Aerosol valve

Abstract

Method for producing a microfoam suitable for use in scleropathy of blood vessels by introducing a physiologically acceptable blood-dispersible gas into a container holding an aqueous sclerosant liquid and releasing the mixture of blood-dispersible gas and sclerosant liquid such that, upon release of the mixture, the components of the mixture interact to form a microfoam. The container is provided with a steam-sterilizable aerosol valve having a valve body of polymeric material having an HDT (heat deflection temperature) at 1.8 MPa stress in the range of 200-275 C.

Claims

1. A method for producing a microfoam suitable for use in scleropathy of blood vessels, comprising introducing a physiologically acceptable blood-dispersible gas into a container holding an aqueous sclerosant liquid and releasing the mixture of blood-dispersible gas and sclerosant liquid, whereby upon release of the mixture the components of the mixture interact to form a microfoam, the container being provided with a steam-sterilizable aerosol valve having a valve body of polymeric material, wherein the valve body consists of a polymeric material having an HDT (heat deflection temperature) at 1.8 MPa stress in the range of 200-275 C.

2. A method as claimed in claim 1, wherein the sclerosant liquid is a solution of polidocanol or sodium tetradecyl sulfate in an aqueous carrier.

3. A method as claimed in claim 2, wherein the solution is from 0.25 to 5% vol/vol polidocanol.

4. A method as claimed in claim 1, wherein the mixture of blood-dispersible gas and sclerosant liquid is pressurized to a pre-determined level in the range 800 mbar to 4.5 bar gauge (1.8 bar to 5.5 bar absolute).

5. A method as claimed in claim 4, wherein the pressure is in the range of 1 bar to 2.5 bar gauge.

6. A method as claimed in claim 1, wherein the microfoam is such that less than 20% of the bubbles are less than 30 m diameter, greater than 75% are between 30 and 280 m diameter, less than 5% are between 281 and 500 m diameter, and there are substantially no bubbles greater than 500 m diameter.

7. A method as claimed in claim 1, wherein the gas/liquid ratio in the mix is controlled such that the density of the microfoam is 0.07 g/ml to 0.19 g/ml.

8. A method as claimed in claim 1, wherein the microfoam has a half-life of at least 2 minutes.

9. A method as claimed in claim 1, wherein the steam-sterilizable aerosol valve comprises a valve body that consists of polyphenylsulphone (PPSU).

10. A method as claimed in claim 1, wherein the steam-sterilizable aerosol valve comprises a valve body, a valve insert and a stem valve that consist of polyphenylsulphone (PPSU).

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows an exploded diagram of an aerosol valve in situ in an aerosol dispenser, as further described in Example 1 below.

(2) FIG. 2 shows a cross-sectional view of a pre-pressurized container for the generation of therapeutic microfoam according to the invention, as further described in Example 2 below.

(3) FIG. 3 shows a shows a cross-sectional view of a device comprising a container provided with engaging means and a mesh stack shuttle according to the invention, as disclosed in WO 02/41872-A1 and further described in Example 3 below.

EXAMPLES

Example 1

Exploded Diagram of an Aerosol Valve

(4) An exploded diagram of an aerosol valve in situ in an aerosol dispenser is shown in FIG. 1.

(5) The stem gasket (104) is pre-assembled onto the stem (107) so that it seals against the seat for the stem gasket (106) on the stem and covers a small side hole in the stem that leads to the stem orifice (105), which acts as an outlet for the contents of the canister. A stainless steel spring (108) is then prefitted to the base of the stem moulding.

(6) The insert (109) is pre-assembled into the valve body (113) and sealingly seats the gas channels formed on the bottom of the insert (110) against the internal flat base of the valve body (113) to create two internal gas metering slots that are in communication with the external slots (114) on the valve body (113), thereby creating a metered gas path from the headspace of the canister to the inside of the valve body (113) when the valve is later clinched onto the canister.

(7) The metal mounting cup (102) is prefitted with a cup gasket (103) to form a gas-tight seal against the canister curl (117) when the assembled valve is clinched to the canister by standard industry means.

(8) The subassemblies described above are then crimped together using a standard pedestal crimping tool to make the fully assembled valve. The stem gasket (104) is compressed by 50% in thickness by the crimping procedure, and the pedestal of the mounting cup (101) is deformed during crimping to engage and retain on the castellations (112) on the external surface of the valve body (113).

(9) A polypropylene dip tube (116) is push-fitted into sealing engagement with the tailpiece of the valve body (115) to complete the valve assembly.

(10) The canister (118) is part-filled with 15 ml of 1% polidocanol solution, and the atmospheric air inside the canister (118) is purged with the desired gas mixture before the assembled valve and dip tube are clinched onto the canister curl (117) by use of conventional clinching equipment to make a gas-tight seal between the assembled valve and the canister. The canister (118) is then pressurized to the desired working pressure (using the desired gas mixture) by gassing through the stein orifice (105).

(11) The entire pressurized unit of canister, clinched valve and contents is then sterilized at 121-125 C. for 30 minutes in a suitable autoclave unit and allowed to cool to room temperature. It is crucial that the pedestal crimp formed before autoclaving remains tight during and after autoclaving. This is achieved by choosing the moulding material of the valve body (113) to have a sufficiently high heat distortion temperature to avoid stress relaxation in the castellation area of the moulded valve body (112), in order to avoid a gas leak path developing between the bottom of the stem gasket (104) and the valve housing ridge (111) which it is compressed against in the assembled state.

(12) A small metering hole (not shown) at the top of the tailpiece of the valve body (115) meters the liquid into the valve body (113) from the bottom of the canister (118) via the dip tube (116) and mixes the metered liquid with the gas entering the valve body through the gas slots on the base of the insert to form a crude foam with large bubbles. This crude foam is homogenized and conditioned to yield microfoam suitable for use in sclerotherapy by subsequent passage through a mesh stack shuttle (not shown) that sealingly engages with the stem valve outlet (105).

(13) When the stem valve is depressed by more than approximately 1 mm through application of external force, the stem gasket deforms away from the side hole in the stem gasket seat area, opening a path between the canister and the external environment. When this external force is released, the spring (108) returns the stem to its fully closed position.

Example 2

Pre-Pressurized Container

(14) A typical apparatus for the generation of therapeutic microfoam according to the invention, is shown in FIG. 2.

(15) The canister has an aluminium wall (201), the inside surface of which is coated with an epoxy resin. The bottom of the canister (202) is domed inward. The canister inner chamber (204) is pre-purged with 100% oxygen for 1 minute, containing 15 ml of a 1% vol/vol polidocanol/20 mmol phosphate buffered saline solution/4% ethanol, then filled with oxygen at 2.7 bar gauge (1.7 bar over atmospheric).

(16) A typical gas mixture is 3% He, and between 25 and 35% CO.sub.2, with the balance O.sub.2 as a final gas mixture at approx. 3.5 bar absolute.

(17) A standard 1 inch diameter aerosol valve (205) is clinched on to the top of the canister after sterile part filling with the solution and may be activated by push-fitting the inlet (210) of the mesh stack connector (206) into sealing engagement with the outlet (209) of the stem valve (216). Activation of the valve (205) is achieved by pushing down on the mesh stack shuttle (206) to depress the engaged stem valve (216) and thereby release the contents of the aerosol canister (201) via an outlet nozzle (213) sized to engage a Luer fitting of a syringe or multi-way connector (not shown). This mesh stack shuttle (206) mounts four Nylon 66 meshes held in high density polyethylene (HDPE) rings (208), all within an open-ended polypropylene casing (214). These meshes have diameter of 6 mm and have a 14% open area made up of 20 m pores, with the meshes spaced 3.5 mm apart.

(18) The valve (205) comprises a housing (207) which mounts the dip tube (212) and includes gas receiving holes (211a, 211b) which admit gas from chamber (204) into the flow of liquid which rises up the dip tube on operation of the mesh stack shuttle (206) to open the valve (205). These are conveniently defined by an Ecosol device provided by Precision Valve, Peterborough, UK, provided with an insert (215). Holes (211a, 211b) have cross-sectional area such that the sum total ratio of this to the cross-sectional area of the liquid control orifice at the base of the valve housing (at the top of the dip tube) is controlled to provide the required gas/liquid ratio.

(19) A valve body (207) of polyphenyl sulfone (PPSU) is provided. The stem valve (216) and valve insert (215) are also made of PPSU.

Example 3

Container with Engaging Means and Mesh Stack Shuttle

(20) A device comprising a container provided with engaging means and a mesh stack shuttle according to the invention, as disclosed in WO 02/41872-A1, is shown in FIG. 3. The device comprises a low pressure container (301) for an aqueous sclerosant liquid and an unreactive gas atmosphere, a container (302) for a physiologically acceptable blood-dispersible gas and an engaging means comprising a connector (303).

(21) The container (302) for a physiologically acceptable blood-dispersible gas is charged at 5.8 bar absolute pressure with oxygen, whereas the container (301) is charged with carbon dioxide. Container (302) is used to pressurize container (301) at the point of use to approx. 3.5 bar absolute and is then discarded, just before the microfoam is required. The two containers will thus be referred to hereinafter as the PD [polidocanol] can (301) and the O.sub.2 can (302).

(22) Each of the cans (301, 302) is provided with a snap-fit mounting (304, 305). These may be made as identical mouldings. The snap-fit parts (304, 305) engage the crimped-on mounting cup (306, 307) of each can (301, 302) with high frictional force. The connector is made in two halves (308, 309), and the high frictional force allows the user to grip the two connected cans (301, 302) and rotate the connector halves (308, 309) relative to each other without slippage between connector (303) and cans. Each of these can mountings (306, 307) has snap-fit holes (310, 311) for engaging mating prongs (312, 313) which are on the appropriate surfaces of the two halves (308, 309) of the connector.

(23) The connector (303) is an assembly comprising a number of injection mouldings. The two halves (308, 309) of the connector are in the form of cam track sleeves which fit together as two concentric tubes. These tubes are linked by proud pins (314) on one half that engage sunken cam tracks (315) on the other half. The cam tracks have three detented stop positions. The first of these detents is the stop position for storage. An extra security on this detent is given by placing a removable collar (316) in a gap between the end of one sleeve and the other. Until this collar (316) is removed it is not possible to rotate the sleeves past the first detent position. This ensures against accidental actuation of the connector.

(24) The cam track sleeves (308, 309) are injection moulded from PSU (polysulfone) or ABS as separate items, and are later assembled so that they engage one another on the first stop of the detented cam track. The assembled sleeves are snap-fitted as a unit onto the O.sub.2 can (302) mounting plate (305) via four locating prongs. The security collar is added at this point to make an O.sub.2 can subassembly.

(25) The connector (303) includes in its interior a series of foaming elements comprising a mesh stack shuttle (317) on the connector half (308) adjacent to the PD can (301). The mesh stack shuttle (317) is comprised of four injection moulded disk filters with mesh hole size of 20 m and an open area of approx. 14%, and two end fittings, suitable for leak-free connection to the two canisters. These elements are pre-assembled and used as an insert in a further injection moulding operation that encases them in an overmoulding (318) that provides a gas-tight seal around the meshes, and defines the outer surfaces of the mesh stack shuttle. The end fittings of the stack (317) are designed to give gas-tight face and/or rim seals against the stem valves (319, 320) of the two cans (301, 302) to ensure sterility of gas transfer between the two cans.

(26) The mesh stack shuttle (317) is assembled onto the PD can valve (319). The PD can (301) and attached shuttle (317) are offered up to the connector (303) and the attached O.sub.2 can (302), and a sliding fit made to allow snap-fitting of the four locating prongs (312) on the PD can side of the connector (303) into the mating holes (310) in the mounting plate (304) on the PD can (301). This completes the assembly of the system. In this state, there is around 2 mm of clearance between the stem valve (320) of the O.sub.2 can (302) and the point at which it will form a seal against a female Luer outlet from the stack.

(27) When the security collar (316) is removed, it is possible to grasp the two cans (301, 302) and rotate one half of the connector (303) against the other half to engage and open the O.sub.2 can valve (320).

(28) As the rotation of the connector (303) continues to its second detent position, the PD can valve (319) opens fully. The gas flow from the O.sub.2 can (302) is restricted by a small outlet hole (321) in the stem valve (320). It takes about 45 seconds at the second detent position for the gas pressure to (almost) equilibrate between the two cans to a level of 3.45 bar0.15 bar.

(29) After the 45 second wait at the second detent position, the connector (303) is rotated further to the third detent position by the user. At this position, the two cans (301, 302) can be separated, leaving the PD can (301) with half (308) of the connector and the shuttle assembly (317) captive between the connector and the PD can. The O.sub.2 can (302) is discarded at this point.

(30) A standard 1 inch diameter aerosol valve (319) (Precision Valve, Peterborough, UK) is clinched on to the top of the PD can (301) before or after filling with the solution and may be activated by depressing the mesh stack shuttle (317), which functions as an aerosol valve actuator mechanism, to release the contents via an outlet nozzle (322) sized to engage a Luer fitting of a syringe or multi-way connector (not shown). The aerosol valve (319) has a valve body (not shown) of polyphenyl sulfone (PPSU). The stem valve and valve insert are also made of PPSU.

Example 4

Alternative Polymer Materials

(31) The resistance to hydrolysis and autoclavability of a number of materials was evaluated by moulding components and assembling them to make functioning valves. Table 1 shows the properties observed with polymers of the invention, whereas Table 2 shows some comparative polymers. Izod impact strength refers to the value measured according to the ASTM D256 and ISO 180 procedure, a swinging pendulum test, and is defined as the kinetic energy needed to initiate fracture and continue the fracture until the specimen is broken.

(32) When the valve body is made of unsuitable material, the failure mode in autoclaving is an easing of the crimp stress between valve castellations and the pedestal (centre bump) of the aluminium mounting cup. At 125 C., the contact stress eases off as the plastic creeps or stress relaxes against unyielding metal. As the valve cools down after autoclaving, thermal contraction of the plastic eases it further out of contact, and the water content of the plastic decreases to equilibrium in 100% relative humidity, further shrinking the plastic away from the mounting cup to give eventually a leak path for headspace gases to enter the valve. In extreme cases the valve falls apart at the pedestal crimp, as the internal spring is always compressed in an assembled valve and drives the valve body away from the mounting cup if the crimp fails.

(33) On the other hand, using a material of the invention gives good results. PPSU especially has been found to have the ability to survive up to two thousand steam sterilization cycles without significant degradation of properties or appearance. The sulfone group, in conjunction with the biphenylene unit that elevates the impact strength, evidently imparts great stiffness and toughness to the polymer chain, giving a heat deflection temperature value that is normally only seen with rather brittle materials.

(34) TABLE-US-00003 TABLE 1 Polymers of the invention Heat Moisture Water deflection Glass absorption take-up at Izod impact Tensile Hydrolytic temperature at transition (after 24 hours saturation strength stiffness resistance and Polymer Polymer grade 1.8 MPa ( C.) temp ( C.) in moist air) in liquid (J cm.sup.1) (GPa) autoclavability PEI RTP 2100 unfilled 200 216 0.25% 1.3% 0.534 3.31 OK, but notch sensitive, so prone to stress crack. PES Solvay Radel 204 220 0.54% 2.1% 0.9 2.65 Stable, good A A-100 PPSU Solvay Radel 207 220 0.37% 1.1% 6.9 2.34 Very stable, R 5000 excellent PI RTP 4200 unfilled 241 330 0.24% 2.9% 1.12 2.41 OK, OK LCP Du Pont Zenite 265 >300 0.03% 0.1% 7.0 12.2 Acceptable, OK FG77340 PEI = polyetherimide PES = polyethersulfone PPSU = polyphenylsulfone PI = polyimide LCP = liquid crystal polymer

(35) TABLE-US-00004 TABLE 2 Comparative polymers Heat Moisture Water deflection Glass absorption take-up at Izod impact Tensile Hydrolytic temperature at transition (after 24 hours saturation strength stiffness resistance and Polymer Polymer grade 1.8 MPa ( C.) temp ( C.) in moist air) in liquid (J cm.sup.1) (GPa) autoclavability PPS Ticona Fortron 120 90 0.02% 0.03% 0.3 4.2 OK, but not auto- 0203B6 or 9203HS (brittle) clavable at 125 C. PEEK Victrex 143 160 143 ?0.5% 0.5% 0.6 3.5 OK, but yield stress at pedestal crimp of valve too low at 125 C. PSU Solvay Udel 174 190 0.3% 0.8% 0.7 2.5 Stable, but yield stress 1700 at pedestal crimp of valve too low at 125 C., stress cracking also an issue PAI Solvay Torlon 278 275 ?1.7% ? 1.33 4.1 Poor, unsuitable 4203L (unacceptable) PBI Hoechst Celanese 427 399 0.4% .sup.5% 0.27 5.86 Poor, unsuitable Celazole PBI 399 (brittle) PPS = polyphenylene sulfide PEEK = polyetheretherketone PSU = polysulfone PAI = polyamide-imide PBI = polybenzimidazole