U.S. patent application number 10/432328 was filed with the patent office on 2004-08-12 for generation of therapeutic microfoam.
Invention is credited to Harman, Anthony David, Harper, Paul, Pollock, Neil, Sinclair, Gary Stewart.
Application Number | 20040156915 10/432328 |
Document ID | / |
Family ID | 9903819 |
Filed Date | 2004-08-12 |
United States Patent
Application |
20040156915 |
Kind Code |
A1 |
Harman, Anthony David ; et
al. |
August 12, 2004 |
Generation of therapeutic microfoam
Abstract
A method for producing a microfoam suitable for use in
scleropathy of blood vessels comprises introducing a
physiologically acceptable blood-dispersible gas into a container
(1) 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.
Inventors: |
Harman, Anthony David;
(Henley-on-Thames, GB) ; Harper, Paul;
(Buckinghamshire, GB) ; Pollock, Neil;
(Hertfordshire, GB) ; Sinclair, Gary Stewart;
(Suffolk, GB) |
Correspondence
Address: |
FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER
LLP
1300 I STREET, NW
WASHINGTON
DC
20005
US
|
Family ID: |
9903819 |
Appl. No.: |
10/432328 |
Filed: |
April 2, 2004 |
PCT Filed: |
November 23, 2001 |
PCT NO: |
PCT/GB01/05186 |
Current U.S.
Class: |
424/600 |
Current CPC
Class: |
A61K 9/122 20130101;
A61J 1/2096 20130101; Y10S 514/945 20130101; A61P 9/14 20180101;
A61J 1/2051 20150501; A61J 1/2055 20150501; A61J 1/2065 20150501;
B65D 83/425 20130101; B65D 81/3211 20130101 |
Class at
Publication: |
424/600 |
International
Class: |
A61K 033/00 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 24, 2000 |
GB |
0028692.2 |
Claims
1. A method for producing a microfoam suitable for use in
scleropathy of blood vessels, characterised in that it comprises
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.
2. A method as claimed in claim 1, characterised in that the
mixture of blood-dispersible gas and sclerosant liquid is
pressurised to a pre-determined level, in the range 800 mbar to 4.5
bar gauge.
3. A method as claimed in claim 2, characterised in that the source
of the blood-dispersible gas is removed before the mixture of
blood-dispersible gas and sclerosant liquid is released, having
pressurised the mixture to a pre-determined level.
4. A method as claimed in any preceding claim, characterised in
that the blood-dispersible gas is introduced through the same
orifice or lumen as is used for the dispensing of the mixture of
blood-dispersible gas and sclerosant liquid.
5. A method as claimed in any preceding claim, characterised in
that the physiologically acceptable blood-dispersible gas is
introduced into the container holding the aqueous sclerosant liquid
on the same day as the foam is to be used in scleropathy of blood
vessels.
6. A method as claimed in any preceding claim, characterised in
that the sclerosant liquid is stored in the presence of an inert
gas or mixture of inert gases.
7. A method as claimed in any preceding claim, characterised in
that the blood-dispersible gas is stored in a container provided
with engaging means for the container holding the aqueous
sclerosant liquid.
8. A method as claimed in any claim 7, characterised in that the
engaging means comprises an intermediate element.
9. A method as claimed in claim 8, characterised in that part of
the intermediate element is removed before the mixture of
blood-dispersible gas and sclerosant liquid is released, having
pressurised the mixture to a pre-determined level.
10. A method as claimed in claim 8 or claim 9, characterised in
that the intermediate element includes a foaming element to allow
the components of the mixture to interact to form a microfoam.
11. A method as claimed in claim 10, characterised in that the
foaming element comprises one or more passages of small
cross-sectional dimension.
12. A method as claimed in any preceding claim, characterised in
that the mixture is passed through one or more passages having at
least one cross-sectional dimension of from 0.1 to 30 .mu.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 a
half-life of at least 2 minutes.
13. A device for producing a microfoam suitable for use in
scleropathy of blood vessels, comprising a housing in which is
situated a pressurisable chamber containing a solution of the
sclerosing agent in a physiologically acceptable solvent; a pathway
with one or more outlet orifices by which the solution may pass
from the pressurisable chamber to the exterior of the device
through said 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 pressurised and the pathway
is open, fluid will be forced along the pathway and through the one
or more outlet orifices; said housing incorporating an inlet for
the admission of a pressurised source of physiologically acceptable
gas that is dispersible in blood; the gas being in contact with the
solution on activation of the mechanism such as to produce a
gas-solution mixture; said pathway to the exterior of the housing
including one or more foaming elements; characterised in that the
blood-dispersible gas is stored in a container provided with
engaging means for the housing holding the aqueous sclerosant
liquid.
14. A device as claimed in claim 13, characterised in the foaming
element(s) comprise one or more passages of cross sectional
dimension 0.1 .mu.m to 30 .mu.m, through which the solution and gas
mixture is passed to reach the exterior of the device, said passing
of said mixture through the passages forming a microfoam of from
0.07 to 0.19 g/ml density and of half-life at least 2 minutes.
15. A device as claimed in claim 13 or claim 14, characterised in
that the source of the blood-dispersible gas is removed before the
mixture of blood-dispersible gas and sclerosant liquid is released,
having pressurised the mixture to a pre-determined level.
16. A device as claimed in claim 15, characterised in that the
inlet for the admission of physiologically acceptable gas comprises
the outlet used for dispensing of the mixture of blood-dispersible
gas and sclerosant liquid.
17. A device as claimed in any one of claims 13 to 16,
characterised in that the engaging means comprises an intermediate
element.
18. A device as claimed in claim 17, characterised in that part of
the intermediate element is removable before the mixture of
blood-dispersible gas and sclerosant liquid is released, having
pressurised the mixture to a pre-determined level.
19. A device as claimed in claim 17 or claim 18, characterised in
that the intermediate element includes a foaming element to allow
the components of the mixture to interact to form a microfoam.
20. A device as claimed in any one of claims 13 to 19,
characterised in that the engaging means comprises a connector
which engages at one end with the container for the aqueous
sclerosant liquid and at the other end with the container for the
blood-dispersible gas.
21. A device as claimed in claim 20, characterised in that the
connector comprises a generally cylindrical element with open
ends.
22. A device as claimed in claim 20 or 21, characterised in that
the connector includes a cam track, whereby rotation of the
containers relative to each other moves them together in a
controlled fashion.
23. A device as claimed in claim 22, characterised in that the cam
track is further provided with a release track, so that the
containers may be separated again.
24. A device as claimed in claim 22 or 23, characterised in that
one or more detents is provided in the cam track, to enable the
user to gauge the progress of the introduction of the
blood-dispersible gas.
25. A device as claimed in any one of claims 13 to 24,
characterised in that a removable spacer is provided to prevent the
containers from being pushed together until required.
26. A device as claimed in claim 25, characterised in that the
removable spacer takes the form of an annular collar positioned in
between a connector in two parts.
27. A device as claimed in any one of claims 20 to 24,
characterised in that the connector includes an aerosol valve
actuator mechanism, and the containers may be separated to leave
the actuator mechanism attached to the container for the sclerosing
agent.
28. A device for producing a microfoam suitable for use in
scleropathy of blood vessels, in the form of a kit comprising: (a)
a housing in which is situated a pressurisable chamber containing a
solution of the sclerosing agent in a physiologically acceptable
solvent; a pathway with one or more outlet orifices by which the
solution may pass from the pressurisable chamber to the exterior of
the device through said 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 pressurised and the
pathway is open, fluid will be forced along the pathway and through
the one or more outlet orifices; and (b) a pressurised container
containing a physiologically acceptable blood-dispersible gas; said
housing incorporating an inlet for the admission of
blood-dispersible gas; the gas being in contact with the solution
on activation of the mechanism such as to produce a gas-solution
mixture.
29. A device as claimed in claim 28, characterised in that said
pathway to the exterior of the housing includes one or more foaming
elements.
30. A device as claimed in any one of claim 28 or claim 29,
characterised in that the housing in which is situated the
pressurisable chamber containing the solution of the sclerosing
agent and the container containing the blood-dispersible gas are
placed in a sealed package.
31. A device as claimed in any one of claims 13 to 30,
characterised in that the sclerosant liquid is stored in the
presence of an inert gas or mixture of inert gases.
32. A method of treating a patient in need of sclerotherapy of a
blood vessel comprising administering a microfoam from a device as
claimed in any one of claims 13 to 31 to that blood vessel.
Description
[0001] The present invention relates to a method and apparatus for
the generation of microfoam comprising a sclerosing material,
particularly a sclerosing liquid, which is suitable for use in the
treatment of various medical conditions involving blood vessels,
particularly varicose veins and other disorders involving venous
malformation.
[0002] Sclerosis of varicose veins is based on the injection into
the veins of liquid sclerosant substances which, by inter alia
causing a localised inflammatory reaction, favour the elimination
of these abnormal veins. When a sclerosing substance is injected in
liquid form, it is mixed with the blood contained in the vein and
is diluted in an unknown proportion. The results are uncertain,
owing to over-dosage or underdosage, and are limited to short
varicose segments. As the size of the varicose veins to be injected
decreases, this dilution is less and the results obtained are more
predictable.
[0003] Until recently, sclerosis was a technique selected in cases
of small and medium varicose veins, those with diameters equal to
or greater than 7 mm being treated by surgery. Sclerosis and
surgery complemented one another but sclerosis treatment continued
not to be applicable to large varicose veins. In these large
varicose veins, if a sclerosing substance was injected, its
concentration in the vein, its homogeneous distribution in the
blood, and the time for which it is in contact with the internal
walls of the vessel treated were not known.
[0004] In 1946, Orbach injected a few cubic centimetres of air into
small varicose veins and confirmed a displacement of the blood
inside the vessel which was occupied by the injected air. A
sclerosing solution introduced immediately afterwards was more
effective than if it had been injected into the blood. However, in
thick varicose veins, when air is injected the phenomenon described
of the displacement of the blood by the injected air does not occur
but the air forms a bubble inside the vein which makes the method
ineffective in these vessels.
[0005] The same author had the idea, a few years later, of
injecting foam obtained by agitation of a container containing
sodium tetradecyl sulfate, which is an anionic sclerosing detergent
with a good foaming capability. The method was of little use owing
to the large size of the bubbles formed and was dangerous owing to
the side effects of atmospheric nitrogen which is only slightly
soluble in blood. Both methods had limited practical repercussion
being used only in small varicose veins.
[0006] WO-A-00/66274 (Garcia) discloses a device for producing
foamed sclerosing agent, preferably for treating varices, which
includes a container in which the sclerosing liquid is deposited
and a connection means to a propellant gas source. The device is
hermetically closed by a head piece into which a small diameter
probe tube is inserted to reduce the pressure. The tube extends
inside the container, which is also closed by a valve whose
actuation causes the escape of the foamed sclerosing agent via an
outlet nozzle in the head piece. However, no information is given
on how the device works. There is no disclosure of a microfoam by
Garcia
[0007] An injectable microfoam suitable for therapeutic uses has
now been developed and is described in EP-A-0656203 and U.S. Pat.
No. 5,676,962 (incorporated herein by reference). These patents
describe a microfoam produced with a sclerosing substance which,
when injected into a vein, displaces blood and ensures that the
sclerosing agent contacts the endothelium of the vessel in a known
concentration and for a controllable time, achieving sclerosis of
the entire segment occupied.
[0008] The advantages of use of this foam are that it allows the
concentration of the sclerosing agent in the blood vessel to be
known, since the microfoam displaces the blood and is not diluted
therein in to the same extent as a simple liquid would be.
Furthermore it allows homogeneous distribution of the sclerosis
product in the vein to be ensured and the time for which it is kept
in contact with the internal walls of the vein to be controlled.
None of which factors is known precisely or is controllable with
the use of sclerosing agents in simple liquid form.
[0009] The preparation of such a microfoam may be carried out with
a solution of any sclerosing substance, particularly polidocanol,
alkali metal tetradecyl sulfate e.g. sodium salt, hypertonic
glucose or gluco-saline solutions, chromic glycerol, ethanolamine
oleate, sodium morrhuate or iodic solutions.
[0010] However, this known method requires production of microfoam
by the physician, pharmacist or an assistant immediately prior to
administration to the patient. Such procedure allows for variation
of agent depending upon the person preparing it, with content of
gas, bubble size and stability all needing attention with respect
to the condition being treated. It also requires a high degree of
care and knowledge that may be difficult to replicate under
pressure, i.e. when time available to prepare the foam is
short.
[0011] A solution to this problem is offered in co-pending
application WO 00/72821-A1 (BTG International Limited),
incorporated herein by reference. This further addresses the
perception that large volumes of nitrogen should not unnecessarily
be introduced into patients, particularly where large vessels are
being filled with foam and eliminated, which is a problem when
using air as the gas for producing the foam. Gas embolism with high
levels of nitrogen or other insoluble gases remains a
possibility.
[0012] The solubility of physiological gases in aqueous fluids,
such as blood, varies considerably. Thus while nitrogen is almost
twice as insoluble in water as oxygen at STP, carbon dioxide is
over fifty times as soluble in aqueous liquids as nitrogen and over
twenty five times as soluble as oxygen.
[0013] One form of device that could potentially provide the
desired properties would be an aerosol dispenser of a type that
produces foams. However, for the purposes of generating a microfoam
to be injected into a human or animal body, it is undesirable to
have a liquefied propellant gas of the type usually employed in
aerosol canisters, e.g. such as butane. This determines that the
gas from which the foam is to be made must itself be pressurised to
allow production of foam.
[0014] Bubbler devices have been used in accessories for use with
`environmentally friendly` aerosol devices that operate using air
under low pressure, i.e. hand pump conditions. Two such devices are
supplied by Airspray International as the `Airspray.TM. Finger Pump
Foamer` and `Airspray.TM. Mini-Foamer`. The former is said to be
suitable for simple water based formulations while the latter is
suggested for cosmetics, hair or skin care preparations. A second
such device is provided as an optional extra in the
Swedspray/Eurospray.TM. hand pump device as a foaming nozzle. This
device is marketed as being suitable for use to `make you own
cleansing foam or shaving lather`.
[0015] The inventors in co-pending application WO 00/72821-A1 found
that use of the available hand-pump devices, which in any case are
not sterile, cannot produce good microfoam owing to outgassing with
high loadings of carbon dioxide, nor with inclusion of significant
amounts of glycerol which otherwise stabilises microfoam.
Furthermore, when significant back-pressure is applied to the
outlet of such device, such as when attached to a syringe to be
loaded for injecting the foam, stuttering occurs. Use of low
ejection velocity with this device can cause wetting at the nozzle
which results in large bubbles caused by air entrapment. In any
case the foams so produced, whether with oxygen or carbon dioxide,
tend to be low-density polyhedral in nature, with a tendency to
break up on passage down a hypodermic needle.
[0016] The inventors in co-pending application WO 00/72821-A1 have
solved this by providing a method and device that are capable of
producing a uniform injectable microfoam made with a relatively low
concentration of a sclerosing agent and a significant amount of a
blood dispersible gas in sterile fashion without volatile liquid
propellants or the need for the operator to directly be concerned
in control of its parameters. The method 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 .mu.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 a
half-life of at least 2 minutes.
[0017] A preferred form of gas in co-pending application WO
00/72821-A1 comprises 50% vol/vol or more oxygen, the remainder
being carbon dioxide, or carbon dioxide, nitrogen and trace gases
in the proportion found in atmospheric air. Preferably the
sclerosing agent is a solution of polidocanol or sodium
tetradecylsulfate in an aqueous carrier, e.g. water, particularly
in a saline.
[0018] However, the present inventors have now identified a
potential problem with this formulation. Up to now, there have been
no reports of the instability of polidocanol when stored in the
presence of oxygen, but the inventors have observed that
polidocanol could slowly decompose in the presence of oxygen. Thus
it appears to be undesirable to store polidocanol in a pressurised
can in the presence of oxygen, for example as taught in co-pending
application WO 00/72821-A1, as it may result in a reduced shelf
life.
[0019] For the purpose of this application terms have the following
definitions. Physiologically acceptable blood dispersible gas is a
gas that is capable of being substantially completely dissolved in
or absorbed by blood. A sclerosant liquid is a liquid that is
capable of sclerosing blood vessels when injected into the vessel
lumen. Scleropathy or sclerotherapy relates to the treatment of
blood vessels to eliminate them. An aerosol is a dispersion of
liquid in gas. A major proportion of a gas is over 50%
volume/volume. A minor proportion of a gas is under 50%
volume/volume. A minor amount of one liquid in another liquid is
under 50% of the total volume. Half-life of a microfoam is the time
taken for half the liquid in the microfoam to revert to unfoamed
liquid phase.
[0020] In a first aspect of the present invention there is provided
a method for producing a microfoam suitable for use in scleropathy
of blood vessels, particularly veins, characterised in that it
comprises 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.
[0021] The mixture of blood-dispersible gas and sclerosant liquid
is preferably pressurised to a pre-determined level. Preferred
pressures are in the range 800 mbar to 4.5 bar gauge (1.8 mbar to
5.5 bar absolute). Pressures in the range of 1 bar to 2.5 bar gauge
have been found to be particularly effective at these pressures,
there is very little change in either the density or the half-life
of the resulting foam.
[0022] The source of blood-dispersible gas may remain in place
while the foam is being dispensed. However, preferably the source
of the blood-dispersible gas is removed before the mixture of
blood-dispersible gas and sclerosant liquid is released, having
pressurised the mixture to a pre-determined level. Thus the
blood-dispersible gas may be introduced through the same orifice or
lumen as is used for the dispensing of the mixture of
blood-dispersible gas and sclerosant liquid. Foaming occurs upon
release of the mixture through this orifice or lumen.
[0023] Alternatively, the blood-dispersible gas may be introduced
through an orifice or lumen remote from that used for the
dispensing of the mixture of blood-dispersible gas and sclerosant
liquid, for example in the bottom of the container holding the
aqueous sclerosant liquid. In this case there would be no need to
remove the source of blood-dispersible gas place while the foam is
being dispensed.
[0024] The sclerosant liquid may be stored at atmospheric pressure
(or just above) before the blood dispersible gas is introduced.
This has the advantage that no ingress of non-sterile air can occur
prior to introduction of the gas. The sclerosant liquid may be
stored in the presence of an inert gas or mixture of inert gases.
"Inert gas", as used in this specification, refers to one which is
unlikely to react with the sclerosant liquid so as to change its
chemical nature. Suitable inert gases include carbon dioxide,
helium, neon, argon, and especially nitrogen.
[0025] Alternatively, the sclerosant liquid may be stored at
sub-atmospheric pressure, thus minimising the amount of nitrogen in
the final pressurised gas mix and also keeping unreactive carbon
dioxide which is soluble in the foam to a minimum level in the
final pressurised gas mix. Preferred storage pressures are in the
range 0.3 bar to 0.7 bar absolute (-0.7 bar to -0.3 bar gauge).
Storage pressures in the range of 0.4 bar to 0.6 bar absolute,
especially 0.5 bar absolute, have been found to be particularly
effective.
[0026] The container holding the aqueous sclerosant liquid would
normally be made to a particular pressure specification. Typically
aluminium cans have a 12 bar burst pressure. Such cans are liable
to implode during handling if a pressure lower than 0.3 bar
absolute is used. Once implosion has occurred, the cans may not
function correctly, and the resultant crimping may cause a
microhole to be produced.
[0027] On the other hand, using a higher pressure level once the
mixture of blood-dispersible gas and sclerosant liquid has been
pressurised renders sub-atmospheric pressures unnecessary.
[0028] The invention allows the physiologically acceptable
blood-dispersible gas to be introduced into the container holding
the aqueous sclerosant liquid immediately before the mixture of
blood-dispersible gas and sclerosant liquid is released. This would
conveniently be performed on the same day as the foam is to be used
in scleropathy of blood vessels, or within a twenty-four period
prior to the foam being so used. The foam does not have to be used
immediately, however; moreover, if the container holding the
aqueous sclerosant liquid is inadvertently shaken while the
blood-dispersible gas is introduced, it can be desirable to leave
it for five or so minutes to allow the contents to settle. Thus the
formation of an undesirable macrofoam is avoided.
[0029] A device such as the `Airspray.TM. Finger Pump Foamer` and
`Airspray.TM. Mini-Foamer`, described above, could be used to
pressurise the container. However, preferably the blood-dispersible
gas is stored in a container provided with engaging means for the
container holding the aqueous sclerosant liquid. The engaging means
may be made integral with the containers, or may comprise an
intermediate element. Part of this intermediate element may
optionally be removed before the mixture of blood-dispersible gas
and sclerosant liquid is released, having pressurised the mixture
to a pre-determined level. The intermediate element may include a
foaming element to allow the components of the mixture to interact
to form a microfoam. The foaming element may take any form, and
generally comprises one or more passages of small cross-sectional
dimension, as discussed below.
[0030] After the blood-dispersible gas has been introduced, the
mixture is preferably passed through one or more passages having at
least one cross-sectional dimension of from 0.1 to 30 .mu.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 a
half-life of at least 2 minutes.
[0031] Preferably the microfoam is such that 50% or more by number
of its gas bubbles of 25 .mu.m diameter and over are no more than
200 .mu.m diameter.
[0032] Preferably the gas/liquid ratio in the mix is controlled
such that the density of the microfoam is 0.09 g/ml to 0.16 g/ml,
more preferably 0.10 g/ml to 0.15 g/ml.
[0033] Preferably the microfoam has a half-life of at least 2.5
minutes, more preferably at least 3 minutes. The half-life may be
as high as 1 or 2 hours or more, but is preferably less than 60
minutes, more preferably less than 15 minutes and most preferably
less than 10 minutes.
[0034] Half-life is conveniently measured by filling vessel with a
known volume and weight of foam and allowing liquid from this to
drain into a graduated vessel, the amount drained in a given time
allowing calculation of half-life i.e. of conversion of microfoam
back into its component liquid and gas phases. This is preferably
carried out at standard temperature and pressure, but in practice
ambient clinic or laboratory conditions will suffice.
[0035] The ratio of gas to liquid used in the final mixture is
important in order to control the structure of the microfoam
produced such that its stability is optimised for the procedure and
the circumstances in which it is being carried out. For optimum
foams it is preferred to mix 1 volume of sclerosant liquid with
from approximately 4 to 10 volumes (STP), more preferably 6 to 8
volumes (STP), of gas.
[0036] A further preferred form of gas in the final mixture
comprises 60% vol/vol or more oxygen, the remainder being carbon
dioxide and nitrogen. One preferred final gas mixture is 60 to 90%
vol/vol oxygen and 5 to 40% vol/vol carbon dioxide and 3 to 10%
vol/vol nitrogen. Such a mixture may be made by introducing a
physiologically acceptable blood-dispersible gas comprising
95%-100% vol/vol oxygen into a container holding an aqueous
sclerosant liquid stored under an gas mix of mainly carbon dioxide
with a small amount of nitrogen, in the ratio 75:25 or greater.
[0037] A preferred composition for the final gas mixture is 81%
vol/vol oxygen, 13% vol/vol carbon dioxide and 6% vol/vol nitrogen.
Such a final gas mixture may be made by introducing oxygen at an
initial pressure of 5-6 bar absolute from a 300 ml container into a
similar 300 ml container holding an aqueous sclerosant liquid
stored under an reduced pressure inert gas atmosphere of 0.5 bar
absolute, such inert gas atmosphere comprising a mix of 75% vol/vol
carbon dioxide and 25% vol/vol nitrogen, until pressure equilibrium
is reached between the two containers.
[0038] The carbon dioxide would be expected to dissolve to some
extent in the sclerosant liquid. The above figures refer to the
proportions of carbon dioxide on the assumption that no dissolving
has occurred.
[0039] It is found that passing a stream of the sclerosant liquid
and the gas under pressure through one or more passages of 0.1
.mu.m to 30 .mu.m as described provides a stable
blood-dispersible-gas-based sclerosant injectable microfoam that
was previously thought to be only producible by supply of high
amounts of energy using high speed brushes and blenders.
[0040] Preferably the sclerosing agent is a solution of polidocanol
or sodium tetradecylsulfate in an aqueous carrier, e.g. water,
particularly in a saline. More preferably the solution is from 0.25
to 5% v/v polidocanol, preferably in sterile water or a
physiologically acceptable saline, e.g. in 0.5 to 2% v/v saline.
Concentration of sclerosant in the solution will be advantageously
increased for certain abnormalities such as Klippel-Trenaunay
syndrome.
[0041] The sclerosant may also contain additional components, such
as stabilising agents, e.g. foam stabilising agents, e.g. such as
glycerol. Further components may include alcohols such as ethanol.
Even though this can reduce foam stability, it is thought to
solubilise low-molecular-weight oligomers of polidocanol.
[0042] Most preferably the concentration of sclerosant in the
aqueous liquid is a 0.25-2% vol/vol solution, preferably of
polidocanol, in water or saline. The water or saline also, in some
cases at least, preferably contain 2-5% vol/vol physiologically
acceptable alcohol, e.g. ethanol. The polidocanol solution is
preferably phosphate buffered. The pH of the buffer is preferably
adjusted to be physiological, e.g. from pH 6 to pH 8. In the
presence of dissolved carbon dioxide, the value would be expected
to be around pH 6.8.
[0043] Suitable pressures before the mixture of blood-dispersible
gas and sclerosant liquid is released are typically in the range
0.01 to 9 bar over atmosphere. For use of meshes, e.g. one to eight
meshes arranged in series, having apertures of 10-30 .mu.m
diameter, 0.8 to 4.5 atmospheres over bar will, inter alia, be
suitable. For use of three to five meshes of 20 .mu.m aperture it
is found that 1.5-1.7 bar over atmospheric is sufficient to produce
a good foam. A pressure of 2-2.5 bar over atmospheric may
advantageously be used. For a 1 .mu.m pore size membrane, a
pressure of 5 bar or more over atmospheric pressure is
preferred.
[0044] In one preferred form of the invention the passages are in
the form of a membrane, e.g. of polymer such as
polytetrafluoroethylene, wherein the membrane is formed of randomly
connected fibres and has a rated effective pore size which may be
many times smaller than its apparent pore size. A particularly
suitable form of this is a biaxially oriented PTFE film provided by
Tetratec.TM. USA under the trade mark Tetratex.TM., standard
ratings being 0.1 to 10 .mu.m porosity. Preferred pore sizes for
the present method and devices are 3 to 7 .mu.m. This material may
be laminated with a porous backing material to give it strength and
has the advantage that one or two such meshes may be sufficient to
produce a foam that meets the use requirements set out above with
regard to stability.
[0045] In a second aspect of the present invention there is
provided a device for producing a microfoam suitable for use in
scleropathy of blood vessels, particularly veins, comprising a
housing in which is situated a pressurisable chamber containing a
solution of the sclerosing agent in a physiologically acceptable
solvent referred to in the first aspect; a pathway with one or more
outlet orifices by which the solution may pass from the
pressurisable chamber to the exterior of the device through said
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 pressurised and the pathway is open, fluid
will be forced along the pathway and through the one or more outlet
orifices;
[0046] said housing incorporating an inlet for the admission of a
pressurised source of physiologically acceptable gas that is
dispersible in blood; the gas being in contact with the solution on
activation of the mechanism such as to produce a gas-solution
mixture;
[0047] said pathway to the exterior of the housing including one or
more foaming elements;
[0048] characterised in that the blood-dispersible gas is stored in
a container provided with engaging means for the housing holding
the aqueous sclerosant liquid.
[0049] The foaming element(s) may comprise one or more passages of
cross sectional dimension, preferably diameter, 0.1 .mu.m to 30
.mu.m, through which the solution and gas mixture is passed to
reach the exterior of the device, said passing of said mixture
through the passages forming a microfoam of from 0.07 to 0.19 g/ml
density and of half-life at least 2 minutes.
[0050] The source of blood-dispersible gas may remain in place
while the foam is being dispensed. However, preferably the source
of the blood-dispersible gas is removed before the mixture of
blood-dispersible gas and sclerosant liquid is released, having
pressurised the mixture to a pre-determined level. Thus the inlet
for the admission of physiologically acceptable gas may be the
outlet used for dispensing of the mixture of blood-dispersible gas
and sclerosant liquid.
[0051] The engaging means may be made integral with the containers,
or may comprise an intermediate element. Part of this intermediate
element may optionally be removable before the mixture of
blood-dispersible gas and sclerosant liquid is released, having
pressurised the mixture to a pre-determined level. The intermediate
element may include a foaming element to allow the components of
the mixture to interact to form a microfoam.
[0052] The engaging means may comprise a connector which engages at
one end with the container for the aqueous sclerosant liquid and at
the other end with the container for the blood-dispersible gas. The
ends may be at any angle, but to ensure that the apparatus is held
in the correct position when the blood-dispersible gas is
introduced the ends are preferably parallel to each other. Most
conveniently the connector comprises a generally cylindrical
element with open ends.
[0053] The connector may take any form which allow the containers
to be pushed together for the introduction of the blood-dispersible
gas and for them to be separated again. Thus it may include a snap
mechanism for the rapid pushing together of the containers, or a
screw thread for their slower pushing together. However, preferably
the connector includes a cam track, whereby rotation of the
containers relative to each other moves them together in a
controlled fashion. The cam track may be further provided with a
release track, so that the containers may be separated again. One
or more detents may be provided in the cam track, to enable the
user to gauge the progress of the introduction of the
blood-dispersible gas.
[0054] A removable spacer may be provided to prevent the containers
from being pushed together until required. Preferably this takes
the form of an annular collar positioned in between a connector in
two parts. One part of the connector is equipped with an engaging
pin and the other with the cam track.
[0055] An additional removable sleeve may be provided sealing the
connector before use. This may take the form of a tamper-evident
shrink wrapped sleeve of thin plastics material positioned over the
removable spacer.
[0056] The two parts of the connector may be separated after the
introduction of the blood-dispersible gas. Preferably the connector
includes an aerosol valve actuator mechanism, whereby separation
leaves the actuator mechanism attached to the container for the
sclerosing agent. Preferably the connector includes an aerosol
valve actuator in position on the container holding the aqueous
sclerosant liquid. The foaming element may be made integral with
the aerosol valve actuator mechanism.
[0057] The connector may engage with the mounting cup flanges of
the two containers, such as the guide sleeve disclosed in EP-A-0
217 582 (Unilever PLC et al.). Alternatively, it may be provided
with a male element, such as pin, which engages with a female
element, such as a plug, made integral with the containers.
[0058] Either inside the pressurisable chamber disposed in the
pathway to the valve, or on the downstream side of the valve, is
provided an element having the one or more passages described in
the first aspect mounted such that the gas liquid mixture, i.e.
dispersion of bubbles in liquid, aerosol or macrofoam, passes
through the passage or passages and is caused to foam. This element
may conveniently be located in a cap on the canister in between the
valve mounting and an outlet nozzle. Conveniently, depression of
the cap operates the valve. Alternatively the element is within the
canister mounted above the gas liquid interface.
[0059] The gas pressure employed will be dependent upon materials
being used and their configuration, but conveniently will be 0.01
to 9 bar over atmospheric, more preferably 0.1-3 bar over
atmospheric, and still more preferably 1.5-2.5 bar over atmospheric
pressure.
[0060] The blood-dispersible gas is stored in a container provided
with engaging means for the housing holding the aqueous sclerosant
liquid. The engaging means may be made integral with the
containers, or may comprise an intermediate element. Part of this
intermediate element may optionally be removable before the mixture
of blood-dispersible gas and sclerosant liquid is released, having
pressurised the mixture to a pre-determined level. The intermediate
element may include a foaming element to allow the components of
the mixture to interact to form a microfoam.
[0061] Preferred forms of the one or more elements defining the
multiple passages for use in the device of the present invention
are meshes, screens or sinters. Thus one or more meshes or
perforated screens or sinters will be provided, with some preferred
forms employing a series of such elements arranged in parallel with
their major surfaces perpendicular to the path of solution/gas
expulsion.
[0062] It is preferred that any elements in the devices according
to the invention which have a critical dimension, and which are
likely to be exposed to an aqueous solution for more than a few
minutes, are made of a material that does not change dimension when
exposed to aqueous material. Thus such elements preferably should
not be of a water-swellable material such as Nylon 66, but of a
polyolefin such as polypropylene or polyethylene. On the other
hand, Nylon 66 is ideal for elements where exposure to aqueous
solution is so short that swelling is unlikely, such as the element
defining the passages of 0.1 .mu.m-30 .mu.m dimension.
[0063] Preferably the canister is sized such that it contains
sufficient gas and solution to form up to 500 ml of microfoam, more
preferably from 1 ml up to 200 ml and most preferably from 10 to 60
ml of microfoam. Particularly the amount of gas under pressure in
such canisters should be sufficient to produce enough foam to
treat, i.e. fill, at least one varicosed human saphenous vein. The
most preferred canister device is disposable after use, or cannot
be reused once opened such as to avoid problems of maintaining
sterility.
[0064] In a third aspect of the present invention there is provided
a device for producing a microfoam suitable for use in scleropathy
of blood vessels, in the form of a kit comprising:
[0065] (a) a housing in which is situated a pressurisable chamber
containing a solution of the sclerosing agent in a physiologically
acceptable solvent; a pathway with one or more outlet orifices by
which the solution may pass from the pressurisable chamber to the
exterior of the device through said 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
pressurised and the pathway is open, fluid will be forced along the
pathway and through the one or more outlet orifices; and
[0066] (b) a pressurised container containing a physiologically
acceptable blood-dispersible gas;
[0067] said housing incorporating an inlet for the admission of
blood-dispersible gas; the gas being in contact with the solution
on activation of the mechanism such as to produce a gas-solution
mixture.
[0068] The pathway to the exterior of the housing may include one
or more foaming elements.
[0069] The housing in which is situated the pressurisable chamber
containing the solution of the sclerosing agent and the container
containing the blood-dispersible gas are preferably placed in a
sealed package, or otherwise sold as a single unit. This would
normally be intended for a single treatment, and discarded after
use.
[0070] The sclerosant liquid may be stored in the presence of an
inert gas or mixture of inert gases, as discussed above.
[0071] In a fourth aspect of the present invention there is
provided a device for producing a microfoam suitable for use in
scleropathy of blood vessels, particularly veins, comprising a
housing in which is situated a pressurisable chamber containing a
solution of the sclerosing agent in a physiologically acceptable
solvent referred to in the first aspect; a pathway with one or more
outlet orifices by which the solution may pass from the
pressurisable chamber to the exterior of the device through said
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 pressurised and the pathway is open, fluid
will be forced along the pathway and through the one or more outlet
orifices;
[0072] said housing incorporating an inlet for the admission of a
pressurised source of physiologically acceptable gas that is
dispersible in blood; the gas being in contact with the solution on
activation of the mechanism such as to produce a gas-solution
mixture;
[0073] said pathway to the exterior of the housing including one or
more foaming elements;
[0074] characterised in that the blood-dispersible gas is stored in
the presence of an inert gas or mixture of inert gases.
[0075] The present invention will now be described further by way
of illustration only by reference to the following Figures and
Examples. Further embodiments falling within the scope of the
invention will occur to those skilled in the art in the light of
these. These include those disclosed in EP-A-0 217 582 (Unilever
PLC et al.) and EP-A-0 997 396 (Kurt Vogelsang GmbH).
FIGURES
[0076] FIG. 1 shows a cross-sectional view of a device of the
second aspect of the invention incorporating a cam track mechanism,
as further described in Example 1 below.
[0077] FIG. 2 shows an exploded view of a canister device of the
second aspect incorporating a variant of the cam track mechanism of
FIG. 1, as further described in Example 2 below, in which FIG. 2a
shows the connector, FIG. 2b shows the complete assembly, FIG. 2c
shows a cut-away portion of the connector, and FIG. 2d and FIG. 2e
show cross-sections of the cam mechanism.
[0078] FIG. 3 shows an exploded view of a canister device of the
second aspect incorporating a screw thread mechanism, as further
described in Example 3 below, in which FIG. 3a shows the complete
assembly FIG. 3b shows a cross-section of the assembled device.
[0079] FIG. 4 shows an exploded view of a canister device of the
second aspect incorporating a snap mechanism, as further described
in Example 4 below, in which FIG. 4a and FIG. 4b shows the
connector in open and closed position, FIG. 4c shows the complete
assembly, FIG. 4d shows a cut-away portion of the connector, and
FIG. 4e, FIG. 4f, FIG. 4g and FIG. 4h show cross-sections of the
snap mechanism.
[0080] FIG. 5 is a view of the secure actuator of FIGS. 2, 3 and 4,
in which FIG. 5a shows the lid, FIG. 5b shows the body and FIG. 5c
shows the assembled secure actuator.
EXAMPLES
Example 1
[0081] FIG. 1 illustrates a device of the second aspect of the
invention incorporating a cam track mechanism. The device comprises
a container (1) for an aqueous sclerosant liquid, a container (2)
for a physiologically acceptable blood-dispersible gas and an
engaging means comprising a connector (3).
[0082] The device is designed to be used with the container (1) for
the aqueous sclerosant liquid charged with 18 ml of a polidocanol
formulation, comprising 1% polidocanol in a pH 7.3
phosphate-buffered aqueous solution including a small proportion of
ethanol to solubilise the polidocanol, and a mixture of 75%
CO.sub.2/25% N.sub.2 gas at 0.5 bar absolute pressure. The aerosol
valve on the can continuously meters a specified mix ratio of
liquid to gas to create a foam of specified density.
[0083] The container (2) for a physiologically acceptable
blood-dispersible gas is charged with pure oxygen gas at 5.8 bar
absolute pressure. It is used to pressurise the container (1) for
the aqueous sclerosant liquid just before the microfoam is
required, and is then discarded. The reason for adding the oxygen
at the last moment before use is that polidocanol appears
incompatible with long term exposure to pressurised oxygen.
[0084] The two containers will thus be referred to hereinafter as
the PD [polidocanol] can (1) and the O.sub.2 can (2).
[0085] The connector assembly (3) between the two cans allows
one-time sterile transfer of oxygen from the O.sub.2 can (2) to the
PD can (1) when actuated by a user. This action produces a
pressurised gas mix in the PD can (1) at 3.15.+-.0.15 bar absolute
pressure when the sterile gas transfer is completed.
[0086] Each of the cans (1, 2) is provided with a snap-fit mounting
(4, 5). These may be made as identical mouldings. The snap-fit
parts (4, 5) engage the crimped-on mounting cup (6, 7) of each can
(1, 2) with high frictional force. The connector is made in two
halves (8, 9), and the high frictional force allows the user to
grip the two connected cans (1, 2) and rotate the connector halves
(8, 9) relative to each other without slippage between connector
(3) and cans. Each of these can mountings (6, 7) has snap-fit holes
(10, 11) for engaging mating prongs (12, 13) which are on the
appropriate surfaces of the two halves (8, 9) of the connector.
[0087] The connector (3) is an assembly comprising a number of
injection mouldings. The two halves (8, 9) 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 (14) on one half that
engage sunken cam tracks (15) 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 (16) in a gap between the end
of one sleeve and the other. Until this collar (16) is removed it
is not possible to rotate the sleeves past the first detent
position. This ensures against accidental actuation of the
connector.
[0088] A further element of security is given by providing a
tamper-evident label across the join between the cam track sleeve
(9) and the removable collar (16).
[0089] The cam track sleeves (8, 9) are injection moulded from 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 (2) mounting
plate (5) via four locating prongs. The security collar and
tamper-evident label are added at this point to make an O.sub.2 can
subassembly.
[0090] The connector (3) includes in its interior a mesh stack
shuttle (17) on the connector half (8) adjacent to the PD can (1).
The mesh stack shuttle (17) is comprised of four injection moulded
disk filters with mesh hole size of 20 microns and an open area of
approx. 10%. These are pre-assembled within a casing tube (18). The
end fittings of the stack (17) are designed to give gas-tight face
and/or rim seals against the stem valves (19, 20) of the two cans
(1, 2) to ensure sterility of gas transfer between the two
cans.
[0091] The mesh stack shuttle (17) is assembled onto the PD can
valve (19) by pushfitting the components together in a sterile
environment.
[0092] The PD can (1) and attached shuttle (17) are offered up to
the connector (3) and the attached O.sub.2 can (2), and a sliding
fit made to allow snap-fitting of the four locating prongs (12) on
the PD can side of the connector (3) into the mating holes (10) in
the mounting plate (4) on the PD can (1). This completes the
assembly of the system. In this state, there is around 2 mm of
clearance between the stem valve (20) of the O.sub.2 can (2) and
the point at which it will form a seal against a female luer outlet
from the stack.
[0093] When the tamper-evident sleeve and security collar (16) are
removed, it is possible to grasp the two cans (1, 2) and rotate one
half of the connector (3) against the other half to engage and open
the O.sub.2 can valve (20).
[0094] As the rotation of the connector (3) continues to its second
detent position, the PD can valve (19) opens fully. The gas flow
from the O.sub.2 can (2) is restricted by a small outlet hole (21)
in the stem valve (20). It takes about 30 seconds at the second
detent position for the gas pressure to (almost) equilibrate
between the two cans to a level of 3.15 bar.+-.0.15 bar.
[0095] After the 30 second wait at the second detent position, the
connector (3) is rotated further to the third detent position by
the user. At this position, the two cans (1, 2) can be separated,
leaving the PD can (1) with half (8) of the connector and the
shuttle assembly (17) captive between the connector and the PD can.
The O.sub.2 can (2) is discarded at this point.
[0096] It is important to keep the PD can (1) vertical and not to
shake the contents, as this would form a macrofoam in the can and
disturb the specified mixing ratio of gas to liquid and hence the
microfoam density. However, if the PD can (1) is inadvertently
shaken while the gas is introduced, it can be left for five or so
minutes to allow the contents to settle. Thus the undesirable
macrofoam is eliminated. Even if the can is not inadvertently
shaken, it is desirable to wait two to three minutes for the
macrofoam formed from the gassing operation to collapse.
[0097] Each canister (1, 2) is of standard 200 to 350 ml design
with an aluminium wall, the inside surface of which is coated with
an epoxy resin resistant to action of polidocanol and oxygen (e.g.
Hoba 7940, Holden UK). The bottom of the PD can (1) is domed
inward. 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 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.
[0098] A standard 1" diameter aerosol valve (19) (Precision Valves,
Peterborough, UK) is crimped into the top of the PD can (1) before
or after sterile filling with the solution and is activatable by
depressing the mesh stack shuttle (17), which functions as an
aerosol valve actuator mechanism, to release the contents via an
outlet nozzle (22) sized to engage a luer fitting of a syringe or
multi-way connector (not shown).
Example 2
[0099] A further embodiment of the present invention is shown in
FIG. 2, which is broadly similar in operation to Example 1, though
incorporating a variant of the cam track mechanism. The device
comprises a container (1) for an aqueous sclerosant liquid, a
container (2) for a physiologically acceptable blood-dispersible
gas and an engaging means comprising a connector (3). The two
containers will again be referred to hereinafter as the PD
[polidocanol] can (1) and the O.sub.2 can (2).
[0100] The connector (3) is an assembly comprising a number of
injection mouldings. It is made in two halves (8, 9), each provided
with ribs to allow the user to grip and rotate the connector halves
(8, 9) relative to each other. The two halves (8, 9) of the
connector are in the form of cam track sleeves which fit together
as two concentric tubes. These tubes are linked by a proud pin (14)
on one half that engage a sunken cam track (15) on the other half.
The cam track has two detented stop positions (23). The first of
these detents (23a) is the stop position for storage following
assembly. An extra security on this detent is given by placing a
removable collar (16) in a gap between the end of one sleeve and
the other. Until this collar (16) is removed it is not possible to
rotate the sleeves past the first detent position. This ensures
against accidental actuation of the connector. The removable collar
(16) comprises a spacer in the form of an ultrasonically welded
strip of plastics material, and until it is removed the pin (14) is
held in a park position engaging the first stop (23a) of the
detented cam track (15).
[0101] The cam track sleeves (8, 9) are injection moulded from ABS
as separate items, comprising a cam collar (8) and a pin collar
(9). The pin (14) is located on a resilient portion of the pin
collar (9). They are later assembled by snapping together in the
direction of arrow A so that the pin moves from position 1 in FIG.
2e to position 2, and the cam track sleeves (8, 9 engage one
another on the first stop (23a) of the detented cam track (15). The
assembled sleeves are snap-fitted as a unit onto the O.sub.2 can
(2) together in the direction of arrow B. The security collar is
added at his point by ultrasonically welding it to the unit to make
an O.sub.2 can subassembly.
[0102] The connector (3) is designed to include on its interior a
secure actuator (17) incorporating a mesh stack shuttle on the cam
collar (8) adjacent to the PD can (1), as in Example 1. The secure
actuator (17) is assembled onto the PD can valve (19) in the
direction of arrow C, and is better shown in FIG. 5. It comprises a
generally cylindrical frustro-conical body (17b) and an annular lid
(17a). The a generally cylindrical body (17b) is connected to an
outlet nozzle (22), sized to engage a luer fitting of a syringe or
multi-way connector, by means of leaf springs (17c). The annular
lid (17a) engages the open end of the generally cylindrical body
(17b), so as to conceal the leaf springs (17c). Within the secure
actuator is concealed the mesh stack shuttle (not shown).
[0103] The PD can (1) and attached secure actuator (17) are offered
up to the connector (3) and the attached O.sub.2 can (2), and a
sliding fit made in the direction of arrow D. This completes the
assembly of the system.
[0104] When the security collar (16) is removed, it is possible to
grasp the ribs on the two connector halves (8, 9) and rotate one
half of the connector (3) against the other half in the direction
of arrow E, moving the pin (14) from its park position 2 engaging
the first stop (23a) of the detented cam track (15) to an actuation
position 3 engaging the second stop (23b) of the cam track (15).
This causes the engagement and opening of the can valves (19, 20).
The actual actuating stroke is the distance f.
[0105] After a 30 second wait at the actuation position 3, the
connector (3) is rotated further by the user in the direction of
arrow F. At this position, the two cans (1, 2) can be separated by
moving the pin (14) to position 4 in FIG. 4e in the direction of
arrow G and leaving the PD can (1) with half (8) of the connector
and the shuttle assembly (17) captive between the connector and the
PD can. The O.sub.2 can (2) is discarded at this point.
Example 3
[0106] A further embodiment of the present invention incorporating
a screw thread mechanism is shown in FIG. 3. The external form of
the various elements is similar to Example 2. The device comprises
a container (1) for an aqueous sclerosant liquid, a container (2)
for a physiologically acceptable blood-dispersible gas and an
engaging means comprising a connector (3). The two containers will
again be referred to hereinafter as the PD [polidocanol] can (1)
and the O.sub.2 can (2).
[0107] The connector (3) is an assembly comprising a number of
injection mouldings. It is made in two halves (8, 9), each provided
with ribs to allow the user to grip and rotate the connector halves
(8, 9) relative to each other. The injection-moulded halves (8, 9)
comprise a male collar (8) and a female collar (9). An extra
security is given by placing a removable collar (16) around the
connector (3). The removable collar (16) comprises a spacer in the
form of a cardboard tube. The two collars (8, 9) are each provided
with drive tangs (24) to enable a corresponding tool to push them
together in the direction of arrows C with the cardboard tube (16)
applied
[0108] The female collar (9) is snapped on to the O.sub.2 can (2)
in the direction of arrow B. The male collar (8) includes on its
interior a secure actuator (17) incorporating a mesh stack shuttle
as in Example 2. The secure actuator (17) is assembled onto the PD
can valve (19) in the direction of arrow A, and the male collar (8)
pushed over this in the direction of arrow D.
[0109] When the cardboard tube (16) is removed, it is possible to
grasp the ribs on the two connector halves (8, 9) and rotate one
half of the connector (3) against the other half in a clockwise
direction. This causes the engagement and opening of the O.sub.2
can valve and the PD can valve, as in Example 2.
[0110] After a 30 second wait, the two halves of the connector (3)
are rotated in an anti-clockwise direction. The two cans (1, 2) can
be separated and the O.sub.2 can (2) discarded.
Example 4
[0111] A further embodiment of the present invention incorporating
a snap mechanism is shown in FIG. 4. The external form of the
various elements is similar to Example 3. The device comprises a
container (1) for an aqueous sclerosant liquid, a container (2) for
a physiologically acceptable blood-dispersible gas and an engaging
means comprising a connector (3). The two containers will again be
referred to hereinafter as the PD [polidocanol] can (1) and the
O.sub.2 can (2).
[0112] The connector (3) is an assembly and includes two
injection-moulded halves (8, 9) comprising a male collar (8) and a
female collar (9). An extra security is given by placing a
removable collar (16). The removable collar (16) comprises a
flexible spacer of plastics material including a resilient plug
(16a) and socket (16b) which serve to lock the removable collar
(16) in place by snapping in the direction of arrow E. The flexible
spacer (16) may in addition be ultrasonically welded. The two
injection-moulded halves (8, 9) are assembled by pushing them
together in the direction of arrows C, as shown in FIGS. 4e and 4f,
FIG. 4f showing the device in its transport position.
[0113] The female collar (9) is snapped on to the O.sub.2 can (2)
in the direction of arrow B. The male collar (8) includes on its
interior a secure actuator (17) incorporating a mesh stack shuttle
as in Example 2. The secure actuator (17) is assembled onto the PD
can valve (19) in the direction of arrow A, and the male collar (8)
pushed over this in the direction of arrow D.
[0114] The female collar (9) is made of resilient material and is
provided with flexible teeth (9a) and tangs (9b). In the transport
position, the teeth rest in corresponding grooves (8a) in the male
collar (8). Additional grooves (8c) are provided adjacent to these,
closer to the PD can (1). The tangs (9b) lock against corresponding
ridges (8b) in the male collar (8).
[0115] When the flexible spacer (16) is removed by pulling the
resilient plug (16a) out of the socket (16b) in the direction of
arrow F, it is possible to grasp the two cans (1, 2) and push one
half of the connector (3) towards the other half in the direction
of arrow G, as shown in FIG. 4g. The flexible teeth (9a) in the
female collar (9) thereby move into the grooves (8c) closer to the
PD can (1). This causes the engagement and opening of the O.sub.2
can valve and the PD can valve, as in Example 2.
[0116] After a 30 second wait, the two halves of the connector (3)
are rotated relative to each other in the direction of arrow H.
This is possible as the tangs (9b) are now free of the ridges (8b)
in the male collar (8). Rotation causes the flexible teeth (9a) in
the female collar (9) to be disengaged. The two cans (1, 2) can be
separated and the O.sub.2 can (2) discarded.
* * * * *