EP0712421A1 - Nanopartikel und mikropartikel aus nichtlinearen hydrophilen-hydrophoben multiblockcopolymeren - Google Patents

Nanopartikel und mikropartikel aus nichtlinearen hydrophilen-hydrophoben multiblockcopolymeren

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Publication number
EP0712421A1
EP0712421A1 EP94925102A EP94925102A EP0712421A1 EP 0712421 A1 EP0712421 A1 EP 0712421A1 EP 94925102 A EP94925102 A EP 94925102A EP 94925102 A EP94925102 A EP 94925102A EP 0712421 A1 EP0712421 A1 EP 0712421A1
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EP
European Patent Office
Prior art keywords
acid
particle
group
polymer
poly
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP94925102A
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English (en)
French (fr)
Inventor
Abraham J. Domb
Ruxandra Gref
Yoshiharu Minamitake
Maria Teresa Peracchia
Robert S. Langer
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Massachusetts Institute of Technology
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Massachusetts Institute of Technology
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Publication date
Priority claimed from US08/096,370 external-priority patent/US5543158A/en
Priority claimed from US08/210,677 external-priority patent/US5565215A/en
Application filed by Massachusetts Institute of Technology filed Critical Massachusetts Institute of Technology
Publication of EP0712421A1 publication Critical patent/EP0712421A1/de
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6927—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
    • A61K47/6929—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
    • A61K47/6931—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer
    • A61K47/6935—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
    • A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
    • A61K49/223—Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A61K51/1241—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A61K51/1241—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins
    • A61K51/1244—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins microparticles or nanoparticles, e.g. polymeric nanoparticles
    • A61K51/1251—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins microparticles or nanoparticles, e.g. polymeric nanoparticles micro- or nanospheres, micro- or nanobeads, micro- or nanocapsules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/66—Polyesters containing oxygen in the form of ether groups
    • C08G63/664—Polyesters containing oxygen in the form of ether groups derived from hydroxy carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G81/00—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • This invention is in the area of biodegradable block copolymers and nanoparticles and microparticles for the controlled delivery of biologically active materials and diagnostic purposes made from the polymers.
  • a major challenge in the area of the parenteral administration of biologically active materials is the development of a controlled delivery device that is small enough for intravenous application and which has a long circulating half-life.
  • Biologically active materials administered in such a controlled fashion into tissue or blood are expected to exhibit decreased toxic side effects compared to when the materials are injected in the form of a solution, and may reduce degradation of sensitive compounds in the plasma.
  • a number of injectable drug delivery systems have been investigated, including microcapsules, microparticles, liposomes and emulsions.
  • a significant obstacle to the use of these injectable drug delivery materials is the rapid clearance of the materials from the blood stream by the macrophages of the reticuloendothelial system (RES) .
  • RES reticuloendothelial system
  • polystyrene particles as small as sixty nanometers in diameter are cleared from the blood within two to three minutes.
  • block copolymers based on poly(ethylene glycol) and poly(propylene glycol) their half-lives were significantly increased.
  • European Patent Application Nos. 0 520 888 Al and 0 520 889 Al disclose nanoparticles made from linear block copolymer of polylactic acid and poly(ethylene glycol) for the controlled administration of biologically active materials.
  • the applications do not disclose how to modify the copolymer to vary the profile of drug release or how modifying the copolymer would affect distribution and clearance of the delivery devices in vivo .
  • the applications also do not teach how to prepare nanoparticles that are targeted to specific cells or organs, or how to prepare nanospheres that are useful for gamma-imaging for diagnostic purposes.
  • injectable particles are described which are formed of a biodegradable solid core containing a biologically active material and poly(alkylene glycol) moieties on the surface or of block copolymers of the poly(alkylene glycol) moieties with biodegradable polymers, which exhibit increased resistance to uptake by the reticuloendothelial system.
  • Non-linear multiblock copolymers are prepared by covalently linking a multifunctional compound with one or more hydrophilic polymers and one or more hydrophobic bioerodible polymers to form a polymer including at least three polymeric blocks.
  • one or more hydrophilic polymers such as polyethylene glycol (PEG) chains or polysaccharide moieties, are covalently attached to a multifunctional molecule such as citric acid or tartaric acid, leaving one or more active hydroxyl, carboxylic acid or other reactive functional groups available to attach the hydrophobic polymer(s) .
  • the hydrophobic polymer such as polylactic acid (PLA) , polyglycolic acid CPGA) , polyanhydrides, polyphosphazenes or polycaprolactone (PCL) , is then covalently linked to the multifunctional compound via an appropriate reaction such as ring opening or condensation polymerization.
  • the multiblock copolymers can have several short PEG chains, for example, with a molecular weight less than 1000, attached to the multifunctional compound.
  • Ligands can be attached to one or more polymer chains to achieve a variety of properties for a wide range of applications.
  • the block copolymers are useful in forming coatings on implantable devices and, in the most preferred embodiment, nanoparticles and microparticles that are not rapidly cleared from the blood stream by the macrophages of the reticuloendothelial system, and that can be modified as necessary to achieve variable release rates or to target specific cells or organs as desired.
  • the particles can incorporate within or on their surface a substance to be delivered for either therapeutic or diagnostic purposes.
  • the hydrophilic polymer is a poly(alkylene glycol) (PAG) .
  • PAG poly(alkylene glycol)
  • the terminal hydroxyl group of the poly(alkylene glycol) or other hydrophilic polymers can be used to covalently attach molecules onto the surface of the particles.
  • Materials incorporated onto or within the particles include biologically active molecules and targeting molecules such as antibodies immunoreactive with specific cells or organs, compounds specifically reactive with a cell surface component, magnetic particles, detectable materials such as radiopaque materials for diagnostic imaging, other substances detectable by x-ray or ultrasound such as air, fluorescence, magnetic resonance imaging, and molecules affecting the charge, lipophiucity or hydrophilicity of the particle.
  • biologically active molecules and targeting molecules such as antibodies immunoreactive with specific cells or organs, compounds specifically reactive with a cell surface component, magnetic particles, detectable materials such as radiopaque materials for diagnostic imaging, other substances detectable by x-ray or ultrasound such as air, fluorescence, magnetic resonance imaging, and molecules affecting the charge, lipophiucity or hydrophilicity of the particle.
  • the typical size of the particles is between approximately 80 nm and 10,000 nm, preferably between 80 nm and 400 nm, although microparticles can also be formed as described herein.
  • the particles can be administered by a variety of ways, although a preferred embodiment is by intravenous administration.
  • the particles are easily lyophilized and redispersed in aqueous solutions. Biodistribution experiments indicate that the particles have a prolonged half-life in the blood compared to particles not containing poly(alkylene glycol) moieties on the surface.
  • Figures la, lb, and lc are schematic representations of nanospheres formed of multiblock copolymers made by covalently linking a multifunctional compound with one or more hydrophilic polymers and one or more hydrophobic bioerodible polymers.
  • Figure 2a is a schematic illustration of the synthesis of (PEG) 3 -citrate-polylactide, (PEG) 3 - citrate-polycaprolactone and (PEG) 3 -citrate- polysebacic acid, in which the polyethylene glycol blocks can be functionalized with a ligand.
  • Figure 2b is a schematic illustration of multiblock copolymers of tartaric acid and mucic acid with polylactic acid (PLA) , polycaprolactone (PCL) , polysebacic acid (PSA) and polyglycolic acid (PGA) hydrophobic blocks, and polyethylene glycol (PEG) hydrophilic blocks.
  • PLA polylactic acid
  • PCL polycaprolactone
  • PSA polysebacic acid
  • PGA polyglycolic acid
  • PEG polyethylene glycol
  • Figure 2c is a schematic illustration of PEG- di-PLA.
  • Figure 2d is a schematic illustration of multiblock copolymers of benzene tetracarboxylic acid with polyethylene glycol (PEG) and polylactic acid (PLA) or polysebacic anhydride (PSA) blocks.
  • PEG polyethylene glycol
  • PLA polylactic acid
  • PSA polysebacic anhydride
  • Figure 2e is a schematic illustration of the synthesis of butane diglycidyl ether-based tetra- arm diblock copolymers with polylactic acid (PLA) and polyethylene glycol (PEG) blocks.
  • PLA polylactic acid
  • PEG polyethylene glycol
  • Figure 2f is a schematic illustration of multiblock copolymers of the 1,4-3,6-dilactone of glucaric acid with ligand, polylactic acid (PLA) and polyethylene glycol (PEG) blocks.
  • Figure 2g is a schematic illustration of (PEG) 3 -citrate-polylactide in which the PEG blocks are further functionalized with a ligand or PLA.
  • Figure 2h is a schematic illustration of PLA-citrate-dextran and PLA-2-hydroxyadipaldehyde- Dextran.
  • FIG. 2i is a schematic illustration of PEG 2-hydroxyadipaldehyde-PLA in which the PEG can be functionalized with a ligand or a methyl group.
  • the non-linear block copolymers in each of figures 2a through 2i were synthesized from poly(ethylene glycol) [PEG] of the molecular weights 600, 1900, 5,000; 12,000; and 20,000, and polylactide (PLA) , polyglycolide, polycaprolactone (PCL) , or polysebacic anhydride (PSA) .
  • Non-linear multiblock copolymers are prepared by covalently linking a multifunctional compound with one or more hydrophilic polymers and one or more hydrophobic bioerodible polymers to form a polymer including at least three polymeric blocks.
  • one or more hydrophilic polymers such as polyethylene glycol (PEG) chains or polysaccharide moieties, are covalently attached to a multifunctional molecule such as citric acid or tartaric acid, leaving one or more active hydroxyl, carboxylic acid or other reactive functional groups available to attach the hydrophobic polymer(s) .
  • the hydrophobic polymer such as polylactic acid (PLA) , polyglycolic acid (PGA) , polyanhydrides, polyphosphazenes or polycaprolactone (PCL) , is then covalently linked to the multifunctional compound via an appropriate reaction such as ring opening or condensation polymerization.
  • Particles formed of the coblock polymers are disclosed that are not rapidly cleared from the blood stream by the macrophages of the reticuloendothelial system as the particles not surface modified with hydrophilic polymers, and that can be modified as necessary to achieve variable release rates or to target specific cells or organs as desired.
  • the particles are useful to administer biologically active materials in a controlled manner for a wide variety of purposes.
  • Hydrophilic Polymers including but not limited to poly(alkylene glycols) (which can also be referred to as a poly(alkylene oxide) , if the polymer was prepared from an oxide instead of a glycol) and polysaccharides, are employed as the hydrophilic portion of the multiblock copolymer.
  • Hydrophilic polymers other than poly(alkylene glycol) that can be used include polypyrrolidone, poly(amino acids), including short non-toxic and non-immunogenic proteins and peptides such as human albumin, fibrin, gelatin and fragments thereof, dextrans, and poly(vinyl alcohol) .
  • poly(alkylene glycol) refers to a polymer of the formula HO-[ (alky1)0] y - OH, wherein alkyl refers to a C ! to C 4 straight or branched chain alkyl moiety, including but not limited to methyl, ethyl, propyl, isopropyl, butyl, and isobutyl.
  • Y is an integer greater than 4, and typically between 8 and 500, and more preferably between 40 and 500.
  • poly(alkylene glycols) include poly(ethylene glycol), polypropylene 1,2- glycol, poly(propylene oxide) and polypropylene 1,3-glycol.
  • a preferred hydrophilic polymeric moiety is PEG of a molecular weight of between approximately 300 to 20,000. To ensure elimination from the body, the molecular weight of the polyethylene glycol should be between approximately 300 and 20,000 Daltons, the molecular weight of polysaccharides should be 40,000 or less, and the molecular weight of proteins should be 70,000 or less.
  • hydrophobic Polymers should be bioerodible, biocompatible, and have a terminal group that can react with the terminal functional group, such as a hydroxyl, thiol, amino, carboxy, aldehyde or other functional group of the multifunctional molecule to form a covalent linkage.
  • Terminal functional group such as a hydroxyl, thiol, amino, carboxy, aldehyde or other functional group of the multifunctional molecule to form a covalent linkage.
  • Multiblock copolymers containing polylactic acid moieties are a preferred embodiment.
  • the copolymer of lactic acid and glycolic acid as well as other polymers such as polyanhydrides, polyphosphazenes, polymers of ⁇ - hydroxy carboxylic acids, polyhydroxybutyric acid, polyorthoesters, polycaprolactone, polyphosphates, or copolymers prepared from the monomers of these polymers can be used to form the multiblock copolymers described herein.
  • the variety of materials that can be used to prepare the block copolymers forming the particles significantly increases the diversity of release rate and profile of release that can be accomplished in vivo .
  • a polyester of poly(lactic-co-glycolic)acid is used as a hydrophobic erodible polymer bound to the multifunctional compound.
  • PLGA poly(lactic-co-glycolic)acid
  • the molecular weight and the chemical composition and stereochemical configuration of the polymer will affect the solubility of the polymer in various organic solvents as well as the crystallinity of the polymer.
  • a copolymer of lactic acid and glycolic acid is preferable.
  • the hydrophobic, bioerodible polymers are soluble in ethyl acetate or acetone.
  • Ethyl acetate or acetone is preferred over other organic solvents such as dichloromethane and chloroform because they are less toxic for in vivo applications.
  • Poly L-lactide is a polymer with a high degree of crystallinity. Poly D,L-lactide is less crystalline and more soluble in organic solvents. A random copolymer of D,L-lactide and glycolide in the ratio of 75:25 is very soluble in organic solvents, in particular in ethyl acetate. This copolymer is completely amorphous, which renders it a useful polymer for the fabrication of nanospheres and microspheres for controlled release.
  • Poly-L-lactide has a degradation time in vitro of months to years. The long degradation time is due to its higher crystallinity which protects the polymer from water penetration. Since D,L-lactide is amorphous, its degradation time is typically one to a number of months. Poly-glycolide also has a crystalline structure and a degradation time of one to several months. D,L-PLGA is amorphous, with a degradation time in vitro of weeks to months. As the glycolic acid ratio is increased, the rate of degradation is enhanced.
  • Lactic acid has bulky methyl groups on the alpha carbon (-0-CH(CH 3 -CH-) which makes it difficult for water molecules to access the ester, while glycolic acid has a proton on the alpha carbon (-0-CH 2 -CO-) , which allows easier access of water molecules to the ester bonds.
  • the molecular weight of the hydrophilic and hydrophobic regions of the particle affect the water solubility of the particles and thus their stability in aqueous solutions.
  • the multiblock copolymers formed by covalently linking a multifunctional compound with one or more hydrophilic polymers, preferably poly(alkylene glycol) (PAG), more preferably poly(ethylene glycol) , and one or more hydrophobic polymers can be prepared by a number of methods.
  • One method involves protecting one end of the hydrophilic polymer, for example, polyethylene glycol, and reacting the functional group at the unprotected end with one or more reactive groups on the multifunctional compound. Then, the remaining reactive groups on the multifunctional compound can be reacted with one or more hydrophobic bioerodible polymers, followed by removal of the protecting groups.
  • Preferred protected polyalkylene glycols include monomethoxy poly(alkylene glycols) , such as monomethoxy-PEG or PEG protected with another oxygen protecting group known to those of skill in the art, such that one terminal hydroxyl group is protected and the other is free to react with the polymer.
  • a second method involves reacting a hydrophobic bioerodible polymer, with one terminal functional group protected, with one or more reactive groups on the multifunctional compound, and then reacting a protected hydrophilic polymer with one or more reactive groups remaining on the multifunctional compound.
  • a carboxylic acid group on the multifunctional compound can be reacted with a poly(alkylene glycol) terminated with an amino function (available from Shearwater Polymers, Inc.) to form an amide linkage, which is in general stronger than an ester linkage.
  • the amide linkage may provide a longer period of retention of the poly(alkylene glycol) on the surface of the nanoparticle.
  • Methods of linking amino groups with carboxylic acid groups to form amides are well known to those skilled in the art.
  • a thiol group on a polymer can be reacted with a carboxy group on the multifunctional compound to form a thioester linkage. Methods of forming thioester linkages are known to those skilled in the art.
  • amino groups on a polymer can be coupled with amino groups on a multifunctional compound using a crosslinking agent such as glutaraldehyde.
  • a crosslinking agent such as glutaraldehyde.
  • Other multiblock copolymers terminated with poly(alkylene glycol), and in particular, poly(ethylene glycol) can be prepared using the reactions described above, using a branched or other suitable poly(alkylene glycol) and protecting the terminal groups that are not to be reacted.
  • a multiblock copolymer is prepared by reacting the terminal group of the hydrophobic polymeric moiety such as PLA or PLGA with a suitable polycarboxylic acid monomer, including but not limited to 1,3,5- benzenetricarboxylic acid, butane-1,1,4- tricarboxylic acid, tricarballylic acid (propane- 1,2,3-tricarboxylic acid), and butane-1,2,3,4- tetracarboxylic acid, wherein the carboxylic acid moieties not intended for reaction are protected by means known to those skilled in the art.
  • a suitable polycarboxylic acid monomer including but not limited to 1,3,5- benzenetricarboxylic acid, butane-1,1,4- tricarboxylic acid, tricarballylic acid (propane- 1,2,3-tricarboxylic acid), and butane-1,2,3,4- tetracarboxylic acid, wherein the carboxylic acid moieties not intended for reaction
  • the protecting groups are then removed, and the remaining carboxylic acid groups reacted with a hydrophilic polymer, such as a poly(alkylene glycol) .
  • a hydrophilic polymer such as a poly(alkylene glycol)
  • a di, tri, or polyamine is similarly used as the branching agent.
  • Nanospheres can be prepared from the block copolymers by emulsion/evaporation techniques using the pre-for ed copolymer.
  • the pre-formed polymer and, optionally, a substance to be delivered, if soluble in an organic solvent, can be dissolved in an organic solvent.
  • Loadings can be about 25 mg polymer/2 ml methylene chloride, and the substance to be delivered in approximately between 10% and 50% of the weight of the polymer.
  • the resulting organic solution can be emulsified with an aqueous phase by vortexing and then sonicated, typically for 1 minute, at approximately a 40 watt output.
  • amphiphilic multiblock copolymers can form nanospheres with a biodegradable and dense core able to entrap drugs or other compounds, and with an effective coating to prevent the rapid recognition by the immune system.
  • the different solubilities of the hydrophilic and hydrophobic blocks, for example, PEG and a polyester or polyanhydride, in water and organic solvents allows one to obtain the desired phase-separated structure of the nanospheres.
  • the organic phase, containing polymer and drug can be emulsified with water without adding any further stabilizer, because of the surfactant properties of the multiblock copolymer.
  • the hydrophilic block migrates to the water interface, and the hydrophobic block remains inside the droplets and forms the solid biodegradable core after solvent evaporation.
  • Sub-200 nm size particles with a high PEG density on the surface can be obtained using a high energy form such as ultrasound.
  • AFM analysis indicates that nanospheres prepared in this manner are spherical, and QELS showed that the particle size of nanospheres prepared in this manner are in the range of between 180 and 240 nm and have a unimodal size distribution.
  • the mixture of block copolymer and substance to be delivered can be mixed in a common solvent such as ethyl acetate or methylene chloride.
  • the organic solvent is a nonsolvent for the hydrophilic polymers, and a solvent for the hydrophobic polymers.
  • An emulsion can be formed by adding water, preferably distilled deionized water, to the solution. Slow evaporation of the organic solvent allows a reorganization of the polymer chains inside and on the surface of the droplets.
  • the hydrophilic polymers which are preferably insoluble in the organic solvent, tend to migrate to the aqueous phase, while the hydrophobic polymers, which are not soluble in water, remain inside the droplets and forms the core of the nanospheres after the solvent is evaporated.
  • PEG chains inside the core should be avoided, because this can lead to absorption of water by the core followed by the accelerated and uncontrolled release of the drugs.
  • the particles can be isolated from the aqueous phase by centrifugation. They can later be readily redispersed in water.
  • acetone, methanol, or ethanol and their aqueous solutions can be used in place of the distilled deionized water.
  • water is preferred because it forces a higher concentration of poly(alkylene glycol) to the surface of the particle.
  • acetone can be used as the precipitating solvent if the hydrophobic polymer, for example, polyanhydride, is sensitive to water.
  • the multiblock copolymer can be blended with a linear hydrophobic-hydrophilic copolymer, for example PLGA-PEG mixed with PLGA or PLA, prior to fabrication into the particles, to provide different properties on the particles, for example, altering their half-life in vivo .
  • a linear hydrophobic-hydrophilic copolymer for example PLGA-PEG mixed with PLGA or PLA
  • PLGA-PEG linear hydrophobic-hydrophilic copolymer
  • PLA linear hydrophobic-hydrophilic copolymer
  • the linear copolymer can be mixed with the multiblock copolymer in a ratio of greater than 0 up to 100 percent by weight and optimally, between 10 and 100 percent by weight.
  • the substance to be delivered can be mixed with the copolymer or copolymer blend in a ratio of greater than 0 to 99, and more preferably, in a ratio of 1 to 70.
  • Characterization studies were carried out at different drug loadings to investigate encapsulation properties and morphological characteristics of PEG-polyanhydride and PEG- polyester nanospheres. Particle size was measured by quasi-elastic light scattering (QELS) .
  • the instruments used were a Lexel Argon-ion laser (Fremont, CA, USA) (model BI-200SM) , with a Brookhaven apparatus consisting of a goniometer and a 136 channel digit correlator and a signal processor. Measurements were made with a laser at a wavelength of 488 nm at a scattering angle of 90°. The image of the nanospheres was taken by atomic force microscopy (AFM) .
  • the apparatus Nanoscope III, Digital Instruments, Santa Barbara, CA, USA
  • XPS Chemical surface analysis
  • DSC Differential scanning calorimetry
  • PEG-coated nanospheres are examples of preferred nanospheres, and can be prepared from multiblock copolymers formed by covalently linking a multifunctional compound with at least one poly(ethylene glycol) (PEG) and at least one hydrophobic bioerodible polymer, such as a polyester, for example, (poly(D,L lactic acid), or poly(lactic co-glycolic acid) , a polylactone such as e-polycaprolactone) or a polyanhydride, such as (poly(sebacic acid) .
  • PEG poly(ethylene glycol)
  • hydrophobic bioerodible polymer such as a polyester, for example, (poly(D,L lactic acid), or poly(lactic co-glycolic acid) , a polylactone such as e-polycaprolactone) or a polyanhydride, such as (poly(sebacic acid) .
  • the size of the resulting particles can be determined by the viscosity of the organic phase, ratio of organic to aqueous phase, and sonication power and time. Increased viscosity yields bigger particles and a higher ratio of the aqueous phase volume as compared to organic phases yields smaller particles.
  • An example of the effect of the sonication power and time is as follows: 25 mg polymer/2 ml CH 2 C1 2 is added to 30 ml of 0.3% polyvinyl alcohol solution. The mixture is vortexed for 30 seconds at the maximum strength and then sonicated by probe sonicator for 30 seconds at the output 7. The conditions can reproducibly yield nanoparticles of a particle size of between 180 and 240 nm.
  • these parameters can be optimized to obtain nanospheres having desired size range with a narrow unimodal size distribution of about 200 nm.
  • the density of the hydrophilic block at the nanosphere surface can be increased and blood circulation of these carriers can " be prolonged, relative to using a linear copolymer.
  • multiblock copolymers containing multiple PEG blocks there is typically more PEG on the surface of nanospheres prepared from brush copolymers than on the surface of nanospheres prepared from linear copolymers, as shown by ESCA.
  • the amount of PEG (deducted from the ratio between PEG and PLA or PLGA comparing C peaks convolution) can be increased from 35.65% to more than 44% using non-linear multiblock copolymers as compared with linear copolymers.
  • Other characterization studies were carried out to investigate morphological characteristics and encapsulation properties of PEG-polyanhydride and PEG-polyester nanospheres, at different drug loadings. Cross-section images of freeze-fractured nanospheres were obtained by TEM, showing the particle dense core. Partial drug recrystallization was shown by DSC data.
  • Nanospheres prepared from multiblock brush copolymers that include a significant amount of PEG on the surface of the particle are typically in the size range of 180 nm or greater.
  • the diameter can increase up to 240 nm in the case of the highest PEG m.w. in (PEG 20K) 3 - PLA particles, in contrast to PLA nanoparticles, where the diameter can be less than 120 nm.
  • this is in contrast to particles prepared from linear copolymers, such as PEG-PLGA particles, in which the PEG in PEG-PLGA particles was able to reduce nanosphere size, as compared to not-coated particles.
  • composition of the hydrophobic block(s) also affects the particle size. For example, using polycaprolactone, which is more soluble in methylene chloride, to form the nanosphere core, particles with a diameter of less than 100 nm can be obtained. Drug loading appears to have little effect on particle size. Particles loaded with lidocaine and prednisolone can show the same size even when the amount of drug loaded is as high as 45%.
  • Microparticles can be prepared using the methods as described above for preparing nanoparticles, without using an ultrasonic bath.
  • the microparticles can also be prepared by spraying a solution of the multiblock copolymer in organic solvent into an aqueous solution.
  • particles are formed from multiblock copolymers prepared by covalently linking a multifunctional compound with at least one hydrophilic polymer, such as a poly(alkylene glycol) with a molecular weight of between 300 and 20,000 or a polysaccharide moiety, and at least one hydrophobic polymer, such as polyorthoesters, polyphosphate esters, poly(lactic-co-glycolic acid), poly(lactic acid), poly(glycolic acid), polyanhydride, polyphosphazenes, polycaprolactone or other biodegradable, biocompatible polymers, and copolymers thereof.
  • hydrophilic polymer such as a poly(alkylene glycol) with a molecular weight of between 300 and 20,000 or a polysaccharide moiety
  • hydrophobic polymer such as polyorthoesters, polyphosphate esters, poly(lactic-co-glycolic acid), poly(lactic acid), poly(glycolic acid), polyanhydride, polyphosphazene
  • the multifunctional compound can be substituted with between one and ten hydrophilic polymers and between one and ten hydrophobic polymers, and preferably is substituted with between one and six hydrophilic polymers and between one and six hydrophobic polymers.
  • a hydrophilic polymer refers to a polymer that is soluble in aqueous medium, and if used for medical applications, is biocompatible and readily eliminated from the human body.
  • the preferred molecular weight for PEG is between 300 and 20,000, for polysaccharides, between 1,000 and 40,000, and for polyamino acids (peptides), between 1,000 and 70,000.
  • a hydrophobic bioerodible polymer refers to a polymer that is insoluble in aqueous medium, but may absorb water up to 30% of its weight, and is biocompatible and degradable. Preferred molecular weight ranges are between 500 and 500,000.
  • a polysaccharide refers to a carbohydrate composed of many onosaccharides.
  • a multifunctional compound refers to a compound with at least two functional groups capable of being coupled with functional groups on a polymer.
  • the compound can be a linear, branched or cyclic alkyl group, an aromatic group, a heterocyclic group, or a combination thereof.
  • the types of groups include, but are not limited to, hydroxyl, thiol, amino, carboxylic acid, aldehyde, sulfonic acid, phosphoric acid, amide, isocyanate, imine and derivatives thereof.
  • the compound is non-toxic and biodegradable.
  • Examples of preferred multifunctional compounds include, but are not limited to, tartaric acid, mucic acid, citric acid, glucaronic acid and tri, tetra- and polycarboxylic acids, including benzene tetracarboxylic acid, dextrins and tri, tetra and polyalcohols, and molecules with combinations of carboxyl and hydroxyl groups. Size of Particles
  • the typical size of the particles is between 80 nm and 10,000 nm, preferably between 80 nm and 400 nm.
  • the methodology produces particles between 80 and 10,000 nm, i.e., both nanoparticles, and microparticles having a diameter of 1 micron or greater.
  • both microparticles and nanoparticles will be referred to as particles unless otherwise specified.
  • nanoparticle refers to a solid particle of size ranging from 10 to 1000 nm.
  • the ideal' nanoparticle is biodegradable, biocompatible, has a size of less than 200 nm and has a rigid biodegradable core into which a substance to be delivered can be incorporated.
  • microparticle refers to a particle of size ranging from one or greater up to 1000 microns.
  • FIGS la, lb and lc are schematic representations of embodiments of a nanoparticle prepared as described herein.
  • the particle 10 has a biodegradable solid core 12 containing a biologically active material 14, and one or more poly(alkylene glycol) moieties 16 on the surface.
  • the surface poly(alkylene glycol) moieties 16 have a high affinity for water that reduces protein adsorption onto the surface of the particle.
  • the terminal hydroxyl group of the poly(alkylene glycol) can be used to covalently attach biologically active molecules, as shown in Figure lb, or molecules affecting the charge, lipophiucity or hydrophilicity of the particle, onto the surface of the nanoparticle.
  • the PEG is a branched shorter chain PEG molecule than in Figure la.
  • a nanosphere refers to a nanoparticle that is spherical in shape.
  • the shape of the nanoparticles prepared according to the procedures herein or otherwise known is easily determined by scanning electron microscopy. Spherically shaped nanoparticles are preferred for circulation through the bloodstream. If desired, the particles can be fabricated using known techniques into other shapes that are more useful for a specific application. Degradation Properties.
  • biodegradable or bioerodible refers to a polymer that dissolves or degrades within a period that is acceptable in the desired application (usually in vivo therapy) , usually less than five years, and preferably less than one year, on exposure to a physiological solution with a pH between 6 and 8 having a temperature of between 25 and 37°C.
  • the nanoparticle degrades in a period of between 1 hour and several weeks, depending on the desired application.
  • the period of time of release, and kinetics of release, of the substance from the nanoparticle will vary depending on the copolymer or copolymer mixture or blend selected to fabricate the nanoparticle. Given the disclosure herein, those of ordinary skill in this art will be able to select the appropriate polymer or combination of polymers to achieve a desired effect. III, substances to be Incorporated Onto or Into Particles
  • a wide range of biologically active materials or drugs can be incorporated onto or into the particles.
  • the substances to be incorporated should not chemically interact with the polymer during fabrication, or during the release process.
  • Additives such as inorganic salts, BSA (bovine serum albumin) , and inert organic compounds can be used to alter the profile of substance release, as known to those skilled in the art.
  • Biologically- labile materials for example, procaryotic or eucaryotic cells, such as bacteria, yeast, or mammalian cells, including human cells, or components thereof, such as cell walls, or conjugates of cellular can also be included in the particle.
  • biologically active material refers to a peptide, protein, carbohydrate, nucleic acid, lipid, polysaccharide or combinations thereof, or synthetic inorganic or organic molecule, that causes a biological effect when administered in vivo to an animal, including but not limited to birds and mammals, including humans.
  • Nonlimiting examples are antigens, enzymes, hormones, receptors, and peptides.
  • Examples of other molecules that can be incorporated include nucleosides, nucleotides, antisense, vitamins, minerals, and steroids.
  • Particles prepared according to this process can be used to deliver drugs such as nonsteroidal anti-inflammatory compounds, anesthetics, chemotherapeutic agents, immunotoxins, immunosuppressive agents, steroids, antibiotics, antivirals, antifungals, and steroidal antiinflammatories, anticoagulants.
  • drugs such as nonsteroidal anti-inflammatory compounds, anesthetics, chemotherapeutic agents, immunotoxins, immunosuppressive agents, steroids, antibiotics, antivirals, antifungals, and steroidal antiinflammatories, anticoagulants.
  • hydrophobic drugs such as lidocaine or tetracaine can be entrapped into the particles and are released over several hours. Loadings in the nanoparticles as high as 40% (by weight) have been achieved. Hydrophobic materials are more difficult to encapsulate, and in general, the loading efficiency is decreased over that of a hydrophilic material.
  • an antigen is incorporated into the nanoparticle.
  • the term antigen includes any chemical structure that stimulates the formation of antibody or elicits a cell-mediated humoral response, including but not limited to protein, polysaccharide, nucleoprotein, lipoprotein, synthetic polypeptide, or a small molecule (hapten) linked to a protein carrier.
  • the antigen can be administered together with an adjuvant as desired.
  • suitable adjuvants include synthetic glycopeptide, muramyl dipeptide.
  • Other adjuvants include killed Bordetella pertussis, the liposaccharide of Gram- negative bacteria, and large polymeric anions such as dextran sulfate.
  • a polymer, such as a polyelectrolyte can also be selected for fabrication of the nanoparticle that provides adjuvant activity.
  • antigens that can be loaded into the nanoparticles described herein include, but are not limited to, attenuated or killed viruses, toxoids, polysaccharides, cell wall and surface or coat proteins of viruses and bacteria. These can also be used in combination with conjugates, adjuvants, or other antigens.
  • Haemophilius influenzae in the form of purified capsular polysaccharide (Hib) can be used alone or as a conjugate with diphtheria toxoid.
  • Non-pharmaceutical uses for the particles include delivery of food additives, including stabilizers and dispersants or other viscosity modifying agents, controlled and selective delivery of pesticides, herbicides, insecticides, fertilizer, and pheromones, and in color and ink formulations in the printing and ink industry.
  • a gamma-labelled nanoparticle that can be used to monitor the biodistribution of the particle in vivo.
  • Any pharmaceutically acceptable gamma- emitting moiety can be used, including but not limited to indium and technetium.
  • the magnetic particles can be prepared as described herein, or alternatively, magnetic nanoparticles, including surface-modified magnetic nanoparticles can be purchased commercially, the surface further modified by attaching the hydrophilic polymeric coating.
  • the magnetic nanoparticle can be mixed with a solution of the hydrophilic polymer in a manner that allows the covalent binding of the hydrophilic polymer to the nanoparticle.
  • a gamma-emitting magnetic moiety is covalently attached to the hydrophilic or hydrophobic bioerodible polymeric material of the particle.
  • Other materials can also be incorporated into the particles for diagnostic purposes, including radiopaque materials such as air or barium and fluorescent compounds.
  • Hydrophobic fluorescent compounds such as rhodamine can be incorporated into the core of the particles.
  • Hydrophilic fluorescent compounds can also be incorporated, however, the efficiency of encapsulation is smaller, because of the decreased compatibility of the hydrophobic biodegradable core with the hydrophilic material.
  • the hydrophilic material must be dissolved separately in water and a multiple emulsion technique used for fabrication of the particle.
  • the particles include a substance to be delivered and a multiblock copolymer that is covalently bound to a biologically active molecule, for example, an antibody or antibody fragment, such as the Fab or Fab 2 antibody fragments, wherein the particle is prepared in such a manner that the biologically active molecule is on the outside surface of the particle.
  • a biologically active molecule for example, an antibody or antibody fragment, such as the Fab or Fab 2 antibody fragments
  • the charge, lipophilicity or hydrophilicity of the particle can be modified by attaching an appropriate compound to the hydrophilic polymer on the surface of the particle.
  • the particle can also be coated with a dextran, which are in general more hydrophilic than poly(alkylene glycol) but less flexible. Dextran coated nanoparticles are useful for magnetic resonance imaging (MRI) . Attachment of Specific Ligands to Particle Surfaces.
  • the particles prepared as described herein can be used for cell separation, or can be targeted to specific tissues, by attaching to the surface of the particle specific ligands for given cells in a mixture of cells.
  • the particles can be targeted using the ligands, such as tissue specific receptors or antibodies to tissue specific surface proteins, then maintained at the targeted cells using a magnetic field while the particles are imaged or a compound to be delivered is released.
  • carmustine or other anti-cancer agent such as cis- platin is incorporated in the core of the particles and antibodies to the target cancerous cells are covalently bound to the surface of the particle.
  • Nanospheres can be administered to a patient in a variety of routes, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically, in liquid, cream, gel or solid form.
  • the particles can be lyophilized and then formulated into an aqueous suspension in a range of microgram/ml to 100 mg/ml prior to use.
  • the particles can be formulated into a paste, ointment, cream, or gel, or transdermal patch.
  • the nanoparticle should contain the substance to be delivered in an amount sufficient to deliver to a patient a therapeutically effective amount of compound, without causing serious toxic effects in the patient treated.
  • the desired concentration of active compound in the nanoparticle will depend on absorption, inactivation, and excretion rates of the drug as well as the delivery rate of the compound from the nanoparticle. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.
  • the particles can be administered once, or may be divided into a number of smaller doses to be administered at varying intervals of time, depending on the release rate of the particle, and the desired dosage.
  • Polymers loaded as described herein can also be used to coat implantable devices, such as stents, catheters, artificial vascular grafts, and pacemakers.
  • the device can be coated with the lyophilized powder of the particles, or otherwise as known to those skilled in the art.
  • the coating can release antibiotics, anti-inflammatories, or anti-clotting agents at a predetermined rate, to prevent complications related to the implanted devices.
  • Controlled delivery devices prepared as described herein can also be used as ocular inserts for extended release of drugs to the eye.
  • D,L-lactide was purchased from Aldrich Chemical Company, and glycolide from Polysciences, Inc. These compounds were recrystallized before use from ethyl acetate.
  • High purity monomethoxy PEG (M-PEG) with molecular weight 5,000, 12,000 and 20,000 was purchased from Shearwater Polymers, Inc.
  • the number average molecular weight of the polymer was determined with on a Perkin-Elmer GPC system with an LC-25 refractive index detector equipped with a mixed bed Phenogel column filled with 5 ⁇ m particles from Phenomenex. Chloroform was used as the eluent, with a flow rate of 0.9 ml/min.
  • the molecular weights were determined relative to narrow molecular weight polystyrene and poly(ethylene glycol) standards from Polysciences. Thermal transition data was collected with a
  • PEG citrates were prepared as follows:
  • DCC dicyclohexylcarbodiimide
  • DMAP 4mg, catalyst
  • the - product did not contain acid groups (Bromophenol test) and showed a single peak at the GPC chromatogra in the area of 15,000. IR showed typical ester peak (1720 cm" 1 ) .
  • Methoxy-PEG citrate trimers with PEG of the following molecular weights, 1,900; 12,000; and 20,000 were prepared using this procedure.
  • the PEG derivatives of tartaric acid [ (methoxy-PEG)2-tartrate] , mucic acid [ (methoxy- PEG)-2-mucoate] , and glucaronic acid (methoxy-PEG-mucoate) with various PEG chain length were prepared similarly. All derivatives possessed the appropriate molecular weight (determined by GPC using PEG standards) , showed a negative result in the bromophenol test for carboxylic acids, and had an absorption peak at 1720 typical for amide bonds.
  • Example 2 Esterification reaction between methoxy PEG-OH and citric acid using DCC.
  • Example 3 Direct esterification reaction between methoxy PEG-OH and citric acid.
  • methoxy PEG-OH MW 1900, Polysciences
  • citric acid 0.33 equivalents
  • sulfuric acid 0.33 equivalents
  • the reaction was conducted under reflux using azeotrope for H 2 0 removal.
  • About 75% yield was obtained as determined by GPC.
  • Example 4 Trans esterification reaction between methoxy PEG-OH and methyl citrate ester. Citrate methyl ester was obtained from the reaction between citric acid and access methanol at reflux.
  • PEG 3 -citrate (1 gram) (Sherewater, MW-5,000, 12,000, and 20,000) was dissolved in 20 ml benzene.
  • Lactide (5 grams) (Aldrich, 99%+) was added and the solution was allowed to reflux and azeotrope for 60 in.
  • Stannous octoate (0.2% by weight (per lactide)) was added as a 1% solution in benzene.
  • the reaction was refluxed for 5 hours, the solvent was removed azeotropically and a viscous material was obtained.
  • the polymerization was continued for 2 hours at 130°C.
  • the resulting polymer was a clear, slightly yellow mass, and showed a high molecular weight (Table 1) .
  • the multiblock copolymers of PEG-polycaprolactone were similarly synthesized. The polymers were soluble in common organic solvents.
  • PCL-PEG 5k (1:5 W/w) 29,500 70,100 55-58
  • PCL-PEG 12k (1:5 W/w) 25,500 88,100 55-58
  • PCL-PEG 20k (1:5 w/w) 34,500 105,900 50-56
  • PSA-COO-PEG 5k (3:1 w/w) 19,500 119,100 65-78
  • PSA-COO-PEG 12k (3:1 w/w) 21,000 144,200 65-78
  • PSA-COO-PEG 20k (3:1 w/w) 18,500 105,000 65-78
  • Citric acid (0.1 mole) was reacted with a mixture of methoxy-PEG amine (MW 1900) (0.2 mole) and benzyl ester carboxy-PEG-amine (MW 5,000) (0.1 mole) using DCC (0.33 equivalents) and DMAP (0.01 mole, catalyst) in 100 ml of dry dichloromethane.
  • the PLA-PEG citrate trimer was dissolved in tetrahydrofuran and hydrogenated with Hydrogen-Palladium catalysis to remove the benzylic protecting group at the PEG 5000 chain.
  • the end chain carboxylic acid PEG was then reacted with bovine serum albumin (representing a ligand) using DCC as an activating agent for amide coupling.
  • bovine serum albumin (representing a ligand) using DCC as an activating agent for amide coupling.
  • two or three ligands can be attached to (PEG)3-citrate by using two or three equivalents of benzyl carboxylate-terminated PEG-amines, using the above method.
  • Di-PEG tartrate was prepared from the reaction between amino terminated methoxy PEG and tartaric acid with DCC as the activating agent, using the procedure described for the synthesis of (PEG) 3 -citrate.
  • the di-PEG tartrate derivative was reacted with lactide or glycolide mixtures to form clear polymers (Table 1) .
  • Mucic acid (Aldrich) was reacted with two equivalents of methoxy PEG in the presence of DCC in DMF to form di-PEG-mucoate which was copolymerized with lactide, glycolide or caprolactone to form high molecular weight
  • the penta-PEG compound was polymerized with sebacic acid (1:5 weight ratio) using acetic anhydride as a dehydrating agent. Polymers with a molecular weight of approximately 75,000 were obtained.
  • the gluconate PEG derivative was polymerized with lactide, glycolide or caprolactone (1:5 weight ratio).
  • Methoxy-PEG-epoxide terminated Sherewater was hydrolyzed in a sodium carbonate solution overnight at room temperature. The resulted PEG with two hydroxyl groups was isolated by precipitation in ether: ethanol 1:1 mixture and dried. The dihydroxy-terminated PEG was block copolymerized with lactide, glycolide and caprolactone to form high molecular weight polymers (The molecular weight was in the range of 70,000 to 115,000) .
  • Tri ethoxy-PEG-citrate (0.01 mole, prepared as above) reacted with access adipoyl chloride (0.012 mole) in dichloromethane with triethylamine as a proton acceptor. After 24 hours at room temperature, water was added, the reaction mixture was stirred at room temperature for one hour, and the polymer was isolated by the adding a mixture of methanol-diethyl ether 1:1.
  • BTCA was reacted with two equivalents of methoxy PEG amine in refluxing THF for 5 hours to yield dimethoxy-PEG tetracarboxybenzoate, with two remaining carboxylic groups.
  • the PEG-dimer was reacted with acetic anhydride and then with sebacic anhydride to form the tetra-armed diblock PEG 2 -benzene-PSA 2 .
  • the PEG dimer was block copolymerized with lactide, glycolide or caprolactone in toluene with stannous octoate as catalyst.
  • High molecular weight polymers were obtained (Please define high molecular weight) .
  • Example 15 Multiblock copolymers based on the l,4;3,6-dilactone of glucaric acid (Compound K, Figure 2f)
  • PLA was polymerized in the presence of the dilactone (5:1 weight ratio) using stannous octoate as catalyst in benzene.
  • the two carboxylic acid groups were used to attach methoxy-PEG-amine via an amide bond.
  • Dextran a clinically used biodegradable material, was used as alternative hydrophilic polymer to PEG.
  • the benzyl ester of citric acid was polymerized with lactide to form a PLA- terminated citrate ester which was hydrogenated to remove the benzyl groups.
  • the citric acid terminated-PLA was esterified with dextran to form
  • 2-Hydroxyadipaldehyde is reacted with lactide in the presence of stannous octoate to form adipaldehyde-terminated PLA.
  • the aldehyde groups are reacted with animo side groups of a ligand
  • PLA-terminated with diamino groups This polymer is reacted with an oxidized polysaccharide, such as dextran or amylose, to form a PLA-di-
  • Polyanhydride-terminated PEG was prepared by melt condensing a sebacic acid prepolymer (synthesized by refluxing sebacic acid in acetic anhydride and precipitating the resulting polymer in ether/petroleum ether solution) and methoxy PEG- OH or methoxy PEG-carboxylate acetate anhydride.
  • methoxy-PEG-carboxylate (1 gram) was mixed with sebacic acid prepolymer (3 grams) .
  • the mixture was polymerized at 180°C under vacuum (0.1 mm Hg) for 90 minutes to yield the polymer.
  • the polymer showed IR absorption at 1805 and 1740 cm-1 (typical for aliphatic anhydride bonds) , and the - ⁇ -NMR spectrum fit the polymer structure.
  • Example 20 Preparation of Nanoparticles from Mixtures of Non-Linear Multiblock Copolymers and Linear Polymers and
  • Nanospheres were prepared from a mixture of
  • PEG 3 -citrate-PLA a PLGA-PEG copolymer and a polycaprolactone homopolymer in a ratio of 1:1:3 by weight, using an emulsion/evaporation technique as described above.
  • the pre-formed polymers were dissolved in an organic solvent (Which solvent) at a concentration of (What concentration?) polymer/solvent.
  • the resulting organic solution was emulsified with an aqueous phase by vortexing and then sonicated for 1 minute at 40-W output.
  • the solvent was evaporated and the nanospheres were collected by centrifugation (30 min, 5,000 rpm) , washed twice and lyophilized, yielding nanospheres with an average size of approximately 200 nm.
  • Lidocaine and prednisolone were selected for encapsulation because of their low water solubility (less than 5 mg/mL in water) , high solubility in organic solvents (more than 20 mg/mL in organic solvents such as chlorinated hydrocarbons, tetrahydrofuran, dimethyl formamide or dioxane) and ease of detection by UV spectrophotometry. Release tests were carried out with nanospheres loaded with lidocaine in different amounts (20% wt, 33% wt) , in phosphate buffer solution (PBS, pH 7.4) at 37°C.
  • PBS phosphate buffer solution
  • a dialysis membrane (50,000 cut-off) was filled with a suspension of lyophilized nanospheres (10 mg/5 ml PBS) and then placed into 25 ml of PBS. Samples were taken from the outer solution, then replaced every time with fresh ones. Drug released was detected spectrophotometrically at 240 nm.
  • the molecular weight does not effect the release pattern of PEG-PLGA nanospheres, since the drug is completely released in about ten hours using copolymers with a PEG m.w. of 5, 12, 20 KDa.
  • the presence of PEG on the surface of the nanospheres is not expected to modify the drug release.
  • factors such as higher PEG density and PEG chain length can slow down drug release. In ten hours, more than 90% of lidocaine was released from PLA nanospheres, but only 60% from (PEG 20K) 3 - PLA particles.
  • Drug release from nanospheres made from PEG-e- polycaprolactone is biphasic. Because of polymer erosion, it would ordinarily be expected that a core made of polyanhydride should lead to a faster drug release. However, after an initial fast release in the first two hours, drug release reached a plateau, although drug was released at a constant rate for an additional eight hours.
  • Polymer degradation kinetics were also investigated in vitro .
  • PEG-PLGA, PEG-PCL and (PEG) 3 -PLA particles the polymers start to degrade after weeks.
  • Nanosphere cores made of polyanhydrides start to degrade immediately.
  • drug release is governed by a diffusion mechanism, since the drug can be completely released before polymer degradation occurs.
  • polyanhydrides polymer erosion affects drug release, and drug characteristics have a more important role in release kinetics.
  • the particle's small size and large surface area increases the rate of polymer erosion relative to other drug delivery systems, such as slabs, and afterwards drug solubility governs the dissolution kinetics.
  • the amount of drug loading can have a strong effect on the release kinetics.
  • PEG-PLGA nanospheres containing 33% wt of lidocaine can release the drug for over 12 hours. Surprisingly, particles loaded with 10% of the drug can show complete drug release in 6 hours. Increased drug loading can cause part of the drug loaded in the core to recrystallize, as shown by DSC. The presence of crystals of a hydrophobic drug, such as lidocaine, can slow down the release kinetics.
  • ESCA studies performed on drug loaded nanospheres confirmed that drug crystals were not located on the nanosphere surface.
  • the polymer composition was also modified and the drug loading was increased up to 45% wt.
  • Example 22 Evaluation of Biodistribution of U1 ln-labeled Nanoparticles in vivo.
  • Indium 111 can be directly attached to the multiblock copolymer chains by complex formation.
  • In and diethyltria iopentaacetic acid (DTPA) are reacted with stearylamine.
  • DTPA diethyltria iopentaacetic acid
  • the resulting compound, In-DTPA-stearyla ide is hydrophobic enough to interact to be encapsulated within the hydrophobic core. In this case, the molecular weights of the hydrophilic and hydrophobic polymers have little effect on the interaction.
  • label loss can be assessed by measuring the radioactivity of the supernatant solutions after centrifugation.
  • This labelling method can therefore be useful for in vivo studies, by gamma-scintography or by direct measurement of the radioactivity in the blood and/or different organs.

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EP94925102A 1993-07-23 1994-07-22 Nanopartikel und mikropartikel aus nichtlinearen hydrophilen-hydrophoben multiblockcopolymeren Withdrawn EP0712421A1 (de)

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US08/096,370 US5543158A (en) 1993-07-23 1993-07-23 Biodegradable injectable nanoparticles
US96370 1993-07-23
US08/210,677 US5565215A (en) 1993-07-23 1994-03-18 Biodegradable injectable particles for imaging
US210677 1994-03-18
US08/265,440 US5578325A (en) 1993-07-23 1994-06-24 Nanoparticles and microparticles of non-linear hydrophilic-hydrophobic multiblock copolymers
US265440 1994-06-24
PCT/US1994/008287 WO1995003356A1 (en) 1993-07-23 1994-07-22 Nanoparticles and microparticles of non-linear hydrophilic-hydrophobic multiblock copolymers

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