# US 2006/0067883 A1 · Microspheres capable of binding radioisotopes, optionally comprising metallic microparticles, and methods of use thereof

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- Number: US 2006/0067883 A1
- Document ID: US20060067883A1
- Status: Published application
- Kind: A1
- Application number: 11/185,449
- Filed: 2005-07-19
- Published: 2006-03-30
- Earliest claimed: 2004-09-24
- Assignees: Biosphere Medical, Inc.
- Inventors: James Krom; Alexander Schwarz
- Web page: https://patentgrep.com/patent/US20060067883A1

## CPC

- A61K 51/1255: {Granulates, agglomerates, microspheres}
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 35/00: Antineoplastic agents
- A61K 2121/00: Preparations for use in therapy
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

One aspect of the present invention relates to a microsphere, comprising a hydrophilic polymer comprising a plurality of pendant anionic groups; a transition-metal, lanthanide or group 13-14 metal oxide, polyoxometalate or metal hydroxide or combination thereof; and a first radioisotope that emits a therapeutic β-particle. In certain embodiments, the microsphere further comprsies a second radioisotope that emits a diagnostic γ-ray; wherein the atomic number of the first radioisotope is not the same as the atomic number of the second radioisotope. In certain embodiments, the microsphere is composed of polymer impregnated with zirconia bound to 32p as the source of the therapeutic β-emissions and 67Ga as the source of the diagnostic γ-emissions. Another aspect of the present invention relates to the preparation of a microsphere impregnated with a radioisotope that emits therapeutic β-particles and a radioisotope that emits diagnostic β-emitting radioisotope and a γ-emitting radioistope; wherein the atomic number of the first radioisotope is not the same as the atomic number of the second radioisotope. In certain embodiments, said microspheres are administered to the patient through a catheter. In another embodiment, the microsphere is combined with the radioisotopes at the site of treatment.

## Claims

### Claim 1

A microsphere, comprising a hydrophilic polymer comprising a plurality of pendant moieties; optionally comprising an insoluble transition-metal, lanthanide or group 13-14 oxide, polyoxometalate, hydroxide, alkoxide, carboxylate or combination thereof; and a first radioisotope.

### Claim 2 (depends on 1)

The microsphere of claim 1, further comprising a second radioisotope; wherein the atomic number of the first radioisotope is not the same as the atomic number of the second radioisotope.

### Claim 3 (depends on 1, 2)

The microsphere of claim 1 or 2, wherein said hydrophilic polymer comprises one or more polymerized monomers selected from the group consisting of acrylics, vinyls, acetals, allyls, cellulosics, methacrylates, polyamides, polycarbonate, polyesters, polyimide, polyolefins, polyphosphates, polyurethanes, silicones, styrenics, and polysaccharides.

### Claim 4 (depends on 1, 2)

The microsphere of claim 1 or 2, wherein said hydrophilic polymer comprises one or more polymerized monomers selected from the group consisting of crosslinked gelatin, oxidized starch, alginate, gellan, gum arabic, galactan, arabinogalactan, chitosan, hyaluronan, chondroitin sulfate, keratan sulfate, heparan sulfate, dermatan sulfate, carboxymethylcellulose, oxidized cellulose, acrylate, methacrylate, ethylene glycol methacrylate phosphate, vinylphosphonate, N-[tris(hydroxymethyl)methyl]-acrylamide, N,N′-methylene-bis-acrylamide, N′,N′-diallyl-tartradiamide, and glyoxal-bis-acrylamide.

### Claim 5 (depends on 1, 2)

The microsphere of claim 1 or 2, wherein said hydrophilic polymer comprises one or more polymerized monomers selected from the group consisting of crosslinked gelatin, N-[tris(hydroxymethyl)methyl]acrylamide and vinylphosphonate.

### Claim 6 (depends on 1, 2)

The microsphere of claim 1 or 2, wherein said hydrophilic polymer comprises one or more polymerized monomers selected from the group consisting of N-[tris(hydroxymethyl)-methyl]acrylamide and vinylphosphonate.

### Claim 7 (depends on 1, 2)

The microsphere of claim 1 or 2, wherein said pendant moieties are selected independently from the group consisting of phosphonic acids, phosphates, bisphosphonic acids, polyphosphates, diphosphates, triphosphates, sulfonic acids, sulfates, carboxylic acids, carbamic acids, hydroxamic acids, acyl hydrazides, thiols, amines, silicates, aluminates, titanates, zirconates, pyridines, imidazoles, thiphenes, thiazoles, furans, purines, pyrimidines, and hydroxyquinolines.

### Claim 8 (depends on 1, 2)

The microsphere of claim 1 or 2, wherein said pendant moieties are selected independently from the group consisting of phosphonic acids, bisphosphonic acids, sulfonic acids, and carboxylic acids.

### Claim 9 (depends on 1, 2)

The microsphere of claim 1 or 2, wherein said pendant moieties are phosphonic acids.

### Claim 10 (depends on 1, 2)

The microsphere of claim 1 or 2, wherein said transition-metal, lanthanide or group 13-14 oxide, polyoxometalate, hydroxide, alkoxide, carboxylate or combination thereof comprises a metal oxide, polyoxometalate, hydroxide, alkoxide, carboxylate or combination thereof zirconium, scandium, yttrium, lanthanum, hafnium, titanium, aluminum, silicon, gallium, indium, thallium, germanium, tin, lead, bismuth, tungsten, tantalum, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium, or lutetium.

### Claim 11 (depends on 1, 2)

The microsphere of claim 1 or 2, wherein said transition-metal, lanthanide or group 13-14 metal oxide, polyoxometalate, hydroxide, alkoxide, carboxylate or combination thereof comprises a metal oxide, polyoxometalate, hydroxide, alkoxide, carboxylate or combination thereof of zirconium, scandium, yttrium, lanthanum, titanium or hafnium.

### Claim 12 (depends on 1, 2)

The microsphere of claim 1 or 2, wherein said transition-metal, lanthanide or group 13-14 metal oxide, polyoxometalate, hydroxide, alkoxide, carboxylate or combination thereof is an oxide, polyoxometalate or hydroxide of zirconium or combination thereof.

### Claim 13 (depends on 1, 2)

The microsphere of claim 1 or 2, wherein said first radioisotope is 90Y, 32P, 18F, 140La, 153Sm, 165Dy, 166Ho, 169Er, 169Yb, 177Lu, 186Re, 188Re, 103Pd, 198Au, 192Ir, 90Sr, 111In or 67Ga.

### Claim 14 (depends on 1, 2)

The microsphere of claim 1 or 2, wherein said first radioisotope is 32P, 90Y, 140La, 169Yb, 111In or 67Ga.

### Claim 15 (depends on 1, 2)

The microsphere of claim 1 or 2, wherein said first radioisotope is 32P.

### Claim 16 (depends on 1, 2)

The microsphere of claim 1 or 2, wherein said second radioisotope is Tc-99m, 111In or 67Ga.

### Claim 17 (depends on 1, 2)

The microsphere of claim 1 or 2, wherein said second radioisotope is 111In.

### Claim 18 (depends on 1, 2)

The microsphere of claim 1 or 2, wherein said first radioisotope is 32P, 90Y, 140La, or 169Yb; and said second radioisotope is Tc-99m, 111In or 67Ga.

### Claim 19 (depends on 1, 2)

The microsphere of claim 1 or 2, wherein said first radioisotope is 32P; and said second radioisotope is 111In.

### Claim 20 (depends on 1, 2)

The microsphere of claim 1 or 2, wherein said hydrophilic polymer comprises one or more polymerized monomers selected from the group consisting of crosslinked gelatin, oxidized starch, alginate, gellan, gum arabic, galactan, arabinogalactan, chitosan, hyaluronan, chondroitin sulfate, keratan sulfate, heparan sulfate, dermatan sulfate, carboxymethylcellulose, oxidized cellulose, acrylate, methacrylate, ethylene glycol methacrylate phosphate, vinylphosphonate, N-[tris(hydroxymethyl)methyl]-acrylamide, N,N′-methylene-bis-acrylamide, N′,N′-diallyl-tartradiamide, and glyoxal-bis-acrylamide; and wherein said pendant moieties are selected independently from the group consisting of phosphonic acids, bisphosphonic acids, phosphates, polyphosphates, diphosphates, triphosphates, sulfonic acids, sulfates, carboxylic acids, carbamic acids, hydroxamic acids, acyl hydrazides, thiols, amines, silicates, aluminates, titanates, zirconates, pyridines, imidazoles, thiphenes, thiazoles, furans, purines, pyrimidines, and hydroxyquinolines.

### Claim 21 (depends on 1, 2)

The microsphere of claim 1 or 2, wherein said hydrophilic polymer comprises one or more polymerized monomers selected from the group consisting of crosslinked gelatin, N-[tris(hydroxymethyl)methyl]acrylamide and vinylphosphonate; and wherein said pendant moieties are selected independently from the group consisting of phosphonic acids, bisphosphonic acids, sulfonic acids, and carboxylic acids.

### Claim 22 (depends on 1, 2)

The microsphere of claim 1 or 2, wherein said hydrophilic polymer comprises one or more polymerized monomers selected from the group consisting of N-[tris(hydroxymethyl)methyl]-acrylamide and vinylphosphonate; and wherein said pendant moieties are phosphonic acids.

### Claim 23 (depends on 1, 2)

The microsphere of claim 1 or 2, wherein said hydrophilic polymer comprises one or more polymerized monomers selected from the group consisting of crosslinked gelatin, oxidized starch, alginate, gellan, gum arabic, galactan, arabinogalactan, chitosan, hyaluronan, chondroitin sulfate, keratan sulfate, heparan sulfate, dermatan sulfate, carboxymethylcellulose, oxidized cellulose, acrylate, methacrylate, ethylene glycol methacrylate phosphate, vinylphosphonate, N-[tris(hydroxymethyl)methyl]-acrylamide, N,N′-methylene-bis-acrylamide, N′,N′-diallyl-tartradiamide, and glyoxal-bis-acrylamide; and wherein said pendant moieties are selected independently from the group consisting of phosphonic acids, bisphosphonic acids, phosphates, polyphosphates, diphosphates, triphosphates, sulfonic acids, sulfates, carboxylic acids, carbamic acids, hydroxamic acids, acyl hydrazides, thiols, amines, silicates, aluminates, titanates, zirconates, pyridines, imidazoles, thiphenes, thiazoles, furans, purines, pyrimidines, and hydroxyquinolines; and wherein said transition-metal, lanthanide or group 13-14 oxide, polyoxometalate, hydroxide, alkoxide, carboxylate or combination thereof comprises a metal oxide, polyoxometalate, hydroxide, alkoxide, carboxylate or combination thereof zirconium, scandium, yttrium, lanthanum, hafnium, titanium, aluminum, silicon, gallium, indium, thallium, germanium, tin, lead, bismuth, tungsten, tantalum, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium, or lutetium.

### Claim 24 (depends on 1, 2)

The microsphere of claim 1 or 2, wherein said hydrophilic polymer comprises one or more polymerized monomers selected from the group consisting of crosslinked gelatin, N-[tris(hydroxymethyl)-methyl]acrylamide and vinylphosphonate; and wherein said pendant moieties are selected independently from the group consisting of phosphonic acids, bisphosphonic acids, sulfonic acids, and carboxylic acids; and wherein said transition-metal, lanthanide or group 13-14 metal oxide, polyoxometalate or metal hydroxide or combination thereof comprises a metal oxide, polyoxometalate or metal hydroxide or combination thereof of zirconium, scandium, yttrium, lanthanum, titanium or haffnium.

### Claim 25 (depends on 1, 2)

The microsphere of claim 1 or 2, wherein said hydrophilic polymer comprises one or more polymerized monomers selected from the group consisting of N-[tris(hydroxymethyl)methyl]-acrylamide and vinylphosphonate; and wherein said pendant moieties are phosphonic acids; and wherein said transition-metal, lanthanide or group 13-14 metal oxide, polyoxometalate, hydroxide, alkoxide, carboxylate or combination thereof is an oxide, polyoxometalate, hydroxide, alkoxide or carboxylate of zirconium or a combination thereof.

### Claim 26 (depends on 1, 2)

The microsphere of claim 1 or 2, wherein said hydrophilic polymer comprises one or more polymerized monomers selected from the group consisting of crosslinked gelatin, oxidized starch, alginate, gellan, gum arabic, galactan, arabinogalactan, chitosan, hyaluronan, chondroitin sulfate, keratan sulfate, heparan sulfate, dermatan sulfate, carboxymethylcellulose, oxidized cellulose, acrylate, methacrylate, ethylene glycol methacrylate phosphate, vinylphosphonate, N-[tris(hydroxymethyl)methyl]-acrylamide, N,N′-methylene-bis-acrylamide, N′,N′-diallyl-tartradiamide, and glyoxal-bis-acrylamide; and wherein said pendant moieties are selected independently from the group consisting of phosphonic acids, bisphosphonic acids, phosphates, polyphosphates, diphosphates, triphosphates, sulfonic acids, sulfates, carboxylic acids, carbamic acids, hydroxamic acids, acyl hydrazides, thiols, amines, silicates, aluminates, titanates, zirconates, pyridines, imidazoles, thiphenes, thiazoles, furans, purines, pyrimidines, and hydroxyquinolines; and wherein said transition-metal, lanthanide or group 13-14 oxide, polyoxometalate, hydroxide, alkoxide, carboxylate or combination thereof comprises a metal oxide, polyoxometalate, hydroxide, alkoxide, carboxylate or combination thereof zirconium, scandium, yttrium, lanthanum, hafnium, titanium, aluminum, silicon, gallium, indium, thallium, germanium, tin, lead, bismuth, tungsten, tantalum, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium, or lutetium; and wherein said first radioisotope is 90Y, 32P, 18F, 140La, 153Sm, 165Dy, 166Ho, 169Er, 169Yb, 177Lu, 186Re, 188Re, 103Pd, 198Au, 192Ir, 90Sr, 111In or 67Ga.

### Claim 27 (depends on 1, 2)

The microsphere of claim 1 or 2, wherein said hydrophilic polymer comprises one or more polymerized monomers selected from the group consisting of crosslinked gelatin, N-[tris(hydroxymethyl)methyl]acrylamide and vinylphosphonate; and wherein said pendant moieties are selected independently from the group consisting of phosphonic acids, bisphosphonic acids, sulfonic acids, and carboxylic acids; and wherein said transition-metal, lanthanide or group 13-14 metal oxide, polyoxometalate, hydroxide, alkoxide, carboxylate or combination thereof comprises a metal oxide, polyoxometalate, hydroxide, alkoxide, carboxylate or combination thereof of zirconium, scandium, yttrium, lanthanum, titanium or hafnium; and wherein said first radioisotope is 32P, 90Y, 140La, 169Yb, 111In or 67Ga.

### Claim 28 (depends on 1, 2)

The microsphere of claim 1 or 2, wherein said hydrophilic polymer comprises one or more polymerized monomers selected from the group consisting of N-[tris(hydroxymethyl)methyl]-acrylamide and vinylphosphonate; and wherein said pendant moieties are phosphonic acids; and wherein said transition-metal, lanthanide or group 13-14 metal oxide, polyoxometalate, hydroxide, alkoxide, carboxylate or combination thereof is an oxide, polyoxometalate, hydroxide, alkoxide, or carboxylate of zirconium or combination thereof; and wherein said first radioisotope is 32p.

### Claim 29 (depends on 1, 2)

The microsphere of claim 1 or 2, wherein said hydrophilic polymer comprises one or more polymerized monomers selected from the group consisting of crosslinked gelatin, oxidized starch, alginate, gellan, gum arabic, galactan, arabinogalactan, chitosan, hyaluronan, chondroitin sulfate, keratan sulfate, heparan sulfate, dermatan sulfate, carboxymethylcellulose, oxidized cellulose, acrylate, methacrylate, ethylene glycol methacrylate phosphate, vinylphosphonate, N-[tris(hydroxymethyl)methyl]-acrylamide, N,N′-methylene-bis-acrylamide, N′,N′-diallyl-tartradiamide, and glyoxal-bis-acrylamide; and wherein said pendant moieties are selected independently from the group consisting of phosphonic acids, bisphosphonic acids, phosphates, polyphosphates, diphosphates, triphosphates, sulfonic acids, sulfates, carboxylic acids, carbamic acids, hydroxamic acids, acyl hydrazides, thiols, amines, silicates, aluminates, titanates, zirconates, pyridines, imidazoles, thiphenes, thiazoles, furans, purines, pyrimidines, and hydroxyquinolines; and wherein said transition-metal, lanthanide or group 13-14 metal oxide, polyoxometalate, hydroxide, alkoxide, carboxylate or combination thereof comprises a metal oxide, polyoxometalate, hydroxide, alkoxide, carboxylate or combination thereof of zirconium, scandium, yttrium, lanthanum, haffnium, titanium, aluminum, silicon, gallium, indium, thallium, germanium, tin, lead, bismuth, tungsten, tantalum, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium, or lutetium; and wherein said first radioisotope is 90Y, 32P, 18F, 140La, 153Sm, 165Dy, 166Ho, 169Er, 169Yb, 177Lu, 186Re, 188Re, 103Pd, 198Au, 192Ir, 90Sr, 111In or 67Ga; and wherein said second radioisotope is Tc-99m, 111In or 67Ga.

### Claim 30 (depends on 1, 2)

The microsphere of claim 1 or 2, wherein said hydrophilic polymer comprises one or more polymerized monomers selected from the group consisting of crosslinked gelatin, N-[tris(hydroxymethyl)-methyl]acrylamide and vinylphosphonate; and wherein said pendant moieties are selected independently from the group consisting of phosphonic acids, bisphosphonic acids, sulfonic acids, and carboxylic acids; and wherein said transition-metal, lanthanide or group 13-14 metal oxide, polyoxometalate, hydroxide, alkoxide, carboxylate or combination thereof comprises a metal oxide, polyoxometalate or metal hydroxide or combination thereof of zirconium, scandium, yttrium, lanthanum, titanium or hafnium; and wherein said first radioisotope is 32P, 90Y, 140La, 169Yb, 111In or 67Ga; and wherein said second radioisotope is Tc-99m, 111In or 67Ga.

### Claim 31 (depends on 1, 2)

The microsphere of claim 1 or 2, wherein said hydrophilic polymer comprises one or more polymerized monomers selected from the group consisting of N-[tris(hydroxymethyl)methyl]-acrylamide and vinylphosphonate; and wherein said pendant moieties are phosphonic acids; and wherein said transition-metal, lanthanide or group 13-14 metal oxide, polyoxometalate, hydroxide, alkoxide, carboxylate or combination thereof is an oxide, polyoxometalate, hydroxide, alkoxide or carboxylate of zirconium or combination thereof; and wherein said first radioisotope is 32P; and wherein said second radioisotope is Tc-99m, 111In or 67Ga.

### Claim 32 (depends on 1, 2)

The microsphere of claim 1 or 2, wherein said hydrophilic polymer comprises one or more polymerized monomers selected from the group consisting of N-[tris(hydroxymethyl)methyl]-acrylamide and vinylphosphonate; and wherein said pendant moieties are phosphonic acids; and wherein said transition-metal, lanthanide or group 13-14 metal oxide, polyoxometalate, hydroxide, alkoxide, carboxylate or combination thereof is an oxide, polyoxometalate, hydroxide, alkoxide or carboxylate of zirconium or combination thereof; and wherein said first radioisotope is 32P; and wherein said second radioisotope is 111In.

### Claim 33 (depends on 2)

The microsphere of claim 2, wherein the ratio of the radioactivity of the second radioisotope to the first radioisotope is in the range from about 1:10 to about 1:107 at the time of use.

### Claim 34 (depends on 2)

The microsphere of claim 2, wherein the ratio of the radioactivity of the second radioisotope to the first radioisotope is in the range from about 1:102 to 1:106 at the time of use.

### Claim 35 (depends on 2)

The microsphere of claim 2, wherein the ratio of the radioactivity of the second radioisotope to the first radioisotope is in the range from about 1:104 to 1:105 at the time of use.

### Claim 36 (depends on 2)

The microsphere of claim 2, wherein the ratio of the radioactivity of the second radioisotope to the first radioisotope is in the range from about 1:10 to 1:103 at the time of use.

### Claim 37 (depends on 2)

The microsphere of claim 2, wherein said first radioisotope is not leached from said microsphere to an extent greater than about 3%; wherein said second radioisotope is not leached from said microsphere to an extent greater than about 3%.

### Claim 38 (depends on 2)

The microsphere of claim 2, wherein said first radioisotope is not leached from said microsphere to an extent greater than about 1%; wherein said second radioisotope is not leached from said microsphere to an extent greater than about 1%.

### Claim 39 (depends on 1, 2)

The microsphere of claim 1 or 2, wherein said microsphere further comprises a biologically active agent.

### Claim 40 (depends on 1, 2)

The microsphere of claim 1 or 2, wherein said microsphere further comprises a contrast-enhancing agent.

### Claim 41 (depends on 1, 2)

The microsphere of claim 1 or 2, wherein said contrast-enhancing agent is selected from the group consisting of radiopaque materials, paramagnetic materials, heavy atoms, transition metals, lanthanides, actindes, and dyes.

### Claim 42 (depends on 1, 2)

The microsphere of claim 1 or 2, wherein the diameter of said microsphere is in the range from about 1-2000 micrometers.

### Claim 43 (depends on 1, 2)

The microsphere of claim 1 or 2, wherein the diameter of said microsphere is in the range from about 1-1000 micrometers.

### Claim 44 (depends on 1, 2)

The microsphere of claim 1 or 2, wherein the diameter of said microsphere is in the range from about 1-500 micrometers.

### Claim 45 (depends on 1, 2)

The microsphere of claim 1 or 2, wherein the diameter of said microsphere is in the range from about 1-100 micrometers.

### Claim 46 (depends on 1, 2)

The microsphere of claim 1 or 2, wherein the diameter of said microsphere is in the range from about 10-40 micrometers.