GENERATION OF THERAPEUTIC MICROFOAM

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

1-67. (canceled)

68. A microfoam comprising a gas component and an aqueous sclerosant liquid wherein the microfoam is produced by passing the gas component and the aqueous sclerosant liquid through one or more passages, each passage having a diameter greater than about 5 m and less than about 25 m, wherein: the gas component comprises a physiologically acceptable blood dispersible gas including a mixture of oxygen and carbon dioxide, the aqueous sclerosant liquid comprises at least one sclerosing agent chosen from polidocanol and sodium tetradecylsulfate (STS), and the microfoam comprises gas bubbles, at least 95% by number of the gas bubbles having a diameter less than 250 m.

69. The microfoam of claim 68, wherein the physiologically acceptable blood dispersible gas comprises 10 to 99% vol/vol carbon dioxide.

70. The microfoam of claim 69, wherein the physiologically acceptable blood dispersible gas comprises a mixture of 10 to 99% vol/vol carbon dioxide with the remainder oxygen.

71. The microfoam of claim 68, wherein the physiologically acceptable blood dispersible gas comprises 20 to 99% vol/vol carbon dioxide.

72. The microfoam of claim 71, wherein the physiologically acceptable blood dispersible gas comprises a mixture of 20 to 99% vol/vol carbon dioxide with the remainder oxygen.

73. The microfoam of claim 68, wherein the physiologically acceptable blood dispersible gas comprises 10 to 40% vol/vol carbon dioxide.

74. The microfoam of claim 73, wherein the physiologically acceptable blood dispersible gas comprises a mixture of 10 to 40% carbon dioxide vol/vol with the remainder oxygen.

75. The microfoam of claim 68, wherein the physiologically acceptable blood dispersible gas comprises 20 to 30% vol/vol carbon dioxide.

76. The microfoam of claim 75, wherein the physiologically acceptable blood dispersible gas comprises a mixture of 20 to 30% carbon dioxide vol/vol with the remainder oxygen.

77. The microfoam of claim 68, wherein the density of the microfoam ranges from 0.07 g/ml to 0.19 g/ml.

78. The microfoam of claim 68, wherein a ratio of gas to liquid is such that the microfoam that is produced has a half-life of at least two minutes.

79. The microfoam of claim 68, wherein the aqueous sclerosant liquid is a solution of polidocanol in an aqueous carrier or sodium tetradecylsulfate (STS) in an aqueous carrier.

80. The microfoam of claim 68, wherein the aqueous sclerosant liquid comprises 1% vol/vol polidocanol in an aqueous carrier.

81. The microfoam of claim 68, wherein the aqueous sclerosant liquid is a solution of polidocanol in an aqueous carrier having a concentration of polidocanol from 0.5 to 4% vol/vol in the solution.

82. The microfoam of claim 68, wherein the aqueous sclerosant liquid further comprises glycerol.

83. The microfoam of claim 68, wherein the gas component comprises a physiologically acceptable blood dispersible gas including a mixture of oxygen and carbon dioxide and other physiological gases, the other physiological gases including less than 40% vol/vol nitrogen.

84. The microfoam of claim 83, wherein the physiologically acceptable blood dispersible gas comprises 10 to 99% vol/vol carbon dioxide.

85. The microfoam of claim 83, wherein the physiologically acceptable blood dispersible gas comprises 10 to 40% vol/vol carbon dioxide.

Description

FIGURES

[0106] FIG. 1: Shows a cross-sectional view of a canister device of the second aspect of the invention as further described in Example 2 below.

[0107] FIG. 2: Shows a cross-sectional view of a canister device of the second aspect incorporating a bag-on-valve reservoir for the sclerosant with the gas being in the outer chamber and separated therefrom by a one way duck-bill valve.

[0108] FIG. 3: Shows a cross-sectional view of a syringe-like device of the third aspect incorporating a set of meshes across its dispensing chamber.

[0109] FIG. 4: Shows a cross-sectional view of a syringe-like device of the third aspect incorporating a porous membrane supported on an inner plunger rod such that it can be reciprocated within the syringe chamber contents.

[0110] FIG. 5: Is a bar chart and graph illustrating distribution of gas bubble diameter in a preferred 0.13 g/ml oxygen/air/polidocanol microfoam of the fourth aspect.

[0111] FIG. 6: Is a bar chart and graph illustrating distribution of gas bubble diameter in microfoams of 0.09 g/ml and 0.16 g/ml of the fourth aspect.

[0112] FIG. 7: Is a graph showing the effect of passing a preferred foam of the fourth aspect down a 21 gauge needle as compared to control fresh and similarly aged microfoams.

[0113] FIG. 8: Is a graph showing the effect of passing a 2% vol polidocanol solution dry microfoam of 0.045 g/ml, such as producible by use of a prior art bubbler device (Swedspray valve, Ecosol insert and head), down a 21 gauge needle.

[0114] FIG. 9: Is a graph showing the effect of passing a 1% vol polidocanol dry microfoam of 0.045 g/ml such as producible by use of the prior art bubbler device (Swedspray valve, Ecosol insert and head), down a 21 gauge needle.

[0115] FIG. 10: is an elevation view of a syringe filling device of the fourth aspect.

[0116] FIG. 11: Is a plan view of the device of FIG. 10.

EXAMPLES

Example 1

[0117] A standard aerosol canister with a one way depressible action valve is charged half full with a 3% v/v solution of polidocanol in sterile water and pressurised to 3 atmospheres with a 50:50 mix of carbon dioxide and oxygen. On the valve stem is mounted an actuator and delivery head which carries four plastics screens, just under 0.5 mm thick, perforated with 20 m diameter passages, these screens being of the general type provided in the Swedspray-Eurospray foaming actuator cap ApRisC device. The valve is fed through an Ecosol gas liquid interface insert from a dip-tube and the surrounding chamber. Gas inlet sizes (2) into the insert are 0.0060.01 while the single liquid inlet is 0.024, as controlled by selecting Ecosol insert size. On depression of the head the aerosol valve releases pre-mixed solution and gas onto the screens whereupon a microfoam suitable for scleropathy and that is dimensionally stable for at least 2 minutes, preferably 5 minutes using glycerol in the is produced.

Example 2

[0118] FIG. 1 illustrates a further canister design of the invention wherein the passages through which the gas liquid mixture must travel are placed within the pressurised chamber, thus increasing hygiene of the device.

[0119] The canister is of standard 500 ml design with an aluminium wall (1), the inside surface of which is coated with an epoxy resin resistant to action of polidocanol and oxygen (eg Hoba 7940-Holden UK)). The bottom of the canister (2) is domed inward. The canister inner chamber (4) is pre-purged with 100% oxygen for 1 minute, containing 15 ml of a 2% vol/vol polidocanol/20 mmol phosphate buffered saline solution (3) then filled with the oxygen at 2.7 bar gauge (1.7 bar over atmospheric). This is provided by overpressuring the polidocanol part filled can with 1.7 bar oxygen.

[0120] The dome provides a perimeter area around the bottom of the inner chamber in which a level of polidocanol solution is retained sufficient for the bottom open end of a dip tube to be submerged therein when the top of the dome is no longer covered with the solution. In this manner, by use of an indicia on the outside of the canister to indicate the position of the dip tube, the canister can be oriented to extract the last fraction of solution if desired. In practice a vertical orientation is sufficient.

[0121] A standard 1 diameter aerosol valve (5) (Precision Valves, Peterborough) is crimped into the top of the canister after sterile part filling with the solution and is activatable by depressing an actuator cap (6) to release content via an outlet nozzle (13) sized to engage a luer fitting of a syringe or multi-way connector (not shown). A further connector (7) locates on the bottom of the standard valve and mounts, preferably by interference fit, four Nylon 66 meshes held in high density polyethylene (HDPE) rings (8) all within an open ended polypropylene casing. These meshes have diameter of 8 mm and have a 15% open area made up of 20 m pores, with the meshes spaced 3.5 mm apart by the HDPE rings.

[0122] A further connector (9) locates on the bottom of the connector holding the meshes and receives a housing (10) which mounts the dip tube (12) and includes gas receiving holes (11a, 11b) which admit gas from chamber (4) into the flow of liquid which rises up the diptube on operation of the actuator (6). These are conveniently defined by an Ecosol device with insert as before. Holes (11a,11b) have cross-sectional area such that the sum total ratio of this to the cross-sectional area of the diptube is controlled to provide the required gas/liquid ratio. This is for example 0.0100.013 each hole (11a, 11b) to 0.040 liquid receiving hole.

Example 3

[0123] A further canister embodiment of the present invention is shown in FIG. 2, which is broadly as shown in FIG. 1, but for the inclusion of a modified bag-on-valvearrangement. In this embodiment the polidocanol sclerosing solution (3) is enclosed in a foil bag (22), comprising an aluminium foil/plastics laminate (Coster Aerosols Stevenage UK) sealed in gas tight fashion to dip-tube (12). At the top end of the dip-tube is a one-way duck-bill valve (Vernay Labs Inc Ohio USA) that serves to prevent contact of polidocanol with the contents of the dip-tube (12) and chamber (4) until the valve (5) is operated. On said operation the valve (21) opens and polidocanol solution (3) is caused to rise up the dip-tube (12), whereby it becomes mixed with the air/oxygen gas mixture entering through holes (11a, 11b). In this manner the can may be safely sterilised with ionising radiations which may otherwise cause interactions between radical species in the gas and the organic component of the polidocanol solution. Such arrangement can also improve the operation of the canister with regard to start up of foam delivery. The bag (22) preferably substantially only contains the liquid (3), with no head-space gas above it.

Example 4

[0124] The device of this example is identical with that of Example 3, save that the polidocanol in the liquid is replaced with a sodium tetradecylsulphate at 1% vol/vol, all other ingredients being the same.

Example 5

[0125] FIG. 3 shows a syringe device that is specifically designed to produce microfoam according to the invention using the method of the invention. Syringe body (13) has a luer opening (14) and locating flanges (15) and cooperates with a plunger (16) to define a chamber (19). Chamber (19) is prefilled, or filled in use, with sclerosing solution (18), in this case polidocanol as above. The plunger has a sealing face (17) that is inert with respect to the polidocanol solution and which ensures that said solution does not escape around the sides of the plunger when that is depressed to pressurise the contents of chamber (19).

[0126] Located between the plunger sealing face (17) and luer opening (14) is a series of three spaced meshes (20) of the type and configuration referred to in Example 2. In this example the meshes are located such as to leave a space between them and the luer opening such that a physician can see the foam produced by passage of gas/liquid mixture through the meshes.

[0127] In operation such a syringe is preferably provided with the plunger pushed in such as to define a reduced chamber (19) volume filled with sclerosing solution with the luer opening sealed in a sterile fashion, eg. by a foil seal cap attached to its exterior. The cap is peeled off, the luer attached to a source of required blood dispersible gas and the plunger withdrawn to admit a required amount of gas to give a ratio of gas to liquid suitable such that when agitated, eg. by shaking the syringe, a macrofoam is produced containing a 7:1 to 12:1 ratio gas to liquid. For production of foam the plunger is depressed with an even pressure, such as to depress at 1 ml/second, and the macrofoam is converted to microfoam.

[0128] It will be realised that the microfoam could be directly applied to a patient, but more conveniently would be transferred directly to a chamber, eg a second syringe, where viewing of a large volume of foam such as would be required to eliminate a large saphenous vein, would be more readily performed. In this manner, should it be desired, the microfoam could be passed between the two chambers via the meshes in order to render it still more uniform in nature.

Example 6

[0129] FIG. 4 shows a further syringe device embodiment of the invention designed to produce microfoam according to the invention using the method of the invention. Syringe body (13) has a luer opening (14) and locating flanges (15) and cooperates with a plunger (16) to define a chamber (19). Chamber (19) is prefilled, or filled in use, with sclerosing solution (18), in this case polidocanol as above. The plunger has a sealing face (17) that is inert with respect to the polidocanol solution and which ensures that said solution does not escape around the sides of the plunger when that is depressed to pressurise the contents of chamber (19).

[0130] Passing down the central longitudinal axis of the plunger is a rod (21) mounting a porous Tetratex membrane (22) of effective pore size about 5 m in a double ring mounting. The rod (21) has a handle (23) located outside the syringe chamber which allows the membrane to be moved independently of the plunger such as to force the contents of chamber (19) to pass through its pores.

[0131] In operation such a syringe is preferably provided with the plunger pushed in such as to define a reduced chamber (19) volume filled with sclerosing solution with the luer opening scaled in a sterile fashion, eg. by a foil seal cap attached to its exterior. The cap is peeled off, the luer attached to a source of required blood dispersible gas and the plunger withdrawn to admit a required amount of gas to give a ratio of gas to liquid. Eg. a 7:1 to 12:1 ratio gas to liquid. For production of foam the handle (23) on rod (21) is operated to pass the membrane up and down the chamber a number of times, eg 2 to 10 times, causing the gas and liquid to mix and produce foam. For dispensing of foam directly to a patient, or to another syringe or container, the rod (21) is withdrawn such that membrane mounting (22) abuts the plunger sealing face and the plunger is such depressed with an even pressure, eg. at 1 ml/second. Obviously when the foam is passed directly into a patient a suitable needle is affixed to the luer connection.

Example 6

[0132] A microfoam of the invention is produced in a device as described in Example 1, having critical passage and gas mixing dimensions as set out in Example 2 but differing therefrom in that mesh is located in the dispensing cap, downstream of the valve, while gas/liquid mixing occurs in an Precision Valves Ecosol insert device upstream of the valve. The chamber (500 ml) is charged with 15 ml of an aqueous solution containing per 100 ml polidocanol (Kreussler-Germany) (2 ml), 96% ethanol (4 ml) and 55 mmol Phosphate Buffer (pH7.0) (94 ml) with gas being air overpressured with 1.5 bar 100% oxygen. The characteristics of the microfoam produced on operation of the valve are shown in FIGS. 5 and 6. FIG. 5 shows bubble size distribution immediately after microfoam generation; foam density being 0.138 g/ml. FIG. 6 shows bubble size produced with varying ratio of gas to liquid, provided by altering the gas/liquid interface hole size (11a, 11b) to give foams of 0.09 g/ml (closed diamonds) and 0.16 g/ml (open circles). FIG. 7 shows the effect on bubble size distribution of a preferred microfoam (0.13 g/ml) after passage through a 21G needle: Open circles show fresh foam, crosses control foam aged to match injection time and closed diamonds show after passage through the needle. FIG. 8 shows the effect of passing a microfoam made using a Swedspray device density 0.045 g/ml through the needle. Closed diamonds are control aged while open circles are after needle passage.

[0133] Note, when 5% glycerol is added to the formulation, half life was increased to approximately 4 minutes.

[0134] Bubble sizes are calculated by taking up foam into a syringe through its luer opening, optionally attaching a 21G needle, and injecting foam between two glass slides that are separated using 23.25 micron diameter beads (eg. available as microspheres from Park Labs USA). Maxtascan/Global Lab Image technique was used to analyse bubble size. Diameters of uncompressed bubbles (Dr) were calculated from diameters of bubbles between slides (Df) using the equation Dr=3 3Df.sup.2x/2 where x is the distance between the slides. These measurements thus are made at ambient temperature and pressure.

[0135] It will be realised that bubbles much smaller than 25 m diameter may be present but not counted. The % figures given with respect to bubble thus relate to bubbles in the range 25 m and above.

Example 7

[0136] For filling of a syringe with microfoam of the invention the bottom of a canister of Example 1, 2 or 3 is placed into a receiving recess in the base of a syringe filling device as shown in elevation in FIG. 10 and plan (FIG. 11). Canister (24) is inserted into a 1 cm deep recess (25) in a plastics base element (26), the recess being approximately 1 mm in diameter more than the canister such that a snug fit is provided. The canister is further supported by two resilient fixed arms (27a, 27b), fixed on vertical support rod (28) that deform to receive the canister diameter.

[0137] Just above the top of the position of the canister cap in use, the support rod (28) mounts an actuator arm that is lockable between a first actuating position (full lines) an and an off position (dotted lines). In the actuating position the arm depresses the canister actuator cap (30), thus opening the canister valve and causing microfoam to be released.

[0138] Also on the base (26) is a recess (32) sized to snugly receive a syringe (34) with its plunger. A stop element (33) is provided that is positioned such that on filling the plunger is limited in its range of longitudinal movement such that the syringe cannot be overfilled.

[0139] A flexible transparent plastics tube (35), inert to the sclerosant foam, is attached to the canister outlet nozzle (31) in use and is fixed to a three way valve (36) affixed to the base (26). The valve is operated by turning a tap (37) to one of three positions: (a) valve shut-no microfoam passage (b) valve open to waste (38) whereby any microfoam that by visual inspection of the contents of tube (35) appears unsuitable, is vented and (c) valve open to syringe, whereby a set amount of microfoam passes through the syringe luer and fills it until the syringe plunger abuts the stop (33)

Example 8

[0140] 20 mls microfoam of Example 6 is loaded into a 20 ml syringe using the device of Example 7 and the syringe disengaged from the device. A 19 gauge needle is attached either directly to the syringe luer fitting or via a catheter. The microfoam is administered into to a varicose vein while its advance and final position is monitored using a hand held ultrasound scanner such that the fresh foam is restricted in location to the vein being treated. After between 1 and 5 minutes the vein contracts and subsequently becomes fibrosed.