Microspheres capable of binding radioisotopes, optionally comprising metallic microparticles, and methods of use thereof

• US 20060067883A1
• Filed: 07/19/2005
• Published: 03/30/2006
• Est. Priority Date: 09/24/2004
• Status: Abandoned Application

• Current Assignee: Biosphere Medical Inc. (Merit Medical Systems, Inc.)
• Original Assignee: Biosphere Medical Inc. (Merit Medical Systems, Inc.)
• Inventors: Schwarz, Alexander, Krom, James A.
• Application Number:
  US11/185,449
• Publication Number:
  US 20060067883A1
• Time in Patent Office: Days
• US Class Current: 424/1.290
• CPC Class Codes: A61K 2121/00 Preparations for use in therapy
• CPC Class Codes: A61K 51/1255 Granulates, agglomerates, microspheres
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 35/00 Antineoplastic agents

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

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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

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

10. 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.

11. 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.

12. 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.

13. 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.

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

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

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

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

18. 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.

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

and said second radioisotope is ¹¹¹In.

20. 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.

21. 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.

22. 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.

23. 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.

24. 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.

25. 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.

26. 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.

27. 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.

28. 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.

29. 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.

30. 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.

31. 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.

32. 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.

33. 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.

34. 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.

35. 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.

36. 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.

37. 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%.

38. 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%.

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

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

41. 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.

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

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

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

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

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