Stable microbubbles suspensions injectable into living organisms

• US 5,271,928 A
• Filed: 11/20/1991
• Issued: 12/21/1993
• Est. Priority Date: 04/02/1990
• Status: Expired due to Term

• Current Assignee: Bracco Suisse SA
• Original Assignee: Sintetica SA
• Inventors: Schneider, Michel, Bussat, Philippe, Bichon, Daniel, Puginier, Jerome, Hybl-Sutherland, Eva
• Primary Examiner(s): Russell, Mark
• Application Number:
  US07/775,989
• Time in Patent Office: 762 Days
• Field of Search: 424/9, 424/450, 128/662.02, 514/619
• US Class Current: 424/9.51
• CPC Class Codes: A61K 49/223 Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
• CPC Class Codes: A61K 49/227 Liposomes, lipoprotein vesicles, e.g. LDL or HDL lipoproteins, micelles, e.g. phospholipidic or polymeric

Abstract

Gas or air filled microbubble suspensions in aqueous phases usable as imaging contrast agents in ultrasonic echography. They contain laminarized surfactants and, optionally, hydrophilic stabilizers. The laminarized surfactants can be in the form of liposomes. The suspensions are obtained by exposing the laminarized surfactants to air or a gas before or after admixing with an aqueous phase.

Claims

1. A composition suitable for injection into the bloodstream and body cavities of living beings, comprising a suspension of stabilized air or gas microbubbles in a physiologically acceptable aqueous carrier phase having from about 0.01 to about 20% by weight of one or more dissolved or dispersed surfactants, at least one of said surfactants being a film forming surfactant present in the composition at least partially in lamellar or laminar form.

2. The composition of claim 1, wherein the lamellar surfactant is in the form of mono- or pluri-molecular membrane layers.

3. The composition of claim 1, containing about 10⁸ -10⁹ bubbles of 0.5-10 μ

m size/ml.

4. The composition of claim 1, wherein the surfactant is a phospholipid.

5. The composition of claim 4, wherein said phospholipid is selected from the group consisting of lecithins, phosphatidic acid, phosphatidyl-choline, phosphatidyl-ethanolamine, phosphatidyl-serine, phosphatidyl-glycerol, phosphatidyl-inositol, cariolipin and sphyngomyelin.

6. The composition of claim 4, and further comprising a substance affecting the properties of liposomes selected from the group consisting of phosphatidyl-glycerol, dicetyl-phosphate, cholesterol, ergosterol, phytosterol, sitosterol, lanosterol, tocopterol, propyl gallate, ascorbyl palmitate and butylated hydroxy-toluene.

7. The composition of claim 1, and further comprising a dissolved viscosity enhancer or stabilizer selected from the group consisting of linear and cross-linked poly- and oligo-saccharides, sugars, hydrophilic polymers and iodinated compounds in a weight ratio to the surfactants of between about 1:

5 to 100;

1.

8. The composition of claim 7, wherein said iodinated compound is Iopamidol.

9. The composition of claim 1, wherein the surfactants comprise up to 50% by weight of non-laminar surfactants selected from the group consisting of fatty acids, esters and ethers of fatty acids and alcohols with polyols.

10. The composition of claim 9, wherein the non-laminar surfactant is selected from the group consisting of polyalkylene glycols, polyalkylenated sugars and polyalkylenated glycerol.

11. A method for the preparation of a composition as defined in claim 1, said method comprising the steps of:

(a) selecting at least one film forming surfactant and converting it into lamellar form;

(b) contacting the surfactant in lamellar form with air or an adsorbable or entrapable gas for a time sufficient for that air or gas to become bound by said surfactant; and

(c) admixing the surfactant in lamellar form with an aqueous liquid carrier, to form a stable dispersion of air or gas microbubbles in said liquid carrier.

12. The method of claim 11, wherein step (c) is performed before step (b), step (b) being effected by introducing pressurized air or gas into the liquid carrier and thereafter releasing the pressure.

13. The method of claim 11, wherein step (c) is brought about by gentle mixing of the components with no shaking, whereby air or gas bound to the lamellar surfactant in step (b) develops into a suspension of stable microbubbles.

14. The method of claim 11, wherein the aqueous liquid carrier contains dissolved therein stabilizer compounds selected from the group consisting of hydrosoluble proteins, polypeptides, sugars, poly- and oligo-saccharides and hydrophilic polymers.

15. The method of claim 11, wherein step (a) is effected by coating the surfactant onto particles of soluble or insoluble materials, wherein step (b) is effected by letting the coated particles stand for a while under air or gas and step (c) is effected by admixing the coated particles with an aqueous liquid carrier.

16. The method of claim 11, wherein step (a) is effected by sonicating or homogenizing under high pressure an aqueous solution of film forming lipids, leading, at least partly, to the formation of liposomes.

17. The method of claim 16, wherein step (b) is effected by freeze-drying the liposome containing solution and contacting the resulting freeze-dried product with air or a gas.

18. The method of claim 17, wherein in step (b) the liposome containing solution contains hydrophilic stabilizers.

19. The method of claim 16, wherein the aqueous solution of film forming lipids also contains viscosity enhancers or stabilizers selected from the group coasting of hydrophilic polymers and carbohydrates in weight ratio relative to the lipids of between 1:

5 and 100;

1.