Composition for therapy of diseases with ultrasonic and pharmaceutical liquid composition containing the same

• US RE36,939 E
• Filed: 05/30/1996
• Issued: 10/31/2000
• Est. Priority Date: 03/22/1991
• Status: Expired due to Term

• Current Assignee: EKOS Corporation (Boston Scientific Corporation)
• Original Assignee: EKOS Corporation (Boston Scientific Corporation)
• Inventors: Tachibana, Katsuro, Tachibana, Shunro
• Primary Examiner(s): Bockelman, Mark
• Application Number:
  US08/652,690
• Time in Patent Office: 1,615 Days
• Field of Search: 604/22, 601/2, 424/9, 424/450, 424/9.5-9.52, 424/94.1, 424/94.6, 424/94.63
• US Class Current: 604/22
• CPC Class Codes: A61K 41/0004 Homeopathy; Vitalisation; Resonance; Dynamisation, e.g. esoteric applications; Oxygenation of blood
• CPC Class Codes: A61K 41/0028 Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
• CPC Class Codes: A61K 41/0047 Sonopheresis, i.e. ultrasonically-enhanced transdermal delivery, electroporation of a pharmacologically active agent
• CPC Class Codes: A61K 49/223 Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
• CPC Class Codes: A61K 9/0009 involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis microelectromechanical systems A61K9/0097
• CPC Class Codes: A61K 9/5052 Proteins, e.g. albumin

Abstract

A booster comprising a plenty of microbubbles of a gas in a liquid, e.g. about 4×10⁷ cells/ml of microbubbles of a gas having a diameter of 0.1 to 100 μm in a 3 to 5% human serum albumin solution, and a pharmaceutical liquid composition comprising the booster as set forth above and a medicament, which are useful for the therapy of various diseases together with exposure of ultrasonic, where the therapeutic effects of the medicament is enhanced by the application of ultrasound in the presence of the booster.

Claims

1. A .[.booster.]. .Iadd.composition .Iaddend.for enhancing effects of ultrasound in the therapy of diseases, which comprises:

.Iadd.a liquid;

.Iaddend.

.[.a..]. a medicament.Iadd.;

.Iaddend.and

.[.b..]. microbubbles of a gas having a diameter of 0.1 to 100 μ

m.Iadd., .Iaddend..[.in a liquid.]. .Iadd.wherein a majority of the medicament is present outside of the microbubbles.Iaddend..

2. The .[.booster.]. .Iadd.composition .Iaddend.according to claim 1, wherein the microbubbles are formed from air or oxygen gas in the liquid.

3. The .[.booster.]. .Iadd.composition .Iaddend.according to claim 1, wherein the liquid is a 3 to 5% human serum albumin solution.

4. A pharmaceutical liquid composition for the therapy of diseases with application of ultrasound, which comprises:

.Iadd.a liquid;

.Iaddend.

.[.a..]. microbubbles of a gas having a diameter of 0.1 to 100 μ

m.Iadd.;

.Iaddend.and

.[.b..]. a medicament selected from the group consisting of thrombolytic agents, hormones, antibiotics and antineoplastic agents.Iadd., .Iaddend..[.in a liquid.]. .Iadd.wherein a majority of the medicament is present outside of the microbubbles.Iaddend..

5. The composition according to claim 4, wherein the microbubbles are formed from air or oxygen gas in the liquid.

6. The composition according to claim 4, wherein the liquid is a 3 to 5% human serum albumin solution. .[.7. The composition according to claim 4, wherein the medicament is a member selected from thromobolytic agents,

7. hormones, antibiotics, and antineoplastic agents..].8. The composition according to claim 4, wherein the medicament is selected from the group consisting of urokinase, tissue plasminogen activator, insulin,

8. theophylline, and lidocaine. 9. A method for enhancing the therapeutic effects of a medicament, comprising:

.[.a. applying ultrasound to a pharmaceutical liquid composition according to claim 4 and

b..]. administering .[.said.]. .Iadd.a .Iaddend.pharmaceutical liquid composition .Iadd.comprising a liquid, a medicament, and microbubbles of a gas having a diameter of 0.1 to 100 μ

m, wherein a majority of the medicament is present outside of the microbubbles; and

9. applying ultrasound to the pharmaceutical liquid composition.Iaddend.. 10. The method according to claim 9, wherein the liquid composition comprises about 4×

10⁷ cells/ml of microbubbles .[.of a gas having a diameter of 0.1 to 100 μ

m and a medicament in the liquid.]..

11. human serum albumin solution. 12. The method according to claim 9, wherein the medicament is selected from the group consisting of urokinase, tissue

10. The method according to claim 10, wherein the liquid is a 3 to 5%

12. plasminogen activator, insulin, theophylline, and lidocaine. 13. A method of dosing subjects with a pharmaceutical preparation by:

.[.a. applying ultrasound to a pharmaceutical liquid composition and.].

.[.b..]. administering .[.said.]. .Iadd.a .Iaddend.pharmaceutical liquid composition comprising .Iadd.a liquid, .Iaddend.microbubbles of a gas having a diameter of 0.1 to 100 μ

m.Iadd., .Iaddend.and a medicament .[.in a liquid in the therapy of diseases.]. .Iadd.wherein a majority of the medicament is present outside of the microbubbles; and

13. applying ultrasound to the pharmaceutical liquid composition.Iaddend.. 14. The method of dosing according to claim 13, wherein the microbubbles

14. are formed from air or oxygen gas in the liquid. 15. The method of dosing according to claim 13, wherein the liquid is a 3 to 5% human serum albumin

15. solution. 16. The method of dosing according to claim 13, wherein the medicament is selected from the group consisting of urokinase, tissue

16. plasminogen activator, insulin, theophylline, and lidocaine. .Iadd.17. A composition for enhancing the effects of ultrasound in the therapy of diseases when said ultrasound is administered in conjunction with a medicament, said composition comprising a liquid, a medicament, and microbubbles of a gas made of a shell having a diameter of 0.1 to 100 μ

m, wherein a majority of the medicament is present outside of the shell and is not incorporated in the shell. .Iaddend..Iadd.18. A composition for enhancing the effects of ultrasound in the therapy of diseases which comprises a liquid, a medicament, and microbubbles of a gas made of a shell having a diameter of 0.1 to 100 μ

m, wherein at least a majority of the medicament is present outside of the shell.

17. Iaddend..Iadd.9. A method for enhancing the therapeutic effects of ultrasound comprising:

creating a mixture comprising a liquid, microbubbles of a gas having a diameter of 0.1 to 100 μ

m, and a medicament, wherein a majority of the medicament is present outside of the microbubbles; and

applying ultrasound to the mixture. .Iaddend..Iadd.20. The method of claim 19 wherein the mixture is administered in proximity to a diseased part. .Iaddend..Iadd.21. The method of claim 19 wherein the mixture is injected into a blood vessel near a diseased part. .Iaddend..Iadd.22. A method for enhancing the therapeutic effect of a medicament administered to a patient comprising;

administering to the patient a liquid composition comprising microbubbles of a gas having a diameter of 0.1 to 100 μ

m; and

applying ultrasound to the liquid composition and the medicament, wherein a majority of the medicament is present outside of the microbubbles. .Iaddend..Iadd.23. The method of claim 22 wherein the mixture is injected into a blood vessel near a diseased part. .Iaddend..Iadd.24. A method of enhancing the therapeutic effects of ultrasound of a medicament comprising;

creating microbubbles of a gas having a diameter of 0.1 to 100 μ

m in a liquid containing the medicament, wherein a majority of the medicament is present outside of the microbubbles; and

18. applying ultrasound to the microbubbles. .Iaddend..Iadd.25. The method of claim 24 wherein the liquid is administered in the proximity of a diseased part. .Iaddend..Iadd.26. The method of claim 24 wherein the liquid is injected in a blood vessel near the diseased part. .Iaddend.