Generation of therapeutic microfoam

• US 20030082243A1
• Filed: 11/21/2002
• Published: 05/01/2003
• Est. Priority Date: 05/26/1999
• Status: Active Grant

• Current Assignee: BTG International Limited (Boston Scientific Corporation)
• Original Assignee: BTG International Limited (Boston Scientific Corporation)
• Inventors: Harman, Anthony David, Wright, David Dakin Iorwerth, Osman, Tariq, Flynn, Sheila Bronwen, Boorman, Timothy David
• Granted Patent: US 7,025,290 B2
• Time in Patent Office: Days
• US Class Current: 424/600
• CPC Class Codes: A61K 31/08 acyclic, e.g. paraformaldehyde
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/122 Foams; Dry foams edible foams A61K9/0056
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: B05B 11/02 Membranes or pistons acting on the contents inside the container, e.g. follower pistons
• CPC Class Codes: B05B 7/0037 including sieves, porous members or the like
• CPC Class Codes: B65D 83/14 for delivery of liquid or semi-liquid contents by internal gaseous pressure, i.e. aerosol containers comprising propellant for a product delivered by a propellant
• CPC Class Codes: B65D 83/20 operated by manual action, e.g. button-type actuator or actuator caps actuators formed as a rigid elongate spout B65D83/306
• CPC Class Codes: B65D 83/48 Lift valves, e.g. operated by push action B65D83/50 takes precedence
• CPC Class Codes: B65D 83/60 Contents and propellant separated
• CPC Class Codes: B65D 83/62 by membrane, bag, or the like containers in which the content is delivered by the contracting forces inherent in the bag B65D83/0061

Abstract

Improved therapeutic sclerosing microfoams and methods and devices for making them are provided that have advantage in producing a consistent profile injectable foam with minimal input by the physician yet using high volume percentages of blood dispersible gases, thus avoiding use of potentially hazardous amounts of nitrogen.

Claims

1. A method for producing a microfoam suitable for use in sclerotherapy of blood vessels characterized in that it comprises passing a mixture of a physiologically acceptable blood dispersible gas and an aqueous sclerosant liquid through one or more passages having at least one cross-sectional dimension of from 0.1 to 30 μ

m, the ratio of gas to liquid being controlled such that a microfoam is produced having a density of between 0.07 g/mL to 0.19 g/mL and has a half-life of at least 2 minutes

2. A method as claimed in claim 1 the gas/liquid ratio in the mixture is controlled such that the density of the microfoam is 0.09 g/mL to 0.16 g/mL.

3. A method as claimed in claim 1 or claim 2 characterized in that at least 50% by number of the gas bubbles of 25 μ

m diameter and above are of no more than 200 μ

m diameter and at least 95% of these gas bubbles are no more than 280 μ

m diameter.

4. A method as claimed in any one of the preceding claims characterized in that at least 50% by number of the gas bubbles of 25 μ

m diameter and above are of no more than 150 μ

m diameter and at least 95% of these gas bubbles are no more than 250 μ

m diameter.

5. A method as claimed in any one of the preceding claims characterized in that the mixture of gas and sclerosant liquid is in the form of an aerosol, dispersion of bubbles in liquid or macrofoam.

6. A method as claimed in any one of the preceding claims characterized in that the ratio of gas to liquid used in the mixture is 1 gram sclerosant liquid to from 6.25 to 14.3 volumes of gas at standard temperature and pressure.

7. A method as claimed in any one of the preceding claims characterized in that the physiologically acceptable blood dispersible gas comprises a major proportion of carbon dioxide and/or oxygen.

8. A method as claimed in any one of the preceding claims characterized in that the aqueous sclerosant liquid is a solution of polidocanol or sodium tetradecylsulfate (STS) in an aqueous carrier.

9. A method as claimed in claim 8 characterized in that the carrier comprises a saline solution.

10. A method as claimed in any one of the preceding claims characterized in that the cross-sectional dimension is diameter and the one or more passages through which the gas and liquid mixture are passed to produce the microfoam have diameter of from 5 μ

m to 25 μ

m.

11. A method as claimed in claim 10 characterized in that the passages are of from 10 μ

m to 20 μ

m diameter and are openings in a mesh or screen placed perpendicular to the direction of flow of the gas/liquid mixture.

12. A method as claimed in claim 10 or claim 11 characterized in that the passages are provided as multiple openings in one or more elements through which the mixture flows.

13. A method as claimed in claim 12 characterized in that the multiple openings provide a 2% to 65% open area in the one or more elements.

14. A method as claimed in claim 12 characterized in that the element comprises porous material and a number said elements are arranged sequentially such that the gas and liquid pass through the passages of each element.

15. A method as claimed in claim 14 characterized in that the elements are spaced and are placed along the direction of flow of the mixture in series.

16. A method as claimed in any one of the preceding claims characterized in that the mixture of gas and liquid is passed through the same passage or passages a number of times.

17. A method as claimed in any one of the preceding claims characterized in that the gas is pressurized to 0.01 to 9 bar over atmospheric pressure.

18. A method as claimed in claim 17 characterized in that the gas is pressurized at 0.1 to 3 bar over atmospheric pressure.

58. A device as claimed in any one of claims 19 to 43 characterized in that it produces a microfoam according to the method of any one of claims 1 to 18.

19. A device for producing a microfoam suitable for use in sclerotherapy of blood vessels comprising a housing in which is situated a pressurisable chamber containing an aqueous sclerosant liquid;

a pathway with one or more outlet orifices by which the liquid may pass from the pressurisable chamber to exterior of the device through one or more outlet orifices and a mechanism by which the pathway from the chamber to the exterior can be opened or closed such that, when the container is pressurized and the pathway is open, fluid in the chamber will be forced along the pathway and through the one or more outlet orifices

said housing including one or more of (a) a pressurized source of physiologically acceptable gas that is dispersible in blood and (b) an inlet for admission of said gas;

the gas being contacted with the liquid on activation of the mechanism such as to produce a gas liquid mixture

said pathway to the exterior of the housing includes one or more elements defining one or more passages of cross-sectional dimension 0.1 μ

m to 30 μ

m, through which the gas liquid mixture is passed to reach the exterior of the device, said passing of the mixture through the passages forming a microfoam of from 0.07 to 0.19 g/mL density and having a half-life of at least 2 minutes.

20. A device as claimed in claim 19 further comprising a gas liquid interface junction, prior to the passages, the junction controlling the ratio of gas to liquid passing through it such as to produce the required density microfoam.

21. A device as claimed in claim 19 or claim 20 characterized in that the ratio of gas and liquid in the mixture is controlled such that the microfoam is from 0.09 to 0.16 g/mL density.

22. A device as claimed in claim 20 or claim 21 wherein the housing includes a chamber charged with the blood dispersible gas and the sclerosant liquid. the pathway including a dip-tube with an inlet opening in liquid in the chamber.

23. A device as claimed in claim 22 wherein the dip-tube has an outlet opening at the gas liquid interface junction where the gas has access to the pathway to the pathway to the one or more outlet orifices.

24. A device as claimed in any one of claims 19 to 23 wherein the pathway is opened or closed by a valve having an actuator element that is depressed or tilted to open up a pathway to the exterior, whereby said liquid rises up the dip-tube under gas pressure and is mixed in the interface junction with said gas to produce an aerosol, dispersion of bubbles in liquid or macrofoam.

25. A device as claimed in any one of claims 19 to 24 wherein the one or more elements having one or more passages of 0.1 μ

m to 30 μ

m cross-sectional dimension are mounted inside the chamber in the pathway to the valve, such that the gas liquid mixture passes through the passage or passages and is caused to produce said microfoam.

26. A device as claimed in any one of claims 19 to 24 wherein the one or more elements having one or more passages of 0.1 μ

m to 30 μ

m cross-sectional dimension are mounted on the downstream side of the valve, such that the gas liquid mixture passes through the passage or passages and is caused to produce said microfoam

27. A device as claimed in claim 26 wherein the one or more elements are located in a cap mounted on the valve, upstream of the gas liquid interface, the cap including an outlet nozzle

28. A device as claimed in claim 25 wherein the one or more elements are located within the housing mounted between the gas liquid interface and the valve.

29. A device as claimed in any one of claims 19 to 28 characterized in that the gas liquid interface junction comprises holes in the dip tube above the surface of the liquid in use.

30. A device as claimed in any one of claims 22 to 29 characterized in that the chamber is pressurized at 0.01 to 9 bar over atmospheric.

31. A device as claimed in any one of claims 19 to 28 characterized in that the aqueous sclerosant liquid is contained within a second flexible gas and liquid tight disposed within the pressurisable chamber, the second chamber being sealed around the dip-tube.

32. A device as claimed in claim 31 characterized in that the dip-tube has a one-way valve positioned between the gas liquid interface junction and the dip-tube opening within the second flexible chamber, which when the pathway to the exterior of the device is closed, also remains closed such as to separate the liquid from the physiologically acceptable blood dispersible gas around it in the chamber and on opening the pathway to the exterior, the one way valve also opens and releases liquid up the dip-tube to the gas liquid interface junction where an aerosol, dispersion of bubbles in liquid or macrofoam is produced which is passed through the passages and converted to microfoam.

38. A device as claimed in any one of claims 19 to 37 wherein the one or more elements defining one or more passages are provided in the form of porous membranes, meshes, screens or sinters.

39. A device as claimed in any one claims 19 to 38 characterized in that it comprises a series of the elements defining said passages arranged in parallel with their major surfaces perpendicular to the pathway.

40. A device for delivering microfoam to a syringe from a microfoam generating device as claimed in any one of claims 19 to 39 characterized in that it comprises an inlet conduit for engaging the outlet of the microfoam producing device in a microfoam tight fashion, the conduit being connected to and leading through a multipath valve for directing microfoam passing down the conduit, the valve being capable of being set to direct microfoam down either of first and second outlet conduits or for closing the inlet conduit, the syringe luer outlet being received by one of the first and second outlet conduits.

41. A device as claimed in claim 40 further comprising one or more elements for engaging the microfoam producing device other than by its outlet nozzle to hold it securely.

42. A device as claimed in claim 41 further comprising a base element, sufficiently stable to mount a microfoam producing device adjacent a multipath-valve said inlet being attachable to the microfoam producing device outlet conduit.

43. A device as claimed in claim 42 further comprising an activating element which operates to cause the pathway within the microfoam producing device to be opened to the inlet conduit.

59. A device as claimed in any one of claims 19 to 43 characterized in that it produces a microfoam as described in any one of claims 44 to 57.

33. A device for producing a microfoam suitable for use in sclerotherapy of blood vessels comprising a housing in which is situated a pressurisable chamber with one or more outlet orifices;

a pathway by which contents of the chamber may be passed to exterior of the housing through the one or more outlet orifices and a mechanism by which the chamber can be pressurized such that its contents therein pass to the exterior along the pathway and through the one or more outlet orifices

said pathway to the exterior of the housing or the chamber including one or more elements defining one or more passages of cross sectional dimension 0.1 μ

m to 30 μ

m, through which contents of the chamber are passed upon actuation of the mechanism.

37. A device as claimed in claim 33 or claim 34 wherein the elements defining the passages in the pathway or chamber are mounted on a moveable support, said support being moveable by manipulation from outside of the chamber.

34. A device as claimed in claim 34 wherein the chamber contains an aqueous sclerosant liquid and/or a physiologically acceptable blood dispersible gas

35. A device as claimed in claim 34 or 35 wherein actuation of the mechanism causes the mixture of solution and gas to pass through the passages and form a microfoam of from 0.07 to 0.19 g/mL and having a half-life of at least 2 minutes.

36. A device as claimed in claim 35 characterized in that the microfoam is of density 0.09 to 0.16 g/mL.

44. A microfoam comprising a physiologically acceptable gas that is dispersible in blood and an aqueous sclerosant liquid characterized in that the microfoam has a density of from 0.07 to 0.19 g/cm and is capable of being passed down a 21 gauge needle without reverting back to gas and liquid by more than 10%, based on liquid content reverting back to unfoamed liquid phase.

46. A microfoam as claimed in claim 44 or claim 45 characterized in that it has a half-life as measured by drainage through a funnel of 1 cm neck diameter of at least 2 minutes, more preferably 2.5 minutes and most preferably 3 minutes.

47. A microfoam as claimed in any one of claims 44 to 46 characterized in that the gas includes less than 40% v/v nitrogen.

48. A microfoam as claimed in any one of claims 44 to 47 characterized in that the density is from 0.09 to 0.16 g/mL.

49. A microfoam as claimed in any one of claims 44 to 48 characterized in that 50% or more by number of the gas bubbles of at least 25 μ

m diameter are of no more than 120 μ

m diameter and at least 95% of these gas bubbles are of no more than 250 μ

m.

50. A microfoam as claimed in any one of claims 44 to 49 characterized in that it is of density of from 0.11 to 0.14 g/cm.

51. A microfoam as claimed in any one of claims 44 to 50 characterized in that the gas comprises at least 50% oxygen or carbon dioxide.

52. A microfoam as claimed in any one of claims 44 to 51 characterized in that the sclerosant liquid is aqueous polidocanol or sodium tetradecyl sulfate.

53. A microfoam as claimed in claim 52 characterized in that the sclerosant is aqueous polidocanol, the concentration of polidocanol being is from 0.5 to 4% vol/vol in the liquid.

54. A microfoam as claimed in claim 52 or claim 53 characterized in that sclerosant is made up in water or saline solution.

55. A microfoam as claimed in claim 54 characterized in that the saline is phosphate buffered saline pH 6.0 to pH 8.0.

56. A microfoam as claimed in claim 53, 54 or 55 characterized in that the aqueous solution contains a minor amount of alcohol.

57. A microfoam as claimed in any one of claims 44 to 56 characterized in that it contains 1 to 10% vol/vol glycerol.

60. A method of treating a patient in need of sclerotherapy of a blood vessel comprising administering a microfoam as claimed in any one of claims 44 to 57 to that blood vessel.

45. A microfoam comprising a physiologically acceptable gas that is dispersible in blood and an aqueous sclerosant liquid characterized in that the microfoam has a density of from 0.07 to 0.19 g/cm and is capable of being passed down a 21 gauge needle such that 50% or more by number of its gas bubbles of at least 25 μ

m remain at 150 μ

m diameter or less and at least 95% of these bubbles at 280 μ

m diameter or less.