutions per minute). In some embodiments, the method can include mixing the mixture at a speed of at most about !O 5 C 1 OO revolutions per minute (e.g., at most about 6,000 revolutions per minute), and/or at less! about 1 ,000 revolutions per minute. In certain embodiments, the method can include mixing the mixture at a temperature of at least about 3O 0 C (e.g.. at least about 35 G C).
  • the aqueous first solution and/or the second solution can include a therapeutic agent.
  • the method of administration can be by percutaneous injection.
  • the composition can be used to treat a cancer condition, (e.g., ovarian cancer, colorectal cancer, thyroid cancer, gastrointestinal cancer, breast cancer, prostate cancer, lung cancer).
  • the method can include embolking a lumen of a subject (e g., a lumen that is associated with a cancer condition).
  • the panicles can be relatively durable and/or flexible, and thus can be unlikely to be damaged during storage, delivery, or use.
  • the particles can have a relatively high mechanical integrity (e.g., such that contact with the walls of a catheter will not harm the particles).
  • the particles can be relatively flexible, and thus can be adapted tor use in many different environments.
  • the particles can include a swellable material (e.g., a hydrogel), such that the particles can he delivered to a target site while the panicles are in a relatively compressed state, and can ialer expand at the target site as a result of swelling of the swdlable material ( e.g., to enhance occlusion).
  • the particles can have good delivcrab ⁇ ily, while also being effective in occluding the target site.
  • the particles can be used to deliver one or more therapeutic agents to a target site effectively and efficiently; and/or to occlude the target site.
  • the particles can be used to deliver a raetered dose of a therapeutic agent to a target site over a period of time.
  • the release of a therapeutic agent from the particles can be delayed until the peers have .reached a target site.
  • the peers can include a bioerodible coating thai erodes during delivery, such that when the particles reach the target site, they cars begin to release the therapeutic agent.
  • the particles can be used to deliver multiple therapeutic agents, either to the same target site, or to different target sites.
  • the particles can deliver one type of therapeutic agent (e.g., an antiinflammatory) as the particles are being delivered to a target site, and another type of therapeutic agent (e.g.. a chemotherapeutie agent) once the particles have reached the target site.
  • therapeutic agent e.g., an antiinflammatory
  • chemotherapeutie agent e.g. chemotherapeutie agent
  • FIG. 1 is a side view of an embodiment of a particle.
  • Fl(I 2 A is a schematic illustrating an embodiment of injection of a composition including particles into a vessel.
  • FlG 28 is a greatly enlarged view of region 2B in Pl(I 2A, FlG 3 is a cross-sectional view of an embodiment of a particle, FiG. 4 is a cross-sectional view of an embodiment of a particle. FKi 5 is a cross-sectional view of an embodiment of ⁇ particle.
  • FIGS, 6A-6C are an illustration of an embodiment of a system and rnethud for produci ng particles.
  • FIG 7 is an illustration of an embodiment of a drop generator.
  • FKJS, 8A and 813 are an illustration of an embodiment of a system and method for producing particles.
  • FIGS. 9 ⁇ 4)F are an illustration of an embodiment of a system for producing particles.
  • FIG 10 is a scanning electron micrograph (SEM) image of styxene- i sob uty j cne- styrene particl es .
  • PIG. I i is an SEM. image of styre ⁇ e-is ⁇ biityiene-styrene particles
  • FlG 12 is an SEM image of styrcne-isohulylexie-styrcne particles.
  • FIG 13 is an SKM image of styrene-isobutylene-styrene particles.
  • FIG 14 is an SEM image of styrene-isobutyl ⁇ ne-styrene particles.
  • FIG. 15 is an SEM image of styre ⁇ e-isob ⁇ tylene-styre ⁇ e particles.
  • FIG 16 is an SEM image of styrene-isoirutylene-styrene particles.
  • FIG 17 is an SEM image of styrene-isobutylene-styrene particles.
  • FIG I S is an SEM image of styrene-isobutylene-styrene particles.
  • FlG 1 ⁇ 1 is ao SEM image of styre ⁇ e-isobutylene-styrene particles.
  • FlG. 20 is an SBM image of siyre ⁇ e-isobutylette-styreue particles
  • FICs. 2 ⁇ is an SE:M image of Rhod amine- loaded styrene-isobutyle ⁇ e-styrene particles ,
  • FKl 22 is an SEM image of Rhodamine-ioaded styrenc-isobutySene-styrene particles.
  • FIG 23 is cm SEM image of Rhodamme-loaded shrene-isobuiylerie-styrene particles.
  • FlG 24 is an SEM image of Rhodamioe-loaded styrene-isobutylene-st> ⁇ ene panicles.
  • FlG 25 is an SEM image of Rhoda ⁇ tme-loaded styrene-isobiuylene-slyrene particles.
  • MG 26 is an SEM image of Riiodaraine-kiaded .styfene-isob ⁇ tyle ⁇ e-si> ⁇ e ⁇ e particles.
  • HG 27 is an SEM image of iluorescein-loaded .styrene-isobuty!ene-sly ⁇ ene particles
  • FKJ. 28 is an SIBM image of fluoreseein-loaded styrene-isob ⁇ lylene-atyre ⁇ c particles.
  • FIG 29 is an SEM image of fluorescein-ioaded styre ⁇ e-isobutylene-.styrc ⁇ ie particles
  • FIG 30 is a cross-seetiona ⁇ view of an embodiment of a particle. DETAIL ED DESCRIPTION
  • FIG. I shows a particle 100 that can be used to deliver one or more therapeutic agents ⁇ e.g., drugs) to a targe! site within the body.
  • the therapeutic agents can be included o.n particle 100 and/or within panicle 100 (e.g., dispersed throughout particle 100), Particle 100 is formed of a block copolymer that includes a first block having a glass transition temperature (T g ) of at most 37°C and a second block having a glass transition temperature of greater than 37 0 C.
  • T g glass transition temperature
  • Slock copolymers are copolymers that contain two or more differing polymer blocks selected, for example, from homopo ⁇ ymer blocks, copolymer blocks (e.g., random copolymer blocks, statistical copolymer blocks, gradient copolymer blocks, periodic copolymer blocks), and combinations of homopolyraer and copolymer blocks
  • a polymer "block” refers to a grouping of multiple copies of a single type (homopolymer block) or multiple types (copolymer block) of constitutional units
  • a "'chain' 1 is an u ⁇ branched polymer block.
  • a polymer block can be a grouping of at least two (e.g., at least five, at least 10, at least 20, ai least 50, at least HK). ai least 250, at least 500, at least 750 ⁇ and/or at most 1000 (e.g., at mast 750, at most 500, at most 250, ai most 100, at most 50, at most 20, at most KL at most five) copies of a single type or multiple types of constitutional units.
  • a polymer block may take on any of a number of different architectures.
  • the block copolymer in particle 100 can include a central block having a glass transition temperature of at most 37 0 C and end blocks each having a glass transition temperature of greater than 37 0 C. (n certain embodiments, the block copolymer can have one of the following general structures: (a) BAB or ABA (linear triblock), Cb) B(AS) n or A ⁇ BA) n (linear alternating block), or
  • X- — (AB) n or X (BA) n includes dibiock, tribloek and other radial block copolymers
  • A is a block having a glass transition temperature of a. most 37 9 C
  • B is a block having a glass transition temperature of greater than 37XL ⁇ is a positive svhole number
  • aad X is an initiator (e.g., a monofu ⁇ crjonal initiator, a multifunctional initiator).
  • the X — (AB) 11 structures are frequently referred to as diblock copolymers (when n : ⁇ ⁇ ) or t ⁇ bk ⁇ ck copolymers (when rv ⁇ 2).
  • the A blocks have a glass transition temperature of at most 37 0 C.
  • the A blocks can have a glass transition temperature of at most about 3O 0 C (e.g., at most about 25°C, at most about 20 0 C, at most about I 0' ; C, at most about 0 0 C, at most about -H) 0 C;, at most about -2O 0 C, at 10 most about -30 '3 C, at most about -5O 0 C 5 at most about
  • the glass transition temperature of a material is determined according to ASTM E l 356,
  • blocks having a glass transition temperature of at most 37 Q C when the blocks are in the dry state include blocks including at. least one i:> of the following monomers;
  • ⁇ I) acrylic monomers including:
  • alky? acrylates such as methyl acryiate, ethyl acrylate, propyl acrylate, isopropyl aery! ale (e.g., isotactic isopropy ⁇ aerylaie), butyl acrylate, sec -butyl acrylate, isobittyl acrylate, cyclohesyl
  • (C) alkoxyalkyl acrylatcs such as 2-etboxyeihyl acrylate and 2- raethoxyeihyl acrylatc, 25
  • haJo-alkyl acrylates such as 2,2,2-trifiuoroctbyl acrylate
  • cyano-aikyi acrylates such as 2-cyan ⁇ ethyi acrylate
  • methaeryik mrmoraers including:
  • (a) alky! methacrylates such as butyl methacrylate, hex>l metbacrylate, 2-ethylhexyl methacrylate. octyl methacrylate,
  • (a) alky! vinyl ethers such as methyl vinyl ether, ethyl vinyl elher, P ? ⁇ y5 vinyl ether, butyl vinyl ether, isobutyi vinyl ether, 2- ethyihexyl vinyl, ether and dodccyi vinyl ether;
  • cyclic ether monomers such as tetrahydrofuran, tri methylene sjxide, ethylene oxide, propylene oxide, methyl glyeklyl ether, butyl glycidyl ether, ally! glycidyl ether, epibromohydrm, epichlorohydrin, 12 ⁇ cp ⁇ xybutane, 1 ,2-e-poxyoetane, and 1 ,2-epoxydecaBe;
  • ester nionomers other than acrylates and methacrylates, such as ethylene makmate, vinyl acetate, and vinyl propionate;
  • alkcnc monomers such as ethylene, propylene, isobi ⁇ tyl ⁇ ne, I -butene, trans-butadiene, 4-methy! pentene, 1 -octe ⁇ e and other ⁇ -oi ⁇ fsns, cisisoprenc, and traiis-isoprene;
  • Huoride eis-chiorobiitadiene, and trans-ehlorobutadiene;
  • (Sj si ⁇ oxane monomers such as dimethylsiloxane, di.ethylsiioxane, metliyiethyls ⁇ oxaiw, metliylphenyisii ⁇ xant;, ajid diphe ⁇ ylsiloxane; and ⁇ 9 ⁇ maleie monomers, such as ma ⁇ eie anhydride.
  • the A blocks can include one or more derivatives of the above monomers.
  • the A blocks can he based upon one or more poiyokfhis.
  • the A blocks can be poiyoiefinic blocks having alternating quaternary and secondary carbons of the general formulation; — (CRR'-
  • R and R * are linear or branched aliphatic groups (e.g., methyl, ethyl propyl, isopropyl, butyl, isobutyi) or cyclic ahphatie groups (e.g., cyclohexane, cydope ⁇ tane), with and without pendant groups.
  • the A blocks can be polyoidmie blocks having the above formula, in which R and R' ai-e the same.
  • the A blocks can be based on isohistylene:
  • the block copolymer can include at least about 40 mol percent (e.g., from about 45 mo! percent to about 95 mol percent) of polyolef ⁇ s blocks.
  • the B blocks have a glass transition temperature of greater thars 37 0 C.
  • the B blocks cars have a glass transition temperature of at least about 4O 0 C (e.g., at least about 50''C, at least about 7(FC, at least about 9(PC, at least about 100 ⁇ C, at least about 12O 0 C).
  • blocks having a glass transition temperature of greater than 37°C when the blocks are in the dry state include blocks including at least one of ⁇ e following monomers.
  • (I) vinyl aromatic monomers including:
  • ring-substituted vinyl aromaties including ring-alky! at ed vinyl aromaties (e.g., 3- ⁇ nethylstyrene, 4-methyIsiyrene, 2,4- dimethylstyrene, 3,5-dimethylstyrene, 2,4,6-trimethylsty ⁇ eae, 4-tert-butyl styrene), ring-alkoxylated vinyl aromaties (e.g., 4-me ⁇ i ⁇ xystyr ⁇ ne, 4-etlioxysty ⁇ ene,), ring-habgenated vinyl aromaties (e.g., 2-chiorostyre ⁇ , 3- chlorostyrene, 4-chlorostyrene, 2,6-dichSorostyrene. 4- bromostyrene, 4-fluorostyrenc), ring-ester-substituted vinyl aromaties (e.g.,
  • vinyl esters such as vinyl benzoate.
  • vinyl amines such as 2-vinyl pyridine, 4-vinyl pyridine, and vinyl carbazole,
  • alkyl vinyl ethers such as tert-bulyl vinyl ether and cydchexyl vinyl ether, and i ⁇ (e) other vinyl compounds such as vinyl ferrocene;
  • alkyl niethacrylaies such as atactic methyl mctha ⁇ yktc, syndiotactic methyl methacrviate, ethyl methacryiate, iaopropvi methacrylate, isobutyi meihacrylat ⁇ , t-buiyl methacrylate and cyclohexy!
  • aromatic methacrylates such as phenyl methacrylate and 20 including aromatic alkyl melhacrytates such as benzyl methaerylale,
  • hydroxyalkyl mcthacr>'Iates such as 2-hydroxyethyi methacrylate and 2-hydroxypropvi methacrylate,
  • additional nidhaerylates including isobornyi S methacrylate and trimethylsily! methacrylate
  • acrylic monomers including:
  • the B blocks can include one or more derivatives of the above monomers.
  • the B blocks can be polymers of rrs ⁇ thaeryiates or polymers of vinyl aroroatks. In some embodiments, the B blocks can be either; (a) made from monomers of styrersc
  • stymie derivatives ⁇ e.g., ⁇ -methyistyrene, ⁇ ng-alkyiated styrenes or ri ⁇ g- halogenated styrenes
  • monomers of metbyimethaervlate, ethylmethacrylate, hydroxyethyl rnethaerylat ⁇ , or mixtures thereof or (b) made from monomers of metbyimethaervlate, ethylmethacrylate, hydroxyethyl rnethaerylat ⁇ , or mixtures thereof.
  • the block copolymer can include at least about five mo! percent (e.g., at least about 30 mo! percent, about 60 mo! percent) of styretie blocks.
  • An example of one of the above copolymers is styrene-isobutylene-styxene
  • SiBS siBS
  • a blocks arc based on isoburylene.
  • B blocks are based on slyrenc.
  • SMA styrene maleie anhydride
  • the combined molecular weight of the block copolymer can be more lhan about 40,0(K) Dalto ⁇ s ⁇ e.g., more than about 60,(K)O Daltons),
  • the combined molecular weight of the block copolymer can be from about SO 1 GOO Daltons to about 300,000 Daltons (e.g., from about 90J ) OO Daltons to about 300,000 DaitOBs).
  • the combined molecular weight of the A blocks can be from about 60,00*') Daltons to about 2.00,000 Daltons.
  • the combined molecular weight of the B blocks can be from about 20,000 Daltons to about 100.000 Daltons.
  • the properties of the block, copolymer used in panicle 100 can depend upon the lengths of the A block chains and B block chains m the block copolymer, and/or on the .relative amounts of A block and B blocks hi the block copolymer,
  • blocks with a glass transition temperature of at most 37 '1 C may be elastomeric.
  • the elastomers c properties of the block copolymer can depend on the length of the A block chains.
  • the A block chains can have a weight average molecular weight of from about 2,000 Dailo ⁇ s to about 30,000 Dal ions, in such CnIHiJdIo-SeBtS. the block copolymer (and, therefore, particle 100) may be relatively inelastic.
  • the A block chains can have a weight average molecular weight of at least about 40.000 Dalto ⁇ s.
  • the block copolymer (and, therefore, particle 300) may be relatively soft and/or rubbery.
  • blocks with a glass transition temperature of greater than 37' 5 C may be relatively hard at 37 0 C.
  • the hardness of the block copolymer at 37 "1 C can depend on the relative amount of B blocks in the block copolymer.
  • the block copolymer can have a hardness of from about Shore 2OA to about. Shore 75D (e.g., from about Shore 4OA to about Shore 90A).
  • a copolymer with a desired degree of hardness may be formed by varying the proportions of the A and B blocks in the copolymer, with a lower relative proportion of B blocks resulting in a copolymer of lower hardness, and a higher relative proportion of B blocks resulting in a copolymer of higher hardness.
  • high molecular weight (i.e., greater than 100,000 Daltons) polyisobutyiene is a relatively soft and gummy material with a Shore hardness of approximately K)A
  • polystyrene is much harder, typically having a Shore hardness on the order of IGOD.
  • the resulting copolymer when blocks of polyisobutyiene and styrene are combined, the resulting copolymer can have a range of hardnesses from as soft as Shore I OA to as hard as Shore KX)I), depending upon the relative amounts of polystyrene and polyisobuiylene in the copolymer. In some embodiments, from about two mo! percent to about 25 mol percent (e.g., from about five mol percent to about 20 mol percent) of polystyrene can he used to form a block copolymer with a hardness of from about Shore 30A to about Shore 9OA (e.g., from about Shore 35A to about Shore 70A).
  • PoSydispersity (the ratio of weight average molecular vveiglii to number average molecular weight ⁇ gives an indication of the molecular weight distribution of the copolymer, with values significantly greater than four indicating a broad molecular weight distribution. When all molecules within a sample are the same size, the polydispersity has a value of one.
  • copolymers used in particle 100 can Siavc a relatively tight molecular weight distribution, with a polydispersity of from about 1 , 1 to about 1.7.
  • one or more of the above-described copolymers can have a relatively high tensile strength.
  • trihiock copolymers of polystyrene-polyisobuiy ⁇ c ⁇ e-polystyrene can have a tensile strength of at bast about 2,000 psi (e.g., from about 2,000 psl to about 4,000 psi).
  • one or more of the above-described copolymers can be relatively resistant to cracking and/or other tonus of degradation under in vivo conditions. Additionally or alternatively, one or more of the above-described polymers can exhibit excellent bioconipatibiSrty, including vascular compatibility. For example, the polymers can provoke minimal adverse tissue reactions, resulting in reduced polymorphonuclear leukocyte and reduced macrophage activity. In some embodiments, one or more of the above-described polymers can generally be hemoeompaiible, and can thereby minimize thrombotic occlusion of, lor example. small vessels.
  • the block copolymers can be made using any appropriate method known in the art. Irs some embodiments, the block copolymers can be made by a carboeatio ⁇ ie polymerization process that includes an initial polymerization of a monomer or mixtures of monomers to form the A blocks, followed by the subsequent addition of a monomer or a mixture of monomers capable of forming the B blocks.
  • Such polynie ⁇ zatiorj reactions are described, for example., in Kennedy et &!., U.S. Patent " No. 4,276,394; Kennedy, U.S. Patent No. 4,316,9/3; Kennedy, 4 5 342,849, Kennedy et a]., U.S.
  • Patent No.4,910,321 ; Kennedy et aL, U.S. Patent No. 4,929,683; Kennedy d &! represent U.S. Patent No. 4,946,899: Kennedy et a!.
  • U.S. Patent No, 5,066,730; Kennedy et ah, U.S. Patau No. 5,122,572; and Kennedy et ⁇ l U.S. Patent No. Re. 34.64(L Bach of these patents is incorporated herein by reference
  • the techniques disclosed in these patents generally involve an "initiator", which can be used to create X- — (AB) n strue-ures, where X is the initiator, and n can be 1. 2, 3 or more.
  • the initiator can be monofunctional or multifunctional.
  • the resulting molecules are referred to as diblock copolymers where n is 1, lrihtoek copolymers (disregarding the presence of the initiator) where n is 2, and star- shaped block copolymers where rs is 3 or more.
  • the polymerisation reaction can be conducted under conditions that minimize or avoid chain transfer and termination of the growing polymer chains. Steps can be takers to keep active hydrogen atoms (water, alcohoi and the like) to a minimum.
  • Hie temperature for the polymerization is usually from about -10' ; C to about -WC (e.g., from about -6(FC to about -8(FC), although lower temperatures can be used.
  • one or more A blocks can he formed in a first step, followed by the addition of B blocks (e.g., polystyrene blocks) at the ends of the A blocks.
  • B blocks e.g., polystyrene blocks
  • the first polymerization step is genera) Iy carried out in an appropriate solvent system, such as a mixture of polar and non-polar solvents (e.g., methyl chloride and hexarses).
  • the reaction bath can contain the aforementioned solvent system, olefin monomer (e.g., isobiitykne), an initiator (e.g., a t ⁇ rt -ester, tort- ether, ten-hydroxyl or fert-halogen containing compound, a eumy! ester of a hydrocarbon acid, an alky! curnyl ether, a eumyl haiide, a eumyl hydroxy) compound, or a hindered version of the above), and a eoinitiator (e.g.. a Lewis acid, such as boron trichloride or titanium tetrachloride).
  • olefin monomer e.g., isobiitykne
  • an initiator e.g., a t ⁇ rt -ester, tort- ether, ten-hydroxyl or fert-halogen containing compound, a eumy! ester of a hydro
  • electron pair donors e.g., dimethyl acetamkie, dimethyl sulfoxide, dimethyl phthalate
  • electron pair donors e.g., dimethyl acetamkie, dimethyl sulfoxide, dimethyl phthalate
  • proton-scavengers that scavenge water, such as 2,6-di-tert-butyIpyridine, 4 ⁇ methy!-2,6-di-tert-buty)pyridi ⁇ e, I ,S- bis(dimcthyknijno)-naphtha)en ⁇ . or diisopropyl ethyl amine can be added.
  • the reaction is commenced by removing the tert-ester. tert-ether, iert -hydroxy) or tert-halogeo (herein called the "tert-leavmg groups") from the initiator by reacting the initiator with the Lewis acid, in place of the tert-Ie&ving groups is a quasi-stable or "living" cation which is stabilized by the surrounding tertiary carbons, as well as the polar solvent system and electron pair donors.
  • die A block monomer e.g., isobutylene
  • cationicaliy propagates or polymerizes from each cation on the initiator.
  • the propagated cations remain on the ends of the A blocks.
  • the B block monomer e.g., stymie
  • a termination molecule such as methanol, water and the like.
  • Product molecular weights are generally determined by reaction time, reaction temperature, the nature and concentration of the re&ctants, and so forth. Consequently, different reaction conditions may produce different products, in general, synthesis of the desired reaction product is achieved by an iterative process in which the course of the reaction is monitored by the examination of samples taken periodically during the reaction a technique widely employed in the art. To achieve the desired product, an additional reaction may be required in which reaction ⁇ n ⁇ i and temperature, reactant concentration, and so forth are changed. Additional details regarding cationic processes for making copolymers are found, for example, in Kennedy et a!.. U.S. Patent No. 4,276,394; Kennedy, U.S. Patent Na.
  • the block copolymer may be recovered from the reaction mixture by any of the usual techniques including evaporation of solvent, precipitation wife a non-solvent such as an alcohol or alcohol/acetone mixture, followed by drying, and so forth, in addition, purification of the copolymer can be performed by sequential extraction in aqueous media, both with and without the presence of various alcohols, ethers and ketones.
  • particle 100 can be formed of a block copolymer that includes one or more functional groups.
  • the functional groups can be negatively charged or positively charged, and/or can be ionically bonded to the polymer.
  • the functional groups can enhance the biocompatibility of the polymer. Alternatively or additionally, the functional groups can enhance the clot-
  • a polytner can be a sulfonated styrenic polymer, such as sulfonated SOiJS. Sulfoustion of styrene block copolymers is disclosed, for example, in Ehrenherg, et al, U.S. Patent No. 5,468.574; Vacboa et aL, U.S. Patent No. 6,306,419; and Beriowilz-Tarrant, et at, U.S. Patent No.
  • a polymer ears include more than one different type of functional group.
  • a polymer can include both a sulfonate group and a phosphate group, hi some embodiments, a polymer that includes a functional group can be reacted with a cross- linking and/or gelling agent during particle formation.
  • a particle that includes a sulfonates group such as sulfonated Sf BS
  • a cross- linking and/or gelling agent such as calcium chloride
  • Functional teed polymers and cross-Unking and/or gelling agents are described, for example, m Richard et aL, U.S. Pended Application Serial No. 10/927,868, filed on August 27, 2004, and entitled ' ⁇ mhcsh/.atiorT, which is incorporated herein by reference.
  • particle 100 can be used to deliver one or more therapeutic agents to a target site.
  • Therapeutic agents include genetic therapeutic agents, non-genetic therapeutic agents, and cells, and can he negatively charged, positively charged, amphoteric, or neutral.
  • Therapeutic agents can be, for example, materials that are biologically active to treat physiological conditions; pharmaceutically active compounds; proteins; gene therapies; nucleic acids with and without carrier vectors f eg,, recombinant nucleic acids, DNA (e.g., naked DNA), cDNA, RNA, genomic DNA, cDNA or RNA in a non-infectious vector or in a viral vector which may have attached peptide targeting sequences, antisense nucleic acids (RNA, DNA)); oligonucleotides; gene/vector systems (e.g,, anything that allows for the uptake and expression of nucleic acids); DNA chimeras (e.g., DNA chimeras which include gene sequences and encoding for ferry proteins such as membrane translocating sequences (' 1 MTS”)
  • Non-limiting examples of therapeutic agents include ami-thrombogenic agents; antioxidants; angiogenic and ⁇ nti-a ⁇ giogenic agents arid factors; antiproliferative agents (e.g., agents capable of blocking smooth muscle cell proliferation, such as rapamycin); calcium entr> r blockers (e.g., verapamil, dihiazeni, nifedipine); and survival genes which pr ⁇ tect against cell death (e.g., anti- apoptotic BcI-2 family factors and Aki kinase),
  • Exemplary non-genetic therapeutic agents include: anti-thrornbotie agents such as heparin, heparin derivatives, urokinase, and PPack (dextrophenylalanine proline arginme chloroinelhyiketonc); antiinflammatory agents such as dexamethasune, prednisolone, cortieosterone, budesonide, estrogen, acetyl salicylic
  • anti ⁇ ieopiasiic/anuproliferativc/anii-r ⁇ itoiic agents such as pach ' taxeL 5-iluorouracil, cispiatin, .methotrexate, doxorubicin, vinblastine, vincristine, cpothilones, endostatin, angiostatin, angiopeptin, monoclonal a ⁇ libodies capable of blocking smooth muscle eel ⁇ proliferation, and thymidine kinase inhibitors; anesthetic agenis such as ⁇ idocaine, bi ⁇ ivacahie and ropivacaine; anti-coagulants such as ⁇ -Plie-Pro-Arg chloro ⁇ iethyl ketone, an RGD peptid ⁇ -contaimng compound, heparin, hirudin, antithrombin compounds, platelet receptor antagonists, arm- thrombin an bodies, anti-platelet receptor antibodies, aspirin, prostaglandin
  • cytotoxic agents >4 nitrofurantoin; cytotoxic agents, cytostatic agents and cell proliferation affectors; vasodilating agents; and agents that interfere with endogenous vasoactive mechanisms.
  • Exemplary genetic therapeutic agents include: an ti -sense DNA and UNA; DMA coding ibr anti-sense RNA, tRN A or rRN A to replace defective or deficient endogenous molecules, angiogenic factors including growth factors such as acidic and basic fibroblast growth (actors, vascular endothelial growth factor, epidermal growth factor, transforming growth factor ⁇ and ⁇ , platelet-derived endothelial growth factor, platelet-derived growth factor, tumor necrosis factor a, hepaioeyte growth factor, and insulin Like growth factor, cell cycle .inhibitors including CD inhibitors, thymidine kinase ("TK" ' ) and other agents useful for interfering with ceil proliferation, and Hie family of bone morphogenk proteins (“BMP's”), including BMP2, BM P3, BM P4, BMP5, BMP6 (Vgrl ), BMP?
  • growth factors such as acidic and basic fibroblast growth (actors
  • BMP8 BMP9
  • BMPlO BMl 1
  • BMP12 BMP 13
  • BMP9 BMP9
  • BMPlO BMl 1
  • BMP12 BMP 12
  • BM P 13 BMPH
  • BMPl 5 BMP 16
  • BMP8 BMP9
  • BMPlO BMl 1
  • BMP12 BMP12
  • BM P 13 BMPH
  • BMPl 5 BMP 16
  • BMP 16 BM P5
  • BMP6 BMP7
  • Such dimerie proteins can be provided as hornodimers, heterodirncrs, or combinations thereof, alone or together with other molecules.
  • molecules capable of inducing an upstream or downstream effect of a BMP can be provided.
  • Such molecules include any of the "hedgehog" proteins, or the DNA's encoding them.
  • Vectors of interest for delivery of genetic therapeutic agents include: plasmids; viral vectors such as adenovirus (AV), adersoassociaied virus (AAV) and l ⁇ niivirus; and non-Viral vectors such as lipids, liposomes mid cationic lipids.
  • viral vectors such as adenovirus (AV), adersoassociaied virus (AAV) and l ⁇ niivirus
  • non-Viral vectors such as lipids, liposomes mid cationic lipids.
  • Cells include cells of human origin (autologous or allogeneic), including stern cells, or from a.n animal source (xenogeneic), which can he genetically engineered if desired to deliver proteins of interest.
  • cytostatic agents i.e., agents that prevent or delay cell division in proliferating cells, for example, by inhibiting replication of DNA or by inhibiting spindle fiber formation.
  • Representative examples of cytostatic agents include modified toxins, methotrexate, adriamycin, radionuclides (e.g., such as disclosed in Fritzbeig ei al., U.S. Patent No. 4,897,255), protein kinase inhibitors, including siaurosporin, a protein kinase C inhibitor of the following fo ⁇ xmfa;
  • diindoloalkaloids having one of the following general, structures;
  • TGF-beta including TmYK)Xi fen and derivatives of functional equivalents (e.g., plasmiru heparin, compounds capable of reducing the level or inactivating the lipoprotein Lp(a) or the glycoprotein apolipoprotein(a)) thereof, TGF-beta or funeiiorsal equivalents, derivatives or analogs thereof, suramin, nitric oxide releasing compounds (e.g., nitroglycerin) or analogs or functional equivalents thereof, pacHiaxel or analogs thereof (e.g., taxotere), inhibitors of specific enzymes (such as die nuclear enzyme DNA topotsornerase 11 and DNA polymerase, RNA polymerase, adenyl guanyl cyclase), superoxide dismutase inhibitors, terminal deoxynucleotidyl -transferase, reverse transcriptase
  • functional equivalents e.g., plasmir
  • cytostatic agents include peptidic or mimetic inhibitors (i.e., antagonists, agonists, or competitive or non-competitive Inhibitors) of cellular factors thai may (e.g., in the presence of extracellular matrix) trigger proliferation of smooth muscle cells or pericytes: e.g., cytokines (e.g., interleukhis such as IL-I), growth factors (e.g., PDGF, TGF-aipha or -beta, tumor necrosis factor, smooth nruscie- and endoihelial-derived growth factors, i.e., endotbelin, FGF), homing receptors (e.g., for platelets or leukocytes), arsd extracellular matrix receptors (e.g., integrals).
  • cytokines e.g., interleukhis such as IL-I
  • growth factors e.g., PDGF, TGF-aipha or -beta, tumor necrosis factor
  • cytostatic agents addressing smooth muscle proliferation include: sub fragments of heparin, triazolopyriniidme (trapidil; a PDGF antagonist), lovastatin, and prostaglandins El or 12, Agents that inhibit the intracellular increase in cell volume (i.e., the tissue- volume occupied by a cell), such as cytoskeietal inhibitors or metabolic inhibitors.
  • cytoskdetal inhibitors include colchicine, vinblastine cytochalasirss, psdilaxel and the like, which act on microtubule and microfilament networks within a cell.
  • metabolic- inhibitors include staurosporin, t ⁇ chothecenes, and modified diphtheria and riein toxins, Pseudor ⁇ onas exotoxin and the like.
  • T ⁇ chothecenes include simple triehotheeenes (i.e., those that have only a centra! sesqurterpenoid stiiict ⁇ re) and ⁇ iacrocyclic triehotheccnes (i.e., those that h&ve an additional macrocyclic ring), e.g..
  • Vermcarin A 5 Verruearf ⁇ B 5 Verrucarin..1 (Satratoxl ⁇ (?), Roridin A, Roridin C, Roridin D, Roridin E (Satratoxin D), Roridin H.
  • Agents acting as an inhibitor that blocks cellular protein synthesis and/or secretion or organization of extracellular matrix i.e., an ' t anti-niatrix agent.
  • exemplary-malrix agents include mhibiiors (i.e., agonists and antagonists axi ⁇ competitive and non-competitive inliibitois) of matrix synthesis, secretion and assembly, organizational cross-linking (e.g., transglutaminases cross- linking collagen ⁇ , and matrix remodeling (e.g., following wound healing).
  • a representative example of a useful therapeutic agent in this category of anti-matrix agents is colchicine, an inhibitor of secretion of extracellular matrix.
  • tamoxifen for which evidence exists regarding its capability to organize and/or stabilize as well as diminish smooth muscle cell proliferation following angioplasty.
  • the organization or stabilization may stein from the blockage of vascular smooth muscle eel) maturation in to a pathologically proliferating form.
  • agents that are cytotoxic to cells, particularly cancer cells ['referred agents arc Roridi ⁇ A, Pseudomonas exotoxin and the like or analogs or functional equivalents thereof, A plethora of such therapeutic agents, including radioisotopes and the like, have been identified and are known m the art. in addition, protocols ibr the identification of cytotoxic .moieties are known and employed routinely in the art, A number of the above therapeutic agents and several others have also been identified as candidates for vascular treatment regimens, for example, as agents targeting restenosis. Such agents include one or more of the following: calcium- channel blockers, ineludmgbenz0thiazapin.es (e.g., diltiazem.
  • dentiazera dentiazera
  • ⁇ thy drop yri dines e.g., nifedipine, amkxlipine, nicardipine
  • phenylalkyiammes e.g., verapamil
  • serotonin pathway modulators including 5-HT antagonists (eg,, ketanse ⁇ n, naftidrofuryl) and 5-MT uptake inhibitors (e.g., fluoxetine); cyclic .nucleotide pathway agents, including phosphodiesterase inhibitors (e.g..).
  • adenySate/guanylate cyclase stimulants e.g., forskolmK and adenosine analogs; catecholamine modulators, including ⁇ -antago ⁇ ists (e.g., prazosin, bunaxosme).
  • p-antagonists e.g..
  • propranolol and c ⁇ / ⁇ -antagonists (e.g., iabetalol, carvediJol); cndothelin receptor antagonists; nitric oxide donors/releasing molecules, including organic nitrates/nitrites (e.g., nitroglycerin, isosorbide dinitrate, amyl nitrite), inorganic rsilroso compounds (e.g., sodium nnroprasside ⁇ , sydnonimi ⁇ es (eg., molsidomine, linsidomine), nonoates (e.g...
  • organic nitrates/nitrites e.g., nitroglycerin, isosorbide dinitrate, amyl nitrite
  • inorganic rsilroso compounds e.g., sodium nnroprasside ⁇ , sydnonimi ⁇ es (eg., mols
  • S-nitroso compounds including low molecular weight compounds (e.g., S-nitroao derivatives of captopril, glutathione and N-acety!
  • penicillamine and high molecular weight compounds
  • high molecular weight compounds e.g., S-m ' troso derivatives of proteins, peptides, oligosaccharides, polysaccharides, synthetic polymers/oligomers and natural poSyrners/oiigomers), C-nitroso ⁇ , O-nitroso- and N-nitroso ⁇ ci>mpou ⁇ ds, and L- arginine
  • ACE inhibitors e.g., cilazapril, fbsinopril, enalapril
  • AT ⁇ -receptor antagonists c g., saralasin, iosartin
  • platelet adhesion inhibitors eg,, albumin, polyethylene oxide
  • platelet aggregation inhibitors including aspirin and lhienopyridine (tielopidi ⁇ e, clopidogrel) and GP fib/I Ha inliibitors (e.
  • inhibitors e.g., warfarin
  • activated protein C cyclooxygenase pathway inhibitors (e.g., aspirin, ibuprofen, flurbiprofen, iodorn ⁇ thacrn, sulfinpyrazone); natural and synthetic corticosteroids (e.g., dexamethasojie, prednisolone, methprednisolone, hydrocortisone); lipoxygenase pathway inhibitors (e.g., nordlhydroguairetie acid, cal ⁇ eic acid; ieuk ⁇ tiiene receptor antagonists; antagonists of E- and P-selectins; inhibitors of VCAM- i and ICAM-I interactions; prostaglandins and analogs thereof, including prostaglandins such as FGEl and PGI2; prostacyclins and prostacyclin analogs ⁇ e.g., eiprostene, epoprost ⁇ nol,
  • iioprost beraprost
  • macrophage activation preventers e.g., bisphosphonates
  • HMG-CoA reductase inhibitors e.g., lovastatin, pravastatin, Huvastatin, simvastatin, cerivastatin
  • fish oils and omega-3-fatty acids e.g., fish oils and omega-3-fatty acids
  • tree-radical scavengers/antioxidants e.g., probucol. vitamins C and E, ebselen, retinoic acid (e.g., trans-rctinoic acid).
  • FGF pathway agents e.g., bFGF antibodies, chimeric fusion proteins
  • PDC PDCF receptor antagonists
  • IGF pathway agents e.g.. somatostatin analogs such as arsgiopep ⁇ n and ocreoiide
  • TGF- ⁇ pathway agents such as poiyamonic agents (heparin, f ⁇ coidi ⁇ ), decorin, and TGF- ⁇ antibodies
  • EOF pathway agents e.g., EGF antibodies, receptor antagonisLs, chimeric fusion proteins
  • pathway agents e.g., thalidomide a.nd analogs thereof), thromboxane A2 CTXA2 ⁇ pathway modulators (e.g., suiotroban, vapiprost, da ⁇ roxiben, ridogrel), protein tyrosine kinase inhibitors (e.g., tyrphostm, genistcin, and quinoxaline derivatives); MMF pathway inhibitors (e.g., marimasiat, ilomastat, metastat), and cell molility inhibitors (e.g., cytochalasin B); aiitiproliferativ ⁇ 'antineoplastjc agents including antimetabolites such as purine analogs (e.g., 6-rnercaptopurme), pyrimidine analogs (e.g., cylarabme and 5- fiuuujuraci! ⁇ and methotrt-xate, nitrogen mustards, alkyl sulfonates, ethylenimine
  • therapeutic agents include anti-tumor agents, such as docctaxeL alkylating agents (e.g., mechloreihamine, chlorambucil, cyclophosphamide, nielphalan, ifosiami.de ⁇ , plant alkaloids (e.g., eioposide), inorganic sons (e.g , cispiatin), biological response modifiers (e.g.. interferon. ⁇ , and hormones (e.g., tamoxifen, fh ⁇ amidt 1 ⁇ , as well as their homologs, analogs, fragments,
  • anti-tumor agents such as docctaxeL alkylating agents (e.g., mechloreihamine, chlorambucil, cyclophosphamide, nielphalan, ifosiami.de ⁇ , plant alkaloids (e.g., eioposide), inorganic sons (e.g , c
  • therapeutic agents include organic-soluble therapeutic agents, such as rnuhr&myein, cyclosporins and plicamycia
  • FunJier examples of therapeutic agents include pharmaceutically active compounds, anti-sense genes, viral, liposomes and cationic polymers (e.g., selected based on the application.), 0 biologically active solutes (e.g., heparin), prostaglandins, prostcydlns, L-arginine, ⁇ iiric oxide (NO) donors (e.g., lisidotninc, molsidomine, NO-protei ⁇ adduets, NO- polyssccharide adduets, polymeric or oligonieric NO adduets or chemical complexes), enoxaparin, Waraii ⁇ sodium, dicuniarol, interferons, r ⁇ t ⁇ rkuki ⁇ s, cbymase inhibitors (e.g., Traniiast),
  • Tlierapeutie agents are described, for example, in DiMatieo et al, U.S. Patent Application Publication No. US 2004/0076582 A l, published on April 22, 2004, ⁇ m ⁇ 0 entitled "Agent Delivery Particle", and in Schwarz et al., U.S. Paie ⁇ t No. 6,368,658, both of which are incorporated herein by reference.
  • particle JOO can include one or more radiopaque materials, materials that arc visible by magnetic resonance imaging fMRl-visible materials), ferromagnetic materials, and/or contrast agents (e.g., ultrasound contrast agents), Radiopaque materials, MRI-visible materials, ferromagnetic materials, and contrast agents are described, tor example, in Rioux ei a!.. U.S. Patent Application Publication No. US 2004/0101564 Al 5 published on May 27, 2004, which is incorporated herein by reference.
  • contrast agents e.g., ultrasound contrast agents
  • particle 100 can have a diameter of about 3,000 microns or less (e.g., from, about two microns to about 3,000 microns, from about 10 microns to about 3,000 microns, from about 40 microns to about 2,000 microns; from about 100 microns to about 700 microns; from about 500 microns to about 700 microns; from about 100 microns to about 500 microns; from about 100 microns to about 300 microns; from about 300 microns to about 500 microns; from about 500 microns to about 1 ,200 microns; from about 500 microns to about 700 microns; from about 700 microns io about 900 microns; from about 900 microns to about J ,200 microns, from about 1,000 microns to about L200 microns).
  • a diameter of about 3,000 microns or less e.g., from, about two microns to about 3,000 microns, from about 10 microns to about 3,000 microns
  • particle 100 can have a diameter of about 3,000 microns or less (e.g., about 2,500 microns or less; about 2,000 microns or less; about 1 ,500 microns or less; about 1 ,200 microns or less; about 1 , ! 50 microns or less; about 1,100 microns or less; about 1 ,090 microns or less; about 1,080 microns or less; about 1,070 microns or less; about 1 ,060 microns or less; about 1 ,050 microns or less; about 1 ,040 microns or less; about 1 ,030 microns or loss; about 1 ,020 microns or less; about !
  • microns or less about i ,000 microns or less: about 900 microns or less; about 700 microns or less; about 500 microns or less; about 400 microns or less; about 300 microns or less; about 100 microns or less) and/or about 10 microns or more (e.g., about 100 microns or more; about 300 microns or more; about 400 microns or more; about 500 microns or more; about 700 microns or more; abo ⁇ i 900 microns or more; about 1,000 microns or more; about !
  • particle 100 can have a diameter of less than about 100 microns (e.g., less than about 50 microns).
  • particle 100 can be substantially spherical.
  • particle 100 can have a sphericity of about 0.8 or more (e.g., about 0,85 or more, about 0.9 or more, about 0.95 or more, about 0,97 or more).
  • Particle 100 can be, for example, manually compressed, essentially flattened, while wet to about 5(J percent or less of its original diameter and then, upon exposure to Ouid, regain a sphericity of about 0.S or more (e.g., about 0.S5 or more, about 0.9 or mo ⁇ e, about 0,95 or more, about 0.97 or more).
  • the sphericity of a particle can be determined using a Beekman Coulter Rapid VU E Image Analyzer version 2,06 (Beekma ⁇ Coulter, Miami, FL). Briefly, the RapidVUE takes an image of continuous-tone (gray-scale) form and converts if to a digital form through the process of sampling and quantitation. The system software identifies and measures particles in an image in the lbmi of a fiber, rod or sphere.
  • the sphericity of a particle which is computed as Da/Dp (where Da - V(4A/ ⁇ t); Dp ::: P/JT ; A ⁇ pixel area; P - : pixel perimeter), is a value itom ⁇ .ero to one, with one representing a perfect circle.
  • Particle 100 can include one or more of the block copolymers described above, In some embodiments, particle 100 can include multiple (e.g., two, three, lour, live, six, severs., eight, nine, 10 ⁇ different block copolymers. For example, in some; embodiments, a particle can include a blend of at least two different block copolymers. Alternatively or additionally, particle 100 can include oilier types of materials, such as other polymers that arc not block copolymers.
  • polymers examples include polyvinyl alcohols (' 1 PVA"), poiyacrylic acids, polyraethaerylic acids, poly vinyl sulfonates, carb ⁇ xymethyj celluloses, hydroxyethyl celluloses, substituted celluloses, poiyacryiamides, polyethylene glycols, polyatrsi ⁇ es, polyureas, poiyurethanes, polyesters, polyethers, polystyrenes, polysaccharides, polylaetic acids, polyethylene ⁇ , poly ⁇ Sefins, poiypropyienes, polymethylmethacrylates.
  • ' 1 PVA polyvinyl alcohols
  • poiyacrylic acids poiyacrylic acids
  • polyraethaerylic acids poly vinyl sulfonates
  • carb ⁇ xymethyj celluloses hydroxyethyl celluloses, substituted celluloses
  • poiyacryiamides examples include polyethylene glycols,
  • particle 100 can include a highly water insoluble, high molecular weight polymer.
  • An example of such a polymer is a high molecular weight PVA that has been acetalized.
  • Particle 100 can include substantially pure irstradiain 1 ,3 ⁇ aeela&ed .PVA .
  • particle 100 can include a minor amount (e.g.. about 2,5 weight percent or less, about one weight percent or less, about 0.2 weight percent or less) of a gelling material (e.g., a polysaccharide, such as alginate), m certain embodiments, particle 100 can include a bioabsorbable (e.g., resorbable) polymer (e.g., alginate, gelatm, albumin, resorbable polyvinyl alcohol, albumin, dextran, starch, ethyl cellulose, p ⁇ lyglyeoiic acid, polylactic acid, polylactic acid/polygiveolie acid copolymers, poly(lactic-co-glycolic) acid).
  • Particle 100 can include, for example, polyvinyl alcohol, alginate, or both polyvinyl alcohol and alginate.
  • particle 100 in addition to or as an alternative to being used to deliver a therapeutic agent to a target site, particle 100 can be used to ernhoiize a target site (e.g., a lumen of a subject).
  • a target site e.g., a lumen of a subject
  • multiple particles can be combined with a carrier fluid (e.g., a pharmaceutically acceptable carrier, such as a saline solution, a contrast agent, or both) to form a composition, which can then be delivered to a site and used to embolize the site.
  • a carrier fluid e.g., a pharmaceutically acceptable carrier, such as a saline solution, a contrast agent, or both
  • FIGS. 2A and 2B illustrate the use of a composition including particles to embolics a lumen of a subject
  • a composition including particles 300 and a carrier fluid
  • Catheter 1 150 is connected to & syringe barrel I U Q with a plunger 1 160
  • Catheter 1 150 is inserted, for example, into a femoral artery U 20 of a subject.
  • Catheter 1 150 delivers the composition to, for example, occlude a uterine artery 1130 leading to a fibroid 1 140.
  • Fibroid t 140 is located m the uterus of a female subject
  • the composition is initially loaded into syringe 1 1 10.
  • Plunger 1 160 of syringe I l 10 is then compressed to deliver the composition through catheter 1 150 into a lumen 1 165 of uterine artery 1 130.
  • FKJ. 2B which is an enlarged view of section 2B of FIG. 2A 5 shows a uterine artery 1 130 thai is subdivided into smaller uterine vessels 1 170 (e.g., having a diameter of about two millimeters or less) which feed fibroid 1 140,
  • the particles 100 in. the composition partially or totally fill the lumen of uterine artery 1 130, either partially or completely occluding the lumen of the uterine artery 1 130 that feeds uterine fibroid 1 140.
  • compositions that include particles such as particles 100 can be delivered to various sites m the body, including, for example, sites having cancerous Jesious, such as the breast, prostate, lung, thyroid, or ovaries.
  • the compositions can be used in, for example, neural , pulmonary, and/or AAA (abdominal aortic, aneurysm) applications.
  • the compositions can be used in the treatment of, for example, fibroids, tumors, internal bleeding, arteriovenous malformations (AVMs), and/or hypervascular tumors.
  • the compositions can be used as, for example, fillers for aneurysm sacs.
  • Fibroids cars include uterine fibroids which grow within the uterine wall (intramural type), on the outside of the uterus (suhserosal type), inside Ae uterine cavity (submucosal type), between the layers of broad ligament supporting the uterus
  • AVMs are for example, abnormal collections of blood vessels, e.g. in the brain, which shunt blood from a high pressure artery to a low pressure vein, resulting in hypoxia and malnutrition of those regions from which the blood is diverted.
  • a composition containing the particles can be used to prophylactically treat a condition.
  • compositions can be administered as pharmaceutically acceptable compositions to a subject in any therapeutically acceptable dosage, including those administered to a subject intravenously, subeutaneously, percutaneous! y, mtratraehe&ly, intramuscularly, intrarrmeosaly, intracutaneous])-', intra-articularly, orally ⁇ ;r parenteral Iy.
  • a composition can include a mixture of particles (e.g., particles that include different types of block copolymers, particles that mdiicte different types of therapeutic agents), or can include particles that are all of Ae .same type.
  • a composition can be prepared with a calibrated concentration of particles for case of delivery by a physician.
  • a physician can select a composition of a particular concentration based on, for example, the type of procedure to be performed,
  • a physician can use a composition with a relatively high concentration of particles during one part of an embolization procedure, and a composition with a relatively low concentration of particles during another part of the embolization procedure.
  • Suspensions of particles in saline solution car. be prepared to remain stable (e.g., to remain suspended in solution and not settle and/or float) over a desired period of time
  • a suspension of particles can be stable, for example, for from about, one minute to about 20 minutes (e.g. from about one minute to about 10 minutes, from about two minutes to about seven minutes, from about three minutes to about six minutes).
  • particles can be suspended in a physiological solution by matching the density of the solution to the density of the particles.
  • the particles and/or the physiological solution can have a density of fmm about one gxar ⁇ per cubic centimeter to about. 1 .5 grams per cubic centimeter (e.g., from about 1.2 grams per cubic centimeter to about L4 grams per cubic centimeter, from about 1.2 grams per cubic centimeter to about 1.3 grams per cubic centimeter).
  • the earner fluid of a composition can include a surfactant.
  • the surfactant can h&lp the particles to mix evenly in the carrier fluid and/or can decrease the likelihood of the occlusion of a delivery device (e.g., a catheter) by me particles.
  • the surfactant can enhance delivery of the composition (e.g.. by enhancing the wetting properties of the particles and facilitating the passage of the particles through a delivery device),
  • the surfactant can decrease the occurrence of air entrapment by the particles in a composition.
  • liquid surfactants include Tween* SO (available from Sigma-AMrich) aid Cremophor Elf (available from Sigma-Aklrich), An example of a powder .surfactant is Pluromc 5 * Fl 27 NF (available from BASF).
  • a composition can include from about 0.05 percent by weight Io about one percent by weight (e.g., about 0.1 percent by weight, about 0.5 percent by weight) of a surfactant.
  • a surfactant can be added to the carrier fluid prior to mixing with the particles and/or can be added to the particles prior to mixing with the carrier fluid.
  • the majority e.g., about 50 percent or more, about 60 percent or more, about 70 percent or more, about 80 percent or more, about 90 percent or more ⁇ of the particles cars have a diameter of about 3,000 microns or less (e.g., about 2,500 microns or less; about 2,000 microns or less; about 1 ,500 microns or less; about, 1 ,200 microns or less; about 1,150 microns or less; about LlOO microns or less; about 1,090 microns or less; about 1,080 microns or less; about 1 ,070 microns or less; about 1,060 microns or less; about 1 ,050 microns or less; about 1 ,040 microns or less; about 1 ,030 microns or less; about 1 ,020 microns or less; about 1,010 microns or less; about 1,000 microns or ess
  • the majority of the particles cars have a diameter of less than about 100 microns (e.g., less than about 50 microns).
  • the panicles delivered to a subject can hav € an arithmetic mean diameter of about 3,000 microns or less (e.g., about 2.500 microns or less; about 2,000 microns or less; about 1.500 microns or less; about 1 ,200 microns or less; about 1 ,150 .microns or less; about I J OO microns or less; about 1 ,090 microns or less; about 1,080 microns or less; about 1 ,070 .microns or less; about 1 ,060 microns or less; about 1,050 microns or less; about 1 ,040 microns or less; about 1 ,030 .microns or less; about 1,020 microns or less; about L010 microns or less; about 1 ,000 microns or less; about 900 microns or less; about 700 microns or less; about 500 microns or less; about 400 microns
  • the particles delivered to a subject can have an arithmetic mean diameter of less tbars about 100 microns ⁇ e.g., less than about 50 microns).
  • Exemplary ranges for the arithmetic mean diameter of particles delivered to a subject include from about 100 microns to about 500 microns; from about 100 microns to about 300 microns; from about 300 microns to about 500 microns; from aboui 500 microns to about 700 microns; from about 700 microns to about 900 microns; from about 900 microns to about 1 ,200 microns; and from about 1 ,(.K)O microns to about 1,200 microns,
  • the particles delivered to a subject e.g., irs a composition
  • cars have an arithmetic mean diameter in approximately the middle of the range of the diameters of the individual particles, and a variance of about 20 percent or less ⁇ e.g.
  • the arithmetic mean diameter of the particles delivered to a subject ⁇ e.g., in a composition) can vary depending upon the particular condition to be treated.
  • the particles delivered to the subject can have an arithmetic mean diameter of about 500 microns or less (e.g., from about 100 microns to about 300 microns; from about 300 microns to about 500 microns).
  • the particles delivered to the subject eaa have an.
  • arithmetic mean diameter of about 1 ,200 microns or less e.g., from about 500 microns to about 700 microns; from about 700 microns to about 900 microns; from about 900 microns to about 1,200 microns).
  • the particles delivered, to the subject can have an arithmetic mean diameter of less than about 100 microns (e.g., less than about 50 microns)-
  • the particles delivered to the subject can have an arithmetic mean, diameter of less than about 100 microns (e.g., less than about 50 microns).
  • the particles can have a diameter of about 1 ,200 microns or less (e.g., from about KOOO microns to about 1 ,200 microns).
  • the arithmetic mean diameter of a group of particles can be determined using a Beckr ⁇ an Coulter RapidVUE Image Analyzer version 2.06 (Beckman Coulter, Miami. FL), described above.
  • the arithmetic mean diameter of a group of particles e.g., ITS a composition
  • the arithmetic mean diameter of a group of particles can be determined by dividing the sum of the diameters of all of the particles in the group by the number of particles in the group.
  • a particle that includes one of the above-described block copolymers can also include a coating.
  • FIG. 3 shows a particle 200 with an interior region 202 formed of a block copolymer, and a coating 204 formed of a different polymer (e.g., polyvinyl alcohol).
  • Coating 20-4 can, for example, regulate the release of therapeutic agent from particle 200. and/or provide protection to interior region 202 of particle 200 (e.g., during delivery to a target site).
  • coating 204 can be formed of a bioerodihie- and/or bioabsorbabie material that can erode and/or be absorbed as particle 200 is delivered to a target site, such that interior region 202 can deliver a therapeutic ageni to the target site orsee particle 200 has reached the target site.
  • a bioerodible material can be, for example, a polysaccharide ⁇ e.g., alginate); a polysaccharide derivative; an inorganic, ionic sail; a water soluble polymer (e.g., polyvinyl alcohol, such as polyvinyl alcohol that has not been cross-linked); biodegradable poly DL-taetide-poly ethylene glycol (PELA); a hydrogel (e.g., poiyaeryiie acid, hyaluronic acid, gelatiu, earboxymcthyl cellulose); a polyethylene glycol (PEG); chitossn; a polyester (e.g., a polycaprolaetone); a poly(oriho ester); a polyanhydride; a poly(laciic-co-glycolic) acid (e.g., a poly(d-iactic-co-giycolic) add); a ⁇ o!y(lactic
  • the swellable material can be made to swell by, for example, changes in pH, temperature, and/or salt hi embodiments in which particle 200 is used in an embolization procedure, coating 204 can swell at a target site, thereby enhancing occlusion of the target site by particle 200.
  • a particle can include a coating that is formed of a block copolymer.
  • FlG. 4 shows a particle 300 that includes an interior region.
  • interior region 302 can be formed of a polymer (e.g., polyvinyl alcohol), and a coating 304 formed of a block copolymer (e.g., SIBS),
  • interior region 302 can be formed of a swe ⁇ able material.
  • coating 304 can be formed of a porous material. The pores in coating 304 can expose interior region 302 to changes in, for example, pi t temperature, and/or salt.
  • coating 304 can be made of a relatively flexible material (e.g., SiBS) that can accommodate the .swelling of interior region 302.
  • SiBS a relatively flexible material
  • swellable materials include hydrogel s, such as poiyaeryiie acid, polvao ⁇ yb ⁇ de co-acrylic acid, hyaluronic acid, gelatin, carboxymethy) cellulose, noryi ethylene oxidcj-based polyurethane, polyaspartahydrazide. ethyleneglycoldiglycidyiether (EGDGE), and polyvinyl alcohol (PVA) hydrogds.
  • EGDGE ethyleneglycoldiglycidyiether
  • PVA polyvinyl alcohol
  • a particle can include a coating that includes one or snore therapeutic agents.
  • a particle can have a coating that includes a high concentration of one or more therapeutic agents.
  • One or more of the therapeutic agents can also be loaded into the interior region of the particle.
  • the surface of the particle can release an initial dosage of therapeutic agent after which the body of ihe particle can provide a burst release of therapeutic agent.
  • the therapeutic agent on the surface of the particle can be the same as or different from the therapeutic agent in the body of the particle.
  • the therapeutic agent on the surface can be applied by exposing the particle to a high concentration solution of the therapeutic agent.
  • the therapeutic agent coated particle can include another coating over the surface the therapeutic agent (e.g., a bioerod ⁇ bte polymer which erodes when the particle is administered).
  • the coating can assist in controlling the rate at which therapeutic agent is released from the particle.
  • the coating can be in the form of a porous membrane, The coating can delay an initial burst of therapeutic agent release.
  • the coating can be applied by dipping or spraying the particle.
  • the credible polymer can be a polysaccharide (such as an alginate).
  • the coating can be an inorganic, ionic salt.
  • Other credible coatings include polysaccharide derivatives, water-soluble polymers (such as polyvinyl ulcohoK e.g., that has not been cross-linked), biodegradable poly DL ⁇ lactkk-poly ethylene glycol (PELA), hydrogcls (e.g., polyacrylie acid, hyaluronic acid, gelatm, carhoxymethyl cellulose), polyethylene glycols (PEG) 5 ehitosari, polyesters (e.g., polycaprolactones ⁇ , polyi ' ortho esters), poiyanhydrides, ⁇ oly ⁇ lactic acids) (PI. A).
  • PEG polyethylene glycols
  • the coating cars include therapeutic agent or can be substantially free of therapeutic agent.
  • the therapeutic agent m the coating can be the same as or different from an agenl on a surface layer of the panicle and/or within the particle.
  • a polymer coating e.g. an credible coating
  • Coatings are described, for example, in DiMa ⁇ eo et ai, U.S, Patent Application Publication No. US 2004/0076582 Ai, published on April 22, 2004, which is incorporated herein by reference,
  • a particle can include one or more smaller sub- particles.
  • FIG. 5 shows a particle 4Of) that includes a matrix 402, within whkh are embedded sub-panicles 404.
  • Matrix 402 can be formed of, for example, one or more polymers ⁇ e.g., block copolymers such as SlBS), Alternatively or additionally, sub-particles 404 can be formed of one or more polymers (e.g., block copolymers such as SIBS). hi some embodiments, both matrix 402 and sub-particles 404 can be formed of one or more block copolymers.
  • Block copolymer ⁇ ) in matrix 402 can be the same as, or different from, block, copolymers) in sub-partkles 404.
  • particle 400 can include one or more therapeutic agents, such as water-soluble therapeutic agents and/or organic-soluble therapeutic agents. This ears allow particle 400 to be used, for example, to deliver multiple therapeutic agents to a target sue in one procedure.
  • the therapeutic- agents can be included in (e.g., dispersed throughout) matrix 402 and/or sub-particles 404, hi some embodiments, matrix 402 can include one type of therapeutic agent (e.g., an organic-soluble therapeutic agent), while sub-pariieles 404 include another type of therapeutic agent (e.g., a water-soluble therapeutic agent), in certain embodiments .
  • matrix 402 can be made out of a porous material, which can help in the release of therapeutic agent from sub-particles 404.
  • water- soluble therapeutic agents include DNA, oligonucleotides, heparin, urokinase, halofuginone, &n ⁇ protein.
  • organic-soluble therapeutic agents include paclitax ⁇ l, trans-retinoic acid, mithramyem, prob ⁇ col, rapamycin, dexamethason, 5-fluor ⁇ uracil, methotrexate, doxorubicin, da ⁇ norubiein, cyclosporins, eisplatin, vinblastine, vincristine, colchicine, epothikmes, encSostatin, angiostatiri, and plicamyoin.
  • FIGS. 6A-6C show a single-emulsion process that can be used, for example, to r ⁇ ake particle 100 (FiG. 1 ⁇ .
  • a drop generator 500 e.g., a pipette
  • aforms drops 510 of a solution including a block copolymer e.g., SIBS
  • a therapeutic agent e.g., a drug that is administered to a patient.
  • an organic solvent e.g., methylene chloride, chloroform, te!.ra.bydrofura ⁇ (THF), toluene.
  • the solution can include at least about onu percent weight/volume ⁇ w/v ⁇ (e.g., from about one percent w/v to about 20 percent w/v) of the block, copolymer.
  • Drops 510 fall from drop generator 500 into a vessel 520 that contains an aqueous solution including a surfactant.
  • the surfactant can be water-soluble. Examples of surfactants include polyvinyl alcohols, poly(virry! pyrroiidone) (PVf 1 ), and poiysorbates (e.g., 1 T ween ⁇ ' 20.
  • the aqueous solution can be mixed (e.g., homogenized) while drops 510 are being added to it.
  • the aqueous solution can be mixed at a speed of at most about 10,000 revolutions per minute (e.g., at most about 5,000 revolutions per minute, at most about 1 ,500 revolutions per minute).
  • the concentration of the surfactant in the aqueous solution can be at least 0.05 percent w/v (e.g., from 0,05 percent w/v to about 10 percent w/v). In general, ss the concentration of surfactant in the aqueous solution increases, particle, size can decrease.
  • the solution is mixed using a stirrer 530,
  • the solution can be mixed (e g., homogenized) at a speed of at least about LOOO revolutions per minute (e.g., at least about 2,500 revolutions per minute, at least about S 5 OOO revolutions per minute, at least about 6,000 revolutions per minute, at least about 7,500 revolutions per minute) and/or at most, about 10,000 revolutions per minute (e.g., at most about 7,500 revolutions per minute, at most about 6,000 revolutions per minute, ai most about 3,000 revoiist.io.ns per minute, at most about 2,500 revolutions per minute).
  • LOOO revolutions per minute e.g., at least about 2,500 revolutions per minute, at least about S 5 OOO revolutions per minute, at least about 6,000 revolutions per minute, at least about 7,500 revolutions per minute
  • 10,000 revolutions per minute e.g., at most about 7,500 revolutions per minute, at most about 6,000 revolutions per minute, ai most
  • the solution can be mixed at a speed of from about 1000 revolutions per minute to about 6000 revolutions per minute.
  • particle size can decrease.
  • the solution cars be mixed for a period of at least about 0.5 hour (e.g., at least about one hour, at. least about two hours, at least about three hours, ai least about lour hours) and -Or at most about five hours (e.g., at most about four hours, at most about three hours, at most about two hours, at most about one hour).
  • the solution can be mixed for a period of from about one hour to about three hours (e.g., lor about one hour).
  • mixing can occur at a temperature of at least about 25°C (e.g., at least about 30 0 C, at least about 35"C),
  • particle size can increase.
  • the mixing results in a suspension 540 that includes particles 100 suspended in the solvent (FiG. 6C). Particles 100 are then separated from the solvent 6 by, for example, filtration, or centrituging followed by removal of the supernatant Thereafter, particles KK) are dried (e.g., by evaporation, by lyophilization, by vacuum drying).
  • the therapeutic agent can be omitted from the above- described process, such ihat the particles thai are produced do not include therapeutic
  • one or more therapeutic agents can be added to the particles (e.g., by injection) after the particles have been formed.
  • the particles thai are formed by the above-described process can be coated (e.g., with a polymer).
  • the coating can be added to the particles by, for example, spraying and/or dip-coating.
  • FKJ. 7 shows a drop generator system 601 that includes a flow controller
  • Flow controller 600 delivers a solution (e.g.. a solution that contains a block copolymer such as SIBS), a therapeutic agent, and an organic solvent) to a viscosity controller 605, which heals the solution to reduce viscosity prior to delivery to drop generator 610.
  • a solution e.g.. a solution that contains a block copolymer such as SIBS
  • a therapeutic agent e.g., a therapeutic agent
  • an organic solvent e.g. a solution that contains a block copolymer such as SIBS
  • the solution passes through an orifice in a nozzle in drop generator 610,
  • Drop generators axe described, for example, in Lanphexe ct aL, U.S. Patent Application Publication No. US 2004/0096662 A l, published on May 20, 2004, and in DiCarlo cf aL U.S. Patent Application Serial No. 1 1/1 1 1 ,51 L filed on April 21 , 2005, and
  • FIGS. SA and UB show an embodiment of a system 602 thai includes drop generator system (SOl, and that can be used to make particles like particle 200 (F ⁇ G. 3 ⁇ and particle 300 (FiG. 4).
  • System 602 Includes a drop generator system 601 , a reactor vessel 630, a gel dissolution chamber 640 and a filter 650.
  • controller 600 delivers a solution that contains one or more polymers ⁇ e.g., a block copolymer) and a gelling precursor (e.g., alginate) to viscosity controller 60S. which heats the solution to reduce viscosity prior to delivery to drop generator 610.
  • a gelling precursor e.g., alginate
  • the solution passes through an orifice in a nozzle in drop generator 610, forming drops of the solution.
  • the drops are then directed into vessel 620 (in this process, used as a gelling vessel), where the drops contact a gelling agent (e.g., calcium chloride) that converts the gelling precursor from a sokui ⁇ form into a gel tbrm, stabilizing the drops md forming particles.
  • a gelling agent e.g., calcium chloride
  • the particles may be transferred from vessel 620 to reactor vessel 630, where one or more polymers m the gei-stabilized particles may be reacted (e.g., cross- linked), in certain embodiments, the particles may be transferred to gel dissolution chamber 640, where the gelling precursor (which was converted to a gel) can be removed irons the adherel.es. After they have been formed, the particles can be filtered hi filter 650 to remove debris, in some embodiments, the particles may thereafter be coated with, for example, a polymer (e.g., a polyvinyl alcohol), finally, the particles can he sterilized and packaged as, for example, an embolic composition including the particles.
  • a polymer e.g., a polyvinyl alcohol
  • Gelling precursors include, for example, alginate salts, xanthan gums, natural gum, agar, agarose, chitosan, earrageenan, fueoidan, furceiiaran, laminaraa hyp ⁇ ea, eueheuma, gum arahie, gum ghan ' i gum karaya, gum tragaca ⁇ th, hyaluronic acid, locust beam gum, arahlnogalacian, peciin, arnyiopeetin, other water soluble polysaccharides and other io ⁇ iealSy cross-linkable polymers.
  • a particular gelling precursor is sodium alginate, such as high guluronic acid, stem- derived alginate (e.g., about 50 percent or more, about 60 percent or more guluronie acid) with a low viscosity (e.g., from about 20 eentipoise to about 80 eentipoix ⁇ at 2O 0 C!), which can produce a high tensile, robust gel .
  • vessel 620 can include a gelling agent such as calcium chloride. The calcium cations in the calcium chloride have an affinity for carboxylic groups in the gelling precursor.
  • the cations complex with carboxylic groups in the gelling precursor.
  • the eompiexing of the cations with carboxylie groups in the gelling precursor can cause different regions of the gelling precursor to be pulled closer together, causing the gelling precursor to gel hi certain embodiments, the completing of the cations with carboxylic groups in the gelling precursor can result in encapsulation of one or more oilier polymers (e.g., a block copolymer) in a matrix of gelling precursor.
  • gelling agents include divalent cations such as alkali metal salts, alkaline earth metal sails, or transition metal sails that can ionicaHy cross-link with the gelling precursor, hi some embodiments, an inorganic salt such, as a calcium, barium, zinc or magnesium salt, can be used as a gelling agent.
  • cross-linking agents that may be used to react one or more of the polymers (e.g., polyvinyl alcohol) in reactor vessel 630 include one or more aldehydes (e.g., formaldehyde, glyoxal, benzaldehyde, a.erephthalaldehyde, succirsaldebyde, gluiaraklehyde) in combination with one or more acids, such as relatively strong acids (e.g.. sulfuric acid, hydrochloric acid, nitric acid) and/or relatively weak acids (e.g., acetic acid, formic acid, phosphoric acid).
  • aldehydes e.g., formaldehyde, glyoxal, benzaldehyde, a.erephthalaldehyde, succirsaldebyde, gluiaraklehyde
  • acids such as relatively strong acids (e.g.. sulfuric acid, hydrochloric acid, nitric acid) and
  • a gas e.g., air, nitrogen, argon, krypton, helium, neon
  • particles can be formed by omitting one or more of the- steps from the process described with reference to FIGS. 8A and SB.
  • one or snore of the polymers may noi be crosslinked, and/or the gelling precursor may not be removed.
  • FIGS. 9A- ⁇ F show a double-emulsion process that can be used, for example, to make particles that, like particle 400 (FlG. 5), include sub-pariicfes.
  • drop generator 800 e.g., a pipette
  • drops S 10 of art aqueous solution containing a water-soluble therapeutic agent (e.g., DNA) and a surfactant ,
  • the surfactant can be water-soluble,
  • surfactants include polyvinyl alcohols, poly(vinyl pyrrolidone) (PVP) 5 and polvsorbaies (e.g..
  • Drops 810 fell into a vessel 820 that includes a solution of a block copolymer (e.g., SlBS) and an organic-soluble therapeutic agent ⁇ e.g.. paelitaxel) dissolved in an organic solvent, forming a mixture 830.
  • a block copolymer e.g., SlBS
  • an organic-soluble therapeutic agent e.g.. paelitaxel
  • mixture 830 is then mixed (e.g., homogenized) using a stirrer 835, to produce a suspension 832 that includes sub-particles 404 suspended in solvent (PiG. 9C).
  • Mixing of mixture 830 can occur at a speed of. for example, at least about 5,000 revolutions per minute (e.g., at least about 7,500 revolutions per minute) and/or at most about 10,000 revolutions per minute (e.g., at most about 7,500 revolutions per minute).
  • mixture 830 can be mixed for a period of at least about one minute (e.g., at bast about two minutes, at least about five minutes, at least about seven minutes) and/or at roost about 10 minutes (e.g., at most about seven minutes, at most about five minutes, at most about two minutes).
  • mixture 830 may be mixed for a period of from about one minute to about five
  • suspension 832 is added Io a drop generator 840 (FiG, 9O) to produce drops 850.
  • Drops B50 fall into a vessel 870 that includes an aqueous solution, forming a mixture. 880.
  • the aqueous solution in vessel 870 includes a surfactant (e.g., PVA).
  • PVA surfactant
  • FIG. 9E shows, mixture SSO is mixed (e.g., homogenized) using a stirrer 885, at a mixing speed that is lower than the speed of the first mixing.
  • mixture 880 can be mixed at a speed of at most about 2,000 revolutions per minute (e.g., at most about 1 ,500 revolutions per minute, at most about 1,000 revolutions per minute, at most about 500 revolutions per minute) and/or at least about 100 revolutions per minute (e.g., at least about 500 revolutions per minute . , at least about LOOO revolutions per minute, at least about 1 ,500 revolutions per minute).
  • This .second mixing can last for a period of, for example, at least about one minute (e.g., at least about two minutes, at least about tour minutes, at least about six .minutes, at least about eight minutes, at least about 10 minutes, at.
  • mixture 880 produces a suspension 89(5 including particles 400 in solvent (FIG. 9F).
  • Particles 400 are then separated from the solvent Ce. i>., bv filtration) and dried fe.t»,. hv evaporation), In some embodiments, particles 400 are separated from the solvent by evaporating the solvent.
  • one or more of the therapeutic agents can be omitted frora the above-described process, in some embodiments, all of the therapeutic agents can be omitted from, the above-described process, such that the panicles that are produced do not include any therapeutic agent.
  • one or more therapeutic agents can be added to the particles (e.g., by injection) after the particles have been formed.
  • S IBS particles were prepared by a single-emulsion process as follows.
  • SfBS solutions were prepared by dissolving two grams (to form a two percent w/v solution), four grams (to form a four percent w/v solution), seven grams (to form a seven percent w/v solution), H ) grams (to forr ⁇ a 10 percent w/v solution ⁇ , or 15 grams ( to ibrm a 15 percent w/v solution) of SIBS (60 mol percent stymie) in 100 milliliters of methylene chloride (model 27056-3. 99.9 percent I! PLC grade, from Sigma).
  • the SIBS solutions were stirred overnight at ambient temperature in a sealed beaker at SOU revolutions per minute, using a multi-position stirrer (a model PC-171 Coming Scholar 171 stirrer) and stir bars (model 14-51 1-60, from Fisher)-
  • Polyvinyl alcohol (PVA) solutions were prepared by dissolving one gram (for a 0.1 percent w/v solution), two grams (for a 0,2 percent w/v solution), five grams (for a 0.5 percent w/v solution), 10 grams (for a one percent w/v solution), 20 grams (for a two percent w/v solution), or 50 grams (for a five percent w/v solution) of polyvinyl alcohol in 1000 milliliters of distilled water.
  • the polyvinyl alcohol was lot number Pl 763, from Sigma (average molecular weight: 70,000-100,000).
  • the PVA solutions were stirred overnight at 4O 0 C (samples 1 -12) or 35°C (sample 13) using a hot plate (a model PC620 hotplate from Coming).
  • the SfBS solutions were combined with the PVA solutions in a ratio of i :20
  • SIBS PVA, to form samples 1-13 of SlBS particles.
  • the starting materials that, were used to form each of these samples of SIBS particles are shown in Tabic ! , Five milliliters of each SIBS solution were added into a PVA solution by continuous dropping using a pipette, as the PVA solution was being homogenized at.
  • SIBS particles were filtered out of each SiBS/PVA solution using a vacuum filter (a MiHpore 47 mm All Glass Vacuum Fi Her fielder) and a filter paper of smaller than five microns (a Milipore Filter Membrane).
  • SIBS particles were then collected and dried by evaporation overnight at room temperature (25°C),
  • Table 1 shows fee SIBS solution COnCeOtXiUiOn 5 the PVA solution i ;.t concentration, and the SlBSiPVA Volume Ratio for the different samples of SIBS particles that were produced according to the above-described method.
  • RGS. 10-14 are scanning election micrograph images, at 2Ox magnification, of sample I particles, sample 2 particles, sample 4 particles, sample 5 particles, and sample 6 particles, respectively.
  • FIG. 15 is a scanning electron micrograph image, at 20x magnification, of sample 12 particles, which were formed at a homogenization speed of 5,000 revolutions per minute.
  • a comparison of the sample 12 particles of FiG, 15 with the sample 2 particles of FiG. 11 (which were formed at a h ⁇ roogemzation speed of 10,000 revolutions per minute) indicates that homogenkation speed may not have a significant effect on the sizes of the SIBS particles that are produced,
  • FIG. 16 is a scanning electron micrograph image, at 20x ⁇ iag ⁇ iicaiion, of the sample 13 panicles, which were formed at a hornogenizatio ⁇ temperature of about 35 0 C.
  • a comparison, of the sample 13 particles of FlG. 16 with the sample 2 panicles FiG. 1 1 indicates that hom ⁇ genization. temperature may affect particle size. It appears that as the homogenization temperature increases, particle size can also increase.
  • FIGS. 17-20 are scanning electron micrograph images, at 2 Ox magnification, of sample 7 particles, sample 9 particles, sample 10 particles, and sample 1 S particles, respectively.
  • SIBS particles including Rhodamine-B were prepared by a single-emulsion process as follows. ' The R!iodaminc-B was used as a substitute for therapeutic agent, because it was relatively easy to determine whether the Rhodar ⁇ ke-B, a highly visible dye, had been incorporated into the particles. Because Rhodarnine-B is soluble in organic solvents, the Rhodaraine-B m this example was used as an. indicator of whether an organic-soluble therapeutic agent (e.g., pac ⁇ taxel) could be incorporated into the particles.
  • an organic-soluble therapeutic agent e.g., pac ⁇ taxel
  • SiSS-Rhodamine solutions (four percent SlBS w/v) were prepared by dissolving two grams of SIBS ( ⁇ O inoi percent stymie) and different amounts of Rhociamine-B ⁇ 10 milligrams, ! 00 milligrams, 200 milligrams, 300 milligrams, 400 milligrams, 100? ) milligrams) in 50 milliliters of methylene chloride.
  • the SlBS- Rhodami ⁇ e solutions were stirred overnight in a sealed beaker, using a multi-position stirrer (a model PC-171 Corning Scholar 171 stirrer) and stir bars (mode! 14-51 1 -60, from Fisher),
  • PVA solutions (0.2 percent w/v) were prepared by dissolving from 0.2 gram of PVA in 1 (K ) milliliters of distilled water. The PVA solutions were stirred overnight at a temperature of between 35' J C and 4QX using a hot plate (a model PC620 hotplate from Coming).
  • the PVA solutions ( 1 (K ) milliliters) were poured into 100 ⁇ milH!iter beakers and homogenized at IS 0 C and at foil speed (10,000 revolutions per minute), using a FoxverGeu Models 700D homogenizes * (Fisher Scientific). Five milliliters of each SISS-Rhodamine solution were slowly added to each PVA solution using a or.e- mifliliter pipette, and the resulting SIBS-Rhodarnine-PVA mixtures were homogenized for about one hour at ambient temperature, at about 1500 revolutions per miniile.
  • caeh S ⁇ BS-Rhodamine-PVA solution was transferred into a larger beaker and stirred for at least 24 hours at. ambient temperature to allow the methylene chloride to evaporate, using a multi- position .stirrer (a model PC- 171 Coming Scholar 171 .stirrer) and sdr bars (model 14- 511-60. from Fisher),
  • the resulting SIBS-iihodamine particles were filtered through a U, 22 micron filter by vacuum filtration using a vacuum filter (a Milipore 47 mm All Glass Vacuum Filter Holder) and a filter paper of smaller than five microns (a M ⁇ Hpore Filter JViembrane ⁇ .
  • the SIBS-Rhodami «e particles: were lyopbilixcd overaighi using a Vir ' Tis SentryTM lyopliilizer (SP industries, Gardiner, NY), set at a temperature of -50 0 C for the entirety of the iyophiiizatkm.
  • Table 2 shows the SlBS solution concentration, the PVA solution concentration, the SlBS ⁇ Rbodami ⁇ e;PVA volume latio, and the amount of Rhodamms-B used for the different samples of SIBS-Rhodaiiiinc particle*; that were produced according to the above-described method.
  • FIGS 21-26 show sample 14 particles, sample 15 particles, sample 16 particles, sample ) 7 particles, sample 18 particles, and sample 19 particles, respectively.
  • SIBS particles including fluorescein were prepared by a d ⁇ ubk-eraulsiorc process as follows, The fluorescein, another highly visible dye, was used as a substitute for therapeutic agent. Because fluorescein is water-soluble, the fluorescein in this example was used as an indicator of whether a water-soluble therapeutic agent ⁇ e.g., DNA) could be incorporated into the particles.
  • SIBS SIBS
  • the S IBS- fluorescein- PVA emulsion was then added ⁇ U ⁇ 540 milliliters of a 0, 1 percent PVA solution (including PVA and distilled water) and homogenized at 10,000 revolutions per raioute at 25 0 C, for a total of 90 minutes.
  • the resulting SIBS-flxjorescein secondary particles were stirred for about 18 hoars to harden the particles and evaporate the methylene chloride.
  • Example 4 Example 4:
  • Sf BS particles including fluorescein were prepared by a double vortex emulsion process as follows.
  • SIBS 60 moi percent styrene
  • the resulting mixture was then poured into a beaker containing 100 milliliters of a 0.2 percent PVA solution, and stirred for one minute using a multi-position stirrer (a model PCM 71 Corning Scholar 171. stirrer) and stir bars (model 14-51 1-60, from Fisher).
  • a multi-position stirrer a model PCM 71 Corning Scholar 171. stirrer
  • stir bars model 14-51 1-60, from Fisher
  • a particle can include a block copolymer and a bioabsorbabie and/or bioerodible material dispersed uniformly or rsors-uniforaily throughout the block copolymer.
  • the bioabsorbabie and/or bioerodibl ⁇ material can. for example, help to delay and/or moderate therapeutic agent release (mm the particle.
  • the particle can also include one 5 or more other embolic agents, such as a sclerosing agent (e.g., etbanol), a liquid embolic agent (e.g., n-bulyl-cyanoacrykte), and/or a fibrin agent.
  • a sclerosing agent e.g., etbanol
  • a liquid embolic agent e.g., n-bulyl-cyanoacrykte
  • fibrin agent e.g., a fibrin agent.
  • the other embolic agent(s) can enhance the restriction of blood How at a target site.
  • a particle that includes a hydrogel can also include a coating that is formed of a hberodibie and/or
  • a particle can include an interior region thai is formed of a hydrogel and that is coated with a coating including a bioerodibie and/or bioabsorbable material, As another example, a particle can include an interior region that is coated with a hydrogel, and the hydrogel coating can further be coated with a bioerodibie and/or bioabsorbable material. As an additional example, a particle
  • the 15 can include an interior region that is formed of a hydruge ⁇ and that is coated with a block, copolymer, and the block copolymer coating can further be coated with a bioerodibie and/or bioabsorbable material '
  • the presence of the bioerodibie and/or bioabsorbable material in the above particles can, for example, cause a delay in the swelling of the hydrogel.
  • the hydrogel may not begin to swell
  • bioerodibie and/or bioabsorbable material has at least partially or completely eroded and/or been absorbed.
  • a particle does not include any therapeutic agents.
  • a particle can be porous, In certain embodiments,
  • a porous particle can have a substantially uniform pore structure, In some embodiments, a porous particle can have a non-uniform pore structure.
  • the particle can have a substantially non-porous interior region (e.g., formed of a polyvinyl alcohol) and a porous exterior region (e.g., formed of a mixture of a polyvinyl alcohol and alginate).
  • Porous particles are described, for example, in 0 Lanphere et al., U.S. Patent Application Publication No, US 2004/0096662 Al , published on May 20, 2004, which is incorporated herein by reference.
  • a particle can be formed without pores (non-porous particle).
  • a particle ⁇ either porous or non- porous can include ai least one cavity (a hollow central region in the particle).
  • the particle can further include pores in the material surrounding the cavity.
  • FIG, 30 shows a particle 900 with a cavity 902 surrounded by a matrix material 906 (e.g., s piiJymer) that includes pores 904.
  • a particle that includes a block 0 copolymer can a ⁇ so include a shape memory material, which is capable of being configured to remember (e.g., to change to) a predetermined configuration or shape.
  • particles that include a .shape memory material can be selectively transUioned from a first state to a second state.
  • a heating device provided in the .interior of a delivery catheter can be used to cause a particle 5 including a shape memory material to transition from a first state to a second stale.
  • Shape memory materials and particles that include shape memory .materials are described in, for example. Boil et aL U.S. Patent Application Publication No.
  • a particle that includes a block copolymer can also include a surface preferential material.
  • Surface preferential materials are described, for example, in DiCarlo et a)., U.S. Patent Application Publication No. US 2005/0196449 A L published on September S, 2005, and entitled 5 "Embolization 1* , which is incorporated herein by reference.
  • particles can be linked together to form particle chains, for example, the particles can be connected to eaeh otber by links that are formed of one or more of the same materials) as the particles, or of one or more different rnateriai(s) from the particles.
  • Particle chains and methods of making particle chains are described, for example, in Buiser et al, U.S. Patent Application Publication No. US 2005/0238870 Al . published on October 27, 2005, and entitled "Embolization", which is incorporated herein by reference.
  • one or more particles is/arc substantially nonspherical.
  • particles can be mechanically shaped during or after the particle formation process to be nonspberical (e.g., ellipsoidal ⁇ .
  • particles can be shaped (e.g., molded, compressed, punched, and/or agglomerated with other particles) at different points in the particle manufacturing process.
  • the particles can be sufficiently flexible and/or mold able to be shaped.
  • the panicles can be physically deformed into a sped Sc shape and/or size after the particles have been contacted with the gelling agent, but before the polymer(s) in the particles have been cross-linked.
  • the po!yme ⁇ (s ⁇ e.g., polyvinyl alcohol
  • the po!yme ⁇ (s ⁇ e.g., polyvinyl alcohol
  • the po!yme ⁇ (s ⁇ ) in the particles can be cross-linked, optionally followed by substantial removal of gelling precursor (e.g., alginate). While substantially spherical particles have heesi described, in some embodiments, no ⁇ sphe ⁇ ca!
  • no ⁇ spherkal particles can be Conned by post-processing the particles (e.g., by cutting or dicing into other shapes). Particle shaping is described, for example, in Robinson er. a!., U.S. Patent Application Publication No. IJS 2003/0203985 AL published on October 30, 2003, which, is incorporated herein by reference.
  • particles can be used for tissue bulking.
  • the particles can be placed (e.g., injected) into tissue adjacent to a body passageway.
  • the particles can narrow the passageway, thereby- providing bulk and allowing the tissue to constrict the passageway more easily.
  • the particles can be placed in the tissue according to a number of different methods, for example, pere ⁇ ta ⁇ eomly; laparoscopically, and/or through a catheter, ⁇ n certain embodiments, a cavity can be formed in the tissue, and the particles can be placed in (he cavity.
  • Particle tissue bulking can be used to treat, for example, intrinsic sphincteric deficiency (ISD), vesicoureteral reflux, gastroesophageal reflux disease (GERD), and/or vocal cord paralysis (e.g., to restore glottic competence in cases of 5 paralytic dysphoria).
  • particle tissue bulking can be used to treat urinary incontinence and/or fecal incontinence.
  • the particles can be used as a graft material or a tiller to fill and/or to smooth out soft tissue defects, such as for reconstructive or cosmetic applications (e.g.. surgery). Examples of soft tissue defect applications include clef! Lips, scars (e.g., depressed scars from chicken pox or acne
  • particles can be used in an organic solvent
  • the particles may include one or more ferromagnetic materials and may he used to enhance ablation at a target site.
  • Ablation is described, for example, in Rioux et aL, U.S. Patent Application. Publication No, US 2004/0101564 Al , published on May 27, 2004; La.nph.ere et aL U.S. Patent Application Publication No. US 2005/0129775 A l. published on June 16, 2005, and
  • a solution can be added to the nozzle of a drop generator to enhance the porosity of particles produced by the drop
  • Ox am pies of porosity-enhancing solutions include starch, sodium chloride at a relatively high concentration (e.g., more than about 0.9 percent, from about one percent to about five percent, from about one percent to about two percent), and calcium chloride (e.g., at a concentration of at least about 50 mM).
  • sodium chloride at a relatively high concentration (e.g., more than about 0.9 percent, from about one percent to about five percent, from about one percent to about two percent)
  • calcium chloride e.g., at a concentration of at least about 50 mM.
  • calcium chloride can be added to a sodium alginate gelling precursor solution to
  • particles can be formed. using rotor/stator technology (e.g., Folytron* roior/stator technology from Kinmatica hie), high-pressure homogen ⁇ ation (e.g., using an APV-Gauli ⁇ micro tlokfeer or Gaulin homogeuizer), mechanical shear (e.g.. using a Gifford Wood colloid mill), and/or ultrasonification (e.g., using either a probe or a flow-through cell),
  • rotor/stator technology e.g., Folytron* roior/stator technology from Kinmatica hie
  • high-pressure homogen ⁇ ation e.g., using an APV-Gauli ⁇ micro tlokfeer or Gaulin homogeuizer
  • mechanical shear e.g. using a Gifford Wood colloid mill
  • ultrasonification e.g., using either a probe or a flow-through cell
  • particles having different shapes, sizes, physical properties, and/or chemical properties can be used together in an embolization procedure.
  • the different particles can be delivered into the body of a subject in a predetermined sequence or simultaneously, hi certain embodiments, mixtures of different particles can he delivered using a multi-lumen catheter and/or syringe.
  • particles having different, shapes and/or sizes can be capable of interacting synergistieaily (e.g., by engaging or interlocking) to .form a well -packed occlusion, thereby enhancing embolization.

Abstract

Block copolymer particles, and related compositions and methods, are disclosed.

Description

Block Copolymer Particles
TECHN)CAL FiHLD
'The invention relates to block copolymer particles, and to related compositions and methods.
BACKCROiLM)
Agents, such as therapeutic agents, can be delivered systemically, for example, by injection through the vascular system or oral ingestion, or they can be applied directly to a sue where treatment is desired. In some eases, particles are used to deliver a therapeutic agent to a target Site. In the case of delivery of a therapeutic agent, it is oflen desirable that the therapeutic agent be delivered ai desired dosages for an extended period of time.
SUMMARY
In one aspect, the invention features a particle that includes a biocompatible block copolymer with at least one block having a glass transition temperature of at most 37 '-'C and at least one block having a glass transition temperature of greater than 37°C. The pariide has a diameter ofless than about 100 microns, from about 300 microtis to about 500 microns, from about 700 microns to about 900 microns, or from about 1 ,CM)O microns to about 1 ,200 microns.
In another aspect, the invention features a particle that includes a biocompatible block copolymer with at least one block having a glass transition temperature of at most 37''1C and at least one block having a glass transition temperature of greater than 37°C. The particle has a diameter of about 1 ,050 microns or more (e.g., about i ,060 microns or more, about 1 ,070 microns or more, about 1 ,080 microns or more, about 1 ,090 microns or more, about 1 , 100 microns or more). hi an additional aspect, the invention features a particle that includes a block copolymer with the formula X-(AB)fls in which A is a block having a glass transition temperature of at most 370C, B is a block having a glass transition temperature of greater than 37'"Cl π is a positive whole number, and X is an initiator. The particle has a diameter of less than about 100 microns, from about 300 microns to about 500 microns, from about 700 microns to about 900 microns, or from about 1, 000 microns io about !,2(K) microns.
In a further aspect, the invention features a particle that includes a block. copolymer having the formula X-(AB)n, m which A is a block having a glass transition, temperature of at most 37°C, B is a block having a glass transition temperature of greater than 37 C5 n is a positive whole number, and X is an initiator. T lie parlieic has a diameter of about 1 ,050 microns or more (e.g., about 1,060 microns or more, about 1,070 microns or more, about KOSO microns or more, about 1 ,090 microns or more, about 1 , 100 microns or more).
In another aspect, the invention features a particle that has a matrix including a biocompatible block copolymer including at least one block having a glass transition temperature of at most 37"'C and at least one block having a glass transition temperature of greater than 370C. The particle also includes at least one sub-particle (eg., a plurality of sub-particles) that is at least partially disposed within the matrix. The particle has a diameter of about 3,000 microns or less (e.g., fro.ni about two microns to about 3,00O microns, less than about 100 microtis, from about 300 microns to about 500 microns, .from about 700 microns to about 900 microns, from about 1 ,000 microns to about 1 ,200 microns). hi a further aspect, the invention features a particle that includes a matrix including a biocompatible block copolymer having at least one block with a glass transition temperature of at most 37QC and at least one block with a glass transition temperature of greater than TPC. The particle also includes at least, one sub-particle that is at least partially disposed within the matrix. The particle has a diameter of about 1,050 microns or more.
In an additional aspect, the invention features a particle that has a matrix including a biocompatible block copolymer having the formula X-(AB)1x, in which A is a block having a glass transition temperature of at most 37'"C, 8 is a block having a glass transition temperature of greater than 37°C, n is a positive whole number, and X is an initiator, The particle also includes at least one sub-particle that is at least partially disposed within the matrix. The particle has a diameter of about 3,000 microns or less (e.g., from about two microns to about 3,(K)O microns, less than about 100 microns, from about 300 microns to about 500 microns, from about 700 microns to about 900 microns, from about 1 ,000 microns to about 1 ,200 microns).
In a further aspect, the invention features a particle thai includes a matrix. including a biocompatible block copolymer having the formula X-(AB)1,, and at least one sub-parUdε that is at least partially disposed within the matrix. The particle has a diameter of about 1,050 microns or more, and A is a block having a glass transition temperature of at most 37°€, B is a block having a glass transition temperature of greater ϊh&n 3713C. n is a positive whole number, and X is an initiator. In an additional aspect, the invention features a composition including a plurality of particles, at least some of the particles having a diameter of less than about H)O microns, from about 300 microns to about 500 microns, from about 700 microns to about 900 microns, or from about 1 ,000 microns to about 1 ,200 microns. At least some of the particles having a diameter of at less than about 100 microns, rrom about 300 microns to about 500 microns, from about 700 microns to about 900 microns, or irom about 1,000 microns to about 1 ,200 microns include a biocompatible block copolymer including at least one block having a glass transition temperature of at most 370C and at least one block having a glass transition temperature of greater than 37C€. The composition also includes a carrier fluid, the plurality of particles being in the carrier fluid.
In a further aspect, the invention features a composition including a plurality of particles, at least some of the particles having a diameter of about 1 ,050 microns or more (e.g.. about i ,060 microns or more, about 1,070 microns or more, about 1,080 microns or more, about 1 ,090 microns or more, about L! 00 microns or more). At least some of the panicles having a diameter of about 1 ,050 microns or more include a biocompatible block copolymer including at least one block having a glass transition temperature of at most 37QC and at least one block having a glass transition temperature of greater than 370C. 'The composition also includes a carrier fluid, the plurality of particles being in the carrier fluid. In another aspect, the invention features a composition including a plurality of πartieles, at least some of the plurality of particles having a diameter of less than about 100 microns, from about 300 microns to about 500 microns, from about 700 microns to about 900 microns, or from about KOOO microns to about 1 ,200 microns. At least soTTic of the particles having a diameter of less than about 100 microns, from •shout 300 microns to about 50C) microns, from about 700 microns to about 900 microns, or frora about IJ)OO microns to about 1,200 microns include a block copolymer. The block copolymer has the formula X-(AB)n, in which. A is a block having a glass transition temperature of at most 370C, B is a block having a glass transition temperature of greater than 37"C, n is a positive whole number, and X is an initiator. The composition also includes a carrier fluid, the plurality of particles being in the carrier fluid.
In an additional aspect, the invention features a composition including a plurality of particles, at least some of the plurality of particles having a diameter of about 1 ,050 microns or more (e.g., about 1 ,060 microns or more, about ! „070 microns or more, about 1,080 microns or more, about 1 ,090 microns or more, about 1 ,100 microns or more). At least some of the particles having a diameter of about 1,050 microns or .more include a block copolymer. The block copolymer has the formula X- (AB)n, in which A is a block having a glass transition temperature of at most 37'"C, B is a block having a glass transition temperature of greater than 3"αiC, n is a positive whole number, and X is an initiator. The composition also includes a earner -fluid, the plurality of particles being in the carrier fluid,
In a further aspect, the invention features a method of making particles. The method includes contacting an aqueous first solution with a second solution while the aqueous first solution is being mixed (e.g., homogenized), to form a mixture. The second solution includes a solvent, and a biocompatible block copolymer having at least on c block with a glass transition temperature of at most 37°€ and at least one block with a glass transition temperature of greater than 370C, At least .some of the particles have a diameter of about 3,000 microns or less, in another aspect, the invention features a method of making particles. The method includes contacting an aqueous first solution with a second solution while the aqueous first solution is being mixed (e.g., homogenized), to form s mixture. The second solution includes a solvent and a biocompatible block copolymer. The biocompatible block copolymer has the formula X-(AB)n, in which A is a block having a glass transition temperature of at most 370C, B is a block having, a glass transition temperature of greater than 37°C, n is a positive whole number, and X is an initiator. At least some of the particles have a diameter of about 3,000 microns or less.
In an additional aspect, the invention features a method of making particles. The method includes contacting an aqueous first solution with a second solution including a solvent and a biocompatible block copolymer to form a mixture. The biocompatible block copolymer has at least one block with a glass transition temperature of at most 370C and at least one block with a glass transition temperature of greater than 37°C. The method also includes mixing (e.g., homogenizing) the mixture, At least some of die particles have a diameter of about 3,000 microns or less.
Ia another aspect, the invention features a method of making particles. The method includes contacting an aqueous first solution with a second solution including a solvent, and a biocompatible block copolymer, to form a mixture. The method also includes mixing (e.g., homogenizing) the mixture. The biocompatible block copolymer has the formula X-(AB)n, in which A is a block having a glass transition temperature of at most 3?°C, B is a block having a glass transition, temperature of greater than 37°C, ft is a positive whole number, and X is an initiator. At leasi some of the panicles have a diameter of about 3,000 microns or icss.
In an. additional aspect, the invention features a method of making particles. The method includes contacting an aqueous first solution with a second solution including a solvent and a biocompatible block copolymer, to form a mixture. The biocompatible block copolymer has at least one block with a glass transition temperature of at most 3"10C and at least one block with a glass transition temperature of greater than 370C. At least some of the particles include a first therapeutic agent that is dispersed throughout the particles, and at least some of the particles have a diameter of about 3,000 microns or less. In a further aspect, the invention features a method of making particles. The method includes contacting an aqueous first solution with a second solution including a solvent and a biocompatible block copolymer, to form a mixture. The biocompatible Mock copolymer has the formula X-(AB)n, in which A is a block having a glass transition temperature of at most 37"C5 B is a block having a glass transition temperature of greater than 3?°C, n is a positive whole number, and X is an initiator. Al. least, some of the particles include a first therapeutic agent that is dispersed throughout the particles, and at least some of the particles have & diameter of about 3,000 microns or less. ϊn an additional aspect, the invention features a method including administering to a patient a therapeutically effective amount of a composition including particles. At least some of the particles have a diameter of leas than about K)O microns, rrom about 30(J microns to about 500 microns, from about 700 microns to about 900 microns, or From about i ,000 microns to about 1 ,200 microns. At least some of the particles having a diameter of less than about 100 microns, from about 300 microns to about 500 microns, from about 700 microns to about 90?) microns, or from about 1 ,000 microns to about 1 ,200 microns include a block copolymer having at least one block with a glass transition temperature of at most 37°€ and at least one block with a glass transition temperature of greater than 371Xl
In another aspect, the invention features a method including administering to a patiem a therapeutically effective amount of a composition including particles, Ai least, some of the particles have a diameter of about ! ,050 microns or more (e.g. , about 1,060 microns or .more, about 1 ,070 microns or more, about 1,080 microns or more, about 1.090 microns or .more, about LlOO microns or more). At least some of the particles having a diameter of about 1 ,050 microns or more include a block copolymer having at least one block with a glass transition temperature of at most 37°C and at least one block with a glass transition temperature of greater than 37"C. in a further aspect, the invention features a method including administering to a patient a therapeutically effective amount of a composition including particles. At least some ofthe particles have a diameter of less than about 100 microns, irora about 300 miercms to about 500 microns, from about 700 microns to about 900 microns, or from about 1 ,000 microns to about 1 ,200 microns. At least some of the particles having a diameter of less than about 100 microns, from about 300 microns to about SCO microns, from about 700 microns to about 900 microns, or from about 1 ,000 microns to about 1 ,200 microns include a block copolymer having the fbrmuk X- (AB)!f, hi which A is a block having a glass transition temperature of at most 370C, B is a block having a glass transition temperature of greater than 37°C. rs is a positive whole number, and X is an iniύaior.
In a further aspect, the invention features a method Including administering to Ά patient a therapeutically effective amount of a composition including particles. At least some of the particles 'have a diameter of about 1 ,050 microns or more (e.g., about 1 ,060 microns or more, about 1,070 microns or more, about 1 ,0B0 microns or more, about \ ,090 microns or more, about 1 ,100 microns or more). At least some of the particles having a diameter of about 1,050 microtis or more include a block copolymer having the formula X-(AB)n, in which A is a block having a glass transition temperature of at most 37°C, B is a block having a glass transition temperature of greater than 370C. n is a positive whole number, and X is an initiator. Embodiments can also include one or more of the following.
In some embodiments, the block copolymer can be biocompatible. "In certain embodiments, n block having a glass transition temperature of at most 37"-"C cars be a polyolefm block, hi sonic embodiments, a block having a glass transition temperature of at most 370C can include at least one isobυtyleae monomer, In certain embodiments, a block having a glass transition temperature of greater than 3?''C can be a vinyl aromatic block or a methaerykte block. In some embodiments, a block having a glass transition temperature of greater than 37"C can include Ά\ least one monomer selected from styrene, u-methylsiyrene, ami combinations thereof. In certain embodiments, the block copolymer can have the formula X-(AB)11, in which n is a positive number and X is an initiator, hi some embodiments, A can be a block having a glass transition temperature of at most 370C, and/or can be a polyolefm block, hi certain embodiments, B can be a block having a glass transition temperature of greater than 3?°€, and/or can be a vinyl aromatic block or a methacrvlaie block. In .some embodiments, the block copolymer can have the formula BAB or ABA, in which A is a block having a glass transition temperature of at most 37CC and B is a block having a glass transition temperature of greater than 37*C. In certain embodiments, the block copolymer can have the formula has the formula B(AB), or A(BA X-., in which A is a block having a glass transition temperature of at most 37°C. B is a block having a glass transition temperature of greater than 370C5 and n is a positive whole number. in certain embodiments, A can be a polyoiefin block (e.g., a polyoleiki block {hat includes at least one isobutylene monomer), In some embodiments, B can be a vinyl aromatic block or a methacrylaie block, hi certain embodiments, B can include at least one monomer selected from methylmethacrylate, ethylmεihaerylate, hydroxyelhyl methacrylate, and combinations thereof. Is some embodiments, the polyolefjH block can include at least one isobutylene monomer and/or the vinyl aromatic block can include at least, one monomer selected from siyrene. a- methylstyreπe, and combinations thereof, In certain embodiments, A can have the formula (CRR' -CHb)5* > in which R and R' are linear or branched aliphatic groups or cyclic aliphatic groups, and B can be a nielhacrylate block or a vinyl aromatic block. in some embodiments, the block copolymer can include from about 45 mol percent to about 95 mol percent of pαlyo) efm blocks,
In certain embodiments, the block copolymer can have a molecular weight of more ihan about 40,000 Daϊtons (e.g., from about 80,000 Daltons to about 300,OtM) Dslions). In some embodiments, the block copolymer can include poiyolefiπ blocks having a molecular weight (e.g., a combined molecular weight) of from about 60,000 Daltons to about 200.000 Daltons and vinyl aromatic blocks having a molecular weight (e.g., a combined .molecular weigh!) of from about 20,000 Daltons to about 100,0(K) Daltons.
In certain embodiments, the particle can have a diameter of less than about KM) microns. In some embodiments, the particle can have a diameter of from about 300 microns to about 500 microns, from about 700 microns to about 900 microns, or irom about KOOO .microns to about 1,200 microns. In certain embodiments, the particle can have a diameter of about K050 microns or more (e,g,? ! ,060 nneroriS or more, 1 ,070 microns or more, 1 t0S0 microns or more, 1 ,090 microns or more, ! , 1 (K) microns or more, ! ,150 microns or more), hi some embodiments, the particle can have a diameter of about 3,000 microns or less (e.g., from about two microns to about 3.000 microns).
In some embodiments, the particle (e.g., the block copolymer) can include a therapeutic agent (e.g., from about 0.1 weight percent to about 70 weight percent of a therapeutic agent). In certain embodiments, the therapeutic agent can be dispersed throughout the particle, ia some embodiments, the particle can include at least two therapeutic agents that are different from each other. hi certain embodiments, the particle can further include at least one other polymer (e.g., in a blend with the block copolymer). The other polymer can also be a copolymer (e.g., a block copolymer), or can be a homopolymer. In some embodiments, the other polymer can he a polyvinyl alcohol, a polyaerylic acid, a poiymeth&crykc acid, a poly vinyl sulfonate, a carboxymeihyl cellulose, a hydroxyethyl cellulose, a substituted cellulose, a polyacrylamidc, a polyethylene glycol, a poh-arrύde, a poly urea, a polyurethane, a polyester, a polyeslter, a polystyrene, a polysaccharide, a polylactic acid, a polyethylene, a polymethylmethacrylate, a polycaprolactone, a poSyglycolic acid, & pofyflaetic-co- glycolic) acid, or a styrenc maleic anhydride copolymer, hi certain embodiments, combinations of two or more of these polymers can be used, hi some embodiments, the particle can further include a biαahsorbable material, !n certain embodiments, the particle can further include a hydrogel (e.g.. poiyacrylamκie co-acrylic acid). The hydrogel may be cross-linked or may not be cross-linked, hi some such embodiments, the block copolymer can form a coating over the hydrogel, and/or the hydrogel can form a coating over the block copolymer. In some embodiments, the block, copolymer can form a coating on the particle. In certain embodiments, the carrier fluid can include a saline solution and/or a contrast agent. hi some embodiments, the method can include forming a suspension from the mixture ami contacting the suspension with an aqueous third solution hi certain embodiments, the aqueous first solution cars be mixed at a speed of d l most about 10,000 revolutions per minute (e.g., at most about 5,000 revolutions per minute, at most about 1 ,500 revolutions per minute). In some embodiments, the method can include mixing the mixture at a speed of at most about !O5C1OO revolutions per minute (e.g., at most about 6,000 revolutions per minute), and/or at less! about 1 ,000 revolutions per minute. In certain embodiments, the method can include mixing the mixture at a temperature of at least about 3O0C (e.g.. at least about 35GC).
In some embodiments, the aqueous first solution and/or the second solution can include a therapeutic agent. hi certain embodiments, the method of administration can be by percutaneous injection. Lrs some embodiments, the composition can be used to treat a cancer condition, (e.g., ovarian cancer, colorectal cancer, thyroid cancer, gastrointestinal cancer, breast cancer, prostate cancer, lung cancer). The method can include embolking a lumen of a subject (e g., a lumen that is associated with a cancer condition).
HmbodimeMs can include one or more of the following advantages. The panicles can be relatively durable and/or flexible, and thus can be unlikely to be damaged during storage, delivery, or use. In some embodiments (e. g., embodiments in which the particles are formed of styrene-isobutyiene-slyrene}, the particles can have a relatively high mechanical integrity (e.g., such that contact with the walls of a catheter will not harm the particles). \n certain embodiments (eg,, embodiments in which the particles are formed of styrene-isobutyiene-styrene), the particles can be relatively flexible, and thus can be adapted tor use in many different environments. Ln some embodiments in which the particles are relatively flexible, the particles can include a swellable material (e.g., a hydrogel), such that the particles can he delivered to a target site while the panicles are in a relatively compressed state, and can ialer expand at the target site as a result of swelling of the swdlable material (e.g., to enhance occlusion). In such embodiments, the particles can have good delivcrabϋily, while also being effective in occluding the target site. The particles can be used to deliver one or more therapeutic agents to a target site effectively and efficiently; and/or to occlude the target site. In some embodiments, the particles can be used to deliver a raetered dose of a therapeutic agent to a target site over a period of time. In certain embodiments, the release of a therapeutic agent from the particles can be delayed until the partieles have .reached a target site. For example, the partieles can include a bioerodible coating thai erodes during delivery, such that when the particles reach the target site, they cars begin to release the therapeutic agent.
The particles can be used to deliver multiple therapeutic agents, either to the same target site, or to different target sites. For example, the particles can deliver one type of therapeutic agent (e.g., an antiinflammatory) as the particles are being delivered to a target site, and another type of therapeutic agent (e.g.. a chemotherapeutie agent) once the particles have reached the target site.
Features am! advantages are in the description, drawings, and claims.
DESCRIPTION OF DRAWINGS
FIG. 1 is a side view of an embodiment of a particle. Fl(I 2 A is a schematic illustrating an embodiment of injection of a composition including particles into a vessel.
FlG 28 is a greatly enlarged view of region 2B in Pl(I 2A, FlG 3 is a cross-sectional view of an embodiment of a particle, FiG. 4 is a cross-sectional view of an embodiment of a particle. FKi 5 is a cross-sectional view of an embodiment of α particle.
FIGS, 6A-6C are an illustration of an embodiment of a system and rnethud for produci ng particles.
FIG 7 is an illustration of an embodiment of a drop generator. FKJS, 8A and 813 are an illustration of an embodiment of a system and method for producing particles.
FIGS. 9Λ4)F are an illustration of an embodiment of a system for producing particles.
FIG 10 is a scanning electron micrograph (SEM) image of styxene- i sob uty j cne- styrene particl es . PIG. I i is an SEM. image of styreπe-isαbiityiene-styrene particles, FlG 12 is an SEM image of styrcne-isohulylexie-styrcne particles.
FIG 13 is an SKM image of styrene-isobutylene-styrene particles.
FIG 14 is an SEM image of styrene-isobutylεne-styrene particles.
FIG. 15 is an SEM image of styreπe-isobυtylene-styreαe particles. FIG 16 is an SEM image of styrene-isoirutylene-styrene particles.
FIG 17 is an SEM image of styrene-isobutylene-styrene particles.
FIG I S is an SEM image of styrene-isobutylene-styrene particles.
FlG 1Λ1 is ao SEM image of styreπe-isobutylene-styrene particles.
FlG. 20 is an SBM image of siyreαe-isobutylette-styreue particles, FICs. 2 \ is an SE:M image of Rhod amine- loaded styrene-isobutyleπe-styrene particles ,
FKl 22 is an SEM image of Rhodamine-ioaded styrenc-isobutySene-styrene particles.
FIG 23 is cm SEM image of Rhodamme-loaded shrene-isobuiylerie-styrene particles.
FlG 24 is an SEM image of Rhodamioe-loaded styrene-isobutylene-st>τene panicles.
FlG 25 is an SEM image of Rhodaπtme-loaded styrene-isobiuylene-slyrene particles. MG 26 is an SEM image of Riiodaraine-kiaded .styfene-isobυtyleπe-si>τeπe particles.
HG 27 is an SEM image of iluorescein-loaded .styrene-isobuty!ene-slyτene particles,
FKJ. 28 is an SIBM image of fluoreseein-loaded styrene-isobαlylene-atyreπc particles.
FIG 29 is an SEM image of fluorescein-ioaded styreαe-isobutylene-.styrcτie particles,
FIG 30 is a cross-seetionaϊ view of an embodiment of a particle. DETAIL ED DESCRIPTION
FIG. I shows a particle 100 that can be used to deliver one or more therapeutic agents {e.g., drugs) to a targe! site within the body. The therapeutic agents can be included o.n particle 100 and/or within panicle 100 (e.g., dispersed throughout particle 100), Particle 100 is formed of a block copolymer that includes a first block having a glass transition temperature (Tg) of at most 37°C and a second block having a glass transition temperature of greater than 370C.
Slock copolymers are copolymers that contain two or more differing polymer blocks selected, for example, from homopoϊymer blocks, copolymer blocks (e.g., random copolymer blocks, statistical copolymer blocks, gradient copolymer blocks, periodic copolymer blocks), and combinations of homopolyraer and copolymer blocks, A polymer "block" refers to a grouping of multiple copies of a single type (homopolymer block) or multiple types (copolymer block) of constitutional units, A "'chain'1 is an uπbranched polymer block. In some embodiments, a polymer block can be a grouping of at least two (e.g., at least five, at least 10, at least 20, ai least 50, at least HK). ai least 250, at least 500, at least 750} and/or at most 1000 (e.g., at mast 750, at most 500, at most 250, ai most 100, at most 50, at most 20, at most KL at most five) copies of a single type or multiple types of constitutional units. A polymer block may take on any of a number of different architectures. In some embodiments, the block copolymer in particle 100 can include a central block having a glass transition temperature of at most 370C and end blocks each having a glass transition temperature of greater than 370C. (n certain embodiments, the block copolymer can have one of the following general structures: (a) BAB or ABA (linear triblock), Cb) B(AS)n or A{ BA)n (linear alternating block), or
(e) X- — (AB)n or X (BA)n (includes dibiock, tribloek and other radial block copolymers), where A is a block having a glass transition temperature of a. most 379C, B is a block having a glass transition temperature of greater than 37XL π is a positive svhole number aad X is an initiator (e.g., a monofuπcrjonal initiator, a multifunctional initiator). The X — (AB)11 structures are frequently referred to as diblock copolymers (when n:~ \ ) or tπbkϋck copolymers (when rv~2). (This terminology disregards the presence of the initiator, for example, treating A — X- — A as a single A block with the Ui block therefore denoted as BAB.) Where iv-3 or more, these structures are 5 commonly referred to as star-shaped block copolymers.
As described above, the A blocks have a glass transition temperature of at most 370C. hi some embodiments, the A blocks can have a glass transition temperature of at most about 3O0C (e.g., at most about 25°C, at most about 200C, at most about I 0';C, at most about 00C, at most about -H)0C;, at most about -2O0C, at 10 most about -30'3C, at most about -5O0C5 at most about
~?()f'C, st most about -900C). As referred to herein, the glass transition temperature of a material (e.g., a polymer block) is determined according to ASTM E l 356, Examples of blocks having a glass transition temperature of at most 37QC when the blocks are in the dry state (e.g., in powder form) include blocks including at. least one i:> of the following monomers;
{ I) acrylic monomers including:
(a) alky? acrylates, such as methyl acryiate, ethyl acrylate, propyl acrylate, isopropyl aery! ale (e.g., isotactic isopropyϊ aerylaie), butyl acrylate, sec -butyl acrylate, isobittyl acrylate, cyclohesyl
20 acrylate, 2~etbylhexyl acrylate, dodecyl aery I ale and liexadecyi acrylate,
(b) aryialky! acrylatcs, such as benzyl acrylate,
(C) alkoxyalkyl acrylatcs, such as 2-etboxyeihyl acrylate and 2- raethoxyeihyl acrylatc, 25 (d) haJo-alkyl acrylates, such as 2,2,2-trifiuoroctbyl acrylate, and
(e) cyano-aikyi acrylates, such as 2-cyanαethyi acrylate; (2) methaeryik mrmoraers including:
(a) alky! methacrylates, such as butyl methacrylate, hex>l metbacrylate, 2-ethylhexyl methacrylate. octyl methacrylate,
30 dodecyl metbacrylate, hexadecy! methacrylate and octadecyi methacrylale, and (b) ammoallcyl methacrylaf.es, such as diethylaminoethyi methacrylate and 2~tert-buty[~amiiioethyl methacrylate;
(3) vinyl ether monomers including;
(a) alky! vinyl ethers, such as methyl vinyl ether, ethyl vinyl elher, P?<ψy5 vinyl ether, butyl vinyl ether, isobutyi vinyl ether, 2- ethyihexyl vinyl, ether and dodccyi vinyl ether;
(4) cyclic ether monomers, such as tetrahydrofuran, tri methylene sjxide, ethylene oxide, propylene oxide, methyl glyeklyl ether, butyl glycidyl ether, ally! glycidyl ether, epibromohydrm, epichlorohydrin, 12~ cpαxybutane, 1 ,2-e-poxyoetane, and 1 ,2-epoxydecaBe;
{5} ester nionomers (other than acrylates and methacrylates), such as ethylene makmate, vinyl acetate, and vinyl propionate; (6) alkcnc monomers, such as ethylene, propylene, isobiϊtylεne, I -butene, trans-butadiene, 4-methy! pentene, 1 -octeαe and other α-oiεfsns, cisisoprenc, and traiis-isoprene;
(?) halogcnated alket>e monomers, such as vinylidene chloride, vinyiidene
Huoride, eis-chiorobiitadiene, and trans-ehlorobutadiene; (Sj siϊoxane monomers, such as dimethylsiloxane, di.ethylsiioxane, metliyiethylsϋoxaiw, metliylphenyisiiυxant;, ajid dipheπylsiloxane; and {9} maleie monomers, such as maϊeie anhydride.
In certain embodiments, the A blocks can include one or more derivatives of the above monomers.
In some embodiments, the A blocks can he based upon one or more poiyokfhis. hi certain embodiments, the A blocks can be poiyoiefinic blocks having alternating quaternary and secondary carbons of the general formulation; — (CRR'-
CHi)if > where R and R* are linear or branched aliphatic groups (e.g., methyl, ethyl propyl, isopropyl, butyl, isobutyi) or cyclic ahphatie groups (e.g., cyclohexane, cydopeπtane), with and without pendant groups. For example, the A blocks can be polyoidmie blocks having the above formula, in which R and R' ai-e the same. As an example, the A blocks can be based on isohistylene:
S 5
Figure imgf000017_0001
(i.e., in which E and Rf are both methyl groups), hi some embodiments, the block copolymer can include at least about 40 mol percent (e.g., from about 45 mo! percent to about 95 mol percent) of polyolefπs blocks.
As described above, the B blocks have a glass transition temperature of greater thars 370C. in some embodiments, the B blocks cars have a glass transition temperature of at least about 4O0C (e.g., at least about 50''C, at least about 7(FC, at least about 9(PC, at least about 100ϋC, at least about 12O0C). Examples of blocks having a glass transition temperature of greater than 37°C when the blocks are in the dry state (e.g., in powder form) include blocks including at least one of ώe following monomers.
( I) vinyl aromatic monomers including:
(u) unsubstituted vinyl aromaties, such as atactic styrene, isotaciie styrene and 2 - vinyl rsaph thai m e,
(b) vinyl-substituted aromaties, such as α-melhy! styrene, ami
(c) ring-substituted vinyl aromaties including ring-alky! at ed vinyl aromaties (e.g., 3-τnethylstyrene, 4-methyIsiyrene, 2,4- dimethylstyrene,
Figure imgf000017_0002
3,5-dimethylstyrene, 2,4,6-trimethylstyτeae, 4-tert-butyl styrene), ring-alkoxylated vinyl aromaties (e.g., 4-meϋiϋxystyrεne, 4-etlioxystyτene,), ring-habgenated vinyl aromaties (e.g., 2-chiorostyre∞, 3- chlorostyrene, 4-chlorostyrene, 2,6-dichSorostyrene. 4- bromostyrene, 4-fluorostyrenc), ring-ester-substituted vinyl aromaties (e.g.,
4-acetoxystyrene), and hydmxy! styrene;
i f? (2) other vinyl monomers including;
(a) vinyl esters such as vinyl benzoate. vinyl 4-tert-butyi benzoate, vinyl eyelohexanoate, vinyl pivaiate, vinyl triflυoroacetate, vinyl buiyral,
5 (b) vinyl amines such as 2-vinyl pyridine, 4-vinyl pyridine, and vinyl carbazole,
(c) vuvy-1 halides such as vinyl chloride and vinyl fluoride,
(d) alkyl vinyl ethers such as tert-bulyl vinyl ether and cydchexyl vinyl ether, and iθ (e) other vinyl compounds such as vinyl ferrocene;
(3) other aromatic monomers including aeenaphthalene and i∑κkne;
(4) methacryiic monomers including:
(a) iTϊethacrylic acid anhydride,
(b) niethacrylic acid esters (methacryiates) including
15 (i) alkyl niethacrylaies such as atactic methyl mcthaαyktc, syndiotactic methyl methacrviate, ethyl methacryiate, iaopropvi methacrylate, isobutyi meihacrylatε, t-buiyl methacrylate and cyclohexy! methacrylate, (ii) aromatic methacrylates such as phenyl methacrylate and 20 including aromatic alkyl melhacrytates such as benzyl methaerylale, (Ii i) hydroxyalkyl mcthacr>'Iates such as 2-hydroxyethyi methacrylate and 2-hydroxypropvi methacrylate, (iv) additional nidhaerylates including isobornyi S methacrylate and trimethylsily! methacrylate, and
(c) other methacry lie-acid derivatives including inethacrylunitrile;
(5) acrylic monomers including:
(a) certain acrylic acid esters such as tert-butyi aerylatε, hexyi acrylate and isobornyl acrylatc, 30 (b) other acrylic-acid derivatives including aeryioniirϊie; and (6) silicate monomers including polyhedral oligoraerie sϋsesquioxane (POSS) monomers, in certain embodiments, the B blocks can include one or more derivatives of the above monomers.
In ceriam cmbodirncnis, the B blocks can be polymers of rrsεthaeryiates or polymers of vinyl aroroatks. In some embodiments, the B blocks can be either; (a) made from monomers of styrersc
Figure imgf000019_0001
or stymie derivatives {e.g., α-methyistyrene, πng-alkyiated styrenes or riπg- halogenated styrenes) or mixtures thereof, or (b) made from monomers of metbyimethaervlate, ethylmethacrylate, hydroxyethyl rnethaerylatε, or mixtures thereof.
In some embodiments, the block copolymer can include at least about five mo! percent (e.g., at least about 30 mo! percent, about 60 mo! percent) of styretie blocks. An example of one of the above copolymers is styrene-isobutylene-styxene
("SiBS"), in which the A blocks arc based on isoburylene. and the B blocks are based on slyrenc. Another example of one of the above copolymers is styrene maleie anhydride ("SMA"). irs which the A blocks arc based on maielc anhydride and die B blocks are based on styrene, Typically; the combined molecular weight of the block copolymer can be more lhan about 40,0(K) Daltoπs {e.g., more than about 60,(K)O Daltons), For example, the combined molecular weight of the block copolymer can be from about SO1GOO Daltons to about 300,000 Daltons (e.g., from about 90J)OO Daltons to about 300,000 DaitOBs). In some embodiments (e.g., embodiments in which the A blocks are polyosciivϊ blocks), the combined molecular weight of the A blocks can be from about 60,00*') Daltons to about 2.00,000 Daltons. In certain embodiments (e.g., embodiments in which the B blocks are vinyl aromatic blocks), the combined molecular weight of the B blocks can be from about 20,000 Daltons to about 100.000 Daltons.
Generally, the properties of the block, copolymer used in panicle 100 can depend upon the lengths of the A block chains and B block chains m the block copolymer, and/or on the .relative amounts of A block and B blocks hi the block copolymer,
As an example, in some embodiments, blocks with a glass transition temperature of at most 37'1C may be elastomeric. in such embodiments, the elastomers c properties of the block copolymer can depend on the length of the A block chains. In certain embodiments, the A block chains can have a weight average molecular weight of from about 2,000 Dailoπs to about 30,000 Dal ions, in such CnIHiJdIo-SeBtS. the block copolymer (and, therefore, particle 100) may be relatively inelastic. In some embodiments, the A block chains can have a weight average molecular weight of at least about 40.000 Daltoπs. In such embodiments, the block copolymer (and, therefore, particle 300) may be relatively soft and/or rubbery.
As another e&ainpta, in certain embodiments, blocks with a glass transition temperature of greater than 37'5C may be relatively hard at 370C. In such embodiments, the hardness of the block copolymer at 37"1C can depend on the relative amount of B blocks in the block copolymer. In some embodiments, the block copolymer can have a hardness of from about Shore 2OA to about. Shore 75D (e.g., from about Shore 4OA to about Shore 90A). In certain embodiments, a copolymer with a desired degree of hardness may be formed by varying the proportions of the A and B blocks in the copolymer, with a lower relative proportion of B blocks resulting in a copolymer of lower hardness, and a higher relative proportion of B blocks resulting in a copolymer of higher hardness. As a specific example, high molecular weight (i.e., greater than 100,000 Daltons) polyisobutyiene is a relatively soft and gummy material with a Shore hardness of approximately K)A, By comparison, polystyrene is much harder, typically having a Shore hardness on the order of IGOD. As a .result, when blocks of polyisobutyiene and styrene are combined, the resulting copolymer can have a range of hardnesses from as soft as Shore I OA to as hard as Shore KX)I), depending upon the relative amounts of polystyrene and polyisobuiylene in the copolymer. In some embodiments, from about two mo! percent to about 25 mol percent (e.g., from about five mol percent to about 20 mol percent) of polystyrene can he used to form a block copolymer with a hardness of from about Shore 30A to about Shore 9OA (e.g., from about Shore 35A to about Shore 70A). i9 PoSydispersity (the ratio of weight average molecular vveiglii to number average molecular weight} gives an indication of the molecular weight distribution of the copolymer, with values significantly greater than four indicating a broad molecular weight distribution. When all molecules within a sample are the same size, the polydispersity has a value of one. Typically, copolymers used in particle 100 can Siavc a relatively tight molecular weight distribution, with a polydispersity of from about 1 , 1 to about 1.7.
Lo soπi ε embodiments, one or more of the above-described copolymers can have a relatively high tensile strength. For example, trihiock copolymers of polystyrene-polyisobuiyϊcπe-polystyrene can have a tensile strength of at bast about 2,000 psi (e.g., from about 2,000 psl to about 4,000 psi).
In certain embodiments, one or more of the above-described copolymers can be relatively resistant to cracking and/or other tonus of degradation under in vivo conditions. Additionally or alternatively, one or more of the above-described polymers can exhibit excellent bioconipatibiSrty, including vascular compatibility. For example, the polymers can provoke minimal adverse tissue reactions, resulting in reduced polymorphonuclear leukocyte and reduced macrophage activity. In some embodiments, one or more of the above-described polymers can generally be hemoeompaiible, and can thereby minimize thrombotic occlusion of, lor example. small vessels.
The above-described block copolymers can be made using any appropriate method known in the art. Irs some embodiments, the block copolymers can be made by a carboeatioπie polymerization process that includes an initial polymerization of a monomer or mixtures of monomers to form the A blocks, followed by the subsequent addition of a monomer or a mixture of monomers capable of forming the B blocks. Such polynieπzatiorj reactions are described, for example., in Kennedy et &!., U.S. Patent "No. 4,276,394; Kennedy, U.S. Patent No. 4,316,9/3; Kennedy, 45342,849, Kennedy et a]., U.S. Patent No.4,910,321 ; Kennedy et aL, U.S. Patent No. 4,929,683; Kennedy d &!„ U.S. Patent No. 4,946,899: Kennedy et a!., U.S. Patent No, 5,066,730; Kennedy et ah, U.S. Patau No. 5,122,572; and Kennedy et δl, U.S. Patent No. Re. 34.64(L Bach of these patents is incorporated herein by reference, The techniques disclosed in these patents generally involve an "initiator", which can be used to create X- — (AB)n strue-ures, where X is the initiator, and n can be 1. 2, 3 or more. The initiator can be monofunctional or multifunctional. As noted above, the resulting molecules are referred to as diblock copolymers where n is 1, lrihtoek copolymers (disregarding the presence of the initiator) where n is 2, and star- shaped block copolymers where rs is 3 or more.
(n general, the polymerisation reaction can be conducted under conditions that minimize or avoid chain transfer and termination of the growing polymer chains. Steps can be takers to keep active hydrogen atoms (water, alcohoi and the like) to a minimum. "Hie temperature for the polymerization is usually from about -10';C to about -WC (e.g., from about -6(FC to about -8(FC), although lower temperatures can be used.
Typically, one or more A blocks (e.g., polyisobutylene blocks) can he formed in a first step, followed by the addition of B blocks (e.g., polystyrene blocks) at the ends of the A blocks. More particularly, the first polymerization step is genera) Iy carried out in an appropriate solvent system, such as a mixture of polar and non-polar solvents (e.g., methyl chloride and hexarses). The reaction bath can contain the aforementioned solvent system, olefin monomer (e.g., isobiitykne), an initiator (e.g., a tεrt -ester, tort- ether, ten-hydroxyl or fert-halogen containing compound, a eumy! ester of a hydrocarbon acid, an alky! curnyl ether, a eumyl haiide, a eumyl hydroxy) compound, or a hindered version of the above), and a eoinitiator (e.g.. a Lewis acid, such as boron trichloride or titanium tetrachloride). In some embodiments, electron pair donors (e.g., dimethyl acetamkie, dimethyl sulfoxide, dimethyl phthalate) can be added to the solvent system. Additionally, proton-scavengers that scavenge water, such as 2,6-di-tert-butyIpyridine, 4~methy!-2,6-di-tert-buty)pyridiπe, I ,S- bis(dimcthyknijno)-naphtha)enε. or diisopropyl ethyl amine can be added.
The reaction is commenced by removing the tert-ester. tert-ether, iert -hydroxy) or tert-halogeo (herein called the "tert-leavmg groups") from the initiator by reacting the initiator with the Lewis acid, in place of the tert-Ie&ving groups is a quasi-stable or "living" cation which is stabilized by the surrounding tertiary carbons, as well as the polar solvent system and electron pair donors. After obtaining the cation, die A block monomer (e.g., isobutylene) is introduced, and cationicaliy propagates or polymerizes from each cation on the initiator. When the A black is polymerized, the propagated cations remain on the ends of the A blocks. The B block monomer (e.g., stymie) is then introduced, and polymerizes and propagates from the ends of the A block. On ce the B blocks are polymerized, the reaction is terminated by adding a termination molecule such as methanol, water and the like.
Product molecular weights are generally determined by reaction time, reaction temperature, the nature and concentration of the re&ctants, and so forth. Consequently, different reaction conditions may produce different products, in general, synthesis of the desired reaction product is achieved by an iterative process in which the course of the reaction is monitored by the examination of samples taken periodically during the reaction a technique widely employed in the art. To achieve the desired product, an additional reaction may be required in which reaction ύιn<i and temperature, reactant concentration, and so forth are changed. Additional details regarding cationic processes for making copolymers are found, for example, in Kennedy et a!.. U.S. Patent No. 4,276,394; Kennedy, U.S. Patent Na. 4,316,973; Kennedy, 4S342,&49; Kennedy ct al, U.S. Patent No. 4,91(5,321 ; fCermedy et al., U.S. Patent No. 4,929.683; Kennedy et at, U S, Patent No. 4,946.899; Kennedy et al, U.S. Patent No. 5,066,730; Kennedy et at U.S. Patent No. 5 J 22,572; and Kennedy et aL U.S. Patent No. Re. 34,640, incorporated supra.
The block copolymer may be recovered from the reaction mixture by any of the usual techniques including evaporation of solvent, precipitation wife a non-solvent such as an alcohol or alcohol/acetone mixture, followed by drying, and so forth, in addition, purification of the copolymer can be performed by sequential extraction in aqueous media, both with and without the presence of various alcohols, ethers and ketones.
In some embodiments, particle 100 can be formed of a block copolymer that includes one or more functional groups. The functional groups can be negatively charged or positively charged, and/or can be ionically bonded to the polymer. In some embodiments, the functional groups can enhance the biocompatibility of the polymer. Alternatively or additionally, the functional groups can enhance the clot-
12 forming capabilities of the polymer. Examples of functional groups include phosphate groups, carhoxyhte groups, sulfonate groups, sulfate groups, phosphorate groups, and phenolate groups. For example, a polytner can be a sulfonated styrenic polymer, such as sulfonated SOiJS. Sulfoustion of styrene block copolymers is disclosed, for example, in Ehrenherg, et al, U.S. Patent No. 5,468.574; Vacboa et aL, U.S. Patent No. 6,306,419; and Beriowilz-Tarrant, et at, U.S. Patent No. 5,840,387, all of which are incorporated herein by reference. Examples of other functlonalized polymers include- phospbated SlSS and carboxylaied SiBS. In certain embodiments, a polymer ears include more than one different type of functional group. For example, a polymer can include both a sulfonate group and a phosphate group, hi some embodiments, a polymer that includes a functional group can be reacted with a cross- linking and/or gelling agent during particle formation. For example, a particle that includes a sulfonates group, such as sulfonated Sf BS, may be reacted with a cross- linking and/or gelling agent such as calcium chloride, Functional teed polymers and cross-Unking and/or gelling agents are described, for example, m Richard et aL, U.S. Paient Application Serial No. 10/927,868, filed on August 27, 2004, and entitled 'Εmhcsh/.atiorT, which is incorporated herein by reference.
As described above, particle 100 can be used to deliver one or more therapeutic agents to a target site. Therapeutic agents include genetic therapeutic agents, non-genetic therapeutic agents, and cells, and can he negatively charged, positively charged, amphoteric, or neutral. Therapeutic agents can be, for example, materials that are biologically active to treat physiological conditions; pharmaceutically active compounds; proteins; gene therapies; nucleic acids with and without carrier vectors f eg,, recombinant nucleic acids, DNA (e.g., naked DNA), cDNA, RNA, genomic DNA, cDNA or RNA in a non-infectious vector or in a viral vector which may have attached peptide targeting sequences, antisense nucleic acids (RNA, DNA)); oligonucleotides; gene/vector systems (e.g,, anything that allows for the uptake and expression of nucleic acids); DNA chimeras (e.g., DNA chimeras which include gene sequences and encoding for ferry proteins such as membrane translocating sequences ('1MTS") and herpes simplex virus-] ("VT22")}; compacting agents (e.g., DNA compacting agents); viruses; polymers; hyaluronic acid; proteins (e.g., enzymes such as ribozymes, asparaginase); immunologic species; nonsteroidal anti-inflammatory medications; oral contraceptives; progestins; gonadotropin- releasing hormone agonists; chemotherapeutic agents; and radioactive species (e.g., radioisotopes, radioactive molecules). Non-limiting examples of therapeutic agents include ami-thrombogenic agents; antioxidants; angiogenic and αnti-aπgiogenic agents arid factors; antiproliferative agents (e.g., agents capable of blocking smooth muscle cell proliferation, such as rapamycin); calcium entr>r blockers (e.g., verapamil, dihiazeni, nifedipine); and survival genes which prυtect against cell death (e.g., anti- apoptotic BcI-2 family factors and Aki kinase), Exemplary non-genetic therapeutic agents include: anti-thrornbotie agents such as heparin, heparin derivatives, urokinase, and PPack (dextrophenylalanine proline arginme chloroinelhyiketonc); antiinflammatory agents such as dexamethasune, prednisolone, cortieosterone, budesonide, estrogen, acetyl salicylic acid, sulfasalazine and mesa! amine: antiϊieopiasiic/anuproliferativc/anii-rΩitoiic agents such as pach'taxeL 5-iluorouracil, cispiatin, .methotrexate, doxorubicin, vinblastine, vincristine, cpothilones, endostatin, angiostatin, angiopeptin, monoclonal aυlibodies capable of blocking smooth muscle eelϊ proliferation, and thymidine kinase inhibitors; anesthetic agenis such as ϊidocaine, biφivacahie and ropivacaine; anti-coagulants such as ϋ-Plie-Pro-Arg chloroπiethyl ketone, an RGD peptidε-contaimng compound, heparin, hirudin, antithrombin compounds, platelet receptor antagonists, arm- thrombin an bodies, anti-platelet receptor antibodies, aspirin, prostaglandin .inhibitors, platelet inhibitors and tick antiplatelet factors or peptides; vascular cell growth promoters such as growth factors, transcriptional activators, and tπinskuional promoters; vascular cell growth inhibitors such as growth factor inhibitors (e.g., PDGF inhibitor- Trapid.il), growth factor receptor antagonists, transcriptional repressors, translationai repressors, replication inhibitors, inhibitory antibodies, antibodies directed against growth factors, bi functional molecules consisting of a growth factor and a cytotoxic, bifuncS.io.nal molecules consisting of an antibody and a cytotoxin; protein kinase and tyrosine kinase inhibitors (e.g., tyrphostins, geπi stein, qyino.x alines); prostacyclin analogs; cholesterol-lowering agents; angiopoietiαs; antimicrobial agents such as triclosan, cephalosporins, aminoglycosides and
>4 nitrofurantoin; cytotoxic agents, cytostatic agents and cell proliferation affectors; vasodilating agents; and agents that interfere with endogenous vasoactive mechanisms.
Exemplary genetic therapeutic agents include: an ti -sense DNA and UNA; DMA coding ibr anti-sense RNA, tRN A or rRN A to replace defective or deficient endogenous molecules, angiogenic factors including growth factors such as acidic and basic fibroblast growth (actors, vascular endothelial growth factor, epidermal growth factor, transforming growth factor α and β, platelet-derived endothelial growth factor, platelet-derived growth factor, tumor necrosis factor a, hepaioeyte growth factor, and insulin Like growth factor, cell cycle .inhibitors including CD inhibitors, thymidine kinase ("TK"') and other agents useful for interfering with ceil proliferation, and Hie family of bone morphogenk proteins ("BMP's"), including BMP2, BM P3, BM P4, BMP5, BMP6 (Vgrl ), BMP? (OPi), BMP8, BMP9, BMPlO, BMl 1, BMP12, BM P 13, BMPH, BMPl 5, and BMP 16. Currently preferred BMP's are any of BMP2, BMP3, BMP4, BM P5, BMP6 and BMP7, These dimerie proteins can be provided as hornodimers, heterodirncrs, or combinations thereof, alone or together with other molecules. Alternatively or additionally, molecules capable of inducing an upstream or downstream effect of a BMP can be provided. Such molecules include any of the "hedgehog" proteins, or the DNA's encoding them. Vectors of interest for delivery of genetic therapeutic agents include: plasmids; viral vectors such as adenovirus (AV), adersoassociaied virus (AAV) and lεniivirus; and non-Viral vectors such as lipids, liposomes mid cationic lipids.
Cells include cells of human origin (autologous or allogeneic), including stern cells, or from a.n animal source (xenogeneic), which can he genetically engineered if desired to deliver proteins of interest.
Several of the above and numerous additional therapeutic agents appropriate for the practice of the present invention are disclosed in Kunz ct a!.. U.S. Patent No. 3,733,925, assigned to NeoRx Corporation, which is incorporated herein by reference. Therapeutic agents disclosed in this patent iπdude the following; "Cytostatic agents" (i.e., agents that prevent or delay cell division in proliferating cells, for example, by inhibiting replication of DNA or by inhibiting spindle fiber formation). Representative examples of cytostatic agents include modified toxins, methotrexate, adriamycin, radionuclides (e.g., such as disclosed in Fritzbeig ei al., U.S. Patent No. 4,897,255), protein kinase inhibitors, including siaurosporin, a protein kinase C inhibitor of the following foπxmfa;
Figure imgf000027_0001
as well as diindoloalkaloids having one of the following general, structures;
Figure imgf000027_0002
Figure imgf000028_0001
Figure imgf000028_0002
as wdl as stimulators of the production or activation of TGF-beta, including TmYK)Xi fen and derivatives of functional equivalents (e.g., plasmiru heparin, compounds capable of reducing the level or inactivating the lipoprotein Lp(a) or the glycoprotein apolipoprotein(a)) thereof, TGF-beta or funeiiorsal equivalents, derivatives or analogs thereof, suramin, nitric oxide releasing compounds (e.g., nitroglycerin) or analogs or functional equivalents thereof, pacHiaxel or analogs thereof (e.g., taxotere), inhibitors of specific enzymes (such as die nuclear enzyme DNA topotsornerase 11 and DNA polymerase, RNA polymerase, adenyl guanyl cyclase), superoxide dismutase inhibitors, terminal deoxynucleotidyl -transferase, reverse transcriptase, antisense oligonucleotides that suppress smooth muscle cell proliferation and the like. Other examples of "cytostatic agents" include peptidic or mimetic inhibitors (i.e., antagonists, agonists, or competitive or non-competitive Inhibitors) of cellular factors thai may (e.g., in the presence of extracellular matrix) trigger proliferation of smooth muscle cells or pericytes: e.g., cytokines (e.g., interleukhis such as IL-I), growth factors (e.g., PDGF, TGF-aipha or -beta, tumor necrosis factor, smooth nruscie- and endoihelial-derived growth factors, i.e., endotbelin, FGF), homing receptors (e.g., for platelets or leukocytes), arsd extracellular matrix receptors (e.g., integrals). Representative examples of useful therapeutic agents in this category of cytostatic agents addressing smooth muscle proliferation include: sub fragments of heparin, triazolopyriniidme (trapidil; a PDGF antagonist), lovastatin, and prostaglandins El or 12, Agents that inhibit the intracellular increase in cell volume (i.e., the tissue- volume occupied by a cell), such as cytoskeietal inhibitors or metabolic inhibitors. Representative examples of cytoskdetal inhibitors include colchicine, vinblastine cytochalasirss, psdilaxel and the like, which act on microtubule and microfilament networks within a cell. Representative examples of metabolic- inhibitors include staurosporin, tήchothecenes, and modified diphtheria and riein toxins, Pseudorøonas exotoxin and the like. Tπchothecenes include simple triehotheeenes (i.e., those that have only a centra! sesqurterpenoid stiiictυre) and πiacrocyclic triehotheccnes (i.e., those that h&ve an additional macrocyclic ring), e.g.. a verrucarins or roridins, including Vermcarin A5 Verruearfπ B5 Verrucarin..1 (Satratoxlπ (?), Roridin A, Roridin C, Roridin D, Roridin E (Satratoxin D), Roridin H.
Agents acting as an inhibitor that blocks cellular protein synthesis and/or secretion or organization of extracellular matrix (i.e., an 'tanti-niatrix agent"). Representative examples of "anii-malrix agents" include mhibiiors (i.e., agonists and antagonists axiά competitive and non-competitive inliibitois) of matrix synthesis, secretion and assembly, organizational cross-linking (e.g., transglutaminases cross- linking collagen}, and matrix remodeling (e.g., following wound healing). A representative example of a useful therapeutic agent in this category of anti-matrix agents is colchicine, an inhibitor of secretion of extracellular matrix. Another example is tamoxifen for which evidence exists regarding its capability to organize and/or stabilize as well as diminish smooth muscle cell proliferation following angioplasty. The organization or stabilization may stein from the blockage of vascular smooth muscle eel) maturation in to a pathologically proliferating form.
Agents that are cytotoxic to cells, particularly cancer cells, ['referred agents arc Roridiπ A, Pseudomonas exotoxin and the like or analogs or functional equivalents thereof, A plethora of such therapeutic agents, including radioisotopes and the like, have been identified and are known m the art. in addition, protocols ibr the identification of cytotoxic .moieties are known and employed routinely in the art, A number of the above therapeutic agents and several others have also been identified as candidates for vascular treatment regimens, for example, as agents targeting restenosis. Such agents include one or more of the following: calcium- channel blockers, ineludmgbenz0thiazapin.es (e.g., diltiazem. dentiazera); άthy drop yri dines (e.g., nifedipine, amkxlipine, nicardipine); phenylalkyiammes (e.g., verapamil); serotonin pathway modulators, including 5-HT antagonists (eg,, ketanseπn, naftidrofuryl) and 5-MT uptake inhibitors (e.g., fluoxetine); cyclic .nucleotide pathway agents, including phosphodiesterase inhibitors (e.g.. eϋostazole, dipyridamole), adenySate/guanylate cyclase stimulants (e.g., forskolmK and adenosine analogs; catecholamine modulators, including α-antagoπists (e.g., prazosin, bunaxosme). p-antagonists (e.g.. propranolol), and cϊ/β-antagonists (e.g., iabetalol, carvediJol); cndothelin receptor antagonists; nitric oxide donors/releasing molecules, including organic nitrates/nitrites (e.g., nitroglycerin, isosorbide dinitrate, amyl nitrite), inorganic rsilroso compounds (e.g., sodium nnroprasside}, sydnonimiπes (eg., molsidomine, linsidomine), nonoates (e.g.. diaxcniuπi diolates, NO adduets of alkanediaraines), S-nitroso compounds, including low molecular weight compounds (e.g., S-nitroao derivatives of captopril, glutathione and N-acety! penicillamine) and high molecular weight compounds (e.g., S-m'troso derivatives of proteins, peptides, oligosaccharides, polysaccharides, synthetic polymers/oligomers and natural poSyrners/oiigomers), C-nitroso~, O-nitroso- and N-nitroso~ci>mpouπds, and L- arginine; ACE inhibitors (e.g., cilazapril, fbsinopril, enalapril); ATϋ-receptor antagonists (c g., saralasin, iosartin); platelet adhesion inhibitors (eg,, albumin, polyethylene oxide); platelet aggregation inhibitors, including aspirin and lhienopyridine (tielopidiπe, clopidogrel) and GP fib/I Ha inliibitors (e.g., abcsximab, epitifibatide, tirυfϊban, intcrgrϋin); coagulation pathway modulators, including heparirsoids (e.g., heparin, low røoleeular weight heparin, dexiran sulfate, β- cyckxiextrm ϊetradeeasuliate), thrombin inhibitors (e.g., hirudin, hiruiog, FPACK (D- phe-L-propy]-L-arg-chlororaethylketone)j argatroban), PXa inhibitors {e.g., antistatic, TAP (tick anticoagulant peptide}), vitamin K. inhibitors (e.g., warfarin), and activated protein C; cyclooxygenase pathway inhibitors (e.g., aspirin, ibuprofen, flurbiprofen, iodornεthacrn, sulfinpyrazone); natural and synthetic corticosteroids (e.g., dexamethasojie, prednisolone, methprednisolone, hydrocortisone); lipoxygenase pathway inhibitors (e.g., nordlhydroguairetie acid, calϊeic acid; ieukøtiiene receptor antagonists; antagonists of E- and P-selectins; inhibitors of VCAM- i and ICAM-I interactions; prostaglandins and analogs thereof, including prostaglandins such as FGEl and PGI2; prostacyclins and prostacyclin analogs {e.g., eiprostene, epoprostεnol, earbacyciin. iioprost, beraprost); macrophage activation preventers (e.g., bisphosphonates); HMG-CoA reductase inhibitors (e.g., lovastatin, pravastatin, Huvastatin, simvastatin, cerivastatin); fish oils and omega-3-fatty acids; tree-radical scavengers/antioxidants (e.g., probucol. vitamins C and E, ebselen, retinoic acid (e.g., trans-rctinoic acid). SOD rnknics); agents affecting various growth factors including FGF pathway agents (e.g., bFGF antibodies, chimeric fusion proteins), PDC)F receptor antagonists (e.g., trapidil), IGF pathway agents (e.g.. somatostatin analogs such as arsgiopepϋn and ocreoiide), TGF-β pathway agents such as poiyamonic agents (heparin, fαcoidiπ), decorin, and TGF-β antibodies, EOF pathway agents (e.g., EGF antibodies, receptor antagonisLs, chimeric fusion proteins), TNF-α. pathway agents (e.g., thalidomide a.nd analogs thereof), thromboxane A2 CTXA2} pathway modulators (e.g., suiotroban, vapiprost, daϊroxiben, ridogrel), protein tyrosine kinase inhibitors (e.g., tyrphostm, genistcin, and quinoxaline derivatives); MMF pathway inhibitors (e.g., marimasiat, ilomastat, metastat), and cell molility inhibitors (e.g., cytochalasin B); aiitiproliferativ^'antineoplastjc agents including antimetabolites such as purine analogs (e.g., 6-rnercaptopurme), pyrimidine analogs (e.g., cylarabme and 5- fiuuujuraci!} and methotrt-xate, nitrogen mustards, alkyl sulfonates, ethylenimines, antibiotics (e.g., daisnorubicin, doxorubicin^ daunomycin, bleomycin, mitomycin, penicillins, cephalosporins, ciprofalxin, vancomycins, aminoglycosides, quinoloπes, polymyxins, erythromycins, tertacydhies, chloramphenicols, clindamycins, linornyehis, sulfonamides, and their homologs, analogs, fragments, derivatives, and pharmaceutical salts), nitrosoureas (e.g., carrnustine, lomustiπe) and cisplatm, agents affecting microtubule dynamics (e.g., vinblastine, vincristine, colchicine, pacliiaxel, 6 epothϋone), easpase activators, proteasorae inhibitors, angiogenesis inhibitors (e.g., εndostatin, angiosiattn and squateminc), and rapamydn, cerivasiatin, flavopiridol and suramin; matrix deposition/organization pathway inhibitors (e.g., halαfugino&e or other quinaxolinone derivatives, traniiast); etxiothelialization facilitators (e.g., VEGF and RGO peptide); and blood rheology modulators (e.g., pentoxifylline).
''Q Other examples of therapeutic agents include anti-tumor agents, such as docctaxeL alkylating agents (e.g., mechloreihamine, chlorambucil, cyclophosphamide, nielphalan, ifosiami.de}, plant alkaloids (e.g., eioposide), inorganic sons (e.g , cispiatin), biological response modifiers (e.g.. interferon.}, and hormones (e.g., tamoxifen, fhαamidt1}, as well as their homologs, analogs, fragments,
15 derivatives, and pharπujceutical salts.
Additional examples of therapeutic agents include organic-soluble therapeutic agents, such as rnuhr&myein, cyclosporins and plicamycia, FunJier examples of therapeutic agents include pharmaceutically active compounds, anti-sense genes, viral, liposomes and cationic polymers (e.g., selected based on the application.), 0 biologically active solutes (e.g., heparin), prostaglandins, prostcydlns, L-arginine, πiiric oxide (NO) donors (e.g., lisidotninc, molsidomine, NO-proteiπ adduets, NO- polyssccharide adduets, polymeric or oligonieric NO adduets or chemical complexes), enoxaparin, Waraiiπ sodium, dicuniarol, interferons, røtεrkukiπs, cbymase inhibitors (e.g., Traniiast), A(^E inhibitors (e.g., Eπaiapril), serotonin antagonists, 5-HT uptake 5 inhibitors, and beta blockers, and other antitumor and/or chemotherapy drugs, such as BiCNU, biisulia.il, carbopiatinurn, eispϊatinurπ, Cytoxan, DTIC, Hudaiablne, mitoxantrone, velban, VP- 16, berceptin, leustatin, navdbme, rituxan, and taxotere.
Tlierapeutie agents are described, for example, in DiMatieo et al, U.S. Patent Application Publication No. US 2004/0076582 A l, published on April 22, 2004, <mά 0 entitled "Agent Delivery Particle", and in Schwarz et al., U.S. Paieαt No. 6,368,658, both of which are incorporated herein by reference. In certain embodiments, in addition to or as an alternative to including therapeutic agents, particle JOO can include one or more radiopaque materials, materials that arc visible by magnetic resonance imaging fMRl-visible materials), ferromagnetic materials, and/or contrast agents (e.g., ultrasound contrast agents), Radiopaque materials, MRI-visible materials, ferromagnetic materials, and contrast agents are described, tor example, in Rioux ei a!.. U.S. Patent Application Publication No. US 2004/0101564 Al 5 published on May 27, 2004, which is incorporated herein by reference.
\xi general, particle 100 can have a diameter of about 3,000 microns or less (e.g., from, about two microns to about 3,000 microns, from about 10 microns to about 3,000 microns, from about 40 microns to about 2,000 microns; from about 100 microns to about 700 microns; from about 500 microns to about 700 microns; from about 100 microns to about 500 microns; from about 100 microns to about 300 microns; from about 300 microns to about 500 microns; from about 500 microns to about 1 ,200 microns; from about 500 microns to about 700 microns; from about 700 microns io about 900 microns; from about 900 microns to about J ,200 microns, from about 1,000 microns to about L200 microns). In some embodiments, particle 100 can have a diameter of about 3,000 microns or less (e.g., about 2,500 microns or less; about 2,000 microns or less; about 1 ,500 microns or less; about 1 ,200 microns or less; about 1 , ! 50 microns or less; about 1,100 microns or less; about 1 ,090 microns or less; about 1,080 microns or less; about 1,070 microns or less; about 1 ,060 microns or less; about 1 ,050 microns or less; about 1 ,040 microns or less; about 1 ,030 microns or loss; about 1 ,020 microns or less; about ! ,010 microns or less; about i ,000 microns or less: about 900 microns or less; about 700 microns or less; about 500 microns or less; about 400 microns or less; about 300 microns or less; about 100 microns or less) and/or about 10 microns or more (e.g., about 100 microns or more; about 300 microns or more; about 400 microns or more; about 500 microns or more; about 700 microns or more; aboυi 900 microns or more; about 1,000 microns or more; about ! ,010 microns or more; about 1 ,020 microns or more; about \ ,030 microns or more; about 1.040 microns or .more; about 1,050 microns or more; about ! ,060 microns or more; about 1,070 microns or more; about 1,080 microns or more; about 1 ,090 microns or more; about 1 , 100 microns or more; about 1 , 150 microtis or more; about 1 ,200 microns or more; about 1,500 microns or more; about 2,000 microns or more; about 2,500 microns or more), hi some embodiments, particle 100 can have a diameter of less than about 100 microns (e.g., less than about 50 microns). In some embodiments, particle 100 can be substantially spherical. In certain embodiments, particle 100 can have a sphericity of about 0.8 or more (e.g., about 0,85 or more, about 0.9 or more, about 0.95 or more, about 0,97 or more). Particle 100 can be, for example, manually compressed, essentially flattened, while wet to about 5(J percent or less of its original diameter and then, upon exposure to Ouid, regain a sphericity of about 0.S or more (e.g., about 0.S5 or more, about 0.9 or moτe, about 0,95 or more, about 0.97 or more). The sphericity of a particle can be determined using a Beekman Coulter Rapid VU E Image Analyzer version 2,06 (Beekmaπ Coulter, Miami, FL). Briefly, the RapidVUE takes an image of continuous-tone (gray-scale) form and converts if to a digital form through the process of sampling and quantitation. The system software identifies and measures particles in an image in the lbmi of a fiber, rod or sphere. The sphericity of a particle, which is computed as Da/Dp (where Da - V(4A/τt); Dp ::: P/JT ; A ~ pixel area; P -: pixel perimeter), is a value itom ϊ.ero to one, with one representing a perfect circle.
Particle 100 can include one or more of the block copolymers described above, In some embodiments, particle 100 can include multiple (e.g., two, three, lour, live, six, severs., eight, nine, 10} different block copolymers. For example, in some; embodiments, a particle can include a blend of at least two different block copolymers. Alternatively or additionally, particle 100 can include oilier types of materials, such as other polymers that arc not block copolymers. Examples of polymers include polyvinyl alcohols ('1PVA"), poiyacrylic acids, polyraethaerylic acids, poly vinyl sulfonates, carbøxymethyj celluloses, hydroxyethyl celluloses, substituted celluloses, poiyacryiamides, polyethylene glycols, polyatrsiάes, polyureas, poiyurethanes, polyesters, polyethers, polystyrenes, polysaccharides, polylaetic acids, polyethylene^, polyυSefins, poiypropyienes, polymethylmethacrylates. polycaprolactorses, polyglycolie acids, poly(ϊactie-co-glycolic) acids (e.g., ρoiy(d~ laetie-eo-glycolie) acids}, polysuifones, polyethersulfones, polycarbonates, nylons. silicones, linear υr crosslinked poly silicones, and copolymers or mixtures thereof. In certain embodiments, particle 100 can include a highly water insoluble, high molecular weight polymer. An example of such a polymer is a high molecular weight PVA that has been acetalized. Particle 100 can include substantially pure irstradiain 1 ,3~aeela&ed .PVA . and can be substantially free of animal derived residue such as collagen. In some embodiments, particle 100 can include a minor amount (e.g.. about 2,5 weight percent or less, about one weight percent or less, about 0.2 weight percent or less) of a gelling material (e.g., a polysaccharide, such as alginate), m certain embodiments, particle 100 can include a bioabsorbable (e.g., resorbable) polymer (e.g., alginate, gelatm, albumin, resorbable polyvinyl alcohol, albumin, dextran, starch, ethyl cellulose, pσlyglyeoiic acid, polylactic acid, polylactic acid/polygiveolie acid copolymers, poly(lactic-co-glycolic) acid). Particle 100 can include, for example, polyvinyl alcohol, alginate, or both polyvinyl alcohol and alginate.
In some embodiments, in addition to or as an alternative to being used to deliver a therapeutic agent to a target site, particle 100 can be used to ernhoiize a target site (e.g., a lumen of a subject). For example, multiple particles can be combined with a carrier fluid (e.g., a pharmaceutically acceptable carrier, such as a saline solution, a contrast agent, or both) to form a composition, which can then be delivered to a site and used to embolize the site. FIGS. 2A and 2B illustrate the use of a composition including particles to embolics a lumen of a subject, As shown, a composition, including particles 300 and a carrier fluid, is injected into a vessel through an instrument such as a catheter 1 150, Catheter 1 150 is connected to & syringe barrel I U Q with a plunger 1 160, Catheter 1 150 is inserted, for example, into a femoral artery U 20 of a subject. Catheter 1 150 delivers the composition to, for example, occlude a uterine artery 1130 leading to a fibroid 1 140. Fibroid t 140 is located m the uterus of a female subject The composition is initially loaded into syringe 1 1 10. Plunger 1 160 of syringe I l 10 is then compressed to deliver the composition through catheter 1 150 into a lumen 1 165 of uterine artery 1 130.
FKJ. 2B, which is an enlarged view of section 2B of FIG. 2A5 shows a uterine artery 1 130 thai is subdivided into smaller uterine vessels 1 170 (e.g., having a diameter of about two millimeters or less) which feed fibroid 1 140, The particles 100 in. the composition partially or totally fill the lumen of uterine artery 1 130, either partially or completely occluding the lumen of the uterine artery 1 130 that feeds uterine fibroid 1 140.
Compositions that include particles such as particles 100 can be delivered to various sites m the body, including, for example, sites having cancerous Jesious, such as the breast, prostate, lung, thyroid, or ovaries. The compositions can be used in, for example, neural , pulmonary, and/or AAA (abdominal aortic, aneurysm) applications. 'The compositions can be used in the treatment of, for example, fibroids, tumors, internal bleeding, arteriovenous malformations (AVMs), and/or hypervascular tumors. The compositions can be used as, for example, fillers for aneurysm sacs. AAA sac (Type II endoleaks), entioieak sealants, arterial sealants, and/or puncture sealants, and/or can be used to provide occlusion of other lumens such as fallopian tubes. Fibroids cars include uterine fibroids which grow within the uterine wall (intramural type), on the outside of the uterus (suhserosal type), inside Ae uterine cavity (submucosal type), between the layers of broad ligament supporting the uterus
(inter! igaraeπto us type), attached to another organ (parasitic type), or on a mushroom- like stalk (pedunculated type). Internal bleeding includes gastrointestinal, urinary, renal and varicose bleeding. AVMs are for example, abnormal collections of blood vessels, e.g. in the brain, which shunt blood from a high pressure artery to a low pressure vein, resulting in hypoxia and malnutrition of those regions from which the blood is diverted. In some embodiments, a composition containing the particles can be used to prophylactically treat a condition.
'The magnitude of a dose of a composition can vary based on the nature. location and severity of the condition to be treated, as well as the route of administration. A physician treating the condition, disease or disorder can determine an effective amount of composition. An effective amount of embolic composition refers to the amount sufficient to result in amelioration of symptoms and/or a prolongation of survival of the subject or the amount sufficient to prophylactics!!;/ treat a subject. The compositions can be administered as pharmaceutically acceptable compositions to a subject in any therapeutically acceptable dosage, including those administered to a subject intravenously, subeutaneously, percutaneous! y, mtratraehe&ly, intramuscularly, intrarrmeosaly, intracutaneous])-', intra-articularly, orally ι;r parenteral Iy.
A composition can include a mixture of particles (e.g., particles that include different types of block copolymers, particles that mdiicte different types of therapeutic agents), or can include particles that are all of Ae .same type. In some embodiments, a composition can be prepared with a calibrated concentration of particles for case of delivery by a physician. A physician can select a composition of a particular concentration based on, for example, the type of procedure to be performed, In certain embodiments, a physician can use a composition with a relatively high concentration of particles during one part of an embolization procedure, and a composition with a relatively low concentration of particles during another part of the embolization procedure.
Suspensions of particles in saline solution car. be prepared to remain stable (e.g., to remain suspended in solution and not settle and/or float) over a desired period of time, A suspension of particles can be stable, for example, for from about, one minute to about 20 minutes (e.g. from about one minute to about 10 minutes, from about two minutes to about seven minutes, from about three minutes to about six minutes). in some embodiments, particles can be suspended in a physiological solution by matching the density of the solution to the density of the particles. In certain embodiments, the particles and/or the physiological solution can have a density of fmm about one gxarα per cubic centimeter to about. 1 .5 grams per cubic centimeter (e.g., from about 1.2 grams per cubic centimeter to about L4 grams per cubic centimeter, from about 1.2 grams per cubic centimeter to about 1.3 grams per cubic centimeter).
Ln some embodiments, the earner fluid of a composition can include a surfactant. The surfactant can h&lp the particles to mix evenly in the carrier fluid and/or can decrease the likelihood of the occlusion of a delivery device (e.g., a catheter) by me particles. In certain embodiments, the surfactant can enhance delivery of the composition (e.g.. by enhancing the wetting properties of the particles and facilitating the passage of the particles through a delivery device), In some embodiments, the surfactant can decrease the occurrence of air entrapment by the particles in a composition. Examples of liquid surfactants include Tween* SO (available from Sigma-AMrich) aid Cremophor Elf (available from Sigma-Aklrich), An example of a powder .surfactant is Pluromc5* Fl 27 NF (available from BASF). In certain embodiments, a composition can include from about 0.05 percent by weight Io about one percent by weight (e.g., about 0.1 percent by weight, about 0.5 percent by weight) of a surfactant. A surfactant can be added to the carrier fluid prior to mixing with the particles and/or can be added to the particles prior to mixing with the carrier fluid. In some embodiments, among the particles delivered to a subject (e.g., in a composition), the majority (e.g., about 50 percent or more, about 60 percent or more, about 70 percent or more, about 80 percent or more, about 90 percent or more} of the particles cars have a diameter of about 3,000 microns or less (e.g., about 2,500 microns or less; about 2,000 microns or less; about 1 ,500 microns or less; about, 1 ,200 microns or less; about 1,150 microns or less; about LlOO microns or less; about 1,090 microns or less; about 1,080 microns or less; about 1 ,070 microns or less; about 1,060 microns or less; about 1 ,050 microns or less; about 1 ,040 microns or less; about 1 ,030 microns or less; about 1 ,020 microns or less; about 1,010 microns or less; about 1,000 microns or ess; about 900 microns or less; about 700 microns or less: about 5(K) microns or ess; about 400 microns or less; about 300 microns or less; about 100 microns or less) and/or about 10 microns or more (e.g., about 100 microns or more; about 300 microns or more; about 400 microns or more; about 500 microns or more; about 700 microns or more; about SK)O microns or more; about 1,000 microns or more; about 1 ,010 microns or more; about 1,020 microns or more; about ϊ,030 microns or more; about 1,040 microns or more; about 1,050 microns or more; about .1,060 microns or more; about 1,070 microns or more; about 1,080 microns or more; about
1 ,090 microns or more; about 1 , 100 microns or more; about 1 , i 50 microns or more; about 1 ,200 microns or more; about 1 ,500 microns or more; about 2,000 microns or more; about 2,500 microns or more). In some embodiments, among the particles delivered to a subject, the majority of the particles cars have a diameter of less than about 100 microns (e.g., less than about 50 microns). In certain embodiments, the panicles delivered to a subject (e.g., in a composition} can hav€ an arithmetic mean diameter of about 3,000 microns or less (e.g., about 2.500 microns or less; about 2,000 microns or less; about 1.500 microns or less; about 1 ,200 microns or less; about 1 ,150 .microns or less; about I J OO microns or less; about 1 ,090 microns or less; about 1,080 microns or less; about 1 ,070 .microns or less; about 1 ,060 microns or less; about 1,050 microns or less; about 1 ,040 microns or less; about 1 ,030 .microns or less; about 1,020 microns or less; about L010 microns or less; about 1 ,000 microns or less; about 900 microns or less; about 700 microns or less; about 500 microns or less; about 400 microns or less; about 300 microns or less; about 100 microns or less) and/or about 10 microns or more (e.g., about 100 microns or more; about 300 microns or more; about 400 microns or more; about 500 .microns or more; about 700 microns or more; aboui 900 microns or more; about 1 ,000 microns or more; about 1 ,010 microns or more; about 1 ,020 mkruns or more; aboui i .030 microns or more; about 1,04(J microns or more; about 1 ,050 microns or more; about 1 ,060 microns or more; about 1 ,070 microns or more; about 1 ,080 microns or .more; about 1 ,090 microns or more; about ! , 100 microns or more; about Ll 50 microns or more; about 1 ,200 microns or more; about 1 ,500 .microns or more; about 2,000 microns or more; about 2,500 microns or more), in some embodiments, the particles delivered to a subject can have an arithmetic mean diameter of less tbars about 100 microns {e.g., less than about 50 microns).
Exemplary ranges for the arithmetic mean diameter of particles delivered to a subject include from about 100 microns to about 500 microns; from about 100 microns to about 300 microns; from about 300 microns to about 500 microns; from aboui 500 microns to about 700 microns; from about 700 microns to about 900 microns; from about 900 microns to about 1 ,200 microns; and from about 1 ,(.K)O microns to about 1,200 microns, In genera!, the particles delivered to a subject (e.g., irs a composition) cars have an arithmetic mean diameter in approximately the middle of the range of the diameters of the individual particles, and a variance of about 20 percent or less {e.g. about 15 percent or less, about 10 percent or less). In some embodiments, the arithmetic mean diameter of the particles delivered to a subject {e.g., in a composition) can vary depending upon the particular condition to be treated. As an example, in embodiments in which thepartiei.es are used to emboiize a liver tumor, the particles delivered to the subject can have an arithmetic mean diameter of about 500 microns or less (e.g., from about 100 microns to about 300 microns; from about 300 microns to about 500 microns). As another example, in embodiments in which the particles are used to embolize a uterine fibroid, the particles delivered to the subject eaa have an. arithmetic mean diameter of about 1 ,200 microns or less (e.g., from about 500 microns to about 700 microns; from about 700 microns to about 900 microns; from about 900 microns to about 1,200 microns). As an additional example, in embodiments in which the particles are used to treat a neural condition (e.g., a brain tumor) and/or head trauma (e.g., bleeding in the head}, the particles delivered, to the subject can have an arithmetic mean diameter of less than about 100 microns (e.g., less than about 50 microns)- As a further example, in embodiments in which the particles are used to treat a lung condition, the particles delivered to the subject can have an arithmetic mean, diameter of less than about 100 microns (e.g., less than about 50 microns). As another example, in embodiments in which the particles are used to treat thyroid cancer, the particles can have a diameter of about 1 ,200 microns or less (e.g., from about KOOO microns to about 1 ,200 microns).
The arithmetic mean diameter of a group of particles can be determined using a Beckrøan Coulter RapidVUE Image Analyzer version 2.06 (Beckman Coulter, Miami. FL), described above. The arithmetic mean diameter of a group of particles (e.g., ITS a composition) can be determined by dividing the sum of the diameters of all of the particles in the group by the number of particles in the group. in certain embodiments, a particle that includes one of the above-described block copolymers can also include a coating. For example. FIG. 3 shows a particle 200 with an interior region 202 formed of a block copolymer, and a coating 204 formed of a different polymer (e.g., polyvinyl alcohol). Coating 20-4 can, for example, regulate the release of therapeutic agent from particle 200. and/or provide protection to interior region 202 of particle 200 (e.g., during delivery to a target site). in certain embodiments, coating 204 can be formed of a bioerodihie- and/or bioabsorbabie material that can erode and/or be absorbed as particle 200 is delivered to a target site, such that interior region 202 can deliver a therapeutic ageni to the target site orsee particle 200 has reached the target site. A bioerodible material can be, for example, a polysaccharide {e.g., alginate); a polysaccharide derivative; an inorganic, ionic sail; a water soluble polymer (e.g., polyvinyl alcohol, such as polyvinyl alcohol that has not been cross-linked); biodegradable poly DL-taetide-poly ethylene glycol (PELA); a hydrogel (e.g., poiyaeryiie acid, hyaluronic acid, gelatiu, earboxymcthyl cellulose); a polyethylene glycol (PEG); chitossn; a polyester (e.g., a polycaprolaetone); a poly(oriho ester); a polyanhydride; a poly(laciic-co-glycolic) acid (e.g., a poly(d-iactic-co-giycolic) add); a ρo!y(lactic acid) (PLA); a poly(glyco!ie acid) (PGA); or a combination thereof, In some embodiments, coating 204 can be formed of a sweOabie material, such as a hydrogel (e.g.. poiyaeryiamide co-acrylic acici), The swellable material can be made to swell by, for example, changes in pH, temperature, and/or salt hi embodiments in which particle 200 is used in an embolization procedure, coating 204 can swell at a target site, thereby enhancing occlusion of the target site by particle 200. ϊn some embodiments, a particle can include a coating that is formed of a block copolymer. For example, FlG. 4 shows a particle 300 that includes an interior region. 302 formed of a polymer (e.g., polyvinyl alcohol), and a coating 304 formed of a block copolymer (e.g., SIBS), In certain embodiments, interior region 302 can be formed of a sweϋable material. 1« some such embodiments, coating 304 can be formed of a porous material. The pores in coating 304 can expose interior region 302 to changes in, for example, pi t temperature, and/or salt. When interior region 302 is exposed to these changes, the sweilable material in interior region 302 can swell, thereby causing particle 300 to become enlarged, In certain embodiments, coating 304 can be made of a relatively flexible material (e.g., SiBS) that can accommodate the .swelling of interior region 302. The enlargement of particle 300 can, ibt example, enhance occlusion during an embolization procedure,
Examples of swellable materials include hydrogel s, such as poiyaeryiie acid, polvaoϊybπύde co-acrylic acid, hyaluronic acid, gelatin, carboxymethy) cellulose, noryi ethylene oxidcj-based polyurethane, polyaspartahydrazide. ethyleneglycoldiglycidyiether (EGDGE), and polyvinyl alcohol (PVA) hydrogds. ϊn some embodiments in which a particle includes a fiydrogel, the hydrogeS cars be crossStnked, such that it may not dissolve when it swells. In other embodiments, the hydrogel may not be erosslinked, such that the hydrogel may dissolve when it swells, in. certain embodiments, a particle can include a coating that includes one or snore therapeutic agents. in some embodiments, a particle can have a coating that includes a high concentration of one or more therapeutic agents. One or more of the therapeutic agents can also be loaded into the interior region of the particle. Thus, the surface of the particle can release an initial dosage of therapeutic agent after which the body of ihe particle can provide a burst release of therapeutic agent. The therapeutic agent on the surface of the particle can be the same as or different from the therapeutic agent in the body of the particle. The therapeutic agent on the surface can be applied by exposing the particle to a high concentration solution of the therapeutic agent. The therapeutic agent coated particle can include another coating over the surface the therapeutic agent (e.g., a bioerodϊbte polymer which erodes when the particle is administered). The coating can assist in controlling the rate at which therapeutic agent is released from the particle. For example, the coating can be in the form of a porous membrane, The coating can delay an initial burst of therapeutic agent release. The coating can be applied by dipping or spraying the particle. The credible polymer can be a polysaccharide (such as an alginate). Ln some embodiments, the coating can be an inorganic, ionic salt. Other credible coatings include polysaccharide derivatives, water-soluble polymers (such as polyvinyl ulcohoK e.g., that has not been cross-linked), biodegradable poly DL~lactkk-poly ethylene glycol (PELA), hydrogcls (e.g., polyacrylie acid, hyaluronic acid, gelatm, carhoxymethyl cellulose), polyethylene glycols (PEG)5 ehitosari, polyesters (e.g., polycaprolactones}, polyi'ortho esters), poiyanhydrides, ρoly{ lactic acids) (PI. A). polyglyeoKc acids (PGA), poly(iaetic-eo-giycolie) acids (e.g., polytti-iaetic-eo- glycohc) acids), and combinations thereof. The coating cars include therapeutic agent or can be substantially free of therapeutic agent. The therapeutic agent m the coating can be the same as or different from an agenl on a surface layer of the panicle and/or within the particle. A polymer coating (e.g. an credible coating) can be applied to the particle surface in embodiments in which a high concentration of therapeutic agent lias not been applied to the particle surface. Coatings are described, for example, in DiMaϋeo et ai, U.S, Patent Application Publication No. US 2004/0076582 Ai, published on April 22, 2004, which is incorporated herein by reference,
In some embodiments, a particle can include one or more smaller sub- particles. For example, FIG. 5 shows a particle 4Of) that includes a matrix 402, within whkh are embedded sub-panicles 404. Matrix 402 can be formed of, for example, one or more polymers {e.g., block copolymers such as SlBS), Alternatively or additionally, sub-particles 404 can be formed of one or more polymers (e.g., block copolymers such as SIBS). hi some embodiments, both matrix 402 and sub-particles 404 can be formed of one or more block copolymers. Block copolymer^) in matrix 402 can be the same as, or different from, block, copolymers) in sub-partkles 404. In certain embodiments, particle 400 can include one or more therapeutic agents, such as water-soluble therapeutic agents and/or organic-soluble therapeutic agents. This ears allow particle 400 to be used, for example, to deliver multiple therapeutic agents to a target sue in one procedure. The therapeutic- agents can be included in (e.g., dispersed throughout) matrix 402 and/or sub-particles 404, hi some embodiments, matrix 402 can include one type of therapeutic agent (e.g., an organic-soluble therapeutic agent), while sub-pariieles 404 include another type of therapeutic agent (e.g., a water-soluble therapeutic agent), in certain embodiments., matrix 402 can be made out of a porous material, which can help in the release of therapeutic agent from sub-particles 404. Examples of water- soluble therapeutic agents include DNA, oligonucleotides, heparin, urokinase, halofuginone, &nά protein. Examples of organic-soluble therapeutic agents include paclitaxεl, trans-retinoic acid, mithramyem, probυcol, rapamycin, dexamethason, 5-fluorαuracil, methotrexate, doxorubicin, daαnorubiein, cyclosporins, eisplatin, vinblastine, vincristine, colchicine, epothikmes, encSostatin, angiostatiri, and plicamyoin.
Particles car; be formed by any of a number of different methods. As an example, FIGS. 6A-6C show a single-emulsion process that can be used, for example, to røake particle 100 (FiG. 1 }. As shown in FIGS, 6A-6C, a drop generator 500 (e.g., a pipette) .forms drops 510 of a solution including a block copolymer (e.g., SIBS), a therapeutic agent and an organic solvent (e.g., methylene chloride, chloroform, te!.ra.bydrofuraπ (THF), toluene). In some embodiments, the solution can include at least about onu percent weight/volume {w/v} (e.g., from about one percent w/v to about 20 percent w/v) of the block, copolymer. Drops 510 fall from drop generator 500 into a vessel 520 that contains an aqueous solution including a surfactant. In some embodiments, the surfactant can be water-soluble. Examples of surfactants include polyvinyl alcohols, poly(virry! pyrroiidone) (PVf1), and poiysorbates (e.g., 1T ween Λ' 20. T ween* 80), In certain embodiments, the aqueous solution can be mixed (e.g., homogenized) while drops 510 are being added to it. In some embodiments, the aqueous solution can be mixed at a speed of at most about 10,000 revolutions per minute (e.g., at most about 5,000 revolutions per minute, at most about 1 ,500 revolutions per minute). The concentration of the surfactant in the aqueous solution can be at least 0.05 percent w/v (e.g., from 0,05 percent w/v to about 10 percent w/v). In general, ss the concentration of surfactant in the aqueous solution increases, particle, size can decrease. As FKl 6B shows, after drops 510 have fallen into vessel 520, the solution is mixed using a stirrer 530, In some embodiments, the solution, can be mixed (e g., homogenized) at a speed of at least about LOOO revolutions per minute (e.g., at least about 2,500 revolutions per minute, at least about S5OOO revolutions per minute, at least about 6,000 revolutions per minute, at least about 7,500 revolutions per minute) and/or at most, about 10,000 revolutions per minute (e.g., at most about 7,500 revolutions per minute, at most about 6,000 revolutions per minute, ai most about 3,000 revoiist.io.ns per minute, at most about 2,500 revolutions per minute). For example, the solution can be mixed at a speed of from about 1000 revolutions per minute to about 6000 revolutions per minute. In certain embodiments, as mixing (e.g., homogenϊzaiioπ) speed increases, particle size can decrease. In some embodiments, the solution cars be mixed for a period of at least about 0.5 hour (e.g., at least about one hour, at. least about two hours, at least about three hours, ai least about lour hours) and -Or at most about five hours (e.g., at most about four hours, at most about three hours, at most about two hours, at most about one hour). In certain embodiments, the solution can be mixed for a period of from about one hour to about three hours (e.g., lor about one hour). In some embodiments, mixing can occur at a temperature of at least about 25°C (e.g., at least about 300C, at least about 35"C), In general, as mixing (e.g., horøogenization) temperature increases, particle size can increase. The mixing results in a suspension 540 that includes particles 100 suspended in the solvent (FiG. 6C). Particles 100 are then separated from the solvent 6 by, for example, filtration, or centrituging followed by removal of the supernatant Thereafter, particles KK) are dried (e.g., by evaporation, by lyophilization, by vacuum drying).
In some embodiments, the therapeutic agent can be omitted from the above- described process, such ihat the particles thai are produced do not include therapeutic
10 agent. Alternatively or additionally, one or more therapeutic agents can be added to the particles (e.g., by injection) after the particles have been formed.
In certain embodiments, the particles thai are formed by the above-described process can be coated (e.g., with a polymer). The coating can be added to the particles by, for example, spraying and/or dip-coating. These coating processes can
15 be used, for example, to make particles like particle 200 f FIG. 3).
While a pipette has been described as an example of a drop generator thai can be used in a particle formation process, in some embodiments, other types of drop generators or drop generator systems can be used in a particle formation process. For example, FKJ. 7 shows a drop generator system 601 that includes a flow controller
20 600, a viscosity controller 60S, a drop generator 650, and a vessel 620, Flow controller 600 delivers a solution (e.g.. a solution that contains a block copolymer such as SIBS), a therapeutic agent, and an organic solvent) to a viscosity controller 605, which heals the solution to reduce viscosity prior to delivery to drop generator 610. The solution passes through an orifice in a nozzle in drop generator 610,
?5 forming drops of the solution, The drops are then directed into vessel 620 (e.g., containing an. aqueous solution ihat includes a surfactant such as PVA). Drop generators axe described, for example, in Lanphexe ct aL, U.S. Patent Application Publication No. US 2004/0096662 A l, published on May 20, 2004, and in DiCarlo cf aL U.S. Patent Application Serial No. 1 1/1 1 1 ,51 L filed on April 21 , 2005, and
30 entitled "Particles", both of which are incorporated herein by reference. FIGS. SA and UB show an embodiment of a system 602 thai includes drop generator system (SOl, and that can be used to make particles like particle 200 (F ΪG. 3} and particle 300 (FiG. 4). System 602 Includes a drop generator system 601 , a reactor vessel 630, a gel dissolution chamber 640 and a filter 650. As shown in FIG. 8B; How controller 600 delivers a solution that contains one or more polymers {e.g., a block copolymer) and a gelling precursor (e.g., alginate) to viscosity controller 60S. which heats the solution to reduce viscosity prior to delivery to drop generator 610. The solution passes through an orifice in a nozzle in drop generator 610, forming drops of the solution. The drops are then directed into vessel 620 (in this process, used as a gelling vessel), where the drops contact a gelling agent (e.g., calcium chloride) that converts the gelling precursor from a sokuiøα form into a gel tbrm, stabilizing the drops md forming particles. In some embodiments, the particles may be transferred from vessel 620 to reactor vessel 630, where one or more polymers m the gei-stabilized particles may be reacted (e.g., cross- linked), in certain embodiments, the particles may be transferred to gel dissolution chamber 640, where the gelling precursor (which was converted to a gel) can be removed irons the partiel.es. After they have been formed, the particles can be filtered hi filter 650 to remove debris, in some embodiments, the particles may thereafter be coated with, for example, a polymer (e.g., a polyvinyl alcohol), finally, the particles can he sterilized and packaged as, for example, an embolic composition including the particles.
While alginate has been described as a gelling precursor, other types of gelling precursors can be used. Gelling precursors include, for example, alginate salts, xanthan gums, natural gum, agar, agarose, chitosan, earrageenan, fueoidan, furceiiaran, laminaraa hypπea, eueheuma, gum arahie, gum ghan'i gum karaya, gum tragacaπth, hyaluronic acid, locust beam gum, arahlnogalacian, peciin, arnyiopeetin, other water soluble polysaccharides and other ioπiealSy cross-linkable polymers. A particular gelling precursor is sodium alginate, such as high guluronic acid, stem- derived alginate (e.g., about 50 percent or more, about 60 percent or more guluronie acid) with a low viscosity (e.g., from about 20 eentipoise to about 80 eentipoixε at 2O0C!"), which can produce a high tensile, robust gel . As described above, in some embodiments (e.g., embodiments in which alginate is used as a gelling precursor}, vessel 620 can include a gelling agent such as calcium chloride. The calcium cations in the calcium chloride have an affinity for carboxylic groups in the gelling precursor. In some embodiments, the cations complex with carboxylic groups in the gelling precursor. Without wishing to be bound by theory, it is believed that the eompiexing of the cations with carboxylie groups in the gelling precursor can cause different regions of the gelling precursor to be pulled closer together, causing the gelling precursor to gel hi certain embodiments, the completing of the cations with carboxylic groups in the gelling precursor can result in encapsulation of one or more oilier polymers (e.g., a block copolymer) in a matrix of gelling precursor.
While calcium chloride has been described as a gelling agent, oilier types of gelling agents can be used. Examples of gelling agents include divalent cations such as alkali metal salts, alkaline earth metal sails, or transition metal sails that can ionicaHy cross-link with the gelling precursor, hi some embodiments, an inorganic salt such, as a calcium, barium, zinc or magnesium salt, can be used as a gelling agent.
Examples of cross-linking agents that may be used to react one or more of the polymers (e.g., polyvinyl alcohol) in reactor vessel 630 include one or more aldehydes (e.g., formaldehyde, glyoxal, benzaldehyde, a.erephthalaldehyde, succirsaldebyde, gluiaraklehyde) in combination with one or more acids, such as relatively strong acids (e.g.. sulfuric acid, hydrochloric acid, nitric acid) and/or relatively weak acids (e.g., acetic acid, formic acid, phosphoric acid).
In certain embodiments, it can be desirable to reduce the surface tension of the mixture contained in vessel 620 (e.g., when forming particles having a diameter of about 500 microns or less). This can be achieved, for example, by heating the mixture in vessel 620 (e.g., to a temperature greater than room temperature, such as a temperature of about 3O0C or more), by bubbling a gas (e.g., air, nitrogen, argon, krypton, helium, neon) through the mixture contained in vessel 620, by stirring (e.g., via a magnetic stirrer) the mixture contained in vessel 62O5 by including a surfactant in the mixture containing the gelling agent, and/or by forming a mist containing the gelling agent above the mixture contained in vessel 620 (e.g., to reduce the formation of tails and/or enhance the sphericity of the particles). hi certain embodiments, particles can be formed by omitting one or more of the- steps from the process described with reference to FIGS. 8A and SB. For example, one or snore of the polymers may noi be crosslinked, and/or the gelling precursor may not be removed.
As an additional example, FIGS. 9A-ΦF show a double-emulsion process that can be used, for example, to make particles that, like particle 400 (FlG. 5), include sub-pariicfes. First, drop generator 800 (e.g., a pipette) forms drops S 10 of art aqueous solution containing a water-soluble therapeutic agent (e.g., DNA) and a surfactant ,
In some embodiments, the surfactant can be water-soluble, Examples of surfactants include polyvinyl alcohols, poly(vinyl pyrrolidone) (PVP)5 and polvsorbaies (e.g..
TweerV* 20, Tween* 80). Drops 810 fell into a vessel 820 that includes a solution of a block copolymer (e.g., SlBS) and an organic-soluble therapeutic agent {e.g.. paelitaxel) dissolved in an organic solvent, forming a mixture 830. As shown in FIG, ζ*B. mixture 830 is then mixed (e.g., homogenized) using a stirrer 835, to produce a suspension 832 that includes sub-particles 404 suspended in solvent (PiG. 9C).
Mixing of mixture 830 can occur at a speed of. for example, at least about 5,000 revolutions per minute (e.g., at least about 7,500 revolutions per minute) and/or at most about 10,000 revolutions per minute (e.g., at most about 7,500 revolutions per minute). In some embodiments, mixture 830 can be mixed for a period of at least about one minute (e.g., at bast about two minutes, at least about five minutes, at least about seven minutes) and/or at roost about 10 minutes (e.g., at most about seven minutes, at most about five minutes, at most about two minutes). For example, mixture 830 may be mixed for a period of from about one minute to about five
.minutes.
After suspension 832 lias been formed, suspension 832 is added Io a drop generator 840 (FiG, 9O) to produce drops 850. Drops B50 fall into a vessel 870 that includes an aqueous solution, forming a mixture. 880. Irs some embodiments, the aqueous solution in vessel 870 includes a surfactant (e.g., PVA). As FIG. 9E shows, mixture SSO is mixed (e.g., homogenized) using a stirrer 885, at a mixing speed that is lower than the speed of the first mixing. In certain embodiments, mixture 880 can be mixed at a speed of at most about 2,000 revolutions per minute (e.g., at most about 1 ,500 revolutions per minute, at most about 1,000 revolutions per minute, at most about 500 revolutions per minute) and/or at least about 100 revolutions per minute (e.g., at least about 500 revolutions per minute., at least about LOOO revolutions per minute, at least about 1 ,500 revolutions per minute). This .second mixing can last for a period of, for example, at least about one minute (e.g., at least about two minutes, at least about tour minutes, at least about six .minutes, at least about eight minutes, at least about 10 minutes, at. least about 20 minutes, at least about 30 minutes, at least about 40 minutes, at least about 50 minutes, at least about one hour, at least about two hours, at least about four hours, at least about six hours, at least about eight hours, at least about 10 hours) and/or at most about 12 hours (e.g., at, most about 10 hours, at most about 8 hours, at most about 6 hours, at most about four hours, at most about two hours, at most about one hour, at most about 50 minutes, at most about 40 minutes, at most about 30 minutes, at .most about 20 minutes, at. most about 10 minutes, at most about eight minutes, at most about six minutes, at most about four minutes, at most about two minutes). Mixing (e.g., honiogeπization) of mixture 880 produces a suspension 89(5 including particles 400 in solvent (FIG. 9F). Particles 400 are then separated from the solvent Ce. i>., bv filtration) and dried fe.t»,. hv evaporation), In some embodiments, particles 400 are separated from the solvent by evaporating the solvent.
In certain embodiments, one or more of the therapeutic agents can be omitted frora the above-described process, in some embodiments, all of the therapeutic agents can be omitted from, the above-described process, such that the panicles that are produced do not include any therapeutic agent. Alternatively or additionally, one or more therapeutic agents can be added to the particles (e.g., by injection) after the particles have been formed.
.Methods of forming particles are described in, for example, Buiser el al, U.S. Patent Application Publication No. US 2003/0185896 A 1 , published on October 2, 2003: Lanphere et al., U.S. Patent Application Publication No. US 2004/0096662 Aϊ. published on May 20, 2004; Laiiphere ei. al, U.S. Patent Application Publication Ko. US 2005/0263916 AL published on December 1, 2005, and entitled "Embolization"; and Di€arlo ei a!.. U.S. Patent Application Serial No, 11/111,5! I5 filed on April 21, 2005, and entitled "Particles", all of which are herein incorporated by reference.
Exajngfes
The following examples are intended as illustrative and are not intended to be limiting.
Example 1 :
S IBS particles were prepared by a single-emulsion process as follows.
SfBS solutions were prepared by dissolving two grams (to form a two percent w/v solution), four grams (to form a four percent w/v solution), seven grams (to form a seven percent w/v solution), H) grams (to forrø a 10 percent w/v solution}, or 15 grams (to ibrm a 15 percent w/v solution) of SIBS (60 mol percent stymie) in 100 milliliters of methylene chloride (model 27056-3. 99.9 percent I! PLC grade, from Sigma).
The SIBS solutions were stirred overnight at ambient temperature in a sealed beaker at SOU revolutions per minute, using a multi-position stirrer (a model PC-171 Coming Scholar 171 stirrer) and stir bars (model 14-51 1-60, from Fisher)-
Polyvinyl alcohol (PVA) solutions were prepared by dissolving one gram (for a 0.1 percent w/v solution), two grams (for a 0,2 percent w/v solution), five grams (for a 0.5 percent w/v solution), 10 grams (for a one percent w/v solution), 20 grams (for a two percent w/v solution), or 50 grams (for a five percent w/v solution) of polyvinyl alcohol in 1000 milliliters of distilled water. The polyvinyl alcohol was lot number Pl 763, from Sigma (average molecular weight: 70,000-100,000).
The PVA solutions were stirred overnight at 4O0C (samples 1 -12) or 35°C (sample 13) using a hot plate (a model PC620 hotplate from Coming). The SfBS solutions were combined with the PVA solutions in a ratio of i :20
SIBS: PVA, to form samples 1-13 of SlBS particles. The starting materials that, were used to form each of these samples of SIBS particles are shown in Tabic ! , Five milliliters of each SIBS solution were added into a PVA solution by continuous dropping using a pipette, as the PVA solution was being homogenized at. a full speed of about 10,000 revolutions per minute (samples 1 - 1 1 and 1.3) or 5,000 revolutions per minute {sample 12)5 using a PowerGen Models 700D homogenker (Fisher so Scientific), Once all of a SIBS solution had been added into its corresponding FVA solution, the resulting S1BS/FVA solution was homogenized at K)5(K)O revolutions per minute (samples 3-1 1 and 13) or 5,000 revolutions per minute (sample 12} at room temperature (250C) for about one hour.
After horaogeπiza.ion had been completed, SIBS particles were filtered out of each SiBS/PVA solution using a vacuum filter (a MiHpore 47 mm All Glass Vacuum Fi Her fielder) and a filter paper of smaller than five microns (a Milipore Filter Membrane).
The SiBS particles that were filtered from eaeh solution were then washed
10 with distilled water, and filtered again. This wash and filtration step was repeated for a total of live limes, in order to remove residua! PVA from the SIBS panicles.
The SIBS particles were then collected and dried by evaporation overnight at room temperature (25°C),
Table 1 shows fee SIBS solution COnCeOtXiUiOn5 the PVA solution i ;.t concentration, and the SlBSiPVA Volume Ratio for the different samples of SIBS particles that were produced according to the above-described method.
Table 1
Figure imgf000052_0001
55
Figure imgf000053_0001
RGS. 10-14 are scanning election micrograph images, at 2Ox magnification, of sample I particles, sample 2 particles, sample 4 particles, sample 5 particles, and sample 6 particles, respectively. FIG. 15 is a scanning electron micrograph image, at 20x magnification, of sample 12 particles, which were formed at a homogenization speed of 5,000 revolutions per minute. A comparison of the sample 12 particles of FiG, 15 with the sample 2 particles of FiG. 11 (which were formed at a høroogemzation speed of 10,000 revolutions per minute) indicates that homogenkation speed may not have a significant effect on the sizes of the SIBS particles that are produced,
FIG. 16 is a scanning electron micrograph image, at 20x πiag∑ύiicaiion, of the sample 13 panicles, which were formed at a hornogenizatioπ temperature of about 350C. A comparison, of the sample 13 particles of FlG. 16 with the sample 2 panicles FiG. 1 1 (the main difference between the two samples being the homogeni nation temperature) indicates that homαgenization. temperature may affect particle size. It appears that as the homogenization temperature increases, particle size can also increase.
FIGS. 17-20 are scanning electron micrograph images, at 2 Ox magnification, of sample 7 particles, sample 9 particles, sample 10 particles, and sample 1 S particles, respectively. SIBS particles including Rhodamine-B were prepared by a single-emulsion process as follows. 'The R!iodaminc-B was used as a substitute for therapeutic agent, because it was relatively easy to determine whether the Rhodarøke-B, a highly visible dye, had been incorporated into the particles. Because Rhodarnine-B is soluble in organic solvents, the Rhodaraine-B m this example was used as an. indicator of whether an organic-soluble therapeutic agent (e.g., pacϋtaxel) could be incorporated into the particles.
EE^¥Mi^..o£!^
SiSS-Rhodamine solutions (four percent SlBS w/v) were prepared by dissolving two grams of SIBS (όO inoi percent stymie) and different amounts of Rhociamine-B { 10 milligrams, ! 00 milligrams, 200 milligrams, 300 milligrams, 400 milligrams, 100?) milligrams) in 50 milliliters of methylene chloride. The SlBS- Rhodamiπe solutions were stirred overnight in a sealed beaker, using a multi-position stirrer (a model PC-171 Corning Scholar 171 stirrer) and stir bars (mode! 14-51 1 -60, from Fisher),
PVA solutions (0.2 percent w/v) were prepared by dissolving from 0.2 gram of PVA in 1 (K) milliliters of distilled water. The PVA solutions were stirred overnight at a temperature of between 35'JC and 4QX using a hot plate (a model PC620 hotplate from Coming).
The PVA solutions ( 1 (K) milliliters) were poured into 100~milH!iter beakers and homogenized at IS0C and at foil speed (10,000 revolutions per minute), using a FoxverGeu Models 700D homogenizes* (Fisher Scientific). Five milliliters of each SISS-Rhodamine solution were slowly added to each PVA solution using a or.e- mifliliter pipette, and the resulting SIBS-Rhodarnine-PVA mixtures were homogenized for about one hour at ambient temperature, at about 1500 revolutions per miniile.
After homogenization had been completed, caeh SΪBS-Rhodamine-PVA solution was transferred into a larger beaker and stirred for at least 24 hours at. ambient temperature to allow the methylene chloride to evaporate, using a multi- position .stirrer (a model PC- 171 Coming Scholar 171 .stirrer) and sdr bars (model 14- 511-60. from Fisher),
Thereafter, the resulting SIBS-iihodamine particles were filtered through a U, 22 micron filter by vacuum filtration using a vacuum filter (a Milipore 47 mm All Glass Vacuum Filter Holder) and a filter paper of smaller than five microns (a MϊHpore Filter JViembrane}. Then, the SIBS-Rhodami«e particles: were lyopbilixcd overaighi using a Vir'Tis Sentry™ lyopliilizer (SP industries, Gardiner, NY), set at a temperature of -500C for the entirety of the iyophiiizatkm.
Table 2 shows the SlBS solution concentration, the PVA solution concentration, the SlBS~Rbodamiπe;PVA volume latio, and the amount of Rhodamms-B used for the different samples of SIBS-Rhodaiiiinc particle*; that were produced according to the above-described method.
Table 2
Figure imgf000055_0001
FIGS 21-26 show sample 14 particles, sample 15 particles, sample 16 particles, sample ) 7 particles, sample 18 particles, and sample 19 particles, respectively.
All of the SIBS-Rhodamioe particles that were prepared encapsulated the RhodarainoB. which indicates that the particles can be used to carry a therapeutic agent.
Example 3:
SIBS particles including fluorescein were prepared by a dαubk-eraulsiorc process as follows, The fluorescein, another highly visible dye, was used as a substitute for therapeutic agent. Because fluorescein is water-soluble, the fluorescein in this example was used as an indicator of whether a water-soluble therapeutic agent {e.g., DNA) could be incorporated into the particles.
Preparation of Huoreseem- Loaded SIBS Particles by Double Emulsion:
Five grams of SlBS (60 mo! percent styrene) were dissolved in 60 milliliters of methylene chloride to form a SIBS solution,
Fifty milligrams of fluorescein and 100 milligrams of PVA were dissolved in 50 milliliters of distilled water Io form a PVA-floorescein solution, Ten milliliters of the FVA-fiuoresceiπ solution, were added by pipette into 60 milliliters of the SlBS solution and homogenized for four minutes at 6000 revolutions per minute using a PowcrGeπ Models 700D homαgcmzer (Fisher Scientific). The homogenization produced a SlBS-iluorescein-PVA primary emulsion which included SSBS-lluoreseein primary particles. The SlBS-fluorescein primary particles are shown in PIG. 27.
Using a Pasteur pipette, the S IBS- fluorescein- PVA emulsion was then added ϋUϋ 540 milliliters of a 0, 1 percent PVA solution (including PVA and distilled water) and homogenized at 10,000 revolutions per raioute at 250C, for a total of 90 minutes. The resulting SIBS-flxjorescein secondary particles were stirred for about 18 hoars to harden the particles and evaporate the methylene chloride. A SIBS- iluorescdn secondary particle, which includes sub-particles, is shown in FlG. 28. Example 4:
Sf BS particles including fluorescein were prepared by a double vortex emulsion process as follows.
Figure imgf000057_0001
0,5 gram of SIBS (60 moi percent styrene) was dissolved in two milliliters of methylene chloride to form a S(BS solution, and one milligram uϊ fluorescein was dissolved in one milliliter of distilled water to form a fluorescein solution. The SiBS solution was then vortex ed for several minutes at room temperature
(25°C) using a Fisher Standard Vortex Mixer (catalog number 02-2 i 5-365} set at full speed, and 750 microliters of the fluorescein solution were added by pipette into two milliliters of the SlBS solution. The resulting mixture was vortex ed for 20 seconds. Two milliliters of a two percent PVA solution (including PVA and distilled water) were added by pipette to the mixture, and the mixture was vortex ed for an additional 20 seconds.
The resulting mixture was then poured into a beaker containing 100 milliliters of a 0.2 percent PVA solution, and stirred for one minute using a multi-position stirrer (a model PCM 71 Corning Scholar 171. stirrer) and stir bars (model 14-51 1-60, from Fisher).
Then, 100 milliliters of two percent isopropanαi were added into the beaker and stirred until the methylene chloride evaporated.
The resulting SJBS-fluoreseein particles were vacuum-filtered and washed with distilled water three times, "Che SIBS-fiuorescein particles are shown in FfG. 29.
Other Embodiments
While certain embodiments have been described, other embodiments are possible.
As an example, irs certain embodiments a particle can include a block copolymer and a bioabsorbabie and/or bioerodible material dispersed uniformly or rsors-uniforaily throughout the block copolymer. The bioabsorbabie and/or bioerodiblε material can. for example, help to delay and/or moderate therapeutic agent release (mm the particle.
As ail additional example, in some embodiments in which a particle that includes a block copolymer is used for embolization, the particle can also include one 5 or more other embolic agents, such as a sclerosing agent (e.g., etbanol), a liquid embolic agent (e.g., n-bulyl-cyanoacrykte), and/or a fibrin agent. The other embolic agent(s) can enhance the restriction of blood How at a target site.
As another example, in certain embodiments, a particle that includes a hydrogel can also include a coating that is formed of a hberodibie and/or
10 bioabsorbabie material. As an example, a particle can include an interior region thai is formed of a hydrogel and that is coated with a coating including a bioerodibie and/or bioabsorbable material, As another example, a particle can include an interior region that is coated with a hydrogel, and the hydrogel coating can further be coated with a bioerodibie and/or bioabsorbable material. As an additional example, a particle
15 can include an interior region that is formed of a hydrugeϊ and that is coated with a block, copolymer, and the block copolymer coating can further be coated with a bioerodibie and/or bioabsorbable material 'The presence of the bioerodibie and/or bioabsorbable material in the above particles can, for example, cause a delay in the swelling of the hydrogel. In some embodiments, the hydrogel may not begin to swell
;?Q until the bioerodibie and/or bioabsorbable material has at least partially or completely eroded and/or been absorbed.
As Ά further example, in some embodiments a particle does not include any therapeutic agents.
As another example, in. some embodiments a particle can be porous, In certain
25 embodiments, a porous particle can have a substantially uniform pore structure, In some embodiments, a porous particle can have a non-uniform pore structure. For example, the particle can have a substantially non-porous interior region (e.g., formed of a polyvinyl alcohol) and a porous exterior region (e.g., formed of a mixture of a polyvinyl alcohol and alginate). Porous particles are described, for example, in 0 Lanphere et al., U.S. Patent Application Publication No, US 2004/0096662 Al , published on May 20, 2004, which is incorporated herein by reference. As ixn additional example, In certain embodiments, a particle can be formed without pores (non-porous particle).
As a further example, in some embodiments, a particle {either porous or non- porous) can include ai least one cavity (a hollow central region in the particle). In δ certain embodiments in which a particle includes a cavity, the particle can further include pores in the material surrounding the cavity. For example, FIG, 30 shows a particle 900 with a cavity 902 surrounded by a matrix material 906 (e.g., s piiJymer) that includes pores 904.
As another example, in some embodiments, a particle that includes a block 0 copolymer can aϊso include a shape memory material, which is capable of being configured to remember (e.g., to change to) a predetermined configuration or shape. In. certain embodiments, particles that include a .shape memory material can be selectively transUioned from a first state to a second state. For example, a heating device provided in the .interior of a delivery catheter can be used to cause a particle 5 including a shape memory material to transition from a first state to a second stale. Shape memory materials and particles that include shape memory .materials are described in, for example. Boil et aL U.S. Patent Application Publication No. US 2004/0091543 A J , published on May 13. 2004, and DiCarlo et ai.. U.S. Patent Application Publication No. US 2005/0095428 A L published on May 5, 2005, both of G which are incorporated herein by reference.
As an additional example, in some embodiments, a particle that includes a block copolymer can also include a surface preferential material. Surface preferential materials are described, for example, in DiCarlo et a)., U.S. Patent Application Publication No. US 2005/0196449 A L published on September S, 2005, and entitled 5 "Embolization1*, which is incorporated herein by reference.
As a further example, while homogemzation has been described in the singie- emuision and double-emulsion processes that can be used to form particles (e.g. panicles including SIBS), in some embodiments, voriexing or sonieatioti can be used as an alternative to, or in addition to. homogenmition, 0 As another example, in certain embodiments, particles can be linked together to form particle chains, for example, the particles can be connected to eaeh otber by links that are formed of one or more of the same materials) as the particles, or of one or more different rnateriai(s) from the particles. Particle chains and methods of making particle chains are described, for example, in Buiser et al, U.S. Patent Application Publication No. US 2005/0238870 Al . published on October 27, 2005, and entitled "Embolization", which is incorporated herein by reference.
As an additional example, in some embodiments one or more particles is/arc substantially nonspherical. In some embodiments, particles can be mechanically shaped during or after the particle formation process to be nonspberical (e.g., ellipsoidal}. In certain embodiments, particles can be shaped (e.g., molded, compressed, punched, and/or agglomerated with other particles) at different points in the particle manufacturing process. As an example, in some embodiments in which particles include SIBS, the particles can be sufficiently flexible and/or mold able to be shaped. As another example, in certain embodiments in which particles are formed using a gelling agent, the panicles can be physically deformed into a sped Sc shape and/or size after the particles have been contacted with the gelling agent, but before the polymer(s) in the particles have been cross-linked. After shaping, the po!ymeτ(s} (e.g., polyvinyl alcohol) in the particles can be cross-linked, optionally followed by substantial removal of gelling precursor (e.g., alginate). While substantially spherical particles have heesi described, in some embodiments, noπspheπca! particles can be manufactured and fanned by controlling;, for example, drop formation conditions, in some embodiments, noπspherkal particles can be Conned by post-processing the particles (e.g., by cutting or dicing into other shapes). Particle shaping is described, for example, in Baldwin er. a!., U.S. Patent Application Publication No. IJS 2003/0203985 AL published on October 30, 2003, which, is incorporated herein by reference.
As a further example, in some embodiments, particles can be used for tissue bulking. As an example, the particles can be placed (e.g., injected) into tissue adjacent to a body passageway. The particles can narrow the passageway, thereby- providing bulk and allowing the tissue to constrict the passageway more easily. The particles can be placed in the tissue according to a number of different methods, for example, pereυtaπeomly; laparoscopically, and/or through a catheter, ϊn certain embodiments, a cavity can be formed in the tissue, and the particles can be placed in (he cavity. Particle tissue bulking can be used to treat, for example, intrinsic sphincteric deficiency (ISD), vesicoureteral reflux, gastroesophageal reflux disease (GERD), and/or vocal cord paralysis (e.g., to restore glottic competence in cases of 5 paralytic dysphoria). In some embodiments, particle tissue bulking can be used to treat urinary incontinence and/or fecal incontinence. 'The particles can be used as a graft material or a tiller to fill and/or to smooth out soft tissue defects, such as for reconstructive or cosmetic applications (e.g.. surgery). Examples of soft tissue defect applications include clef! Lips, scars (e.g., depressed scars from chicken pox or acne
10 scars), indentations resulting from liposuction, wrinkles (e.g., glabella frown wrinkles), and soft tissue augmentation of thin lips. Tissue bulking is described, for example, in Bourne el aL U.S. Patent Application Publication No. US 2003/0233150 AK published on December 18. 2003, which is incorporated herein by reference.
As an additional example, in some embodiments, particles can be used in an
15 ablation procedure. For example, the particles may include one or more ferromagnetic materials and may he used to enhance ablation at a target site. Ablation is described, for example, in Rioux et aL, U.S. Patent Application. Publication No, US 2004/0101564 Al , published on May 27, 2004; La.nph.ere et aL U.S. Patent Application Publication No. US 2005/0129775 A l. published on June 16, 2005, and
?.o entitled "Ferromagnetic Particles and Methods": ami Lanphere et aL, U.S. Patent Application Serial No. 1 1/117,156, filed on April 28, 2005, and entitled "Tissue- Treatment Methods", all of which are incorporated herein by reference.
As another example, in some embodiments a solution can be added to the nozzle of a drop generator to enhance the porosity of particles produced by the drop
25 generator. Ox am pies of porosity-enhancing solutions include starch, sodium chloride at a relatively high concentration (e.g., more than about 0.9 percent, from about one percent to about five percent, from about one percent to about two percent), and calcium chloride (e.g., at a concentration of at least about 50 mM). For example, calcium chloride can be added to a sodium alginate gelling precursor solution to
30 increase the porosity of the particles produced from the solution. As a further example, while certain methods of making particles have been described, in some embodiments, other methods can be used to make particles. For example, in some embodiments (e.g., hi some embodiments in which particles having a diameter of less than about one micron are being formed), particles can be formed. using rotor/stator technology (e.g., Folytron* roior/stator technology from Kinmatica hie), high-pressure homogenύation (e.g., using an APV-Gauliπ micro tlokfeer or Gaulin homogeuizer), mechanical shear (e.g.. using a Gifford Wood colloid mill), and/or ultrasonification (e.g., using either a probe or a flow-through cell),
As an additional example, in some embodiments, particles having different shapes, sizes, physical properties, and/or chemical properties, can be used together in an embolization procedure. The different particles can be delivered into the body of a subject in a predetermined sequence or simultaneously, hi certain embodiments, mixtures of different particles can he delivered using a multi-lumen catheter and/or syringe. In some embodiments, particles having different, shapes and/or sizes can be capable of interacting synergistieaily (e.g., by engaging or interlocking) to .form a well -packed occlusion, thereby enhancing embolization. Panicles with different shapes, sizes, physical properties, and/or chemical properties, and methods of embolization using such particles arc described, for example, in Bell et a)., U.S. Patent Application Publication No. US 2004/0091543 Al, published on May 13, 2004, and in DiCario et a!., U.S. Patent Application Publication No. US
2005/0095428 Ai, published on May 5, 2005, both of which are incorporated herein by reference.
Other embodiments arc in the claims.
6 !

Claims

WHAT IS CLAIMED IS:
1. A particle, comprising: s biocompatible block copolymer including at least one first block having a glass transition temperature of at most 37"C and at least one second block having a glass transition temperature of greater than 37°C, wherein the particle has a diameter that is selected from the group consisting ofless than about 100 microns, from about 30(3 microns to about 500 microns, from about 700 microns to about 900 microns, and from about 1 ,000 microns to about 1 ,200 microns.
2, The particle of claim 1 , wherein the particle has a diameter of less than about H)O microns.
3 , The particle of claim 1 , wherein the particle has a diameter of from about 300 micrqπs to about 500 microns.
4. The particle of claim 1 , wherein the particle has a diameter of from about 700 microns to about 900 microns,
5, The particle of claim L wherein tSie particle has a diameter of from about 1 ,000 microns to about 1,200 microns.
6. The particle of claim 1 , wherein the at least one first block comprises at least one polyolefiri block.
7. The particle of claim 1 , wherein the at least one first block comprises at least one isobutvlene monomer.
8. The particle of claim 1. wherein the at least one second block comprises at least one block selected from the group consisting of vinyl aromatic blocks, rnethacrylate blocks, and combinations thereof
(λ The particle of claim 1 , wherein the at least one first block comprises at least one isobtuylene monomer and the at least one second block comprises at least one monomer selected .from the group consisting of. stymie, u-methyistyrsne, and combinations thereof.
10. The particle of claim 1, wherein the block copolymer has the formula
X-(AB),.. A comprises the at least one first block, A is a. polyolefm block, B comprises the at least one second block, B is a vinyl aromatic block or a met!) aery late block, n is a positive whole number, and X is an initiator.
1 1 . The particle of claim 10, wherein A has the formula (CRR'-
OH;;)n , R- and R' are linear or branched aliphatic groups or cyclic aliphatic groups, and B is a methaerylate block.
12. The particle of claim TL wherein B comprises at least one monomer selected from the group consisting of røethyimethaerylate, ethylmethacryiate, hydroxyethyi meihaeryiaie, and combinations thereof.
1 ?. The particle of claim 10, wherein A has the formula — (CRR-
Clhh , R and R* are linear or branched aliphatic groups or cyclic aliphatic groups, and B is a vinyl aromatic block.
14. The particle of claim 13, wherein the at least one poiyolefio block comprises at least one isobulylene .monomer and the at least one vinyl aromatic block composes at least one monomer selected from the group consisting of styrene, α- meihγlstγrene, and combinations thereof.
15. 'The particle of claim ! , further comprising a therapeutic agent.
16, The particle of claim 1 , wherein the block copolymer forms a coating on the particle.
17. The particle of claim 1 , further comprising a hioabsorbable material.
18, The particle of claim 1, further comprising a hydrogel.
19. The particle of claim 1 , wherein the block copolymer has the formula
BAB or ASA, in which A is the at least one first block and B is the at. leas: one second
20, The particle of claim I, wherein the block copolymer has the formula has the formula B(AB)n or A(BA)n, in which A is the at least one first block, B is the at [east one second block, and Ώ is a positive whole number.
21. The particle of claim 1 , further comprising a second polymer.
22. Hie particle of claim 21, wherein the second polymer is blended with the block copolymer,
23. The particle- of claim 21 , wherein the second polymer comprises a second block copolymer.
24, A particle, comprising: a biocompatible block copolymer including at least one first block having a glass transition temperature of at most 370C and at bast one second block having a glass transition temperature of greater than 370C, wherein the particle has a diameter of about 1 ,050 microns or more. 25, The particle of claim 24, wherein the particle has a diameter of about 1 ,070 microns or more.
26, The panicle of claim 24, wherein the particle has a diameter of about i ,0% microns or more.
27, The particle of claim 24, wherein the particle has a diameter of about 1 , 100 microns or more.
28. 'The particle of claim 24, wherein the particle has a diameter of about i ,150 microns or more.
29. A particle, comprising: a matrix comprising a biocompatible block copolymer including at least one first, block having a glass transition temperature of at most 37°C and at least one second block having a glass transition temperature of greater than 370C; and at least orse sub-particle that is at least partially disposed within the matrix, wherein the particle has a diameter that is selected from the group consisting of less than about 100 microns, from about 300 microns to about 500 microns, ironi about 700 microns to about 900 microns, and from about 1 ,000 microns to about 1,200 microtis.
30. The particle of claim 29, wherein the at least one sub-particle comprises a plurality of sub-particles.
31. The particle of claim 29, further comprising a first therapeutic agent,
32. The particle of claim 31 , further comprising a second therapeutic agent- thai is different from the first, therapeutic agent.
33. A particle, comprising: a matrix comprising a biocompatible block copolymer including at least one first block having a glass transition temperature of at most 37°C and at least one second block having a glass transition temperature of greater than 370C; and at least one sub-particle that is at least partially disposed within the matrix, wherein the rmrticle has a diameter of about i .050 microns or more.
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