Porous inorganic ultrasound contrast agents

• US 5,147,631 A
• Filed: 04/30/1991
• Issued: 09/15/1992
• Est. Priority Date: 04/30/1991
• Status: Expired due to Term

• Current Assignee: Lantheus Medical Imaging, Inc. (Lantheus Holdings, Inc.)
• Original Assignee: Du Pont De Nemours (Belgium) Bvba (DuPont de Nemours, Inc.)
• Inventors: Loomis, Gary L., Mahler, Walter, Glajch, Joseph L.
• Primary Examiner(s): JAWORSKI, FRANCIS J
• Application Number:
  US07/693,476
• Time in Patent Office: 504 Days
• Field of Search: 128/660.01, 128/662.02, 424/4, 424/9
• US Class Current: 424/9.52
• CPC Class Codes: A61K 49/223 Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
• CPC Class Codes: A61K 49/225 Microparticles, microcapsules gas-filled to be classified in A61K49/223

Abstract

The invention relates to ultrasound contrast agents comprising porous particles of an inorganic material containing an entrapped gas or liquid and having an average particle diameter of about 0.05 to 500 microns, said inorganic material being selected from one or more of the group consisting of: monomeric or polymeric borates; monomeric or polymeric aluminas; monomeric or polymeric carbonates; monomeric or polymeric silicas; and monomeric or polymeric phosphates; and pharmaceutically acceptable organic or inorganic cationic salts thereof.

Claims

1. An ultrasound contrast agent comprising a pharmaceutically acceptable carrier and porous particles of an inorganic material containing an entrapped gas and having an average particle diameter of 0.01 to 500 microns, said inorganic material being selected from one or more of the group consisting of:

monomeric or polymeric borates;

monomeric or polymeric aluminas;

monomeric or polymeric carbonates and bicarbonates;

monomeric or polymeric silicas and silicates;

monomeric or polymeric aluminosilicates; and

monomeric or polymeric phosphates; and

pharmaceutically acceptable organic or inorganic cationic salts thereof.

2. An ultrasound contrast agent of claim 1, wherein the inorganic material is in a crystalline form.

3. An ultrasound contrast agent of claim 1, wherein the inorganic material is in an amorphous form.

4. An ultrasound contrast agent of claim 1, wherein the inorganic material is a mixture of crystalline and amorphous forms.

5. An ultrasound contrast agent of claim 1, wherein the entrapped gas is selected from the group consisting of air, O₂, N₂, H₂, CO₂, He, Ne, Ar, CF₄, and C₂ F₆.

6. An ultrasound contrast agent of claim 1, wherein the average particle diameter is 0.05 to 10 microns.

7. An ultrasound contrast agent of claim 1, wherein the porous particles have a single pore which is entirely or partially enclosed by a shell of the inorganic material.

8. An ultrasound contrast agent of claim 7, wherein the shell thickness is 1-45% of the average particle diameter.

9. An ultrasound contrast agent of claim 1, wherein the porous particles have a plurality of pores which are entirely or partially enclosed by the inorganic material.

10. An ultrasound contrast agent of claim 9, wherein the pores are interconnected.

11. An ultrasound contrast agent of claim 1, wherein the porous particles of inorganic material have a density of less than about 90% of the density of the inorganic material in a solid non-porous state.

12. An ultrasound contrast agent of claim 1, wherein the porous particles of inorganic material have a density of less than about 60% of the density of the inorganic material in a solid non-porous state.

13. An ultrasound contrast agent of claim 12, wherein the porous particles of inorganic material have a density of 0.2% to 50% of the density of the inorganic material in a solid non-porous state.

14. An ultrasound contrast agent of claim 1, wherein the porous particles of inorganic material are substantially spherical in shape.

15. An ultrasound contrast agent of claim 1, wherein the inorganic material is selected from the group consisting of SiO₂, aluminum oxides, aluminum hydroxides, alkali salts of aluminosilicates, and H₃ BO₃.

16. An ultrasound contrast agent of claim 15, wherein the inorganic material is crystalline or amorphous, or a mixture of crystalline and amorphous forms.

17. An ultrasound contrast agent of claim 16, wherein the average particle diameter is 0.05 to 10 microns.

18. An ultrasound contrast agent of claim 16, wherein the porous particles have a single pore which is entirely or partially enclosed by a shell of the inorganic material.

19. An ultrasound contrast agent of claim 18, wherein the shell thickness is 1-45% of the average diameter of the particle.

20. An ultrasound contrast agent of claim 16, wherein the porous particles have a plurality of pores which are entirely or partially enclosed by the inorganic material.

21. An ultrasound contrast agent of claim 20, wherein the pores are interconnected.

22. An ultrasound contrast agent of claim 16, wherein the porous particles or inorganic material have a density of less than about 70% of the density of the inorganic material in a solid nonporous state.

23. An ultrasound contrast agent of claim 16, wherein the porous particles are substantially spherical in shape.

24. An ultrasound contrast agent of claim 16, wherein the porous particles of inorganic material are coated with an organic material.

25. An ultrasound contrast agent of claim 16, wherein the porous particles of inorganic material are coated with an organic material selected from the group consisting of ethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyethylene glycol, albumin, gelatin, starch, collagen, dextran, modified dextrans, polylactide/polyglycolide, polyalkylcyanoacrylates, polyacrylamide, cholesterol, phosphatidylcholine, phosphatidylinositol, polysorbates, polyethlyene ethers, polyethylene esters, and polyoxyethylene/polyoxypropylene block polymers.

26. In a method of ultrasound imaging a selected tissue or organ system in a mammal, the improvement comprising introducing to the mammal an amount of an ultrasound contrast agent of claim 16, effective to alter the ultrasound echogenicity of the selected tissue or organ system.

27. An ultrasound contrast agent of claim 1, wherein the inorganic material comprises monomeric or polymeric forms, or a mixture of monomeric and polymeric forms, of phosphate.

28. An ultrasound contrast agent of claim 27, wherein the inorganic material is crystalline or amorphous, or a mixture of crystalline and amorphous forms.

29. An ultrasound contrast agent of claim 28, wherein the inorganic material comprises monomeric or polymeric forms, or a mixture of monomeric and polymeric forms, of one or more alkali cation phosphate salts.

30. An ultrasound contrast agent of claim 29, wherein the alkali cations are sodium, potassium, or calcium.

31. An ultrasound contrast agent of claim 29, wherein the porous particles of inorganic material have a density of less than about 70% of the density of the inorganic material in a solid nonporous state.

32. In a method of ultrasound imaging a selected tissue or organ system in a mammal, the improvement comprising introducing to the mammal an amount of an ultrasound contrast agent of claim 29, effective to alter the ultrasound echogenicity of the selected tissue or organ system.

33. An ultrasound contrast agent of claim 28, wherein the average particle diameter is 0.05 to 10 microns.

34. An ultrasound contrast agent of claim 28, wherein the porous particles have a single pore which is entirely or partially enclosed by a shell of the inorganic material.

35. An ultrasound contrast agent of claim 34, wherein the shell thickness is 1-45% of the average diameter of the particle.

36. An ultrasound contrast agent of claim 28, wherein the porous particles have a plurality of pores which are entirely or partially enclosed by the inorganic material.

37. An ultrasound contrast agent of claim 36, wherein the pores are interconnected.

38. An ultrasound contrast agent of claim 28, wherein the porous particles of inorganic material have a density of less than about 70% of the density of the inorganic material in a solid nonporous state.

39. An ultrasound contrast agent of claim 28, wherein the porous particles are substantially spherical in shape.

40. An ultrasound contrast agent of claim 28, wherein the porous particles of inorganic material are coated with an organic material.

41. An ultrasound contrast agent of claim 28, wherein the porous particles of inorganic material are coated with an organic material selected from the group consisting of ethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyethylene glycol, albumin, gelatin, starch, collagen, dextran, modified dextrans, polylactide/polyglycolide, polyalkylcyanoacrylates, polyacrylamide, cholesterol, phosphatidylcholine, phosphatidylinositol, polysorbates, polyethlyene ethers, polyethylene esters, and polyoxyethylene/polyoxypropylene block polymers.

42. In a method of ultrasound imaging a selected tissue or organ system in a mammal, the improvement comprising introducing to the mammal an amount of an ultrasound contrast agent of claim 28, effective to alter the ultrasound echogenicity of the selected tissue or organ system.

43. An ultrasound contrast agent of claim 1, wherein the inorganic material comprises monomeric or polymeric forms, or a mixture of monomeric and polymeric forms, of carbonate or bicarbonate.

44. An ultrasound contrast agent of claim 43, wherein the inorganic material is crystalline or amorphous, or a mixture of crystalline and amorphous forms.

45. An ultrasound contrast agent of claim 44, wherein the inorganic material comprises monomeric or polymeric forms, or a mixture of monomeric and polymeric forms, of one or more alkali cation carbonate or bicarbonate salts.

46. An ultrasound contrast agent of claim 45, wherein the alkali cations are sodium, potassium, or calcium.

47. An ultrasound contrast agent of claim 45, wherein the porous particles of inorganic material have a density of less than about 70% of the density of the inorganic material in a solid nonporous state.

48. An ultrasound contrast agent of claim 44, wherein the average particle diameter is 0.05 to 10 microns.

49. An ultrasound contrast agent of claim 44, wherein the porous particles have a single pore which is entirely or partially enclosed by a shell of the inorganic material.

50. An ultrasound contrast agent of claim 49, wherein the shell thickness is 1-45% of the diameter of the particle.

51. An ultrasound contrast agent of claim 44, wherein the porous particles have a plurality of pores which are entirely or partially enclosed by the inorganic material.

52. An ultrasound contrast agent of claim 51, wherein the pores are interconnected.

53. An ultrasound contrast agent of claim 44, wherein the porous particles of inorganic material have a density of less than about 70% of the density of the inorganic material in a solid nonporous state.

54. An ultrasound contrast agent of claim 44, wherein the porous particles are substantially spherical in shape.

55. An ultrasound contrast agent of claim 44, wherein the porous particles of inorganic material are coated with an organic material.

56. An ultrasound contrast agent of claim 44, wherein the porous particles of inorganic material are coated with an organic material selected from the group consisting of ethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyethylene glycol, albumin, gelatin, starch, collagen, dextran, modified dextrans, polylactide/polyglycolide, polyalkylcyanoacrylates, polyacrylamide, cholesterol, phosphatidylcholine, phosphatidylinositol, polysorbates, polyethlyene ethers, polyethylene esters, and polyoxyethylene/polyoxypropylene block polymers.

57. In a method of ultrasound imaging a selected tissue or organ system in a mammal, the improvement comprising introducing to the mammal an amount of an ultrasound contrast agent of claim 44, effective to alter the ultrasound echogenicity of the selected tissue or organ system.

58. An ultrasound contrast agent of claim 1, wherein the porous particles of inorganic material are coated with an organic material.

59. An ultrasound contrast agent of claim 1, wherein the porous particles of inorganic material are coated with an organic material selected from the group consisting of ethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyethylene glycol, albumin, gelatin, starch, collagen, dextran, modified dextrans, polylactide/polyglycolide, polyalkylcyanoacrylates, polyacrylamide, cholesterol, phosphatidylcholine, phosphatidylinositol, polysorbates, polyethlyene ethers, polyethylene esters, and polyoxyethylene/polyoxypropylene block polymers.

60. In a method of ultrasound imaging a selected tissue or organ system in a mammal, the improvement comprising introducing to the mammal an amount of an ultrasound contrast agent of claim 1, effective to alter the ultrasound echogenicity of the selected tissue or organ system.