Details for Patent: 6,110,443

Title:	Dry stable formation to produce microbubble suspension for ultrasound
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.
Inventor(s):	Schneider; Michel (Troinex, CH), Bichon; Daniel (Montpellier, FR), Bussat; Philippe (Collonges S/Saleve, FR), Puginier; Jerome (Le Chable-Beaunont, FR), Hybl-Sutherland; Eva (Geneva, CH)
Assignee:	Bracco International N.V. (NL)
Filing Date:	May 09, 1997
Application Number:	08/853,936
Claims:	1. A dry pulverulent formulation which, upon dissolution in water, will form an aqueous suspension of stabilized air or gas microbubbles useful in ultrasonic imaging, the formulation comprising at least one film forming surfactant and at least one hydrophilic stabilizer in the presence of air or other entrappable gas, the film forming surfactant being a saturated phospholipid in lamellar or laminar form. 2. The dry formulation of claim 1, wherein the phospholipid is phosphatidic acid. 3. The dry formulation of claim 1, wherein the phospholipid is phosphatidylcholine. 4. The dry formulation of claim 1, wherein the phospholipid is phosphatidylethanolamine. 5. The dry formulation of claim 1, wherein the phospholipid is phosphatidylserine. 6. The dry formulation of claim 1, wherein the phospholipid is phosphatidylglycerol. 7. The dry formulation of claim 1, wherein the phospholipid is phosphatidylinositol. 8. The dry formulation of claim 1, wherein the phospholipid is cardiolipin. 9. The dry formulation of claim 1, wherein the phospholipid is sphyngomyelin. 10. The dry formulation of claim 1, wherein the formulation further contains dicetylphosphate. 11. The dry formulation of claim 1, wherein the formulation further contains cholesterol. 12. The dry formulation of claim 1, wherein the formulation further contains ergosterol. 13. The dry formulation of claim 1, wherein the formulation further contains phytosterol. 14. The dry formulation of claim 1, wherein the formulation further contains sitosterol. 15. The dry formulation of claim 1, wherein the formulation further contains lanosterol. 16. The dry formulation of claim 1, wherein the formulation further contains tocopterol. 17. The dry formulation of claim 1, wherein the formulation further contains propyl gallate. 18. The dry formulation of claim 1, wherein the formulation further contains ascorbyl palmitate. 19. The dry formulation of claim 1, wherein the formulation further contains butylated hydroxy-toluene. 20. The dry formulation of claim 1, further containing dissolved viscosity enhancers or stabilizers in a weight ratio to the surfactants comprised between about 1:5 to 100:1. 21. The dry formulation of claim 20, wherein the viscosity enhancers are linear and cross-linked polysaccharides. 22. The dry formulation of claim 20, wherein the viscosity enhancers are linear and cross-linked oligo-saccharides. 23. The dry formulation of claim 20, wherein the viscosity enhancers are sugars or hydrophilic polymers. 24. The dry formulation of claim 1, wherein the formulation comprises up to 50% by weight of non-laminar surfactants. 25. The dry formulation of claim 24, wherein the non-laminar surfactant is a fatty acid. 26. The dry formulation of claim 24, wherein the non-laminar surfactant is an ester or ether of fatty acids and alcohols. 27. The dry formulation of claim 24, wherein the non-laminar surfactant is a polyalkylene glycols. 28. The dry formulation of claim 24, wherein the non-laminar surfactant is a carbohydrate. 29. The dry formulation of claim 24, wherein the non-laminar surfactant is a polyalkylenated glycerol. 30. The dry formulation of claim 1, wherein the phospholipids in laminar form are in the form of fine layers deposited on the surface of soluble or insoluble solid particulate material. 31. The dry formulation of claim 30, wherein the insoluble solid particulate material is glass or polymer beads. 32. The dry formulation of claim 30, wherein the soluble particles are made of hydrosoluble carbohydrates or polysaccharides. 33. The dry formulation of claim 30, wherein the soluble particle are made of synthetic polymers or Iopamidol. 34. The dry formulation of claim 30, wherein the soluble particles are made of albumin or gelatin. 35. The dry formulation of claim 1, in the form of freeze-dried liposomes. 36. The dry formulation of claim 1, wherein the size of a majority of the microbubbles is below 50 .mu.m. 37. The dry formulation of claim 1, wherein the suspension contains about 10.sup.8 to 10.sup.9 bubbles of 0.5 to 10 .mu.m size/ml. 38. The dry formulation of claim 1, wherein the entrappable gas is a freon, nitrogen, carbon dioxide, argon, methane or mixtures thereof. 39. The dry formulation of claim 1, wherein the entrappable gas is a freon. 40. The dry formulation of claim 1, wherein the entrappable gas is .sup.81 kripton or .sup.133 xeonon. 41. The dry formulation of claim 38, wherein the entrappable gas is a halogenated hydrocarbon gas. 42. The dry formulation of claim 1, wherein the entrappable gas is nitrogen. 43. The dry formulation of claim 1, wherein the entrappable gas is carbon dioxide. 44. The dry formulation of claim 1, wherein the entrappable gas is argon. 45. The dry formulation of claim 1, wherein the entrappable gas is methane. 46. The dry formulation of claim 1, wherein the hydrophilic stabilizer is a hydrosoluble protein. 47. The dry formulation of claim 1, wherein the hydrophilic stabilizer is a polypeptide. 48. The dry formulation of claim 1, wherein the hydrophilic stabilizer is a sugar. 49. The dry formulation of claim 1, wherein the hydrophilic stabilizer is a poly- or oligo-saccharide. 50. The dry formulation of claim 1, wherein the hydrophilic stabilizer is a hydrophilic polymer.