Classifications

• • 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
  • A61K51/1255—Granulates, agglomerates, 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
  • A61K51/1213—Semi-solid forms, gels, hydrogels, ointments, fats and waxes that are solid at room temperature
• • 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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • 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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1658—Proteins, e.g. albumin, gelatin

Definitions

• the present disclosure generally relates to microspheres. More particularly, the present disclosure relates to polymeric hydrogels associated with radioactive metals, metal oxides, and the like.
• colloidal metals especially colloidal gold
• Faraday speculated that the red color of colloidal gold resulted from the reflection of the light, a property which became the basis for its initial use in light microscopy.
• Thiessen proved the particulate nature of colloidal gold in 1942.
• Thiessen et al., Kolloid Z, 101 :241 (1942) Perhaps the first true applications in cell biology were by Harford et al., L Biophys. Biochem. CytoL, 3:749 (1957) and Feldherr et al., J. Biophys. Biochem. CytoL, 12:640 (1962), who used stabilized colloidal gold as an electron-dense tracer in cellular uptake and micro-injection experiments, respectively.
• colloidal metals especially colloidal gold
• colloidal gold has become a very widely used marker in light and electronic microscopy.
• colloidal gold has been used to detect a wide variety of cellular and extracellular constituents by in situ hybridization, immunogold, lectin-gold, and enzyme-gold labeling.
• colloidal gold remains the label of choice for transmission electron microscopy studying thin sections, freeze-etch, and surface replicas, as well as for scanning electron microscopy.
• colloidal metal, especially colloidal gold in vivo, has not been reported.
• using colloidal metals to label or staining a synthetic polymeric material has not been reported either. Labeling of embolization materials
• vascular embolization procedures are used to treat or prevent certain pathological situations in vivo. Most generally they are made using catheters or syringes under imaging control to position solid or liquid embolic agents in the target vessel. Embolization can be used to occlude vessels of a variety of organs including brain, liver, and spinal cord, which results in reduced blood flow or complete occlusion of the vessels.
• One application of embolization is to stop or reduce blood flow in hemorrhagic situations.
• Another application is to stop delivery of vital blood supply and nutrients to tissue, for instance, to reduce or deny blood supply to a solid tumor.
• embolization enables the blood flow to the normal tissue, aids in surgery and limits the risks of hemorrhage.
• embolization can be used for temporary as well as permanent objectives.
• Embolization has been performed with a variety of materials such as small pieces of durable matters, including polyvinyl-alcohol irregular particles, liquid embolic products and more recently with spherical-shaped solid hydrogels.
• materials such as small pieces of durable matters, including polyvinyl-alcohol irregular particles, liquid embolic products and more recently with spherical-shaped solid hydrogels.
• a wide variety of commercially available embolic materials are difficult to see or to trace because they are relatively transparent, cannot be seen clearly with normal light before and during administration, or are difficult to detect after administration because they are not radiopaque and lack features that render them detectable on magnetic resonance imaging, ultrasound, or nuclear medicine procedures.
• U.S. Patent Nos. 5,635,215 and 5,648,100 disclose an injectable microspheres comprising a hydrophilic acrylic copolymer coated with a cell adhesion promoter and a marking agent. Marking agents described in these patents include chemical dyes, magnetic resonance imaging agents, and contrast agents such as barium or iodine salts. Organic dyes are complex molecules composed of aromatic structures and strong ionic charges. They are known especially in affinity chromatography as ligands for several biological structures. Their major limitation as markers for embolic agents are the possible dye release as a result of the hydrolysis of the dye-embolic material link with subsequent delivery in the blood stream. Another limitation of chemical dyes is that they may be absorbed to certain biological structures or tissue, which may produce undesirable results.
• the barium sulphate and methyl iothalamate impregnated PVA microspheres reported therein were prepared by the glutaraldehyde cross-linking of an aqueous dispersion of PVA containing the radiopaques in paraffin oil using dioctyl sulfosuccinate as the stabilizing agent and thionyl chloride as the catalyst.
• HEMA radiopaque poly(2-hydroxyethyl methacrylate)
• the present disclosure provides polymeric materials that are associated with radioactive particles.
• the radioactive particles can include radioactive metals, radioactive inorganic metal compounds, and other radioactive elements.
• the radioactive particles can include a beta-emitting radionuclide.
• a beta-emitting radionuclide can preferably also be a gamma-emitting radionuclide.
• a radionuclide can have a half life in a range of about 2 hours to about 30 days, preferably about 6 hours to about 120 hours.
• the radionuclides can be derived from stable isotopes that have been radioactivated by neutron bombardment.
• the invention encompasses polymeric materials containing radioactive particles (e.g., of metals or inorganic compounds of metals), preferably those of phosphorous, yttrium, iodine, gold, rhenium, or holmium.
• radioactive particles e.g., of metals or inorganic compounds of metals
• Preferred isotopes of iodine include I, l and I.
• the materials can be hydrogels, substantially spherical, and may retain functions and properties of the original polymeric materials.
• the materials are preferably detectable by radio-imaging techniques, such as by gamma camera.
• the present invention is directed to a polymeric material associated with radioactive particles, e.g., comprising metals or inorganic metal compounds.
• the polymeric material is a porous hydrogel.
• the radioactive particles can be associated with the material within the pores.
• the material preferably may be detectable by radiological imaging techniques, for example, but not limited to, detection by gamma camera.
• the materials are further preferably implantable or injectable in humans or animals and are biocompatible and stable, with very little or no release of the radioactive particles within the body.
• Such metal containing polymeric materials can either form part of a traditional prosthetic device or part of microparticles that are implantable or inj ectable for, embolization, or radiation therapy purposes.
• the polymeric material is a hydrogel and comprises at least some of the radioactive particles within the pores therein.
• the polymeric material is preferably selected from the group consisting of acrylics, vinyls, acetals, allyls, cellulosics, polyamides, polycarbonate, polyesters, polyimide, polyolefins, polyurethanes, silicones, styrenics, and polysaccharides.
• the polymeric material is implantable into a human.
• the present invention also provides a microparticle which comprises a polymeric material associated with radioactive particles, e.g., of metal or metal-containing compounds, wherein the microparticle is suitable for injection or implantation into a human.
• a microparticle which comprises a polymeric material associated with radioactive particles, e.g., of metal or metal-containing compounds, wherein the microparticle is suitable for injection or implantation into a human.
• the microparticle comprises polymeric hydrogel material selected from one or more of the group consisting of acrylics, vinyls, acetals, allyls, cellulosics, polyamides, polycarbonate, polyesters, polyimide, polyolefins, polyurethanes, silicones, styrenics, and polysaccharides.
• the polymeric material is porous. Further, the porous polymeric material may comprise at least part of the colloidal metal particles within the pores therein.
• the microparticle preferably comprises polymeric material that is an elastomer, a hydrogel, a water swellable polymer, or combinations thereof.
• the polymeric material is an acrylic polymer, such as a trisacryl based acrylic polymer.
• the material comprises a hydrophilic acrylic copolymer that contains, in copolymerized form, about 25 to about 98%, by weight, of a neutral hydrophilic acrylic monomer, about 2 to about 50%, by weight, of a difunctional monomer, and about 0 to about 50%, by weight, of one or more monomers having a cationic charge.
• the neutral hydrophilic acrylic monomer is preferably selected from the group consisting of acrylamides, methacrylamides and hydroxymethylmethacrylate;
• the difunctional monomer is preferably selected from the group consisting of N,N'- methylenebisacrylamide, N',N'-diallyltartradiamide, and glyoxal-bis-acrylamide;
• the monomer having a cationic charge is preferably a monomer having a tertiary and/or quaternary amine function.
• the microparticle of the present invention may further preferably comprises one or more cell adhesion promoters selected from the group consisting of collagen, gelatin, glucosaminoglycans, fibronectin, lectins, polycations, natural biological cell adhesion agents or synthetic biological cell adhesion agents.
• cell adhesion promoters selected from the group consisting of collagen, gelatin, glucosaminoglycans, fibronectin, lectins, polycations, natural biological cell adhesion agents or synthetic biological cell adhesion agents.
• the polymeric material, especially the microparticle, of the present invention may optionally comprise traditional marking agents, such as a chemical dye, a magnetic resonance imaging agent, and/or a contrasting agent.
• traditional marking agents such as a chemical dye, a magnetic resonance imaging agent, and/or a contrasting agent.
• the polymeric material is a poly(vinyl alcohol) ("PVA"), preferably a cross-linked PVA.
• PVA poly(vinyl alcohol)
• the polymeric material of the present invention may also be a polymethacrylate, such as poly(methyl methacrylate) or poly (2-hydroxyethyl methacrylate).
• the polymeric material is in microparticle form with dimensions ranging from about 1 ⁇ m to about 2000 ⁇ m.
• the microparticles are substantially spherical microspheres with diameters ranging from about 10 ⁇ m to about 2000 ⁇ m, more preferably, from about 40 ⁇ m to about 1200 ⁇ m.
• the microparticle of the present invention is preferably suitable for radiation therapy and/or therapeutic vascular embolization purposes.
• the polymeric material of the present invention may contain pores both on the surface and within the body.
• the pores have sizes, measured by the dimensions of the cross sections, ranging from about 1 nm to about 10 ⁇ m, more preferably, from about 1 nm to about 1000 nm.
• the radioactive particles contained within the polymeric material have dimensions ranging from about 1 nm to about 1000 nm and, preferably, from about 1 nm to about 500 nm.
• the radioactive particles are preferably selected from the group consisting of phosphorus, yttrium, iodine, gold, rhenium, and holmium.
• the radioactive particle can be a metal selected from the group consisting of gold, antimony, lanthanum, samarium, europium, terbium, holmium, ytterbium, lutetium, hafnium, tantalum, tungsten, rhenium, osmium, iridium, scandium, platinum, palladium, copper, titanium, and chromium.
• the radioactive particles are phosphorus, yttrium or iodine. Preferred isotopes of iodine include I, l and I. Most preferably, the metal is gold.
• the present invention provides a substantially spherical microparticle, or a microsphere, which comprises a hydrogel associated with radioactive colloidal gold particles, wherein the microsphere is suitable for injection or implantation into a human.
• the present invention provides a microsphere having a diameter ranging between about 10 ⁇ m and about 2000 ⁇ m, useful for embolization, which comprises a hydrophilic acrylic copolymer associated with radioactive colloidal gold particles, wherein the hydrophilic acrylic copolymer comprises, in copolymerized form, about 25 to about 98%, by weight, of a neutral hydrophilic acrylic monomer, about 2 to about 50%, by weight, of a difunctional monomer, and about 0 to about 50%, by weight, of one or more monomers having a cationic charge.
• a hydrogel can include at least 50% water by weight.
• the microsphere of the present invention may also comprise one or more cell adhesion promoters selected from the group consisting of collagen, gelatin, glucosaminoglycans, fibronectin, lectins, polycations, natural biological cell adhesion agents or synthetic biological cell adhesion agents. Further, the microsphere may optionally comprise a marking agent selected from the group consisting of dyes, imaging agents, and contrasting agents.
• the present invention relates to a process of making a polymeric material associated with non-radioactive particles and radioactivating them. The process comprises contacting the polymeric material with a solution of or a colloidal suspension of a non-radioactive particle.
• the polymeric material is porous and comprises at least part of the non-radioactive particles within the pores therein. More preferably, the polymeric material is in microparticle form and is suitable for injection or implantation into a human.
• the process comprises a step of heating a metal salt solution containing polymeric material at a temperature and for a time sufficient to associate the metal particles with the polymeric material.
• the process further comprises a step of mixing a reducing agent with a metal salt solution or irradiating the mixture with an irradiation source such as ultraviolet light.
• the solution is gold chloride (AuCl 3 or HAuCl ) having a concentration ranging from about 0.01 mg/L to about 5 g/L.
• AuCl 3 or HAuCl gold chloride
• the present invention also embraces a process of making a polymeric material associated with initially radioactive particles, i.e., particles that were radioactive prior to their association with the polymeric material. See, e.g., Example 13.
• radioactivating the particles can include subjecting the particles to neutron activation.
• a non-radioactive particle can be an inorganic metal compound.
• an inorganic metal compound can be a metal oxide.
• the present invention is directed to a process of making a polymeric material associated with radioactive particles, e.g., of metals or metal compounds, which comprises contacting a polymeric material with a solution of non- radioactive particles, e.g., colloidal metal or colloidal metal compound, and radioactivating the particles.
• the polymeric material is porous and comprises at least part of the colloidal particles within the pores therein.
• the polymeric material is in microparticle form having dimensions ranging from about 40 microns to about 2000 microns in diameter.
• the process comprises packing polymeric material, preferably, in porous microparticle form, in a column and perfusing the column with a solution of, e.g., a colloidal metal or colloidal metal compound. More preferably for this process, the colloidal particles have diameters that are smaller than the sizes of the pores, as measured by the cross section dimension.
• the present invention further relates to a process of making a polymeric material associated with radioactive particles, e.g., of metals or metal compounds, by introducing non-radioactive particles into the initial polymerization solution or suspension of polymeric material, and radioactivating the particles.
• the polymeric material is porous and comprises at least part of the particles within the pores therein.
• the non-radioactive or radioactive particles e.g., of metals or metal compounds
• the process further enables colloidal particles that are larger than the pores of the polymeric material to be trapped within the pores, resulting in particles that are more tightly attached to the polymers.
• the initial polymerization solution or suspension for the polymeric material comprises N-
• the present invention provides an injectable composition that comprises polymeric microparticles associated with particles, e.g., of metals or metal compounds, and a biocompatible carrier.
• the injectable composition comprises microparticles that are porous and having at least part of the particles of metals or metal compounds deposited within the pores therein.
• the microparticles comprise one or more polymers selected from the group consisting of acrylics, vinyls, acetals, allyls, cellulosics, polyamides, polycarbonate, polyesters, polyimide, polyolefins, polyurethanes, silicones, styrenics, and polysaccharides.
• the microparticles comprise an elastomer, a hydrogel, a water swellable polymer, or combinations thereof.
• the injectable composition comprises microparticles that are substantially spheric microspheres suitable for radiation therapy or embolization.
• the microspheres comprise a hydrogel associated with colloidal gold particles and are suitable for injection or implantation into a human.
• the microspheres have diameters ranging from about 10 ⁇ m to about 2000 ⁇ m, useful for embolization, comprise at least 50% water by weight, and comprise a hydrophilic acrylic copolymer comprising, in copolymerized form, about 25 to about 98%, by weight, of a neutral hydrophilic acrylic monomer, about 2 to about 50%, by weight, of a difunctional monomer, and about 0 to about 50%, by weight, of one or more monomers having a cationic charge.
• the microspheres may also comprise one or more cell adhesion promoters selected from the group consisting of collagen, gelatin, glucosaminoglycans, fibronectin, lectins, polycations, natural biological cell adhesion agents or synthetic biological cell adhesion agents.
• the present invention provides a method of prophylactic or therapeutic treatment of a mammal, which comprises administering to said mammal polymeric microparticles associated with radioactive particles, e.g., of metals or metal compounds.
• the administration is by means of injection through a syringe or a catheter.
• the method of treatment encompassed by the present invention includes radiation therapy and embolization.
• the present invention further provides a kit for performing a prophylactic or therapeutic treatment of a mammal.
• the kit comprises a sterile container and sterile and biocompatible polymeric microparticles associated with radioactive particles, e.g., of metals or metal compounds.
• the present invention provides a kit for performing a prophylactic or therapeutic treatment of a mammal that comprises a needle or a catheter, means for injecting a liquid based composition through said needle or catheter, and sterile and biocompatible polymeric microparticles associated with particles of metals or inorganic metal compounds.
• a method of treating a neoplasm can include administering radioactive metal or metal compound labeled microparticles to a subject, the microparticles embolizing a blood vessel supplying blood to the neoplasm, and the microparticles delivering a dose of radioactivity is delivered to the neoplasm, thereby treating the neoplasm.
• the dose of radioactivity can be sufficient to kill the neoplasm.
• the dose of radioactivity can be sufficient to prevent recanalization of a blood vessel supplying blood to the neoplasm, hi an embodiment, the neoplasm can be liver cancer.
• FIG. 1 depicts a micrograph of colloidal gold-associated microspheres before neutron activation.
• FIG. 2 depicts a micrograph of colloidal gold-associated microspheres after neutron activation.
• the present invention provides a unique and valuable system useful for labeling, controlling, and tracking implantable or injectable polymeric materials, especially microparticles, that are used in vivo, especially in humans, for prophylactic and/or therapeutic purposes.
• the microparticles can include radioactive isotopes for delivering radiation therapy to tissues.
• the invention allows physicians, e.g., surgeons and radiologists, to safely and effectively control and track the labeled materials during and after administration into the body. Therefore, the invention provides polymeric materials, especially microparticles, that are associated with radioactive metal or metal compound particles, especially radioactive colloidal gold particles, which are visible under regular light through naked eye and optionally detectable by radio imaging and/or magnetic resonance imaging instruments.
• the invention also provides methods and processes of associating the polymeric materials, especially porous polymeric materials, with radioactive particles.
• the invention further provides injectable solutions and kits that comprise polymeric microparticles associated with radioactive particles.
• the invention provides methods of prophylactic and/or therapeutic treatment of various conditions in a mammal by administering to the mammal microparticles associated with radioactive particles, e.g., metals or metal compounds.
• Radioactive isotopes for internal radiotherapy usually emit beta particles or soft x-rays, but other sources, such as alpha- and Auger electron-emitting isotopes, have also been proposed.
• Administering a weakly penetrating radiation source directly to a tumor allows a very large radiation dose to be delivered to the tumor, while minimizing radiation damage to healthy tissue.
• seeds are small metal capsules
• the seeds are implanted directly into the tumor by means of a catheter or syringe.
• catheter or syringe For example, such devices are used in prostate brachytherapy.
• Particulate material has long been employed as a delivery vehicle for internal radiotherapy.
• the intravenous injection of either insoluble radioactive zinc sulfide, or radioactive gold adsorbed onto an inert microparticulate carbon carrier, are described in the earliest reports on localized radiotherapy (Muller and Rossier, Acta Radiologica, 1951, vol. 35, p. 449). Since then, a wide variety of radioactive microparticles has been described, including suspensions or colloids of insoluble radioactive inorganic particles, and ceramic or polymeric microparticles impregnated with radioactive material (Ercan, in Microspheres, Microcapsules, and Liposomes, Vol 2 (Citus Books, 1999)).
• Microparticles can be administered to a subject for a variety of purposes.
• One such purpose is to cause embolization of blood vessels.
• Embolization can block or impede the flow of blood from or to an area of tissue.
• Neoplasm therapy is a typical application of embolization.
• Blood vessels supplying blood to the neoplasm, such as a tumor can be embolized, thus depriving the tumor of its blood supply and thereby promoting tumor death.
• liver cancer such as hepatocellular carcinoma, can be treated and/or palliated using this technique.
• Chemotherapy has also found widespread use in therapy of a large variety of neoplasms. The drugs and applications thereof will be well known to one of ordinary skill in the art.
• Radiation therapy is another technique commonly employed for neoplasm therapy. Radiation is typically delivered to tissue by a variety of methods, such as exposure of a subject to an external source, implantation of radioactive "seeds" into the subject, intravascular administration, and parenteral administration, among others. Radiation has been administered in the form of radioactive metal particles (Muller and Rossier, "A new method for the treatment of cancer of the lungs by means of artificial radioactivity," Acta Radiologica 35: 449-468, 1951), and as microspheres of glass, ceramic, albumin, and certain polymers containing radioisotopes 99m Tc, 90 Y, 188 Re, 32 P, and 166 Ho (Nijsen J.F.W. et al, "Advances in nuclear oncology: microspheres for internal radionuclide therapy of liver tumours," Curr Med Chem 9(l):73-82, 2002).
• Some disadvantages of present radioactive microsphere techniques derive from the undesirable properties of the microspheres.
• glass and ceramic microspheres are dense and thus form poor suspensions that are difficult to make uniform and are difficult to administer by catheter, which is the preferred method. They are heavy and tend to sediment, impeding flow. They can also be difficult to detect after administration because they are not radiopaque or visible on magnetic resonance imaging.
• Materials such as glass, ceramic, protein, and polymer can be damaged by exposure to radiation. The damage can cause disintegration, etching, crosslinking, aggregation, and other changes which can destroy the uniformity of the microspheres and their physical or chemical properties.
• the present invention provides a microsphere including a porous hydrogel associated with radioactive colloidal gold particles.
• the microsphere can be manufactured, for example, by first making a hydrogel infused with nonradioactive
• the hydrogel can be infused with other materials, such as a metal or a metal compound.
• stable 165 Ho can be associated with the hydrogel and then radioactivated (to Ho, half life about 27 hours).
• neutron sources can be used for radioactivation of stable isotopes by neutron activation, such as reactors, accelerators, and radioisotopic neutron emitters.
• Systems and methods for neutron activation are described above and in, e.g., U.S. Patents Nos. 6,149,889, incorporated herein by reference, and 6,328,700.
• Nuclear reactors with their high fluxes of neutrons from uranium fission can offer the highest available sensitivities for most elements.
• Different types of reactors and different positions within a reactor can vary considerably with regard to their neutron energy distributions and fluxes due to the materials used to moderate (or reduce the energies of) the primary fission neutrons.
• most neutron energy distributions are quite broad and include three principal components (thermal, epithermal, and fast).
• the thermal neutron component includes low-energy neutrons (energies below 0.5 eV) in thermal equilibrium with atoms in the reactor's moderator.
• the energy spectrum of thermal neutrons is best described by a Maxwell-Boltzmann distribution with a mean energy of 0.025 eV and a most probable velocity of 2200 m/s.
• 90-95% of the neutrons that bombard a sample are thermal neutrons.
• a one-megawatt reactor has a peak thermal neutron flux of approximately 1E13 neutrons per square centimeter per second.
• the epithermal neutron component includes neutrons (energies from 0.5 eV to about 0.5 MeV) which have been only partially moderated.
• a cadmium foil 1 mm thick absorbs all thermal neutrons but will allow epithermal and fast neutrons above 0.5 eV in energy to pass through.
• the epithermal neutron flux represents about 2% the total neutron flux.
• Both thermal and epithermal neutrons induce (n,gamma) reactions on target nuclei.
• the fast neutron component of the neutron spectrum (energies above 0.5 MeV) includes the primary fission neutrons which still have much of their original energy following fission.
• Fast neutrons contribute very little to the (n,gamma) reaction, but instead induce nuclear reactions where the ejection of one or more nuclear particles - (n,p), (n,n'), and (n,2n) - are prevalent.
• about 5% of the total flux consists of fast neutrons.
• neutron-activated gold can be associated with a hydrogel.
• stable gold atoms 197 Au
• the efficient radioactivation requires comparatively brief exposure to the neutron source, thereby reducing damage to the hydrogel.
• the hydrogel being mostly water, has a density approaching that of water, so a hydrogel microsphere can form a uniform suspension that is readily administered by catheter.
• the radioactive gold in addition to emitting beta particles for therapeutic application, also emits gamma rays, which can be readily detected, such as by a gamma camera, thereby facilitating visualization after administration.
• the amount of radiation being delivered to a target, such as a tumor, as compared to non-target tissue can also thereby be measured, which is important for ensuring that sufficient radiation reaches the target without unduly exposing non-target tissue.
• the amount of radiation delivered to a target by radioisotope-labeled microspheres can be controlled in a variety of ways, as by varying the amount of radioisotope associated with the spheres; the extent of radioactivation of the element; the quantity of microspheres administered; and the size of microspheres administered.
• Radiation can be delivered in amounts sufficient to cause death of the target tissue. Radiation can also be delivered in amounts sufficient merely to prevent recanalization of target tissue. To prevent recanalization, sufficient radiation is delivered to provoke a scarring response in, for example, surrounding capillaries, without so damaging the tissue to kill it. The scarring response helps inhibit the formation of new blood vessels, thereby enfeebling neovascularization stimuli produced by a tumor.
• the term "implant” means a substance that is placed or embedded at least in part within the tissue of a mammal.
• An “implantable” substance is capable of being placed or embedded within the tissue through whatever means.
• a piece of traditional prosthetic device is an implant.
• substances, such as microparticles that are placed within the dermal tissue of a mammal.
• the term “embolization” means the occlusion or blockage of a blood vessel. The occlusion or blockage may occur either due to blood clots or emboli as a result of a physiological condition or due to an artificial act of embolic materials.
• an embolus is different from an implant.
• the term "hydrogel” refers to a polymeric composition, comprising at least 50% water by weight, and can comprise a wide variety of polymeric compositions and pore structures.
• the term "injectable” means capable of being administered, delivered or carried into the body via a needle, a catheter, or other similar ways.
• microparticles means polymer or combinations of polymers made into bodies of various sizes.
• the microparticles can be in any shape, although they are often in substantially spherical shape, in which case the microparticles are referred to as "microspheres" or “microbeads.”
• “Substantially spherical,” as used in the present invention generally means a shape that is close to a perfect sphere, which is defined as a volume that presents the lowest external surface area.
• substantially spherical in the present invention means, when viewing any cross-section of the particle, the difference between the average major diameter and the average minor diameter is less than 20%, preferably less than 10%.
• the microspheres of the present invention may comprise, in addition to the particles, other materials as described and defined herein.
• association with means the condition in which two or more substances having any type of physical contact.
• the metal particles may be deposited on the surface of the polymeric material, within the material, or, if the material is porous, within the pores of the material, through any type of physical or chemical interactions such as through covalent bond, ionic bond, or van der Waal's bond, or through impregnating, intercalating, or absorbing.
• a polymeric material when a polymeric material is associated with metal or metal compound particles, it is "labeled” with the metal or metal compound particles.
• the present invention is directed to a polymeric material that comprises colloidal metal particles.
• the polymeric material of the present invention includes synthetic and natural polymers.
• the polymeric material is porous synthetic polymeric material and comprises at least part of the colloidal metal particles within the pores therein.
• the material comprises one or more polymers selected from the group consisting of acrylics, vinyls, acetals, allyls, cellulosics, polyamides, polycarbonate, polyesters, polyimide, polyolefins, polyurethanes, silicones, styrenics, and polysaccharides.
• the polymeric material of the present invention is or is made to be an elastomer, a hydrogel, a water swellable polymer, or combinations thereof.
• the metal containing polymeric materials may be used in any medical applications, but they are especially suitable as implantable and/or injectable devices.
• the colloidal metal labeled polymeric material is in microparticle form and useful as emboli for prophylactic or therapeutic embolizations. Therefore, the polymeric materials of the present invention are particularly suitable in injectable implantations or embolizations as small particles, such as microparticles, microbeads or microspheres. These microparticles are usually difficult to detect after injection into the body.
• the microparticles are rendered detectable by radiological means, for example, by gamma camera.
• radiological means for example, by gamma camera.
• Many types of polymeric microparticles or microspheres, either for tissue bulking, dermal augmentation, radiation therapy, or embolization purposes, are suitable for the present invention.
• the polymeric material comprises an acrylic polymer. Because of its wide applications in medical implantable devices, polymethacrylates such as poly(methyl methacrylate) and poly (2-hydroxyethyl methacrylate) are especially suitable for the present invention.
• the porous polymeric materials comprise microbeads or microparticles based on a biocompatible, hydrophilic, substantially spherical, and non-toxic polymers.
• the microspheres are injectable and/or implantable and not capable of being digested or eliminated through the mammal's immune or lymphatic system.
• the hydrophilic copolymers usable for this application are those of the acrylic family such as polyacrylamides and their derivatives, polyacrylates and their derivatives as well as polyallyl and polyvinyl compounds. All of these polymers are preferably crosslinked so as to be stable and non-resorbable.
• the microparticle comprises a polymeric material that comprises a hydrophilic acrylic copolymer, which contains, in copolymerized form, about 25 to about 98%, by weight, of a neutral hydrophilic acrylic monomer, about 2 to about 50%, by weight, of a difunctional monomer, and about 0 to about 50% by weight of one or more monomers having a cationic charge.
• a neutral hydrophilic acrylic monomer is selected from the group consisting of acrylamides, methacrylamides and hydroxymethylmethacrylate;
• the difunctional monomer is selected from the group consisting of
• the microparticle may optionally comprise one or more cell adhesion promoters selected from the group consisting of collagen, gelatin, glucosaminoglycans, fibronectin, lectins, polycations, natural biological cell adhesion agents or synthetic biological cell adhesion agents.
• the polymeric material comprises poly (vinyl alcohol).
• Polyvinylalcohol particles are the most common material used to date in a variety of embolization applications.
• WO 00/23054 the content of which is incorporated by reference, discloses substantially spherical shaped microspheres comprising cross-linked PVA. The microspheres described therein has certain advantages in embolization.
• microspheres can properly and completely occlude artery lumen because they can establish complete contact with all the surface of the artery which is cylindrical.
• the microspheres can be easily calibrated, and samples or suspensions containing these microspheres will not block or clog catheters because they always have the same dimension regardless of their space orientation in the catheter.
• the invention described herein encompasses PVA microspheres useful for radiation therapy and/or embolization.
• the PVA microspheres preferably comprise crosslinked polyvinylalcohol. Preferred diameters for the microspheres depend on the type of embolization to be performed and can be readily determined by a skilled artisan.
• the present invention encompasses microspheres, which comprise in crosslinked and hydrogel form, from about 0.5% to about 20% cross-linked poly(vinyl alcohol) by weight.
• the crosslinked polyvinylalcohol microspheres may further comprise one or more of a cell adhesion promoter or a marking agent other than the colloidal metal.
• the polymeric material of the present invention when in microparticle form, preferably have dimensions ranging from about 1 ⁇ m to about 2000 ⁇ m.
• the microparticles are substantially spherical microspheres with diameters ranging from about 10 ⁇ m to about 2000 ⁇ m, more preferably, from about 40 ⁇ m to about 1200 ⁇ m.
• the polymeric material contains or is made to contain pores.
• the material comprises pores both on the surface and within.
• the pores contained within the polymeric material of the present invention have sizes, measured in cross-section diameters, ranging from about 1 nm to about 10 ⁇ m and, preferably, from about 1 nm to about 1000 nm.
• the lengths of the pores vary depending on the dimensions of the material.
• the pores facilitate the impregnation of and actually contain the colloidal metal particles, which are preferably trapped within the pores.
• the porous polymeric material of the present invention preferably contains within the pores radioactive or non-radioactive particles that have dimensions ranging from about 1 nm to about 1000 nm, more preferably, from about 1 nm to about 500 nm.
• the present invention contemplates preferably particles of phosphorus, yttrium, iodine, gold, rhenium, or holmium. However, other particles can be included, as described above.
• the particle can be, e.g., gold, rhenium, holmium, silver, platinum, copper, titanium and chromium, and their inorganic compounds.
• the present invention provides a substantially spherical microparticle, or a microsphere, which comprises a hydrogel associated with colloidal gold particles, wherein the microsphere is suitable for injection or implantation into a human, hi a more preferred embodiment, the present invention provides a microsphere having a diameter ranging between about 10 ⁇ m and about 2000 ⁇ m, useful for embolization, which comprises a hydrophilic acrylic copolymer associated with colloidal gold particles, wherein the hydrophilic acrylic copolymer comprises, in copolymerized form, about 25 to about 98%, by weight, of a neutral hydrophilic acrylic monomer, about 2 to about 50%, by weight, of a difunctional monomer, and about 0 to about 50%), by weight, of one or more monomers having a
• the microsphere of the present invention may also comprise one or more cell adhesion promoters selected from the group consisting of collagen, gelatin, glucosaminoglycans, fibronectin, lectins, polycations, natural biological cell adhesion agents or synthetic biological cell adhesion agents. Further, the microsphere may optionally comprise a marking agent selected from the group consisting of dyes, imaging agents, and contrasting agents.
• the association process can be accomplished in at least three ways.
• the particles can be associated with the polymeric materials in a chemical reaction with a salt solution.
• the particles can be deposited on and/or within the polymeric material through direct contact between the material and a colloidal solution of the particles.
• the metal containing polymeric material can be produced by introducing a metal salt or colloidal solution into the initial polymerization solution or suspension of the polymeric material.
• the metal or metal compound particles may be radioactive before its incorporation into the polymeric material.
• the metal or metal compound particles may be non-radioactive before its incorporation into the polymeric material.
• colloidal metal particles are preferably permanently associated on the polymeric materials, enable better detection and control of such materials in implantation applications.
• the various polymeric materials mentioned above are suitable for the association processes of the present invention.
• colloidal metal particles can be associated with a polymeric material by contacting the polymeric material with a metal salt solution for a time and at a temperature sufficient to reduce the metal salt into metal particles that are deposited on or within the polymeric material, hi a preferred embodiment of the present invention, the polymeric material is porous and that the process enables the porous materials to comprise at least part of the colloidal metal particles within the pores of the material.
• the sizes of the metal particles may either be larger or smaller than the sizes of the pores of the material, as measured by the cross-sections of the pores.
• the associating process can be accelerated by heating the metal salt solution.
• the process can be further accelerated by the addition of a reducing agent.
• Any agent that is known to have the ability to reduce a metal salt into metal particles can be used for this purpose.
• Preferred reducing agents include sodium citrate, ascorbic acid, phosphorous derivatives, tannic acid, citric acid, and combinations thereof.
• Another way of accelerating the reduction process is irradiation of the mixture of the polymeric material and the metal salt solution.
• Preferred sources of irradiation include ultraviolet light such as that from a mercury lamp.
• the metal salt solution is gold chloride (such as HAuCL; or AuCl ) having a concentration ranging from about 0.01 mg/L to about 5 g/L. More preferably, the process comprises heating the gold chloride solution containing the polymeric material. Further, the addition of a reducing agent could accelerate the impregnation process, so could irradiation from source such as ultraviolet light, as discussed above.
• gold chloride such as HAuCL; or AuCl
• the present invention also provides a process of associating colloidal particles of metals or metal compounds with a polymeric material by contacting the polymeric material with a colloidal solution of metal or metal compound particles.
• the polymeric material is porous and that the process enables the porous materials to comprise at least part of the colloidal particles within the pores of the material.
• the sizes of the colloidal metal particles are preferably smaller than the sizes of the pores, as measured by the dimension of the cross sections of the pores.
• the polymeric material is in microparticle form and has dimensions ranging from about 1 ⁇ m to about 2000 ⁇ m.
• a more preferred process for this direct deposition of colloidal particles comprises packing the polymeric material, such as microparticles, in a column and perfusing the column with the colloidal metal solution. This process can be preferably followed by rinsing the column with water or saline.
• colloidal particles are used for porous materials, the particles are preferably of sizes smaller than the pores of the polymeric material. They also should be preferably suspended with a surfactant to maintain in a dissociated form.
• another process of associating colloidal particles of metal or metal compound with the polymeric material comprises adding the colloidal particles or a metal salt solution into the initial polymerization solution or suspension for the polymeric material.
• the resultant polymeric material is porous and that the process enables the porous materials to comprise at least part of the colloidal metal particles within the pores of the material.
• any polymerization process that produces a polymeric material can be incorporated into the process of the present invention by adding a solution of metal salt or colloidal metal into the initial polymerization solution or suspension.
• polymerization processes disclosed in references incorporated herein are encompassed by the present invention.
• polymerization processes disclosed in U.S. Patent No. 5,635,215 for producing acrylic microspheres, and in WO 00/23054 for producing PVA microspheres can be incorporated into the process of the present invention to produce hydrophilic acrylic microspheres or
• PVA microspheres containing colloidal particles When the initial polymerization solution or suspension is transformed into a acrylic or PVA microsphere, preferably in hydrogel form, the colloidal particles are trapped within the polymer network and cannot be released any longer. In this case they are located inside the polymer pores. In case of a porous polymeric material, the resulting metal containing material from this process may contain colloidal metal particles that are larger in size than the sizes of the pores, as measured by the dimensions of the cross sections of the pores. Ini ectable Compositions. Kits, and Methods of Use
• the present invention further encompasses injectable compositions, kits, and methods of use in connection with the colloidal metal containing polymeric materials disclosed above.
• an injectable composition that comprises polymeric microparticles associated with colloidal metal particles and a biocompatible carrier.
• the various embodiments of the colloidal metal containing microparticles disclosed herein are suitable for the injectable compositions, h addition, the microparticles and biocompatible carriers disclosed in the various U.S. patents, U.S. and PCT patent applications incorporated by references herein are also suitable for the injectable compositions of the present invention.
• the present invention provides a method of prophylactic or therapeutic treatment of a mammal, preferably a human, which comprises administering to the mammal polymeric microparticles associated with radioactive particles.
• a mammal preferably a human
• the administration is capable of being well controlled and/or manipulated both before and after the process, as the microparticles are readily visible under regular light before the administration and optionally using radio-imaging and/or magnetic resonance techniques after the administration.
• Suitable treatment encompassed by the present invention includes radiotherapy, dermal augmentation, tissue bulking, embolization, drug delivery, and treatment of gastroesophageal reflux disease, urinary incontinence, and vesicoureteral reflux disease.
• the administration according to the method of treatment of the present invention is preferably carried out by means of injection through a syringe or a catheter.
• the methods of treatment disclosed in the U.S. patents, U.S. and PCT patent applications incorporated by reference herein are also encompassed by the present invention's methods.
• the present invention provides a kit for performing a prophylactic or therapeutic treatment of a mammal.
• the kit preferably comprises a sterile container and sterile and biocompatible polymeric microparticles associated with colloidal metal particles.
• the kit of the present invention for performing a prophylactic or therapeutic treatment of a mammal comprises a needle or a catheter; means for injecting a liquid based composition through said needle or catheter; and sterile and biocompatible polymeric microparticles associated with colloidal metal particles.
• the various embodiments of the microparticles disclosed herein and the various embodiments disclosed in the U.S. patents, U.S. and PCT patent applications incorporated by reference herein are also encompassed by the present invention's kit.
• Example 1 Gold staining of embolic spherical material constituted of a synthetic polymer containing crosslinked collagen ( " e.g., Embosphere® microspheres) Solutions of HAuCl 4 (0.1 to 5.0 g/L) (Solution I) and of sodium citrate as reducing agent (1 % by weight) (Solution LI) were prepared. A suspension of Embosphere® microspheres (10 mL) and Solution I (20 mL of the desired concentration) were heated to boiling and then 2 mL of Solution II was added. After 10 minutes the solution and
• Embosphere ® suspension turned to red, indicating the formation of gold colloidal particles within the solid material network.
• the beads were then filtered and washed several times with water and saline. Similar results were obtained when using other reducing agents, instead of sodium citrate, such as ascorbic acid, phosphorous derivatives or sodium citrate and tannic acid.
• Example 2 The same procedure was used as described in Example 1, but without a reducing agent.
• the suspension of Embosphere® microspheres or PVA particles with Solution I were heated to boiling for an extensive period of time (15 minutes or more).
• the beads and the solution appeared red-brown, which confirmed the formation of gold particles within the solid material network.
• the beads were then treated with the same manner as described in Examples 1 and 2.
• the reduction of gold could also be accomplished by irradiation of the samples with a mercury lamp for about 48 hours at 25 °C.
• Example 7 Staining of a commercially available embolic material
• Example 2 The same procedure was used as described in Example 1, but Ivalon® was used instead of Embosphere® microspheres.
• the suspension of Ivalon® irregular particles with Solution 1 HuCl 4 , 3 g/L was heated to boiling temperature and then 2 mL of Solution II (1% sodium citrate in water) was added. After 10 minutes of agitation, the suspension turned to red-brown, indicating the formation of gold colloidal particles in the Ivalon® particles.
• the particles were then filtered and washed several times with water and saline. Similar results were obtained when using other reducing agents instead of sodium citrate such as ascorbic acid, phosphorous derivatives or sodium citrate/tannic acid.
• the reduction to colloidal gold could also be made by irradiation of the suspension with a mercury lamp for about 48 hours at 25 ° C.
• embolic microparticles (irregular arid spherical) composed of polysaccharide and/or proteins (e.g., albumin).
• biodegradable solid embolic material is used instead of Embosphere® microspheres. 10 mL particles were put in suspension with 20 mL of an aqueous Solution I of HAuCl 6 at 3 g/L. The mixture was then heated to boiling temperature and then 2 mL of 1% sodium citrate solution in water was added. After 10 minutes agitation, the suspension turned to red-brown indicating the formation of gold colloidal particles inside the embolic material. The particles were then filtered and washed several times with water and saline.
• Example 9 Staining of solid embolic material with gold colloidal particles This method of staining applies to embolic material that has porous structure with pores larger than 10 nm in diameter.
• Embolic material in aqueous suspension was packed in a glass column. Through the column a colloidal solution of gold was perfused. Colloidal particles that had a size smaller than the pores of the solid embolic material were trapped within the embolic pore network. The excess of gold colloidal particles or colloidal particles that were larger man the pores of the solid embolic were washed out the column by means of a physiological buffer. After the treatment the embolic material showed a red like color, indicating the presence of colloidal gold entrapped within the pore network.
• Example 10 Injectable compositions containing gold labeled Embosphere® microspheres Gold labeled Embosphere® microspheres, as described in Examples 1, 3 and 4 are washed with normal saline and then sterilized by autoclave. The resultant microspheres are mixed with non-pyrogenic, sterile, physiological saline in ratios ranging from about 0.05 mL microspheres/mL saline to about 0.5 mL microspheres/mL saline.
• a total amount of 8 mL of sterile injectable composition as described in Example 10 is transferred, under sterile condition, into a glass vial of 10 mL in capacity and having a stopper sealed by an aluminum cap equipped with a colored tag.
• the measured gold content is consistent with an estimate of the expected amount.
• a sample of the microspheres after neutron activation was viewed under a microscope (see FIG. 2). Comparison of the visual appearance of the microspheres before and after neutron activation suggested that the beads remained intact.
• a suspension of commercially available Embospheres in 1.5 M aqueous sodium chloride, — 1 mL of microspheres in a total volume of about 5 mL — is treated with up to 50 curies of Au-198, as its trichloride or trinitrate salt. The mixture is heated to 90 °C for 30- 90 minutes, and then allowed to cool. The microspheres are washed with 1.5 M aqueous sodium chloride. The microspheres retain greater than 50% of the radioactivity.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Engineering & Computer Science (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Dispersion Chemistry (AREA)
• Physics & Mathematics (AREA)
• Optics & Photonics (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Applications Claiming Priority (3)

Publications (2)

Family

ID=32312672

Family Applications (1)

Country Status (4)

Families Citing this family (16)

Citations (4)

Family Cites Families (1)

• 2003
  • 2003-10-17 WO PCT/US2003/033140 patent/WO2004040972A2/en not_active Application Discontinuation
  • 2003-10-17 AU AU2003285905A patent/AU2003285905A1/en not_active Abandoned
  • 2003-10-17 EP EP03779133A patent/EP1578455A4/de not_active Withdrawn
  • 2003-10-17 CA CA002507404A patent/CA2507404A1/en not_active Abandoned

Patent Citations (4)

Non-Patent Citations (5)

Also Published As

Similar Documents

Legal Events