Method for the production of medical-grade lipid-coated microbubbles, paramagnetic labeling of such microbubbles and therapeutic uses of microbubbles

• US 5,215,680 A
• Filed: 07/10/1990
• Issued: 06/01/1993
• Est. Priority Date: 07/10/1990
• Status: Expired due to Term

• Current Assignee: Cavitation-Control Technology Incorporated
• Original Assignee: Cavitation-Control Technology Incorporated
• Inventors: D'Arrigo, Joseph S.
• Primary Examiner(s): Lovering, Richard D.
• Assistant Examiner(s): COVERT, JOHN
• Application Number:
  US07/550,620
• Time in Patent Office: 1,057 Days
• Field of Search: 424/9, 436/173, 128/662.02
• US Class Current: 516/11
• CPC Class Codes: A61K 41/0047 Sonopheresis, i.e. ultrasonically-enhanced transdermal delivery, electroporation of a pharmacologically active agent
• CPC Class Codes: A61K 49/18 characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
• CPC Class Codes: A61K 49/1815 compo-inhalant, e.g. breath tests
• CPC Class Codes: A61K 49/223 Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
• CPC Class Codes: A61K 9/5015 Organic compounds, e.g. fats, sugars
• CPC Class Codes: Y10T 436/24 Nuclear magnetic resonance, electron spin resonance or other spin effects or mass spectrometry

Abstract

This invention relates to a large scale method for the production of medical grade lipid-coated microbubbles, to the paramagnetic labeling of such microbubbles and to therapeutic applications for the microbubbles. More particularly, the invention relates to a method of the production of medical grade, concentrated suspensions of stable, paramagnetically derivatized or underivatized microbubbles useful for ultrasonic and magnetic resonance imaging and also relates to therapeutic interventions such as selective tumor destruction.

Claims

1. A method for preparing an imaging about suitable for enhancement of ultrasonic imaging and magnetic resonance imaging comprising the steps of:

A. obtaining a moderately hydrophobic neutral amino acid homopolymer or copolymer which is capable of readily incorporating into a lipid monolayer, and is labeled with a paramagnetic complex comprising a metal ion and organic chelating ligand;

B. dissolving the labeled, hydrophobic polymer in a saline solution in an amount of about 10 mM;

C. adding a surfactant mixture comprising;

(a) a member selected from the group consisting of glycerol monoesters of saturated carboxylic acids containing from about 10 to about 18 carbon atoms and aliphatic alcohols containing from about 10 to about 18 carbon atoms;

(b) a sterol-aromatic acid ester;

(c) a member selected from the group consisting of sterols, terpenes, bile acids and alkali metal salts of bile acids;

(d) a member selected from the group consisting of sterol esters of aliphatic acids containing from one to about 18 carbon atoms;

sterol esters of sugar acids;

esters of sugar acids and aliphatic alcohols containing from about 10 to about 18 carbon atoms, esters of sugars and aliphatic acids containing from about 10 to about 18 carbon atoms;

sugar acids, saponins; and

sapogenins; and

(e) a member selected from the group consisting of glycerol, glycerol di or triesters of aliphatic acids containing from about 10 to about 18 carbon atoms and aliphatic alcohols containing from about 10 to about 18 carbon atoms;

D. shaking said solution mechanically for from about 2 to about 10 seconds in gaseous atmosphere at room temperature, thereby forming a concentrated gas-in-liquid emulsion; and

E. passing the solution obtained after step (D) through a sterile polysulfone membrane filter having an average pore diameter of about 0.40-6.0 μ

m.

2. A method according to claim 1, further comprising the steps of allowing undissolved lipid materials to settle out for a period of about 15-60 minutes before passing the solution through the polysulfone membrane filter.

3. A method according to claim 2, wherein the sterile polysulfone membrane filter has an average pore diameter of about 0.40-0.60 μ

m.

4. A method according to claim 3, wherein the sterile polysulfone membrane filter has an average pore diameter of about 45 μ

m.

5. A method according to claim 3, wherein the moderately hydrophobic polymer is selected from the group consisting of homopolymers of valine, glycine and alanine and copolymers thereof.

6. A method according to claim 5, wherein the paramagnetic complex is selected from the group consisting of gadolinium DTPA, manganese DTPA, gadolinium EDTA and manganese EDTA.

7. A method according to claim 6 wherein the paramagnetic complex is gadolinium DTPA.

8. A method according to claim 7, wherein the surfactant mixture components are present in the surfactant mixture in a weight ratio a:

b;

c;

d;

e of about 2-4;

0.5-1.5;

0.5-1.5;

0.5-1.5;

0-1.5.

9. A method according to claim 8, wherein the surfactant mixture consists essentially of glycerol monolaurate, cholesterol benzoate, cholesterol, cholesterol acetate and glycerol tripalmitate in a weight ratio of 2-4:

1;

1;

1;

1.

10. A method according to claim 1, further comprising the steps of mechanically shaking the solution at least two more times before passing the solution through the polysulfone membrane filter.