U.S. patent application number 14/248715 was filed with the patent office on 2014-08-07 for therapeutic foam.
This patent application is currently assigned to BTG International Ltd.. The applicant listed for this patent is BTG International Ltd.. Invention is credited to Anthony David HARMAN, Garry HODGES, Adil KADAR, Geoffrey D. MOGGRIDGE, Nikki ROBINSON, Hugh VAN LIEW, David Dakin Iorwerth WRIGHT.
Application Number | 20140221501 14/248715 |
Document ID | / |
Family ID | 43013737 |
Filed Date | 2014-08-07 |
United States Patent
Application |
20140221501 |
Kind Code |
A1 |
WRIGHT; David Dakin Iorwerth ;
et al. |
August 7, 2014 |
THERAPEUTIC FOAM
Abstract
A therapeutic foam for the treatment of, inter alia, varicose
veins comprises a sclerosing solution foamed with a physiological
gas such as carbon dioxide, oxygen or a mixture thereof. The foam
has a nitrogen content of less than 0.8%. It may be generated using
a pressurised canister system incorporating a fine mesh of micron
dimensions through which the gas and sclerosing liquid are passed
to make the foam. Alternatively, the foam may be generated by
passing gas and solution between two syringes through a fine mesh.
Techniques are described for minimising the amount of nitrogen in a
canister or syringe based product. A technique for generating and
delivering foam simultaneously using a syringe based device is also
disclosed.
Inventors: |
WRIGHT; David Dakin Iorwerth;
(Oxfordshire, GB) ; HARMAN; Anthony David;
(Oxfordshire, GB) ; ROBINSON; Nikki;
(Aberdeenshire, GB) ; HODGES; Garry;
(Hertfordshire, GB) ; KADAR; Adil; (London,
GB) ; MOGGRIDGE; Geoffrey D.; (Cambridge, GB)
; VAN LIEW; Hugh; (Barnstable, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BTG International Ltd. |
London |
|
GB |
|
|
Assignee: |
BTG International Ltd.
London
GB
|
Family ID: |
43013737 |
Appl. No.: |
14/248715 |
Filed: |
April 9, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13667296 |
Nov 2, 2012 |
8734833 |
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14248715 |
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12765980 |
Apr 23, 2010 |
8323677 |
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13667296 |
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10522527 |
Oct 10, 2006 |
7731986 |
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PCT/GB04/04848 |
Nov 17, 2004 |
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12765980 |
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60542867 |
Feb 10, 2004 |
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60542866 |
Feb 10, 2004 |
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Current U.S.
Class: |
514/723 ;
514/771 |
Current CPC
Class: |
A61B 17/00008 20130101;
A61M 16/00 20130101; A61P 41/00 20180101; A61M 5/19 20130101; B01F
5/0693 20130101; A61K 9/124 20130101; A61K 47/20 20130101; B65B
3/003 20130101; A61B 2017/00495 20130101; B01F 13/0023 20130101;
A61K 47/02 20130101; A61K 47/10 20130101; A61M 2210/12 20130101;
A61M 5/178 20130101; A61B 17/12022 20130101; A61M 2210/086
20130101; A61K 47/32 20130101; A61P 43/00 20180101; A61K 9/122
20130101; Y10S 514/945 20130101; A61B 17/12186 20130101; A61K 31/08
20130101; B01F 5/0685 20130101; A61B 17/00491 20130101; B01F
3/04446 20130101; A61P 9/14 20180101; A61B 17/12109 20130101; B65B
31/00 20130101; A61K 9/0019 20130101; A61P 9/00 20180101; A61K 9/08
20130101; A61M 2202/00 20130101 |
Class at
Publication: |
514/723 ;
514/771 |
International
Class: |
A61K 9/12 20060101
A61K009/12; A61K 31/08 20060101 A61K031/08 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 17, 2003 |
GB |
0326768.9 |
Oct 7, 2004 |
GB |
0422307.9 |
Claims
1. A foam comprising a liquid phase and a gas phase wherein the
liquid phase comprises at least one sclerosing agent and the gas
phase consists essentially of gaseous nitrogen present in an amount
ranging from 0.0001% to 0.8% by volume and at least one
physiologically acceptable gas.
2.-36. (canceled)
Description
[0001] This application claims priority of U.S. Provisional
Application Nos. 60/542,867 and 60/542,866 filed, Feb. 10, 2004.
The application also claims priority of UK Patent Application Nos.
0422307.9, filed Oct. 7, 2004, and 0326768.9, filed Nov. 17, 2003.
All of these applications are herein incorporated by reference.
[0002] The present invention relates to the generation of foam
comprising a sclerosing material, particularly a sclerosing
solution, which is suitable for use in the treatment of various
medical conditions involving blood vessels, particularly varicose
veins and other disorders involving venous malformation.
[0003] 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. Until recently, sclerotherapy was a
technique selected in cases of small and medium calibre varicose
veins, those with diameters equal to or greater than 7 mm being
treated by surgery.
[0004] An injectable microfoam suitable for therapeutic use, on
larger veins in particular, has now been developed and is described
in EP-A-0656203 and U.S. Pat. No. 5,676,962 (Cabrera &
Cabrera), incorporated herein by reference. These describe a
low-density 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.
[0005] Prior to the priority date of these patents it had been
known for many years that injection of liquid sclerosant into
varicose veins, especially smaller varicose veins, could be
effective. It had also been known for many years to inject a small
quantity of air into a vein prior to injecting sclerosing liquid,
the objective being to displace blood from the vein to avoid the
sclerosing agent being diluted too quickly. A development of this
technique was to make a loose foam or froth and to inject this
instead of pure air, prior to injection of the sclerosant liquid.
These techniques, known as "air block" and developed by Orbach,
were generally only effective for treating smaller veins.
[0006] In addition there had been disclosures of finer foams for
treatment of smaller varicose veins (Fluckiger references cited
below), or a combined procedure using both surgery and foam for
treatment of the entire long saphenous vein: Mayer; Brucke: "The
Aetiology and Treatment of Varicosities of the Lower Extremities",
Chirurgische Praxis, 521-528, 1957.
[0007] All of these prior disclosures of foam/froth treatment
describe the preparation of the foam/froth with air as the gaseous
component. None of the documents mentions the air in the injected
foam giving rise to serious problems. One reference mentions an
apparently short lived air embolism: P. Fluckiger:"Non-surgical
retrograde sclerosis of varicose veins with Varsyl foam",
Schweizerische Medizinische Wochenschrift No. 48, pp 1368-1370
(1956). In this article, the author indicates that he reduced the
volume of foam administered to 10 ml from 15 ml as a result of a
patient experiencing chest pain on standing immediately after
treatment with 15 ml of foam. In a later lecture, the same author
indicates that he has in fact subsequently used 15 ml foam without
noting ill effects: lecture dated 1962 entitled "A contribution to
techniques for outpatient treatment of varicose veins" delivered to
the Hamburg Dermatological Society. The reference by Mayer and
Brucke cited above appears to describe the use of as much as 50 ml
of air foam and does not mention any problems.
[0008] However, it is known that rapid intravenous injection of a
large quantity of air, as opposed to air foam, can lead to air
embolism which may be fatal. In spite of this practitioners of the
air block and foam techniques described above do not report that
the volumes of air involved in their techniques were sufficient to
cause serious problems.
[0009] The air block technique had largely fallen out of favour by
the 1980s and the other foam techniques mentioned above were
virtually unheard-of.
[0010] The Cabreras proposed the use of a microfoam, that is to say
a microfoam with microscopically small bubbles, e.g., where the
majority of the bubbles are not visible to the naked eye, for
injection into varicose veins. The use of a microfoam, as opposed
to larger bubbled foam or froth, gives rise to many advantages in
terms of controllability and ability to displace blood in even the
largest varicose veins, allowing treatment of virtually all
varicose veins without recourse to surgery. As used here, the term
foam encompasses foams with bubbles of all sizes including
microfoams.
[0011] The first teaching that potential issues with intravenous
injection of a microfoam product made with air are serious enough
to warrant change is to be found in the Cabrera patent references
mentioned above. These documents indicate that the prior air based
techniques are "dangerous owing to the side effects of atmospheric
nitrogen which is only slightly soluble in blood", though it is not
mentioned exactly what the dangers are nor what volumes or rates of
injection of air or nitrogen gas give rise to these dangers.
[0012] In addition to being the first to propose a microfoam as
opposed to a larger bubbled foam, and to propose treatment of even
the largest veins without surgery, the Cabreras also proposed that
the microfoam be made with oxygen or a mixture of carbon dioxide
and oxygen. In the context of this background, the Cabreras'
contribution can be seen to be highly innovative in a number of
respects--appreciating against the prevailing thinking at the time
(i) the potential of a sclerosant microfoam, (ii) the need for
soluble gases, (iii) the use of oxygen which does not degrade the
microfoam yet is taken up by blood, (iv) the safety of oxygen but
also (v) the possibility of incorporating a percentage of highly
soluble carbon dioxide.
[0013] Since publication of the Cabreras' microfoam technique in
the mid 1990s many practitioners have adopted foam both in Europe
and the USA. At the recent worldwide conference of phlebologists in
San Diego in August 2003, approximately one third of the two
hundred and fifty or so papers which were presented concerned foam
treatment.
[0014] Almost without exception, however, practitioners using
sclerosing foam today make it with air. Opinion varies as to how
much foam should be injected--some advocate as little as 5 ml
whilst others are prepared to inject more.
[0015] The Cabreras' microfoam is prepared extemporaneously in the
clinic immediately prior to use. The preparation involves beating
sclerosant solution with a small brush rotated at high speed by a
motor, under a cover which is connected to a source of oxygen or
oxygen and carbon dioxide. Most practitioners who have followed the
Cabreras use an alternative technique for extemporaneous
preparation of foam which involves passing sclerosant solution and
air repeatedly between two connected syringes. Another alternative
is a syringe with a second plunger with holes in its face and which
is independently movable in the syringe barrel to froth a liquid
and gas mixture in the syringe. Both of these latter types of
procedure are somewhat inconvenient and allow for variation of the
foam composition depending upon the person preparing it: gas
content, bubble size, density and stability all require attention.
These techniques require 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.
[0016] A product which aims essentially to reproduce the Cabreras'
microfoam in a more convenient and easily reproducible way is
currently being developed and is in clinical trials in Europe and
the USA. This product is a pressurised canister system, in which
the foam is produced by passing gas and sclerosant solution under
pressure through a number of fine meshes. In the trials of this
product the aim is to treat an entire long saphenous vein and its
varicosed tributaries in a single treatment, which can mean
injection of 25 ml or even 50 ml of foam.
[0017] WO 00/72821-A1 (BTG International Limited), incorporated
herein by reference, describes the fundamental concepts underlying
this canister product. The foam is produced by passing gas and
sclerosant liquid through one or more meshes having small apertures
measured in microns. Like the Cabrera patents, this document
acknowledges the potential issues with air/nitrogen and seeks to
reduce the levels of nitrogen in the foam. A preferred form of gas
described in 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.
[0018] In a later patent application, WO 02/41872-A1 (BTG
International Limited), incorporated herein by reference, the
sclerosant liquid and an oxygen-rich physiologically acceptable
blood dispersible gas are stored in separate containers until
immediately prior to use, when the blood-dispersible gas is
introduced into the container holding the sclerosant liquid. The
mixture of blood-dispersible gas and sclerosant liquid is then
released, the components of the mixture interacting upon release of
the mixture to form a sclerosing foam. In the system described in
this patent application, a proportion of nitrogen (25%) is
deliberately introduced into the polidocanol canister. After
charging of the sclerosing liquid (polidocanol) can with oxygen
from the higher pressure oxygen canister, the percentage of
nitrogen is reduced to about 7 or 8%. It was believed that this
level of nitrogen could be tolerated.
[0019] The device disclosed in WO 02/41872-A1 gives a good uniform
injectable foam, irrespective of the gases used. Use of 100%
CO.sub.2 as the filling gas in the polidocanol canister is
preferred, as CO.sub.2 is very soluble in the bloodstream, but the
present inventors have observed that increasing CO.sub.2 percentage
in the final gas mix may cause an undesirable decrease in foam
stability, resulting in a shorter half separation time. In
particular, the half-life of the foam can fall short of the figure
of 2.5 minutes which is indicated in WO 00/72821-A1 as being
preferable.
[0020] The present inventors are continuing to research clinical
aspects of the injection of sclerosing foam as well as developing
the canister foam product and putting it through clinical trials in
Europe and the USA. It has always been the intention to develop a
safe foam product which is as well defined as possible but whose
specification has achievable tolerances. There are many parameters
of a foam which may be varied. These include, without limitation:
the chemical, its purity and the strength of the solution; the size
of bubbles, or more accurately the distribution of sizes, the
density (i.e. ratio of liquid to gas), the longevity of the foam
(measured in terms of "half life", or the time taken for half the
foam to revert to liquid) and the gas mixture.
[0021] Nitrogen, which makes up approximately 80% of air, is
difficult as a practical matter to exclude totally from a foam.
This is true whether the foam is made using a canister system, in
which case nitrogen tends to creep into the canister during
manufacture, or using either of the syringe techniques or the
Cabreras' rotating brush technique, or indeed any of a number of
other less common techniques which have been developed since the
Cabreras' disclosure of microfoam.
[0022] In a two syringe technique the likely method for introducing
the gas component, if a foam were to be made with a gas other then
air, would be to connect one syringe to a pressurised source of
gas, then disconnect and reconnect it to another syringe containing
sclerosant. In this sort of technique, the two syringes are pumped
to create foam and then the foam-filled syringe separated. The
potential for ingress of a small percentage of air/nitrogen during
this process is obvious. Similarly, even with the Cabreras'
technique, it may be difficult to exclude 100% of air/nitrogen from
the environment in which the foam is prepared.
[0023] One of the objectives of the foam product being developed by
the inventors is to treat an entire greater saphenous vein together
with major varicose tributaries in a human patient with one
injection. This requires up to 25 ml, 30 ml or possibly even 50 ml
of foam. Currently, the most conservative users of air foam inject
a maximum of 5 ml into the venous system, apparently without
observing any deleterious effects. The inventors therefore reasoned
that an equivalent amount of nitrogen in a relatively large dose of
foam needed to treat the entire saphenous vein should also be safe.
They therefore used this as a starting point: 5 ml of air with 80%
nitrogen will contain 4 ml nitrogen; a corresponding proportion of
nitrogen in, say, 50 ml of low nitrogen foam would be around
8%.
[0024] Until recently, its has been believed by the inventors that
a foam with approximately 8% nitrogen would be acceptable from a
safety standpoint and that this percentage represented an easily
achievable tolerance for nitrogen levels in the foam specification.
Accepting this level of nitrogen also has the advantage that a
small quantity of nitrogen could be introduced deliberately into
the polidocanol canister to reduce the adverse effects of the
highly soluble carbon dioxide on the foam stability (as discussed
above). This foam and a system for making it is described in WO
02/41872-A1, referred to above.
[0025] As discussed above, apart from the above mentioned patent
publications, the published art on foam treatment of varicose veins
mentions little if any danger from injecting air foam up to 15 ml.
The only event noted by Fluckiger was temporary chest pain. The
above mentioned patent publications which mention dangers with
nitrogen are silent regarding the amount of nitrogen which would be
dangerous and what damaging effects it may cause. A great many
practitioners are currently using air based foam, though some
restrict the quantity injected to 5 ml. The inventors have been
involved in a 650 patient multi-centre European phase III clinical
trial of the canister product described above which contains 7-8%
nitrogen; no serious adverse events associated with the gas
component of the foam were noted.
[0026] Now, further research in connection with the clinical trials
of the canister system described above has revealed the presence of
large numbers of bubbles in the heart, some of which endure for a
significant period of time. Ultrasound monitoring of the heart
during treatment of patients in this trial has revealed many
bubbles on the right side of the heart and in associated blood
vessels. Since foam is injected into the venous circulation, i.e.
that connected to the right side of the heart, it was expected that
some bubbles on the right side of the heart would be observed.
However, the number and persistence of the bubbles was
surprising.
[0027] Furthermore, bubbles have been observed on the left side of
the heart in a patient who was subsequently shown to have a minor
septal defect, or patient foramen ovale ("PFO"), i.e. a hole in the
heart. The patient reported experiencing a transient visual
disturbance. This is significant because, once on the left side of
the circulation, the bubbles can progress to the brain, where they
may cause microinfarcts.
[0028] At present it is believed that screening all patients for
even the most minor PFO is not really feasible for an elective
procedure such as varicose vein treatment and may not even be
possible. The techniques required would be fairly sophisticated and
possibly quite invasive. Furthermore this would increase the time
required for the procedure and preclude treatment of patients
having such PFOs, of which it is believed there are significant
numbers.
[0029] In the light of these unexpected findings, considerable
further fundamental research has been carried out by the
inventors.
[0030] Experiments using animal models have been carried out by the
inventors and internationally recognised experts in their field
have been commissioned to carry out detailed mathematical modelling
of the behaviour of oxygen, carbon dioxide and nitrogen bubbles in
blood. In vitro work to measure the absorption of gases in fresh
human venous blood has also been carried out by the inventors. As a
result it has become clear that, contrary to previous thinking by
the inventors, and in stark contrast to the thinking of almost
every practitioner currently preparing extemporaneous foam for use
in varicose vein treatment, even the smallest volume of nitrogen
may be significant in causing persistent bubbles.
[0031] Furthermore, recent studies have been published further
confirming that air foams previously suggested in the art are
causing some complications for certain patient groups. For example,
Dr. Philip Kritzinger, MD has presented case studies where foams
for sclerotherapy of veins that were made using air as the gas
phase may lead to seizures and myocardial infarction in some
geriatrics or patients at high risk of coronary problems.
[0032] The inventors have now determined that in order to produce a
product suitable for administration to patients without the need
for lengthy PFO screening methodology it may be required to reduce
the amount of nitrogen to upper limits that were previously
unrecognised.
[0033] Further developments of the canister system described in
WO00/72821-A1 and WO02/41872-A1 have been devised, specifically
raising the percentage of carbon dioxide in the foam and reducing
the nitrogen present in the foam to near zero. To compensate for
the deleterious effects of the highly soluble carbon dioxide, the
size of the apertures in the mesh has been reduced to 5 microns
from 20 microns. Canisters of this design have been made in
reasonably large numbers for testing. Initially, double canister
systems as described above were prepared by flushing the canisters
with the desired gas before sealing and pressurising them. This
product generated a foam with between 1% and 2% nitrogen. Further
research has led the inventors to believe, however, that even this
level may be too high.
[0034] Recognising that there will always be impurity no matter
what technique is adopted for making the foam, the inventors
believe that a sclerosing foam having a percentage by volume of
nitrogen gas within the range 0.01% and 0.8% is both clinically
safe and consistently reproducible. It may be possible routinely to
produce canisters with as little as 0.0001% nitrogen gas. Examples
presented below illustrate the manufacture/preparation and also the
clinical effects of such a foam.
[0035] The inventors also recognise that techniques such as those
described above using syringes, together with a variety of other
techniques for extemporaneous preparation of sclerosing foam which
have been developed since the Cabreras disclosure, may have their
place in the field of foam scleropathy. These techniques may well
provide a less expensive option than a canister product. The
inventors believe that it is possible to prepare foams having a
very low percentage of nitrogen, as set out above, using these
types of technique as well as using a canister system.
[0036] According to the present invention, a foam comprising a
liquid phase and a gas phase wherein the liquid phase comprises at
least one sclerosing agent and the gas phase consisting essentially
of gaseous nitrogen present in an amount ranging from 0.0001% to
0.8% by volume and at least one physiologically acceptable gas. In
a further embodiment, the gas phase may further comprise other
gases such as trace gases as defined below, which may also effect
at least one of at least one of the density, half life, viscosity,
and bubble size of the resulting foam. As used herein, consisting
essentially of means that one or more additional component may be
added, such as gas, that would not substantially effect at least
one of the density, half life, viscosity, and bubble size of the
resulting foam.
[0037] "Physiologically acceptable gas" means gases which are
relatively readily absorbed by the blood or which can pass rapidly
across the pulmonary gas exchange membranes. Specifically, oxygen,
carbon dioxide, nitrous oxide and helium are contemplated. Other
gases, which may or may not fall within the terms of the definition
of physiologically acceptable gases, may be used at least in small
quantities, e.g. xenon, argon, neon or others.
[0038] As used herein, a gas phase that is "substantially" a
specific gas, such as "substantially O2", refers to a gas phase
that is O2 with the impurities normally found in commercial medical
grade O2 gas. Gases which are found only at trace concentrations in
the atmosphere (such as those just mentioned) may be useful to
incorporate in the formulation, e.g. at relatively low
concentrations of between about 0.1% and 5%, in order to facilitate
the detection of leaks.
[0039] In another embodiment, the said other gas consists
essentially of oxygen. Another possibility is for the other gas to
consist essentially of oxygen and a minor proportion, preferably
40% or less of carbon dioxide, still more preferably 30% or less of
carbon dioxide. For example, the gas phase may comprise at least
50% O2, such as for example, as 70%, 80%, 90% and 99% O2. In
another embodiment, it may also comprise a major portion of CO2,
such great than 50% CO2, such as 70%, 80%, 90% and 99% CO2. In
these cases, between 0.1% and 5% of the other gas may be
constituted by gases which are only found at trace levels in the
atmosphere, e.g. argon, helium, xenon, neon. Alternatively the gas
may be substantially 100% nitrous oxide or a mixture of at least
two of oxygen, nitrous oxide and carbon dioxide.
[0040] For the purpose of this application various other terms have
the following definitions: A sclerosant liquid is a liquid that is
capable of sclerosing blood vessels when injected into the vessel
lumen and includes without limitation solutions of polidocanol,
tetradecyl sulphate, ethanolamine oleate, sodium morrhuate,
hypertonic glucosated or glucosaline solutions, chromated glycerol,
iodated solutions. 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. Atmospheric pressure and bar are
1000 mbar gauge. Half-life of a foam is the time taken for half the
liquid in the foam to revert to unfoamed liquid phase.
[0041] As suggested by Cabrerra and discussed above, one could use
oxygen or mixtures of oxygen and carbon dioxide of the gas
component. Carbon dioxide is very soluble in water (and hence
blood) and oxygen is not very soluble in water but is taken up
relatively rapidly by haemoglobin in blood. The present inventors
have also done studies that have shown that CO2 and O2 are taken up
in blood much faster than N2 or air. However, foams made solely
with carbon dioxide, or other highly water-soluble gases, tend to
be very unstable and do not last long enough to be usable. Because
CO2 foams have a very short half life, foams with a high
concentration of CO2 have not been used in the past to prepare
foams for scelrotherapy.
[0042] For example, a predominantly insoluble gas mix such as air
will yield a stable, stiff foam with a half separation time of
150-200 seconds using the Cabrera method. However, highly soluble
gas atmospheres such as 100% CO2 yield foams with much shorter half
separation times. It is thought that the rapid dissolution and
transport of CO2 in the lamellar cell walls of the foam is
responsible for the reduced stability of some CO2 foams. This
allows the smaller, high pressure bubbles of the foam to rapidly
transfer all their gas content to adjacent larger low pressure
bubbles, which then rise through the foam to burst or accumulate at
a surface. This process is called Ostwalt ripening, and with
all-CO2 foams the liquid cell wall is no longer a significant
barrier to diffusion between adjacent bubbles at different Laplace
pressures. Drainage and separation of foam into gas and liquid
components is also influenced by the viscosity of the liquid
component.
[0043] Oxygen foams do not have this problem, but the injection of
oxygen gas has been reported to be dangerous and, in fact, has been
said to be almost as dangerous as air when injected into the venous
system. See, for example, Moore & Braselton "Injections of Air
and carbon Dioxide into a Pulmonary Vein", Annals of Surgery, Vol
112, 1940, pp 212-218. While another study suggests that for some
high risk patient groups high concentrations of O2 in foams used
for sclerotherapy may increase the risk of side effects.
[0044] Recent studies have also suggested that foams for
sclerotherapy made with high concentrations of N2 or O2 may lead to
potential side effects in certain patient groups. More
specifically, one study suggests that high concentrations of
nitrogen may lead to a higher risk of arterial embolism in certain
patient populations.
[0045] The present inventors, however, have discovered that it is
possible to make an effective foam for use in sclerotherapy using
high concentrations of CO2 as the gas phase and the addition of a
viscosity enhancing agent to the liquid phase. The addition of a
viscosity enhancing agent, however, while increasing the half life
of a CO2 foam, also increases the density of the foam. Too high of
a density can hinder a foams ability to displace blood and
therefore be an effective foam for sclerotherapy. It was discovered
that a balance of density and half life enables the production of
an effective foam. In one embodiment, this balance of density and
half life is achieved by increasing the viscosity enhancing agent
to at least 20% wt/wt and using various methods as described herein
to produce the foam.
[0046] Viscosity enhancing agents include any agent that will
increase the viscosity of the liquid phase, such as PVP and
glycerol. In one embodiment, at least 20% wt/wt viscosity enhancing
agent is present in the liquid phase, such as for example 25%, 30%,
35%, 40%.
[0047] Viscosity of the liquid phase before production of the foam
may also be a factor in the half life of the foam. For example,
increasing viscosity of the liquid phase will increase half life of
the foam. However, a higher viscosity may raise the density of the
resulting foam in some systems.
[0048] Thus, in a further embodiment, the foam of the invention
comprises a liquid phase and a gas phase wherein the liquid phase
comprises at least one sclerosing agent and is at least 20% wt/wt
of at least one viscosity enhancing agent; and the gas phase
comprises at least 50% CO2; and wherein the foam has a density less
than 0.25 g/cm and half life of greater than 100 secs. The gas
phase may, for example be at least 75% CO2, such as at least 90%
CO2, such as at least 99% CO2. In one embodiment, the gas phase
consists essentially of CO2.
[0049] The foam, for example, may have a half life of at least 90
second, such as at least 100, such as at least 110, such as at
least 120 seconds, such as at least 130 seconds, such as at least
140 seconds, such as at least 150 seconds, such as at least 160
seconds, such as at least 170 seconds, such as at least 180
seconds, and such as at least 3.5 minutes. The density of the foam
may range from 0.07 to 0.22, such as 0.07 to 0.19 g/ml, 0.07 to
0.16 g/ml, such as 0.08 to 0.14, also such as 0.8 to 0.15 g/ml,
such as 0.9 to 0.13 g/ml and such as 0.10 to 0.14 g/ml. The gas
phase may further comprises another physiologically acceptable gas
that is dispersible in blood, such as O2. The viscosity of the
liquid phase may range from 2.0 to 10 cP, such 2.0 to 7.0 cP, such
as 2.0 to 5.0 cP, such as 2.0 to 3.5 cP, such as from 2.0 to 3.0
cP, such as 2.0 to 2.5 cP.
FIGURES
[0050] FIG. 1 is a schematic representation of a syringe barrel
part of a first embodiment of device in accordance with the first
aspect of the invention, showing it in a sealed state for
storage;
[0051] FIG. 2 is a schematic representation of a cartridge for use
with the syringe barrel of FIG. 1;
[0052] FIG. 3 is a schematic representation of a modified cartridge
for use with the syringe barrel of FIG. 1;
[0053] FIG. 4 is a further schematic representation of the syringe
barrel of FIG. 1 with a cartridge of the type shown in FIG. 3 being
installed;
[0054] FIG. 5 is a further schematic representation of the syringe
barrel of FIG. 1 with a foaming unit and plunger stem fitted;
[0055] FIG. 6 is a schematic representation of the syringe,
cartridge and foaming device of FIG. 5, with the plunger stem of
the syringe partially depressed;
[0056] FIG. 7 is a schematic representation of a second embodiment
of device in accordance with the first aspect of the invention,
comprising charged syringe with foaming unit fitted;
[0057] FIG. 8 is a schematic representation of the device of FIG. 7
installed in a syringe driver for generation and delivery of foam
at a controlled rate;
[0058] FIG. 9 is a schematic representation of a third embodiment
of device according to the invention;
[0059] FIG. 10 is a schematic representation of the device of FIG.
9 fitted to a motorized driver;
[0060] FIG. 11 is a plan view of a mesh element of an embodiment of
a foaming unit forming part of the invention;
[0061] FIG. 12 is a side sectional view along the line I-I in FIG.
11; and
[0062] FIG. 13 is a side sectional view of an embodiment of foaming
unit forming part of the invention.
[0063] FIG. 14 shows a cross-sectional view of a pre-pressurised
container for the generation of therapeutic foam according to the
invention, as disclosed in WO 00/72821-A1 and further described
below.
[0064] FIG. 15 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 below.
[0065] FIG. 16 shows a graph to compare the results from the four
bi-can conditions tested in Example 3 below, showing the effect of
gas mix, gas pressure and shuttle mesh on foam density and
half-life. Control 1 uses a 75% CO2/25% N2 gas mixture in a 0.5 bar
canister with a 5 .mu.m mesh; Test 1 uses the same gas mixture with
a 5 .mu.m mesh; Control 2 uses 100% CO2 in a 1.2 bar canister with
the 20 .mu.m mesh; Test 2 uses the same gas with a 5 .mu.m
mesh.
[0066] FIG. 17 shows a graph of the average number of bubbles by
diameter from the four bi-can conditions tested below.
[0067] FIG. 18 shows a graph of the proportion of bubbles by
diameter from the four bi-can conditions tested in below.
[0068] FIG. 19 shows a graph of the average volume of bubbles by
diameter from the four bi-can conditions tested in below.
[0069] FIG. 20 shows a graph of the proportion of bubbles by
diameter from the four bi-can conditions tested in below.
[0070] FIG. 21 shows a graph to compare the results from the four
bi-can conditions tested below, showing the effect of shuttle mesh
size on half-separation time and density.
[0071] FIG. 22 shows the effects of (a) glycerol concentration on
viscosity of the liquid phase before mixing with the gas phase to
form a foam and (b) the effects of various viscosity enhancing
agents on viscosity of the liquid phase.
[0072] FIG. 23 (a, b, and c) shows the effects of various viscosity
enhancing agents on the density and half life of a Cabrerra
foam.
DETAILED DESCRIPTION
[0073] For the purpose of this application terms have the following
definitions: 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.
Atmospheric pressure and bar are 1000 mbar gauge. Half-life of a
foam is the time taken for half the liquid in the foam to revert to
unfoamed liquid phase.
[0074] In one embodiment, the foam 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.
[0075] 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 foam 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.
[0076] As used here, the viscosity is determined by Brookfield
DVII+Pro made by Brookfield Engineering Labs at room
temperature.
[0077] In one embodiment, the gas/liquid ratio in the mix is
controlled such that the density of the foam is 0.09 g/mL to 0.16
g/mL, more preferably 0.11 g/mL to 0.14 g/mL.
[0078] In another embodiment, the foam has a half-life of at least
100 seconds, such as for example, 2 minutes, 2.5 minutes, and 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.
[0079] In one embodiment, the mixture of gas and sclerosant liquid
is in the form of an aerosol, a dispersion of bubbles in liquid or
a macrofoam. By macrofoam is meant a foam that has gas bubbles that
are measured in millimetres largest dimension, e.g. approximately 1
mm and over, and over such as can be produced by lightly agitating
the two phases by shaking. In another embodiment, the gas and
liquid are provided in the form of an aerosol where a source of
pressurized gas and a means for mixing the two is provided to the
point of use. It may be that a macrofoam is first produced where
the liquid and gas are brought together only at the point of
use.
[0080] The ratio of gas to liquid used in the mixture may be
important in order to control the structure of the foam produced
such that its stability is optimized for the procedure and the
circumstances in which it is being carried out. For some foams, one
may mix 1 gram sclerosant liquid with from approximately 6.25 to
14.3 volumes (STP), more preferably 7 to 12 volumes (STP), of
gas.
[0081] In one embodiment, the physiologically acceptable blood
dispersible gas comprises a major proportion of carbon dioxide
and/or oxygen. In some embodiments, the foam may comprise a minor
proportion of nitrogen. While a proportion of nitrogen may be
present, as in air, the present invention provides for use of
carbon dioxide and/or oxygen without presence of nitrogen.
[0082] In one form the gas used is a mixture of carbon dioxide and
other physiological gases, particularly containing 3% vol/vol or
more carbon dioxide, such as from 10 to 90% carbon dioxide, such as
from 30 to 50% carbon dioxide. The other components of this gas may
be oxygen.
[0083] Another form of gas 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. One gas is
60 to 90% vol/vol oxygen and 40 to 10% vol/vol carbon dioxide,
another is 70 to 80% vol/vol oxygen and 30 to 20% vol/vol carbon
dioxide. One embodiment is 99% or more oxygen.
[0084] 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 0.5
to 5% v/v polidocanol, preferably in sterile water or a
physiologically acceptable saline, e.g. in 0.5 to 1.5% v/v saline.
Concentration of sclerosant in the solution will be advantageously
increased for certain abnormalities such as Klippel-Trenaunay
syndrome.
[0085] Polidocanol is a mixture of monolauryl ethers of macrogols
of formula C12C25(OCH2CH2)nOH with an average value of n of 9. It
will be realized that mixtures with other alkyl chains, oxyalkyl
repeat units and/or average values of n might also be used, e.g. 7
to 11, but that 9 is most conveniently obtainable, e.g. from
Kreussler, Germany, e.g. as Aethoxysklerol.TM., a dilute buffered
solution of polidocanol.
[0086] The concentration of sclerosant in the aqueous liquid is a
1-3% vol/vol solution, such as polidocanol, in water or saline,
such as about 1% vol/vol. The water or saline also, in some cases
at least, contain 2-4% vol/vol physiologically acceptable alcohol,
e.g. ethanol. Saline may be buffered. Some buffered saline is
phosphate buffered saline. The pH of the buffer may be adjusted to
be physiological, e.g. from pH 6.0 to pH 8.0, more preferably about
pH 7.0.
[0087] The sclerosant may also contain additional components, such
as stabilizing agents, e.g. foam stabilizing agents, e.g. such as
glycerol. Further components may include alcohols such as
ethanol.
[0088] In one embodiment, ranges for the gaseous nitrogen volume at
are 0.0001% to 0.75%, such as 0.7%, such as 0.6%, and such as 0.5%.
Although from a theoretical viewpoint it may be desirable to
eliminate as much nitrogen as possible, it is also understood that
since we live in an atmosphere of 80% nitrogen there are
difficulties in consistently making a foam with a very high degree
of purity with regard to nitrogen gas. Accordingly, the lower end
for the range of nitrogen impurity which is preferable (from the
point of view of being easier and/or less expensive to manufacture)
is 0.0005%, more preferably 0.001%, still more preferably 0.005%,
0.01%, 0.05%, 0.1%, 0.2%, 0.3% or 0.4%. As will be apparent from
the examples below, each incremental increase in the lower end of
the range may result in a purifying step being taken out of the
manufacturing procedure, with resulting cost savings.
[0089] Also according to the invention is provided a canister
system adapted to dispense a foam and whose contents consist of a
liquid phase and a gas phase, wherein the liquid phase comprises a
sclerosing agent and the gas phase consists of a minor proportion
of nitrogen gas and a major proportion of other gas, preferably
physiologically acceptable gas, such that the gas phase of a foam
produced by the canister system consists of between 0.0001% and
0.8% nitrogen gas. The other possible ranges for the nitrogen gas
component, as recited above, also apply.
[0090] It will be appreciated that the term "canister system" can
mean either a single canister containing a liquid and a gas for
dispensing to generate a foam, or a two canister arrangement as
described above, where gas is stored in one canister and liquid,
optionally together with gas, in another.
[0091] In one embodiment, said minor proportion of nitrogen gas in
the canister is also 0.0001% to 0.8% by volume of the total gas
volume in the canister, or optionally the other ranges recited
above.
[0092] In another embodiment, the canister includes an element
through which the liquid and gas contents pass in order to dispense
foam. In one embodiment, this element has apertures of
approximately 0.1 to 15 micron diameter, more preferably 1-7
micron, still more preferably about 5 micron.
[0093] Another aspect of the present invention is a method for
producing a foam suitable for use in scleropathy of blood vessels,
particularly veins, characterized in that it comprises passing a
mixture of gas and an aqueous sclerosant liquid through one or more
passages having at least one cross-sectional dimension of from 0.1
to 15 .mu.m, the ratio of gas to liquid being controlled such that
a foam is produced having a density of between 0.07 g/mL to 0.19
g/mL and a half-life of at least 100 seconds, such as 2 minutes,
such as 2.5 minutes.
[0094] Preferably, the said one or more passages have at least one
cross-sectional dimension of from 1-7 micron, more preferably about
5 micron.
[0095] In accordance with the original specification (as set out in
WO00/72821-A1), the foam is preferably 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. Again in accordance with the original
specification in WO00/72821-A1, preferably the method provides a
foam characterised in that at least 50% by number of its gas
bubbles of 25 .mu.m diameter and over are of no more than 150 .mu.m
diameter. More preferably at least 95% of these gas bubbles by
number are of no more than 280 .mu.m diameter. Still more
preferably at least 50% by number of these gas bubbles are of no
more than 130 .mu.m diameter and still more preferably at least 95%
of these gas bubbles by number are of no more than 250 .mu.m
diameter.
[0096] In one embodiment, the gas comprises from 1% to 50% carbon
dioxide, preferably from 10% to 40%, more preferably from 20% to
30%. Surprisingly, it has been found that by using a smaller
aperture size for the mesh, foams having the specification set out
in WO00/72821-A1 can be made with gas mixtures having higher
proportions of carbon dioxide and correspondingly lower proportions
of insoluble gases such as nitrogen. Carbon dioxide may be a
desirable component of the gas mixture due to its extreme
solubility, greater than that of oxygen.
[0097] Also according to the invention a method for angiologic
treatment comprises injecting an effective amount of a sclerosing
foam whose gaseous component consists of between 0.0001% and 0.8%
by volume gaseous nitrogen, the balance being other gas, preferably
physiologically acceptable gas. The other possible ranges recited
above for the percentage of nitrogen apply and the options for the
other gases recited above apply.
[0098] Preferably the method of treatment comprises the injection
of 10 ml to 50 ml of foam in a single injection, preferably 15 ml
to 50 ml, more preferably 20 ml to 50 ml, still more preferably 30
ml to 50 ml of foam.
[0099] According to the invention a method of treatment of the
human greater saphenous vein comprises treating substantially the
entire greater saphenous vein of one leg with a single injection of
foam as described above.
[0100] According to the invention a method of treatment of a blood
vessel of diameter 7 mm or greater so as to cause damage to the
endothelium of the vessel comprises injecting foam as described
above.
[0101] A further factor in the inventors' developing understanding
of the behaviour in blood of bubbles comprising soluble gases is
the phenomenon of nitrogen diffusing out of blood and adjacent
tissues and into the bubbles due to a difference in the partial
pressure of nitrogen in the bubbles as compared with that in the
surrounding blood and tissues. This phenomenon will generally only
occur when the partial pressure of nitrogen in the bubble is lower
than that in the surrounding blood and tissues.
[0102] It appears that carbon dioxide, and to a lesser extent
oxygen, will diffuse out of the bubble and go into solution in the
surrounding blood relatively very quickly, so that the bubble will
quite quickly reach a point where the partial pressure of nitrogen
in the bubble will be higher than that in the surrounding blood and
tissues and, ultimately, the bubble will become substantially pure
nitrogen. As soon as the nitrogen partial pressure gradient is
reversed, nitrogen will come out of the bubble and into solution in
the blood, though this will happen relatively slowly because of the
low solubility of nitrogen. This phenomenon will also be influenced
by increasing saturation of the surrounding blood with nitrogen, if
this occurs to a significant extent. This phenomenon potentially
affects the partial pressure gradient of nitrogen in the blood and
may also mean that a limit for dissolution of nitrogen is reached
if the surrounding blood becomes fully saturated with nitrogen.
[0103] It is not at present understood to what extent localised
saturation of blood with nitrogen is a factor in the dissolution of
the bubbles in a dispersing foam. Since the bloodstream in constant
motion, however, it is assumed that this effect will only ever be
transient and will not unduly affect the overall picture of
nitrogen dissolution.
[0104] It appears that the initial phase of rapid dissolution of
carbon dioxide and/or oxygen is critical: the shorter this period,
the smaller the volume of nitrogen which is able to diffuse into
the bubble.
[0105] There are several possibilities for eliminating residual
bubbles or reducing them in size and/or number (apart from reducing
the initial quantity of nitrogen in the gas phase of the foam). One
of these is to make the bubbles as small as is practical. The
smaller the bubble, the faster the carbon dioxide and/or oxygen
will dissolve out of the bubble and therefore the shorter the time
available for nitrogen from the blood to diffuse into the bubble
before the partial pressure gradient for nitrogen reverses in
favour of nitrogen diffusing out of the bubble.
[0106] Another is that of the patient breathing oxygen or air
enriched with oxygen, which has the effect of increasing the oxygen
partial pressure in the blood at the expense of the nitrogen
partial pressure. This technique is known in the fields of diving
and space exploration, where it has been used to reduce the risk of
the "bends", i.e. the tendency on depressurisation for nitrogen to
come out of solution in body tissues (as opposed to the blood in
blood vessels which is what we are concerned with here). As far as
the inventors are aware, it has never previously been proposed to
use this technique in connection with injecting gases into the
vascular system.
[0107] According to an aspect of the invention a sclerosant foam is
composed of bubbles of which, ignoring bubbles of 1 micron or less
diameter, 95% or more are of 150 micron diameter or less and 50% or
more are of 100 micron diameter or less. Preferably, 95% or more of
the bubbles are of 100 micron diameter or less and 50% or more of
the bubbles are of 50 micron diameter or less. More preferably, 95%
or more of the bubbles are of 75 micron diameter or less and 50% or
more of the bubbles are of 30 micron diameter or less. Still more
preferably, 95% or more of the bubbles are of 60 micron diameter or
less and 70% or more of the bubbles are of 30 micron diameter or
less. Examples are presented below showing how foams with these
sorts of bubble distributions have been made.
[0108] These very small bubble foams have only to date been
obtained by the inventors by having a relatively dense formulation
of the order of 0.3 to 0.5 g/ml, with a relatively high ratio of
liquid to gas. Such a wet foam is still considerably less dense
than blood and therefore will be buoyant when in a vein full of
blood. It is speculated that this buoyant characteristic may to
some extent be responsible for the advantageous behaviour of foam
in the vascular system in terms of displacing blood. However, the
dense foams produced to date by the inventors behave essentially as
a liquid in terms of their rheological properties--they are not
"stiff".
[0109] It is not impossible that these dense but somewhat fluid
foams may have a sufficiently good therapeutic effect to be useful
and may also eliminate or reduce the residual gas problem. However,
it is probable that the rheological properties of the foam in blood
are important, and that a "stiff" foam is desirable effectively to
displace blood and thus allow consistent, uniform application of
the active to the interior of the vessel wall. For this reason it
may be desirable to add a further ingredient to the foam in order
to increase its stiffness/viscosity, either by adding a
viscosity-enhancing additive to the formulation or by adding an
agent which increases the foaming capacity of the formulation.
[0110] Such ingredients could be, without limitation, Polysorbate
20, Polysorbate 80 or Polygeline. Alternatively, glycerol and PVP
may be added.
[0111] A foam with a bubble size distribution falling within the
definitions set out above may be created by passing gas and liquid
repeatedly through a fine mesh, e.g. a 5 micron mesh. Repeated
passages through the mesh reduce the bubble size, though there
appears to be a limit on this.
[0112] It is envisaged that other known techniques for agitating a
gas and liquid mixture at high energy could be applied to make even
finer bubbles. For example sonic or ultrasonic agitation of a
mixing stream of gas and liquid could be used, or alternatively a
mixture of beating the gas and liquid by mechanical means,
supplemented by the application of sonic or ultrasonic energy.
[0113] The inventors have also prepared a foam having an average
bubble size in the range 50 micron to 80 micron by adapting a
canister to alter the ratio of liquid and gas being passed through
a mesh.
[0114] A further aspect of the invention is a pressurised canister
product adapted to dispense a sterile gas and sclerosing liquid
mixture in predetermined proportions into a syringe, as a solution
to some of the issues with extemporaneous preparation of foam. Thus
a pressurised canister is provided--which may be of any suitable
material such as anodised aluminium or even glass--containing
sterile gas and sclerosing liquid and arranged to dispense the
correct volume of liquid and gas into a syringe. It is envisaged
that the canister would contain sterile gas with a very low
nitrogen concentration etc. as defined above. The canister may have
a pierceable septum for puncturing with a hypodermic needle, or it
may have a break seal which is arranged to be broken by insertion
of a syringe luer nozzle.
[0115] In the latter case, a syringe luer nozzle could be inserted
into the canister in a sealing fashion, with the syringe nozzle
pointing upwards. Liquid in the canister would be dispensed first
under pressure, followed by equalisation of the pressure in the
canister and syringe. The pressure and volume of gas in the
canister could of course be arranged so that the correct
proportions of gas and liquid are dispensed. Alternatively, the
canister could be provided with an internal dip tube so that the
same effect is achieved with the canister in an upright
orientation.
[0116] Also according to the invention is provided a method of
preparing a sclerosing foam which includes the step of cooling the
ingredients of the foam to a sub-ambient temperature prior to
generation of the foam. A suitable temperature range might be 0 to
15 degrees Celsius, preferably 0 to 10 degrees, more preferably 3
to 7 degrees. Decreasing temperature increases liquid viscosity
and, in this way, the inventors believe the half life of the foam
could be extended. Since, during decay of a foam, the bubble size
tends to increase, this methodology may help reduce the average
size of bubbles over time in the body and thereby reduce residual
bubbles.
[0117] Also according to the invention, and in line with the
reasoning presented earlier, a method of angiologic treatment of a
patient comprises causing the patient to breathe oxygen gas or
oxygen-enriched air for a predefined period prior to injection of
foam as described above. Preferably the predefined period is 1 to
60 minutes, more preferably 1-20 minutes, more preferably 5-10
minutes.
[0118] Another embodiment of the present invention provides a foam,
that, for example, can be used in the elimination of blood vessels
and vascular malformations, that are made available by the method
and devices of the invention, comprising a physiologically
acceptable gas that is readily dispersible in blood together with
an aqueous sclerosant liquid wherein in that the foam has a density
of from 0.07 to 0.19 g/cm.
[0119] In one embodiment, the foam is capable of being passed down
a 21 gauge needle without reverting back to gas and liquid by more
than 10%, based on liquid content reverting back to unfoamed liquid
phase.
[0120] 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.
[0121] Most conveniently the funnel is pre-equilibrated in a water
bath to ensure a temperature of 25.degree. C. before drying and
application of foam. Placing of a foam filled syringe upside down,
without its plunger, above the funnel leading into a graduated
receptacle allows convenient measurement of this parameter.
[0122] In one embodiment, the foam, on passage through said needle,
does not revert back to unfoamed liquid by more than 5% based on
liquid content, still more preferably by no more than 2%. This is
measured by measuring the change in volume of the foam versus the
liquid.
[0123] In one embodiment, the foam is capable of being passed down
a needle while retaining at least 50% by number of its gas bubbles
of at least 25 .mu.m diameter at no more than 200 .mu.m diameter.
This is conveniently measured under ambient conditions, more
preferably at STP.
[0124] In one embodiment, the gas includes less than 40% v/v
nitrogen. Preferably the density of the foam is from 0.09 to 0.16
g/mL, more preferably 0.11 g/mL to 0.14 g/mL.
[0125] In one embodiment, the foam density, which is a measure of
liquid/gas ratio, is from 0.13 to 0.14 g/cm and the half-life is at
least 2.5 minutes. The foam more preferably does not move outside
of its parameters of bubble size set out above in such time.
[0126] In one embodiment, the gas consists of at least 50% oxygen
or carbon dioxide, more preferably 75% or more oxygen or carbon
dioxide and most preferably at least 99% oxygen or carbon dioxide,
e.g. substantially 100% oxygen or carbon dioxide. Preferably the
oxygen or carbon dioxide is medical grade.
[0127] As discussed above, addition of glycerol to the aforesaid
sclerosant imparts a longer half-life to the resultant foam.
However, glycerol may increase density and also produces a tendency
for the meshes to block up when using a mesh device as described
above, so should be used carefully where the device it is produced
from may be used multiple times or the bag-on-valve concept is
used.
[0128] The invention also provides:
[0129] a method of treating a patient in need of sclerotherapy of a
blood vessel comprising administering a foam as described above to
that blood vessel; use of a foam described above for the
manufacture of a medicament for sclerotherapy; and a foam as
described above for use in therapy.
[0130] Accordingly the one aspect of the present invention provides
a method for producing a foam suitable for use in scleropathy of
blood vessels, particularly veins, characterized in that it
comprises passing a mixture of a physiologically acceptable blood
dispersible gas and an aqueous sclerosant liquid through one or
more passages having at least one cross-sectional dimension of from
0.1 to 15 .mu.m, the ratio of gas to liquid being controlled such
that a foam is produced having a density of between 0.07 g/mL to
0.19 g/mL and a half-life of at least 100 seconds.
[0131] Apparatuses for Generating Foam
[0132] There are a number of issues with the current practice of
extemporaneous preparation of foam, the use of air as the gas being
only one of these. Other issues are the consistency of the product,
which is by nature highly variable because it depends on the
physician selecting the gas to liquid ratio and then pumping the
gas and air mixture a given number of times and/or at a given speed
to obtain the right product. Foams are highly variable and
different bubble sizes and densities will have different safety and
efficacy profiles.
[0133] Very recently, a machine has been made available which is
designed to receive two syringes and apply a given number of pumps
at a given rate to achieve a roughly consistent product. The
machine is called "Turbofoam".RTM. but the inventors are not at
present aware who is marketing the machine. Two syringes are loaded
into it (one of which is loaded with sclerosant solution). When
activated, the machine automatically draws a predetermined quantity
of atmospheric gas into the syringes and cycles the syringes until
a foam of the desired properties is made.
[0134] Clearly, the arrangement described above addresses at least
the issues of reproducibility of the foam as regards the gas/liquid
ratio (provided the correct amount of liquid is loaded initially by
the user) and also the number and speed of cycles. However, it is
obviously also quite inconvenient in many respects and sterility
may also be compromised by build up of bacteria in the gas channels
of the machine, for example.
[0135] The solution proposed by the inventors is to provide a
sterile pack containing one or two syringes, optionally together
with any connectors etc. The syringe or syringes is/are pre-loaded
with the correct volumes of gas and sclerosing liquid. Most
syringes are made from plastics material such as polypropylene
which allows gas to permeate through it over time. Therefore, the
packaging is preferably substantially gas-impermeable and the
atmosphere in the pack is preferably substantially the same
composition as the gas pre-loaded into the syringe. This sort of
packaging is well known in itself and examples include metallised
plastic sheeting e.g. an aluminium and polyethylene laminate.
[0136] According to one aspect of the invention, there is provided
a substantially sterile pack comprising:
[0137] a syringe charged with a liquid sclerosing agent and a gas
mixture comprising physiologically acceptable gas, such as, for
example, between 0.0001% and 0.8% gaseous nitrogen with the balance
being other gas, such physiologically acceptable gas; and
[0138] a gas atmosphere inside the pack having substantially the
same composition as the said gas mixture in the syringe.
[0139] In one embodiment, the gas mixture consists of 0.001% to
0.8% gaseous nitrogen, preferably 0.01% to 0.8%, more preferably
0.01% to 0.7%, still more preferably 0.01% to 0.6%.
[0140] In one embodiment, the said other gas is oxygen, carbon
dioxide or a mixture thereof. Optionally, a small percentage (e.g.
0.1 to 5%) of a tracer gas, which is not found in significant
amounts in the atmosphere, is added to allow leaks to be detected.
Such a gas might be e.g. helium, neon, argon, xenon or any other
gas which is found in trace concentrations (0.01%) in atmospheric
air.
[0141] To avoid contamination, the pack contents may be at slightly
above atmospheric pressure. This may be achieved by manufacturing
the pack at an ambient temperature below standard room temperature.
Once the pack enters normal ambient surroundings, the temperature
increase of the atmosphere inside the pack will ensure a slight
overpressure.
[0142] Manufacture of the packaged product would be carried out in
aseptic conditions, using techniques standard in that field.
[0143] This pre-packaged product may include one syringe of the
type comprising a barrel, a first plunger and a second plunger, the
second plunger having an apertured plunger head which is adapted to
be movable within the barrel independently of the first
plunger.
[0144] Alternatively the syringe may be a conventional one,
containing an appropriate amount of gas as described above. A
further syringe containing sclerosing agent could be provided in
the same or a different pack, together with the connectors, three
way valves, etc necessary to perform any of the known techniques
for extemporaneous foam preparation.
[0145] In use, the pack is opened and the usual technique followed
for generating foam, without the need to measure out liquid or gas.
In the case of a two syringe technique, the syringes can be
supplied ready connected, to increase convenience and remove a
potential source of contamination.
[0146] Optionally, the pack may include a syringe connector which
incorporates a fine mesh with apertures of 1-200 micron, preferably
2 to 50, more preferably 3 to 20 micron maximum dimensions.
Alternatively, if a single syringe device is used, the apertures in
the plunger may be provided by a mesh with pores of these
proportions.
[0147] Optionally, the package could constitute a cartridge for a
foam generating machine similar to the "Turbofoam".RTM. described
above.
[0148] A further solution to the issues with extemporaneous foam
preparation has been proposed by the inventors. This is to provide
a pressurised canister--which may be of any suitable material such
as anodised aluminium or even glass--containing sterile gas and
sclerosing liquid and arranged to dispense the correct volume of
liquid and gas into a syringe. It is envisaged that the canister
would contain sterile gas as defined above. The canister may have a
pierceable septum for puncturing with a hypodermic needle, or it
may have a break seal which is arranged to be broken by a syringe
luer nozzle.
[0149] In the latter case, a syringe luer nozzle could be inserted
into the canister in a sealing fashion, with the syringe nozzle
pointing upwards. Liquid in the canister would be dispensed first
under pressure, followed by equalisation of the pressure in the
canister and syringe. The pressure and volume of gas in the
canister could of course be arranged so that the correct
proportions of gas and liquid are dispensed. Alternatively, the
canister could be provided with an internal dip tube so that the
same effect is achieved with the canister in an upright
orientation.
[0150] 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 15 .mu.m as described provides a stable blood dispersible
gas based sclerosant injectable foam that was previously thought to
be only producible by supply of high amounts of energy using high
speed brushes and blenders.
[0151] The aerosol, dispersion or macrofoam is preferably produced
by mixing the gas and liquid from respective flows under pressure.
The mixing conveniently is carried out in a gas liquid interface
element such as may be found in aerosol canisters. The interface
device may however be very simple, such as a single chamber or
passage of millimetre dimensions, i.e. from 0.5 to 20 mm diameter,
preferably 1 to 15 mm diameter, into which separate inlets allow
entry of gas and liquid. Conveniently the interface is of design
which is commonly found in aerosol canisters but which is selected
to allow the correct ratio of gas to liquid to allow formation of a
foam of the presently defined density. Suitable inserts are
available from Precision Valves (Peterborough UK) under the name
Ecosol and are selected to produce the ratio specified by the
method above.
[0152] However, the mixing of gas and liquid may also be brought
about within a dip-tube leading from the sclerosant solution
located in the bottom of a pressurized container where holes in the
dip-tube allow gas to enter into a liquid stream entering from the
bottom of the tube. In this case the holes may be of similar
diameter to the Ecosol holes. Such holes may be conveniently
produced by laser drilling of the dip-tube.
[0153] The one or more passages through which the aerosol or
macrofoam so produced are passed to produce the stable foam
preferably have diameter of from 4 .mu.m to 22 .mu.m, more
preferably from 5 .mu.m to 11 .mu.m where simple passages are
provided, such as provided by openings in a mesh or screen, e.g. of
metal or plastics, placed perpendicular to the flow of gas/liquid
mixture. The passage is conveniently of circular or elliptical
cross section, but is not necessarily so limited. A number of such
meshes or screens may be employed along the direction of flow.
[0154] Most preferably the passages are provided as multiple
openings in one or more elements placed across the flow. Preferably
the elements are from 2 to 30 mm diameter, more preferably 6 to 15
mm diameter, face on to the flow, with 5 to 65% open area, e.g. 2%
to 20% open area for woven meshes and 20% to 70% open area for
microporous membranes. Openings in a porous material, such as
provided in a perforated body, preferably provide several hundreds
or more of such passages, more preferably tens or hundred of
thousands of such passages, e.g. 10,000 to 500,000, presented to
the gas liquid mixture as it flows. Such material may be a
perforated sheet or membrane, a mesh, screen or sinter. Still more
preferably a number of sets of porous material are provided
arranged sequentially such that the gas and liquid pass through the
passages of each set. This leads to production of a more uniform
foam.
[0155] Where several elements are used in series these are
preferably spaced 1 to 5 mm apart, more preferably 2 to 4 mm apart
e.g. 3 to 3.5 mm apart. For some embodiments of the present
invention it is found that the passage may take the form of a gap
between fibres in a fibrous sheet placed across the path of the
gas/liquid flow, and the dimension described in not necessarily the
largest diameter, but is the width of the gap through which the
gas/liquid aerosol or macrofoam must flow.
[0156] Alternatively the method provides for passing the mixture of
gas and liquid through the same set of passages, e.g. as provided
by one or more such porous bodies, a number of times, e.g. from 2
to 2,000, more preferably 4 to 200 times, or as many times as
conveniently results in a foam of the required bubble size
distribution set out above. It will be realized that the more times
the foam passes through the meshes, the more uniform it becomes.
Where multiple passes through the meshes are possible, a large mesh
size may be desirable, e.g, 20 to 300 .mu.m, such as 40 to 200
.mu.m, such as 60 to 150 .mu.m.
[0157] The pressure of the gas used as it is passed through the
passages will depend upon the nature of the mechanism used to
produce the foam. Where the gas is contained in a pressurized
chamber and passes only once through the mesh, such as in an
aerosol canister, in contact with the liquid, suitable pressures
are typically in the range 0.01 to 9 bar over atmosphere. For use
of meshes, e.g. 1 to 8 meshes arranged in series, having apertures
of 10-20 .mu.m diameter, 0.1 to 5 atmospheres over bar will, inter
alia, be suitable. For use of 3-5 meshes of 20 .mu.m aperture it is
found that 1.5-1.7 bar over atmospheric is sufficient to produce a
good foam. For a 0.1 .mu.m pore size membrane, a pressure of 5 bar
or more over atmospheric pressure is preferred.
[0158] 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 trademark 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 pass through may be sufficient to
produce a foam that meets the use requirements set out above with
regard to stability. However, it will evident to those skilled in
the art that use of more than one such membrane in series will give
a still more uniform foam for given set of conditions.
[0159] It is believed that the combination of provision of a stream
of solution and gas under pressure through an aerosol valve and
then flow through the passages, e.g. pores in a mesh, screen,
membrane or sinter provides energy sufficient to produce a stable
aqueous liquid soluble gas, e.g. carbon dioxide and/or oxygen,
based sclerosant foam that was previously thought to be only
producible by supply of high amounts of energy using high speed
brushes and blenders as described in the prior art.
[0160] A most preferred method of the invention provides a housing
in which is situated a pressurisable chamber. For sterile supply
purposes this will at least partly filled with a sterile and
pyrogen free solution of the sclerosing agent in a physiologically
acceptable aqueous solvent but otherwise may be charged with such
at the point of use. This convenient method provides a pathway by
which the solution may pass from the pressurisable chamber to
exterior of the housing through an outlet and more preferably a
mechanism by which the pathway from the chamber to the exterior can
be opened or closed such that, when the container is pressurized,
fluid will be forced along the pathway and through one or more
outlet orifices.
[0161] The method is particularly characterized in that the housing
incorporates one or more of (a) a pressurized source of the
physiologically acceptable gas that is readily dispersible in
blood, and (b) an inlet for the admission of a source of said gas;
the gas being contacted with the solution on activation of the
mechanism.
[0162] The gas and solution are caused to pass along the pathway to
the exterior of the housing through the one or more, preferably
multiple, passages of defined dimension above, through which the
solution and gas must pass to reach the exterior, whereby on
contact with, e.g. flow through, the passages the solution and gas
form a foam.
[0163] Preferably the gas and liquid pass through a gas liquid
interface mechanism, typically being a junction between a passage
and one or more adjoining passages, and are converted to an
aerosol, dispersion of bubbles or macrofoam before passing through
the passages, but as explained they may be converted first to a
macrofoam, e.g. by shaking of the device, e.g., by hand, or
mechanical shaking device.
[0164] In another aspect of the present invention there is provided
a device for producing a foam 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
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
pressurized and the pathway is open, fluid will be forced along the
pathway and through the one or more outlet orifices
[0165] said housing incorporating one or more of (a) a pressurized
source of physiologically acceptable gas that is dispersible in
blood and (b) an inlet for the admission of said gas; the gas being
in contacted with the solution on activation of the mechanism such
as to produce a gas solution mixture
[0166] said pathway to the exterior of the housing including one or
more elements defining one or more passages of cross sectional
dimension, preferably diameter, 0.1 .mu.m to 15 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
foam of from 0.07 to 0.19 g/mL density and of half-life at least 2
minutes.
[0167] Preferably the apparatus includes a chamber, e.g. such as in
a sealed canister, charged with the blood dispersible gas and the
sclerosant liquid, e.g. in a single chamber, the device pathway
including a dip tube with an inlet opening under the level of the
liquid in this chamber when the device is positioned upright.
Preferably the dip-tube has an outlet opening at a gas liquid
interface junction where the gas, which resides in the chamber
above the liquid, has access to the pathway to the device outlet.
The pathway is opened or closed by a valve element which is
depressed or tilted to open up a pathway to the exterior of the
device, whereby the liquid rises up the dip tube under gas pressure
and is mixed in the interface junction with that gas to produce an
aerosol, dispersion of bubbles in liquid or macrofoam.
[0168] 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.
[0169] In an alternate embodiment of this device the gas liquid
interface may comprise holes in the dip tube above the level of the
liquid in the canister inner chamber.
[0170] 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 1.5-1.7 bar over atmospheric
pressure.
[0171] A preferred device of this aspect of the invention is of the
tag-on-valve' type. Such device includes a flexible gas and liquid
tight container, forming a second inner chamber within the
pressurisable chamber, which is sealed around the dip-tube and
filled with the liquid. More preferably the dip-tube has a one-way
valve located at a position between its end located in the
sclerosant liquid and the gas liquid interface junction, which when
the passage to the exterior is closed, remains closed such as to
separate the liquid from the physiologically acceptable blood
dispersible gas around it in the chamber. On opening the pathway to
the exterior, the one way valve also opens and releases liquid up
the dip-tube to the gas liquid interface where an aerosol is
produced which is in turn then passed through the passages to be
converted to foam. A suitable one-way valve is a duck-bill type
valve, e.g. such as available from Vernay Labs Inc, Yellow Springs,
Ohio, USA. Suitable bag-on-valve can constructions are available
from Coster Aerosols, Stevenage, UK and comprise an aluminium
foil/plastics laminate.
[0172] Conveniently the one way valve is located at the top of the
dip-tube between that and the gas liquid interface junction, i.e.
an Ecosol device. This allows filling of the bag before application
of the one way valve, followed by sterilization of the contents,
whether in the canister or otherwise.
[0173] Such a preferred device has several potential advantages.
Where oxygen is the gas, this is kept separate from the liquid
before use and thus reduces possibility of oxygen radicals reacting
with organic components in the liquid, e.g. during sterilization
processes such as irradiation. Where carbon dioxide is the gas,
storage can lead to high volumes of gas dissolving in the liquid,
which on release to the atmosphere or lower pressure, could out-gas
and start to destroy the foam too quickly. Such separation also
prevents the deposition of solidified sclerosing agent components
in the dimension sensitive orifices of the device in an unused can
in storage or transit, particularly should that be oriented other
than upright.
[0174] It is preferred that the gas liquid interface is provided as
a defined orifice size device such as the Ecosol device provided by
Precision Valve Peterborough UK. For a device where the passages of
defined dimension are outside of the pressurized chamber, i.e.
mounted on the valve stem, the ratio of area of the gas holes to
the liquid holes should be of the order of 3 to 5, preferably about
4. Where the passages are inside the pressurized chamber this is
preferably higher.
[0175] Another aspect of the invention provides a device for
producing a foam suitable for use in sclerotherapy of blood
vessels, particularly veins, comprising a housing in which is
situated a pressurisable chamber, at least part filled or fillable
with a solution of a sclerosing agent in a physiologically
acceptable solvent and/or a physiologically acceptable blood
dispersible gas; a pathway by which the contents of the chamber may
be passed to exterior of the housing through one or more outlet
orifices and a mechanism by which the chamber can be pressurized
such that its contents pass to the exterior along the pathway and
through one or more outlet orifices
[0176] said pathway to the exterior of the housing or the chamber
including one or more elements defining one or more passages of
cross sectional dimension, preferably diameter, 0.1 .mu.m to 15
.mu.m through which the contents of the chamber may be passed,
whereby on passing through the passages the solution and gas form a
foam of from 0.07 to 0.19 g/mL density and having a half-life of at
least 2 minutes.
[0177] The elements defining the passages in the pathway or chamber
may be static or may be moveable by manipulation of the device from
outside of its interior chamber.
[0178] Preferably the housing is a container defining a chamber in
which is situated the solution and gas under pressure and the
pathway is a conduit leading from the chamber in the interior of
the container to a valve closing an opening in the container
wall.
[0179] 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.
[0180] It is preferred that all elements of any of the devices
according to the invention having a critical dimension are made of
a material that does not change dimension when exposed to aqueous
material. Thus elements with such function such as the air liquid
interface and the element defining the passages of 0.1 .mu.m-15
.mu.m dimension preferably should not be of a water swellable
material such as Nylon 66 where they are likely to be exposed to
the solution for more than a few minutes. Where such exposure is
likely these parts are more preferably being fashioned from a
polyolefin such as polypropylene or polyethylene.
[0181] Preferably the canister is sized such that it contains
sufficient gas and solution to form up to 500 mL of foam, more
preferably from 1 mL up to 200 mL and most preferably from 10 to 60
mL of foam. 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. Thus
preferred canisters of the invention may be smaller than those
currently used for supply of domestic used mousse type foams. The
most preferred canister device is disposable after use, or cannot
be reused once opened such as to avoid problems of maintaining
sterility.
[0182] It may be preferred to incorporate a device which maintains
gas pressure in the canister as foam is expelled. Suitable devices
are such as described under trademarked devices PECAP and Atmosol.
However, where a significant headspace or pressure of gas is
provided this will not be necessary.
[0183] The canister system has some drawbacks, however. It is
relatively complex and thus expensive. Furthermore, the initial
quantity of foam generated using a canister system can be of
unpredictable quality and thus tends to be diverted off to waste
prior dispensing foam for use. It is not easy to deliver foam
direct from a pressurized canister into a cannula in a patient's
vein; although this is theoretically possible, it would require
special valve/control arrangements on the canister output to allow
for the delivery rate to be highly controllable by the clinician
administering the treatment. A further issue is that, whenever
dispensing of foam is stopped or slowed significantly, it is
necessary on re-starting to divert a quantity of foam to waste
again before dispensing usable foam.
[0184] For all these reasons, the canister product mentioned above,
though a well designed and highly effective system, is designed to
deliver foam product into a syringe for subsequent administration
to a patient. A special foam transfer unit is used for this
purpose. The syringe nozzle is inserted into a port on this
transfer device and the device is then used to divert the first
portion of foam before charging the syringe with usable foam.
[0185] A further issue is that the foam, once made, immediately
starts to change--liquid drains out and bubbles coalesce. A period
of time is required time for the clinician to divert an initial
quantity of foam from a canister, charge a syringe with good foam,
connect it to a line to a patient's vein and administer the foam.
This time will vary with different clinicians and even the same
clinician will not always take the same length of time.
Furthermore, each treatment is different and the foam will be
injected over a different period; sometimes the clinician will stop
dispensing foam for a short period and then recommence. All this
time, the properties of the foam will be changing.
[0186] There are other techniques for generating foam for use in
sclerotherapy, including the so called "Tessari" and "DSS"
techniques, each of which involves pumping liquid sclerosant and
gas between two syringes. These two techniques are widely used for
generating sclerosing foams made with air, and there are also a
number of other less widely used techniques. Although these
techniques are simpler than a canister system, they offer no
solutions to the problems mentioned above and they also have their
own problems such as unpredictability of the product and the
difficulty in using any gas other than ambient air.
[0187] The inventors realized that it would be desirable to have a
device which could be connected directly to the patient and would
generate foam as it was needed, so that the foam had the minimum
possible time to degrade before entering a patient's vein. Ideally
the device would also not have the problem of producing an initial
quantity of poor foam. The device should be suitable for containing
a gas other than air for incorporation into the foam.
[0188] The inventors also realized that, particularly for a highly
soluble gas, the device should ideally not store the gas together
with the liquid under a pressure substantially greater than
atmospheric. With a soluble gas, especially a highly soluble gas
such as carbon dioxide, storing the gas and liquid under pressure
can contribute to the speed of decay of the foam. This is because
the pressurised gas tends to go into solution in the sclerosant
liquid. On exit of the foam, the gas comes out of solution into the
bubbles thereby accelerating degradation of the foam. Pressurising
the gas also, of course, adds to the complexity and expense of the
system.
[0189] According to a first aspect of the invention, a device for
generating and dispensing foam for therapeutic use comprises:
[0190] (a) a housing; [0191] (b) the housing having a first chamber
of adjustable volume containing gas at substantially atmospheric
pressure; [0192] (c) the housing further having a second chamber of
adjustable volume containing sclerosant solution; [0193] (d) an
outlet for dispensing the liquid and sclerosant solution in the
form of a foam and a flow path communicating between the outlet and
the said first and second chambers; [0194] (e) the flow path
including a region in which mixing of the gas and solution takes
place; [0195] (f) a foaming unit located downstream of the mixing
region, the foaming unit having holes with a dimension transverse
to the flow direction of between 0.1 and 100 micron.
[0196] It is preferred that the hole dimension be from 1 to 50
micron, more preferably 2 to 20 micron, still more preferably 3 to
10 micron. These holes may be provided by a mesh, perforated
screen, sinter or fabric, for example. Although the shape and
orientation of the holes may not be regular, the unit should have a
major proportion (greater than 50%, preferably greater than 80%) of
holes where at least one dimension in a direction approximately
transverse to the flow should be in the ranges specified above.
[0197] In use, the volumes of the first and second chamber are
adjusted in order to drive the gas and solution out of the chambers
and through the mixing region and foaming unit. A mixture of gas
and solution is formed as the gas and liquid pass through the
mixing region and then a foam is formed as the mixture passes
through the foaming unit.
[0198] It is preferable for the liquid and gas to be driven through
the mixing region and foaming unit at a flow rate which falls
within a predetermined range, the desired flow rate range depending
on the characteristics of the liquid and of the gas, the
characteristics of the mixing region and foaming unit, and possibly
other characteristics of the system. The volume of the chambers may
be varied manually to create the foam, but it is preferred that the
adjustment of the chambers be carried out using some other source
of motive power, e.g. an electric, clockwork, pneumatic or
hydraulic motor or by the direct action of pressurized gas or even
a simple spring. An on/off control is preferably provided for the
user to commence and to stop delivery of foam.
[0199] The source of motive power may be provided as part of the
device. Alternatively, the device may be designed as a cartridge
for insertion into a delivery device which may for example be
similar to known devices for automatically delivering medication
from a syringe over an extended period of time.
[0200] The device may be configured with a flexible housing in form
of e.g. a bag with dual chambers, or two separate bags, connected
to a mixing region and foaming unit. The bag or bags may then be
rolled up in a delivery device or the contents squeezed out by some
other mechanical means. Desirably, the chambers are of a size and
shape which allow them to be squeezed out at the same rate, in
terms of velocity, to achieve a desired foam density. This allows
the mechanical means for squeezing the chambers to be of a more
simple design.
[0201] Alternatively the device may be configured as a syringe,
with the first and second chambers having respective plungers which
may be depressed in order to expel the contents. Preferably size
and shape of the chambers, most notably their cross sectional
areas, are selected so that the plungers may be driven at the same
speed to achieve a desired ratio of gas to liquid in the foam.
[0202] As discussed above, the device may be suitable for
connection to a cannula needle, optionally via a line, for delivery
of foam into the body, e.g. into a vessel such as a blood vessel,
especially a varicose vein or other venous malformation. Since the
foam is generated by the same action which expels the foam from the
outlet, it may be possible to connect the cannula to the outlet of
the device and administer foam to a patient at the same time as
generating it. This is clearly a much simpler procedure than
generating the foam, drawing it up into a syringe, connecting the
syringe to a line/cannula and then administering the foam.
[0203] According to the invention, a method for administering a
foam to the human body, e.g. into a vessel such as a blood vessel,
especially a varicose vein or other venous malformation, comprises
the steps of: (a) schlerosant foam generating device to a cannula
needle inserted into a patient; and (b) operating the device to
generate and dispense foam to the patient. Specifically, the steps
may include: [0204] (a) connecting a device as described above to a
cannula needle inserted into a patient; [0205] (b) adjusting the
volume of the said first and second chambers so as to generate and
deliver foam to the patient.
[0206] A further advantage of the generation and delivery of the
foam in a single step is that the foam has very little time to
degrade prior to entering the body to perform its function, e.g.
the sclerosis of a varicose vein. The device is therefore
particularly suitable for generating foams with very soluble gases,
such as carbon dioxide or nitrous oxide, which tend to revert to
their gaseous and liquid phases relatively quickly.
[0207] Since the gas and liquid are stored in separate chambers
until formation of the foam, there is very little possibility for
the gas to become dissolved in the liquid, which tends to happen
with the pressurized canister systems described in the prior
art.
[0208] According to the invention, a foam is provided which is made
with a sclerosant solution, e.g. polidocanol solution, and a gas,
wherein, on creation of the foam, the dissolved level of the gas in
the solution is not substantially higher than that of the solution
when exposed to atmosphere at s.t.p., and wherein the gas is at
least 70% by volume carbon dioxide, more preferably at least 90%
carbon dioxide, still more preferably substantially 100% carbon
dioxide. The gas may also include 0.1 to 50% oxygen. Alternatively
the gas may be substantially 100% nitrous oxide or a mixture of
nitrous oxide and carbon dioxide.
[0209] Also according to the invention, a device is provided for
generating foam from a sclerosant liquid, e.g. polidocanol
solution, and a soluble gas as described above, wherein the device
incorporates a chamber in which the gas is stored at substantially
atmospheric pressure. Preferably, the device further comprises a
chamber in which sclerosant liquid is stored. Preferably, the
device further includes a foaming unit for creating a foam from the
gas and sclerosant liquid, the foaming unit having holes with a
dimension transverse to the flow direction of between 0.1 and 100
micron, such as 1 to 50, 2 to 20, 3 toll, and especially about
5.
[0210] Further features and advantages of the invention will be
apparent from the following description of various specific
embodiments, which is made with reference to the accompanying
drawings.
[0211] One embodiment of a device according to the invention
comprises a syringe type device comprising a syringe barrel having
an annular chamber containing gas and a central chamber for
receiving a cartridge of sclerosant solution, e.g. 1% polidocanol
solution. FIG. 1 shows a syringe barrel 1 in a storage condition
with its open ends closed with seals 2 of metal/plastic laminate
material. The barrel 1 comprises an outer cylindrical wall 3 having
a conical tapered end portion 4 at the front, from which extends a
standard luer nozzle 5. Disposed within the outer cylindrical wall
is an inner cylindrical wall 6 defining an inner chamber 14. The
front of the inner wall 6 is partly closed by and end face 8, in
which is formed an orifice 9 with a frangible seal 10. The inner
wall is supported at the front end by a web 11, in which apertures
12 are formed.
[0212] The outer and inner walls 3, 6 define between them an
annular space 7 which is filled with substantially 100% pure carbon
dioxide gas. The annular space 7 communicates with the interior
space of the luer nozzle 5 via the apertures 12 in the web 11.
Located at the rear of the barrel, in the annular space 7, is an
annular plunger seal 13 of resilient plastics material which seals
against the outer and inner cylindrical walls 3, 6.
[0213] FIG. 2 shows a cartridge comprising a glass tube 20 filled
with 1% polidocanol and sealed at each end by a resilient plastics
bung 21. One or both of the bungs may function as a plunger seal,
that is to say it may be movable down the length of the tube whilst
retaining a sealing contain with the interior wall of the tube. The
cartridge of FIG. 2 is not suitable for use with the syringe barrel
described above, but could be used with a modified version of the
barrel as discussed below.
[0214] FIG. 3 shows a cartridge suitable for use with the syringe
barrel described above with reference to FIG. 1. The cartridge
comprises a glass tube 30 which is filled with 1% polidocanol
solution. At the rear end of the tube 30 is a resilient bung 31
which is capable of functioning as a plunger seal as described
above. At the front end of the tube is an end face 32 in which is
located a nozzle 33, sealed with an end cap 34. The size and shape
of the tube 30 complements the shape of the inner wall 6 of the
syringe barrel of FIG. 1. In particular, the diameter of the tube
30 is such that the tube is a close fit in the interior space 14
defined within the inner wall 6 of the barrel 1, and the nozzle 33
of the cartridge is sized so that, when fully inserted into the
interior chamber 14 of the barrel, it protrudes through the orifice
9 in the front of the chamber 14 (the end cap 34 having first been
removed).
[0215] Cartridges of the type shown in FIGS. 2 and 3 are well known
for liquid drugs. The cartridges are fitted to specially designed
injection devices to administer the drug, and the empty cartridge
then removed from the device and disposed of.
[0216] FIG. 4 shows a cartridge 30 as shown in FIG. 3 being
inserted into the barrel of FIG. 1. Note that the end cap 34 of the
cartridge has been removed.
[0217] FIG. 5 shows the cartridge 30 fully inserted into the barrel
1 such that the nozzle 32 seals in the orifice 9 of the interior
chamber 14 of the barrel. A syringe plunger stem 40 is fitted to
the rear of the syringe barrel 1.
[0218] The plunger stem 40 comprises a disc 43 for applying manual
pressure, connected via shafts 44 to a central disc shaped pressure
pad 41 and an annular pressure pad 42. The pressure pads 41, 42 are
engaged with bungs/plunger seals 31, 13, respectively, of the
annular barrel chamber 7 and of the cartridge 30.
[0219] At the front of the barrel 1, a foaming unit 50 is fitted to
the luer nozzle 5. The foaming unit comprises a stack of mesh
elements with microscopic perforations. The foaming unit will be
described in more detail below in relation to FIGS. 11, 12 and
13.
[0220] In use, the plunger stem 40 is depressed either manually or
in a syringe driver such as the one shown schematically in FIG. 8
and discussed below. The syringe with partly depressed plunger stem
and foaming unit fitted is shown in FIG. 6. The plunger seals 13,
31 in the annular carbon dioxide chamber and in the chamber defined
within the cartridge are advanced as the plunger stem is depressed,
thereby driving carbon dioxide and polidocanol solution through the
apertures 12 and the orifice 9. Mixing of the gas and liquid takes
place in the region 15 in front of the orifice 9 where the annular
gas flow interacts with the liquid flow. The mixture then proceeds
as indicated by arrow A in FIG. 6 through the syringe nozzle 5 into
the foaming unit 50 where the gas and liquid are passed through
microscopic perforations of average dimension 5 micron to create a
fine foam or foam with an average bubble size of around 100
micron.
[0221] FIG. 7 shows an alternative syringe-based design. A syringe
barrel 101 houses twin parallel gas and liquid chambers 107, 114
which receive respective cartridges 170, 120 of the type shown in
FIG. 2 with resilient bungs 171a, 171b, 121a, 121b at each end. The
gas chamber 107 contains cartridge 170 which is filled with
substantially 100% pure carbon dioxide at substantially atmospheric
pressure. The liquid chamber 114 contains cartridge 120 which is
filled with 1% polidocanol solution.
[0222] At the rear end of the barrel 101 a plunger stem is fitted,
comprising a disc 143 for applying manual pressure, connected via
shafts 144 to two disc shaped pressure pads 41, 42 received within
the gas and liquid chambers 107, 114 respectively.
[0223] At the front end of the syringe barrel is an end wall 104
from which projects a cylindrical hub 116 with a nozzle 105 at the
end. Within the hub 116 is a mixing chamber or mixing region 115.
In this region are located static mixing fins 117. Located at the
front of the chambers 107, 114 are hollow needle-like members 118,
119 respectively, each with a point 118a, 119a facing into the
respective chamber. Each needle-like member is contoured to lie
along the front face of its respective chamber and to extend into
the mixing chamber 115.
[0224] Fitted to the nozzle 105 of the syringe is a foaming unit 50
of similar design to that used in the device of FIGS. 1 to 6. The
foaming unit will be described more fully below with reference to
FIGS. 11-13.
[0225] The syringe is supplied with cartridges 120, 170 pre-fitted.
A clip 119 prevents depression of the plunger stem 140 until the
clip is removed immediately prior to use. When it is desired to use
the syringe, the clip 119 is removed and the plunger manually
depressed so that the cartridges 120, 170, which are a snug fit in
their respective chambers 114, 107, are advanced into contact with
the needle elements 119, 118 respectively. Further depression of
the plunger stem 140 causes the needle points 119a, 118a to
penetrate the resilient bungs 121a, 171a at the front of the
cartridges, thereby opening a communication channel between the
interior of the cartridges and the mixing chamber 115.
[0226] Further depression of the plunger stem 140 causes carbon
dioxide and polidocanol solution to flow together into the mixing
chamber, in a ratio predetermined by the cross-sectional areas of
the cartridges. Fins 117 in the mixing chamber ensure that the gas
and liquid are thoroughly mixed prior to entering the foaming unit
50 where the liquid and gas is converted into a foam.
[0227] When treating a patient, the clinician would go through the
above steps and ensure that consistent foam is being discharged
from the foaming unit 50. Pressure is then released from the
plunger stem 140 and a line from a cannula, which has previously
been inserted into a vein to be treated, is connected by a standard
luer fitting to the exit of the foaming unit. Pressure would then
be applied again to the plunger stem 140 to produce foam and at the
same time inject it through the line and cannula and into the
patient's vein.
[0228] The exact properties of the foam will depend to some extent
on the speed at which the plunger stem 140 is depressed. For this
reason it is preferable that a syringe driver is used to administer
the foam. A syringe driver is shown schematically in FIG. 8, with
the syringe of FIG. 7 fitted in it. The driver 200 comprises a base
201, syringe clamp 202 and motor 204 fitted in a motor mounting
203. The motor 204 is coupled via a coupling 209 to a drive shaft
206 having an external thread 210. Received on the drive shaft is
annular member 207 having an internal thread 211 engaged with the
external thread 210 of the drive shaft. From the annular member 207
extends a driving member which bears on the plunger stem 140 of the
syringe which is clamped in the syringe clamp 202.
[0229] The motor is connected to a DC power supply 212, has a speed
calibration control 209 for setting the correct drive speed, and
also an on/off control 205.
[0230] In use, the clinician would remove the clip 119 from the
syringe of FIG. 7, depress the plunger stem 140 to the point where
consistent foam is being produced, then insert the syringe into the
driver and connect up to a line 80 previously installed in a
patient's vein. The speed of the motor 204 would previously have
been calibrated to a speed appropriate for the syringe being used.
The clinician then has control of the delivery of foam to the
patient by means of the on/off switch.
[0231] As short a line as possible is used, so that a very small
quantity of foam resides in the line when the motor is switched
off. In this way, it is ensured that almost all the foam delivered
to the patient has been generated only a few moments previously and
has had very little opportunity to degrade.
[0232] FIGS. 9 and 10 show an alternative embodiment 300 of foam
generating and dispensing device. This embodiment is based on a bag
301 of metal/plastics laminate material. In the bag are located
chambers 302, 303 separated by ultrasonically welded seams 310. The
chambers 302, 303 contain carbon dioxide and 1% polidocanol
solution respectively. The chambers are disposed in parallel along
substantially the whole length of the bag, and the cross sections
of the chambers, when filled, is selected so as to ensure a correct
gas/air mix as with the syringe embodiments. Each chamber 302, 303
has a channel 304, 305 leading to a mixing region or mixing chamber
306 defined within a housing 307. On the front of the housing 307
is a luer nozzle 308, to which is fitted a foaming unit 50 as with
previous embodiments. Within the mixing chamber 306 are located
mixing fins 311.
[0233] At the rear of the bag 301 is a relatively stiff rod 309. In
use, the bag 301 is rolled around the rod 309 to expel gas and
liquid from the chambers 302, 303 respectively. As with previous
embodiments, the gas and liquid enter the mixing chamber where they
are well mixed before entering the foaming unit 50 and being
converted to foam of preset density.
[0234] As with the other embodiments, the bag is preferably used
with a driver device such as is shown schematically in FIG. 10. In
FIG. 10 the bag 301 can be seen in side view, held in place on a
movable carriage 321, slidably mounted on a base plate 320. The
rear of the bag 301 is clamped by a bag clamp 322 at the rear of
the carriage 321; the rod 309 in this situation serves to help
prevent the bag slipping through the clamp. The mixing chamber
housing 307 at the front of the bag is clamped in a mixing chamber
clamp 323 at the front of the carriage 321.
[0235] To set up the driver, the carriage, complete with bag, is
slid sideways under a roller 324 mounted on the base plate 320. In
order to do this, the bag is manually depressed at the rear end,
adjacent the rod 309 to allow it to fit under the roller 324.
[0236] The roller 324 is driven by an electric motor 325 supplied
from a DC power supply 326. The speed of the motor may be
calibrated using speed control 327 and stopped and started using
on/off switch 328.
[0237] On starting the motor, the roller rotates in the sense
indicated by arrow B, causing the carriage, complete with bag, to
slide under the roller. Gas and liquid contained in the bag is
thereby forced through the mixing chamber 306 and foaming unit 50,
and out of an exit of the foaming unit.
[0238] As with the previous embodiments, the clinician would ensure
that consistent foam is being produced before connecting up a line
80 to a cannula installed in a patient's vein.
[0239] Referring now to FIGS. 11 to 13, the foaming unit comprises
four mesh elements, each comprising a ring 51 having a mesh 52
secured across it. The mesh has perforations of diameter
approximately 5 micron. Each mesh element has male and female
sealing surfaces 53, 54 respectively--these are best seen in FIG.
12.
[0240] FIG. 13 shows four mesh elements stacked together such that
the male sealing surface of one element engages the female surface
of the element next to it. The elements are retained in housing 55
having a socket half 56 and a nozzle half 57. Between these halves
of the housing, the mesh elements are retained under pressure, with
the sealing surfaces 53, 54 engaging with each other and with the
interior of the housing 55 at each end. In this way a good seal is
created between the mesh elements, so that all flow through the
foaming unit must pass through the mesh.
[0241] The socket end 56 of the housing is formed with a standard
luer socket 58 which, in use, fits over the luer nozzle output of
the various devices described above. The nozzle end 57 of the
housing incorporates a standard luer nozzle 59 onto which a medical
line having a standard luer socket may be fitted.
[0242] Alternatives to the mesh elements described are
contemplated: anything which provides pores, perforations,
interstices, etc with a dimension in a direction approximately
transverse to the direction of flow of between 0.1 micron and 100
micron may be suitable. Examples might include a fabric, perforated
screen or sinter.
[0243] The following examples are provided in support of the
inventive concepts described herein.
[0244] 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.
Example 1
[0245] 10 patients were treated for varicose veins by injection of
foam made with 1% polidocanol solution and a gas mix consisting
essentially of 7-8% nitrogen and the remainder carbon dioxide
(about 22%) and oxygen (about 70%).
[0246] The procedure involved the injection of up to 30 ml of foam
(25.5 ml gas) into the thigh section of the greater saphenous vein.
4-chamber cardiac ultrasound examinations were conducted on all the
patients to test for bubbles reaching the heart. Bubbles were
observed in the right atria and ventricles of all 10 patients
examined. In general, bubbles appeared several minutes following
injection of the foam and continued until the ultrasound recording
was stopped about 40 minutes after injection.
[0247] In one patient, microbubbles were observed in the left
atrium and ventricle. This patient was subsequently confirmed to
have a patent foramen ovale.
Example 2
[0248] The objective of this experiment was to investigate the
nature of the residual bubbles that pass into the heart following
injection into the saphenous vein of polidocanol foam made with
different gas mixtures.
[0249] An anaesthetised female hound dog weighing 26 kg was
injected with foam containing polidocanol formulated with varying
gas mixes. Residual bubbles were monitored in the pulmonary artery
using transoesophageal echocardiogram (TEE). Residual bubbles
visualised on TEE were sampled from the pulmonary artery through a
wide-bore catheter. These blood samples were analysed for the
presence of residual bubbles using light microscopy and
ultrasound.
[0250] Three different compositions of foam were used, as
follows:
[0251] 1% polidocanol and air
[0252] 1% polidocanol and a gas mix consisting of 7-8% nitrogen and
the remainder carbon dioxide and oxygen
[0253] 1% polidocanol solution and a gas mix comprising less than
1% nitrogen and the remainder carbon dioxide and oxygen.
[0254] The TEE output was videotaped and subsequently analysed. For
all three compositions, bubbles reached the pulmonary artery in
sufficient quantity to cause a substantially opaque image. It is
believed that the threshold bubble density required to produce such
an image as quite low, and therefore this image in itself did not
provide useful data. The time taken for the occluded image to
revert to a steady state background image was believed to be
approximately indicative of the length of time taken for all or
most the bubbles to have dissolved into the bloodstream. The TEE
was very sensitive (showing activity even when saline was injected
as a control); for this reason exact end points were difficult to
determine. However, the following estimates have been made of the
time period from opacification of the image to decay down to a
background level.
[0255] 4 minutes
[0256] 2 minutes
[0257] 20 seconds.
[0258] In addition to the TEE analysis, observations were made of
samples of blood drawn from the pulmonary artery for each foam
during the period when the TEE image was substantially opaque. The
results of these observations were as follows.
[0259] As soon as the sample was taken, a considerable volume of
bubbles was observed in the syringe. When the syringe was held with
its longitudinal axis horizontal, a continuous strip of bubbles was
observed extending substantially the full length of the 20 ml
syringe.
[0260] Initially on taking the sample no bubbles were observed in
the syringe, but after a few seconds, with the syringe in the
horizontal position, a line of bubbles appeared which was thinner
than the line observed for foam A.
[0261] After taking the sample and holding the syringe in the
horizontal position, no bubbles were observed for a period of a
minute or more. Gradually, a thin line of bubbles began to appear
along the top of the syringe.
[0262] It was not possible to measure the bubbles, but they
appeared to be smaller for composition C than for composition B,
with the bubbles from composition B in turn smaller than those from
composition A.
Example 3
[0263] In vitro experiments were conducted to determine the
absorption of foam made with different gases in fresh human venous
blood.
[0264] A 20 ml polypropylene syringe barrel was prepared by
puncturing its side wall with a relatively large hypodermic needle
to make a hole approximately 1 mm in diameter. This hole was then
covered by securing a piece of clear flexible vinyl sheet over it
with clear adhesive tape. A small magnetic stirrer element was
introduced into the syringe barrel and the plunger then replaced.
20 ml of human venous blood was then with withdrawn in the usual
manner from a human subject using the specially prepared syringe
fitted with a hypodermic needle.
[0265] The hypodermic needle was removed and the syringe then
placed on a magnetic stirrer unit so that the magnetic element in
the syringe thoroughly agitated the blood. The Luer nozzle of the
syringe was then connected to a 50 cm piece of manometer tubing
which was arranged horizontally and left open at one end. The
manometer tubing was secured against a scale.
[0266] A 0.5 ml measuring syringe with a fine pre-fitted needle was
then filled with foam made from 1% polidocanol solution and air.
The density of the foam was 0.13 g/ml (.+-.0.03 g/ml), the liquid
component making up approximately 13% of the total volume of foam
(.+-.3%).
[0267] The needle of the 0.5 ml syringe was then introduced through
the vinyl sheet on the side wall of the 20 ml syringe. A small
volume of blood was found to have entered the manometer tubing and
the position of the distal end of this column of blood was noted
against the scale. The 0.5 ml aliquot of foam was then injected
quickly and simultaneously a timer started (t0). As the foam
displaced blood in the 20 ml syringe, the column of blood from the
20 ml syringe was displaced into the manometer tubing and the
distance along the tubing reached by the distal end of the blood
column was noted against the scale. The scale itself comprised
spaced marker lines equally spaced at about 1 cm intervals. It was
determined that a distance of 45 intervals on this scale
corresponded to an internal volume of in the manometer tubing of
approximately 0.5 ml.
[0268] As the gas in the foam started to be absorbed by the blood,
the blood in the manometer tubing started to recede back towards
the syringe. After the column appeared to have stopped moving, the
timer was stopped (tF). The position of the distal end was again
noted.
[0269] This experiment was then repeated for a foam of the same
density but made with oxygen gas ("medical grade" purity--99.5%
minimum).
[0270] The experiment was repeated again but this time oxygen gas
from a cylinder of medical grade oxygen was introduced directly
into the 0.5 ml syringe instead of foam.
[0271] The results of these three tests are presented below in
Table 1
TABLE-US-00001 TABLE 1 Test Foam/ gas Start position of blood ("x")
Position of blood at t.sub.0 ("y") t.sub.F (seconds) Position of
blood at t.sub.F ("z") Absorbed volume at t F ( ml ) 0.5 ( y - z )
( y - x ) ##EQU00001## Liquid Volume in foam (ml) Unabsorbed gas ml
% 1 Air 2 47 80* 40 0.08 0.13 .times. 0.35 81% foam 0.5 = 0.07 2
Oxygen 4 48 140 11 0.42 0.13 .times. 0.01 2% foam 0.5 = 0.07 Oxygen
2 47 140 5.5 0.46 nil 0.04 8% 3 gas *No further movement of the
blood column was observed after 80 seconds.
[0272] The experimental error in this example is unfortunately too
great to conclude whether there is or is not a residual volume of
gas for the oxygen gas or oxygen foam, although clearly the great
majority at least of the gas is absorbed. There will have been a
small percentage of nitrogen in the gas, from the oxygen cylinder
which is only 99.5% pure, and possibly also introduced during the
experiment. Diffusion of nitrogen into the bubbles from the blood
is also a possibility, as discussed above, and some nitrogen may
have been introduced inadvertently during the procedure.
[0273] In this experiment, the air foam test was only observed for
a few minutes after tF. However, further experiments have been
conducted by the inventors, the results of which are not formally
recorded here, involving foam with a percentage of nitrogen. A 20
ml syringe of fresh human venous blood, as in the above
experiments, was injected with a 0.5 ml aliquot of a foam
containing a percentage of nitrogen. The contents of the syringe
were agitated as above and a period of 24 hours allowed to elapse.
An easily visible volume of bubbles remained in the syringe.
Example 4
Preparation of Ultra-Low Nitrogen Canister
[0274] An anodised aluminium canister with an open top was filled
with water. The canister was then immersed in a bath of water and
inverted. A line from a pressurised cylinder of oxygen gas was then
introduced into the water bath and the supply of oxygen turned on,
thereby flushing the line of any air. A canister head assembly
comprising a valve, dip tube and mesh stack unit was then immersed
in the water bath and connected to the oxygen line for a few
seconds to purge air from the assembly.
[0275] The oxygen line was then introduced into the inverted
canister until all water had been displaced from the canister. The
line was then removed from the canister and the previously purged
head assembly quickly clamped over the top of the canister thereby
sealing the canister. The canister was then removed from the water
bath with the head assembly still clamped against it; the head
assembly was then secured to the canister using a standard crimping
technique.
[0276] The canister was then pressurised to about 8 bar absolute
pressure by connecting the canister valve to a regulated oxygen
line for 1 minute. The pressure as then relieved by opening the
valve until the pressure in the canister was just above 1 bar
absolute; a pressure gauge was applied to the valve intermittently
during the pressure release operation to ensure that the canister
pressure did not drop all the way down to 1 bar absolute. This was
done to avoid the possibility of atmospheric air seeping into the
canister.
[0277] The canister was then pressurised again up to about 8 bar
absolute and the pressure release operation repeated. This process
was then repeated a third time, with the final canister pressure
being from 1.1 to 1.2 bar absolute.
[0278] 18 ml 1% polidocanol solution was then introduced through
the canister valve using a syringe with all air pockets, including
any air in the luer nozzle, removed. The canister valve was then
connected to a carbon dioxide cylinder and pressurised to 2.2 bar
absolute. Then the oxygen line was again connected to the valve and
the pressure increased to 3.6 bar absolute.
[0279] Table 2 below shows the expected result from the oxygen
pressurising and depressurising cycles, assuming 100% pure oxygen
in the cylinder and assuming that despite the precautions taken 1%
of the gas in the canister after the initial oxygen filling
procedure is nitrogen. The worst case is assumed for the canister
pressure values, namely 1.2 bar absolute ("bara") and 7.6 bara.
TABLE-US-00002 TABLE 2 N2 partial pressure Canister pressure (bara)
(bara) % N2 Start 0.012 1.2 1% 1.sup.st cycle 0.012 7.6 0.16%
0.00189 1.2 0.16% 2.sup.nd cycle 0.00189 7.6 0.02% 0.000299 1.2
0.02% 3.sup.rd cycle 0.000299 7.6 0.00% 0.0000472 1.2 0.00%
[0280] As can be seen the percentage of nitrogen drops down to
zero, calculated to two decimal places, after the three oxygen
pressure/release cycles.
[0281] The oxygen cylinder used in the above process was a standard
medical grade oxygen cylinder supplied by B.O.C. and specified at
99.5% or greater purity. The carbon dioxide cylinder used was so
called "CP Grade" from B.O.C. which has a purity level of
99.995%.
[0282] Working to two decimal places, the impurity (which will be
mainly nitrogen) arising from the initial filling procedure should
be reduced to zero after three pressure/release cycles. Similarly
the impurity level in the canister from the carbon dioxide cylinder
can be considered zero to two decimal places, since the purity of
the source was 99.995% and only approximately one third of the gas
in the finished canister was carbon dioxide.
[0283] The inventors will perform further experiments along the
above lines using oxygen and carbon dioxide sources of higher
purity. The following cylinder oxygen is readily available from
B.O.C.:
[0284] "Medical grade" 99.5% purity (as used in the above
procedure)
[0285] "Zero grade" 99.6% purity
[0286] "N5.0 grade" 99.999% purity
[0287] "N5.5 grade" 99.9995% purity
[0288] "N6.0 grade" 99.9999% purity
[0289] In each case the impurity is mainly nitrogen.
[0290] The following cylinder carbon dioxide products are readily
available from B.O.C. They have the following specifications:
[0291] "CP grade N4.5" 99.995% purity (as used in the above
procedure)
[0292] "Research grade N5.0" 99.999% purity.
[0293] It will be appreciated that repeating the procedure
described above using "Zero grade" oxygen would result in a
finished canister having maximum impurity (which will be mainly
nitrogen) of 0.4%.
[0294] Of course the number of pressure/release cycles may be
increased in order further to reduce the theoretical maximum
impurity if the oxygen and carbon dioxide sources were 100% pure.
It is a simple calculation to show the number of cycles necessary
to reduce the maximum percentage impurity level to zero, calculated
to 3, 4 or 5 decimal places. Provided the canister pressure never
drops to or below 1 bar absolute and provided the lines from the
oxygen and carbon dioxide cylinders are flushed through with gas
prior to attachment to the canister valve, there is no reason to
assume that any significant impurity will enter the canister during
the pressure/release cycles.
[0295] A refinement of the procedure to reduce further any
opportunity for impurity to enter would be to introduce the
polidocanol solution immediately after initial flushing. In this
way, any air/nitrogen introduced with the polidocanol will be
eliminated during the subsequent pressure/release cycles.
[0296] A further refinement of the technique might be to maintain
the water bath in an agitated state using a magnetic stirrer, under
a continuously refreshed oxygen atmosphere for 24 hours. In this
way, any dissolved nitrogen in the water bath should be eliminated
and replaced with dissolved oxygen. Filling the canister from this
oxygenated water bath should, it is postulated, remove the water
bath as a possible source of nitrogen impurity.
[0297] It is envisaged that five, ten, twenty or even 100
pressure/release cycles could be performed.
[0298] In this manner, using appropriate sources of oxygen and
carbon dioxide as detailed above, it will be possible to make a
canister charged with polidocanol and an oxygen and carbon dioxide
mix having a percentage impurity of 0.005% or less (mainly
nitrogen) using CP grade carbon dioxide or 0.001% or less using
research grade carbon dioxide. It should also be possible to make a
polidocanol and oxygen canister with a percentage impurity of
nitrogen gas of 0.0001% or less using N6.0 grade oxygen.
[0299] It will of course be appreciated that the production of
canisters in this way having a somewhat higher minimum nitrogen
level is not difficult and may be achieved, for example, by
reducing the number of pressure/release cycles.
[0300] It will also of course be appreciated that substitution of
polidocanol by an alternative liquid component would be a trivial
matter.
Example 5
Preparation of Ultra-Low Nitrogen Canister
[0301] The inventors are at present developing a procedure for
large scale manufacture of ultra-low nitrogen canisters, using a
similar methodology. In this procedure, two canisters are
manufactured, one containing oxygen at 5.8 bar absolute and the
other carbon dioxide and polidocanol solution at about 1.2 bar
absolute. In use, the CO2/polidocanol canister is pressurised
immediately prior to use by connecting it to the oxygen canister.
This is described in WO 02/41872-A1[CDE10].
[0302] There is therefore a separate manufacturing procedure for
the oxygen and carbon dioxide/polidocanol canisters. However, it
will be apparent that either procedure is applicable to production
of a single canister product containing polidocanol and oxygen,
carbon dioxide or a mix of the two.
[0303] The procedure will be described first for an oxygen
canister, which is simply an anodised aluminium canister with a
standard valve assembly in the top. Prior to fitting the valve
assembly, the canister is first flushed with oxygen gas by
inserting an oxygen line into the open top of an upright cylinder
for 10 seconds. The line is then withdrawn. At this stage not all
the air will have been eliminated and it is believed that the
nitrogen impurity level is around 5% or 6%; this has not been
measured specifically, but has been deduced from the measured
impurity level at a later stage in the procedure (see below). It is
not believed that flushing the canister for a longer period would
substantially change this value for nitrogen gas impurity.
[0304] The valve assembly is then loosely fitted and a filling head
brought into engagement around the top of the canister and valve
assembly so as to make a gas-tight seal against the canister wall.
Connected to the filling head is a line for oxygen. The canister is
then brought up to a pressure of approximately 5.5 bar absolute
(bara). Nitrogen gas impurity at this stage has been measured by
standard gas chromatography techniques to be about 1%.
[0305] At one stage it was thought to be acceptable to have the
nitrogen impurity level at around 1%, but following the results of
the clinical trial (Example 1), it has been determined that a lower
nitrogen content is desirable. For this reason, further steps have
been added to the procedure, as follows.
[0306] Maintaining the seal between the canister and filling head,
the contents of the canister are exhausted via the filling head
until the pressure in the canister is just over 1 bara. As with
Example 4 above, this is to prevent any potential ingress of
atmospheric air through the seal.
[0307] Maintaining the seal between the canister and filling head,
the pressure is then increased again to about 5.5 bara and again
this pressure is released down to just over 1 bara. The canister is
then brought up to its final pressure of 5.5 bara.+-.0.4 bara. At
this stage, the nitrogen gas impurity measured by gas
chromatography is about 0.2%.
[0308] It will be appreciated that each of the pressure/release
cycles should reduce the impurity due to residual air/nitrogen by a
factor of about 5 assuming no leakage. It is reasonable to assume
no leakage since a positive pressure is always maintained in the
canister. Assuming a 100% pure source of oxygen, the theoretical
nitrogen impurity after these three pressure/release cycles should
be around 0.05%. Since the measured nitrogen level is around 0.2%,
there is apparently either impurity in the line or nitrogen is
entering the sample during the measuring process. It can at least
be concluded that the impurity level is 0.2% or better.
[0309] It will be appreciated that polidocanol solution, or any
other liquid sclerosing agent, could be added into the canister
during the above procedure and the standard valve and dip tube
could be replaced with a unit including foam generating means such
as a small aperture mesh. In the final step, the pressure in the
canister may be brought up to whatever is required, e.g. around 3.5
bara. In this way, a final pressurised canister product containing
sclerosant and substantially pure oxygen could be made.
[0310] At present, the effects, including possible oxidising
effect, of storing polidocanol solution under pressurised oxygen
are not fully understood. Therefore, it is preferred at present to
have a two canister system in which the polidocanol solution is
stored under carbon dioxide and/or nitrogen.
[0311] In previous versions of the product (as used in Example 1),
the gas mix in the polidocanol canister was 25% nitrogen and 75%
carbon dioxide. The nitrogen was present in order to reduce the
deleterious effect of the highly soluble carbon dioxide on the
stability of the foam. In order to minimise both the carbon dioxide
and the nitrogen content of the foam, this canister was maintained
at 0.5 bara. This meant that, when the canister was connected to
the oxygen canister and the final pressure raised to about 3.5
bara, the nitrogen content reduced to around 7%.
[0312] It was then realised by the inventors that (1) the canister
needed to be maintained at above atmospheric pressure to avoid the
risk of contamination and (2) the percentage of nitrogen was too
high. A new design of can was produced in which the foam generating
mesh has smaller apertures--5 micron instead of 20 micron. Although
it was previously thought that differences in size at this level
would not have a significant effect on the foam, it was in fact
surprisingly found that this reduction in mesh pore size was just
sufficient to compensate for the increased percentage of carbon
dioxide which resulted from having substantially pure carbon
dioxide in the canister and also from maintaining it at just over 1
bara instead of 0.5 bara.
[0313] Using a polidocanol canister of this design, and an oxygen
canister as described above which is pressurised only once, the
resulting foam had a nitrogen impurity of around 1-2%.
[0314] The current procedure is to insert a carbon dioxide line
into the open top of a metal anodised canister for 10 seconds. The
line is then withdrawn. At this stage not all the air will have
been eliminated and it is believed that the nitrogen impurity level
is around 5% or 6%. It is not believed that flushing the canister
for a longer period would substantially change this value for
nitrogen gas impurity.
[0315] 18 ml of 1% polidocanol solution is then introduced into the
canister, a carbon dioxide line reintroduced and the canister
flushed again for a few seconds.
[0316] The head assembly, including dip tube, valve and foam
generating mesh unit, is then loosely fitted and a filling head
brought into engagement around the top of the canister and valve
assembly so as to make a gas-tight seal against the canister wall.
Connected to the filling head is a line for carbon dioxide. The
canister is then brought up to its pressure of approximately 1.2
bara. Nitrogen gas impurity at this stage has not yet been measured
but is expected to be in the region of 0.8%.
[0317] The final nitrogen impurity of a foam generated from the
charged polidocanol canister after it has been connected to the
oxygen canister to bring it up to about 3.5 bara, is given by:
(0.8.times.1.2+0.2.times.2.3)/3.5=0.4%
Example 6
[0318] A unit was prepared comprising a housing with ports at each
end formed as standard luer connections. Within the housing was an
internal pathway between the ports in which pathway four mesh
elements were installed such that flow between the ports was
required to flow through the meshes. The meshes had 5 micron
apertures.
[0319] 8 ml of 1% polidocanol solution was drawn up into a standard
20 ml syringe and this syringe then fitted to one port of the mesh
stack unit described above. A second 20 ml syringe was then taken
and 12 ml of air drawn up into it before fitting it to the other of
the two ports on the mesh stack unit. The internal volume of the
mesh stack unit was measured and determined to be essentially
negligible for these purposes, being 0.5 ml or less.
[0320] The air and polidocanol solution was then shuttled back and
forth between the syringes as fast as possible by hand for one
minute. The number of passes achieved was 15.
[0321] The resulting product was a white liquid of homogeneous
appearance with no visible bubbles. A sample of this liquid was
analysed for bubble size (see Example 9 below) and the results
tabulated below (Table 2).
TABLE-US-00003 TABLE 2 Bubble Frequency diameter (.mu.) Number of
bubbles Cumulative freq. (%) (%) 0-15 1420 28.4 28.4 15-30 1293
54.3 25.9 30-45 1230 78.9 24.6 45-60 819 95.3 16.4 60-75 219 99.7
4.4 75-90 15 100.0 0.3 90-105 0 100.0 0.0 105-120 0 100.0 0.0
120-135 0 100.0 0.0 Totals: 4996 100.0
Example 7
[0322] A similar experiment to Example 6 above was performed with a
housing containing 4 mesh units each comprising a 5 micron mesh.
This time, 10 ml of 1% polidocanol solution was drawn up in one 20
ml syringe and 10 ml of air drawn up in the other. The air and
polidocanol were shuttled back and forth as fast as possible by
hand for 2 minutes; 27 passes were achieved.
[0323] The resulting product was a white liquid of homogeneous
appearance with no visible bubbles. A sample of this liquid was
analysed for bubble size (see Example 9 below) and the results
shown in Table 3 below.
TABLE-US-00004 TABLE 3 Bubble Frequency diameter (.mu.) Number of
bubbles Cumulative freq. (%) (%) 0-15 2387 47.8 47.8 15-30 1293
73.7 25.9 30-45 969 93.1 19.4 45-60 309 99.2 6.2 60-75 32 99.9 0.6
75-90 4 100.0 0.1 90-105 2 100.0 0.0 105-120 0 100.0 0.0 120-135 0
100.0 0.0 Totals: 4996 100.0
Example 8
[0324] A similar experiment to Examples 6 and 7 above was performed
with a housing containing 4 mesh units each comprising an 11 micron
mesh. 8 ml of 1% polidocanol solution was drawn up in one 20 ml
syringe and 12 ml of air drawn up in the other. The air and
polidocanol were shuttled back and forth as fast as possible by
hand for 1 minute; 25 passes were achieved.
[0325] The resulting product was a white liquid of homogeneous
appearance with no visible bubbles. A sample of this liquid was
analysed for bubble size (see example 9 below) and the results
shown in Table 4 below.
TABLE-US-00005 TABLE 4 Bubble Frequency diameter (.mu.) Number of
bubbles Cumulative freq. (%) (%) 0-15 620 12.4 12.4 15-30 753 27.5
15.1 30-45 1138 50.3 22.8 45-60 1279 75.9 25.6 60-75 774 91.4 15.5
75-90 331 98.0 6.6 90-105 85 99.7 1.7 105-120 15 100.0 0.3 120-135
1 100.0 0.0 Total: 4996 100.0
Example 9
Bubble Sizing Technique
[0326] The bubble sizing technique used to measure the bubble size
distribution of the foams from Examples 6 to 8 above comprises
computer analysis of the image of the bubbles though a microscope.
A small sample of the foam is deposited on a specially prepared
slide which has spacers 37 microns high mounted on each side. A
further slide is then carefully positioned on top of the sample and
spacers, thereby spreading the sample into a layer of 37 micron
thickness. A digital image of part of the 37 micron layer of
bubbles is then recorded and processed: the bubbles appear as rings
in the image, the ring representing the outermost diameter of the
bubble. Each bubble is individually identified and numbered, and
its diameter calculated. For bubbles over 37 microns in diameter it
is assumed that the bubble has been flattened to some degree
causing the diameter of the ring in the image to be larger than the
diameter of the undeformed bubble. An algorithm for calculating the
original diameter of the undeformed bubble is applied. For bubbles
37 microns and under, it is assumed that the bubble has floated up
against the underside of the upper slide and is undeformed. From
visual inspection of the digital image, this does not appear to be
an unreasonable assumption since overlapping bubble images are
either absent completely or are very rare. Nevertheless it is
intended to repeat the experiments using a set of slides with a 10
micron gap and suitably amended software, once these things have
been developed, so that substantially all the bubbles will be
flattened between the slides.
Example 10
[0327] Examples 6, 7 and 8 above are repeated using the following
method.
[0328] Polidocanol solution is drawn up into a 20 ml syringe as
described in Examples 6, 7 and 8, ensuring that excess solution is
drawn up and then solution dispensed with the nozzle pointed
upwards, until the appropriate volume of polidocanol solution is
left. In this way any air voids in the syringe, particularly in the
nozzle, are removed.
[0329] The polidocanol-filled syringe is then connected to the mesh
unit, the assembly oriented with syringe pointing upwards, and the
mesh unit filled with solution, eliminating all air bubbles.
[0330] A line from a cylinder of medical grade oxygen (99.5%
purity) is connected to the luer connector of a 20 ml syringe with
the plunger removed. The oxygen line and syringe barrel and luer
connector are then flushed for 10 seconds with oxygen from the
cylinder. The oxygen line is then removed, keeping the supply of
oxygen turned on, and the syringe plunger inserted into the barrel
and the plunger depressed. The oxygen line is then re-attached to
the syringe luer and the pressure of the oxygen allowed to push the
syringe plunger back to fill the syringe with oxygen.
[0331] The oxygen syringe is then immediately connected to the mesh
unit and the foam generating procedure described in Examples 6, 7
or 8 carried out.
Example 11
[0332] A syringe and mesh unit filled with polidocanol solution as
described in Example 10 above are placed in a collapsible "glove
box" (a sealable container with integral gloves incorporated into
the container wall to allow manipulation by a user of the contents
of the container). A further, empty syringe is also placed in the
glove box. The box is then sealingly connected to vacuum source and
thereby collapsed such that substantially all air is removed. The
vacuum source is then replaced by a source of 99.995% pure oxygen
and the glove box filled with oxygen from this source; the oxygen
supply is maintained and a small vent is opened in the wall of the
glove box opposite the point of entry of oxygen. The procedure
described in Example 10 above for filling the empty syringe with
oxygen is then followed, using the 99.995% pure oxygen supply line
within the glove box. The procedure described in Examples 6, 7 and
8 is then carried out to generate foam.
Example 12
[0333] A polidocanol syringe and mesh unit are prepared as in
Example 10 above. A syringe is immersed in a tank of water and the
plunger removed. Once the syringe barrel is completely full of
water with no air pockets, a stopper is secured over the luer
nozzle. The syringe barrel is held with the nozzle pointing upwards
and a line from a 99.9999% pure oxygen cylinder is first purged,
then introduced into the syringe barrel. When all water is replaced
by oxygen (taking care that the water in the nozzle is displaced),
the plunger is inserted and the syringe removed from the water
tank. The procedure of Example 10 is then followed to connect the
syringe to the mesh unit and make foam.
[0334] As with Example 4 above, this procedure could be refined by
storing the water tank under a continually refreshed atmosphere of
99.9999% pure oxygen for 24 hours prior to filling the syringe.
Example 13
[0335] In a modification of Examples 10-12, the mesh unit can be
replaced with a simple connector or three way valve and in all
other respects the technique can remain the same, with the possible
exception of requiring more passes to make acceptable foam. The
aperture in a standard connector or three way valve, through which
the gas and liquid are passed, would be about 0.5 mm to 3 mm in its
largest dimension. By repeatedly passing the liquid and gas through
this aperture it is still possible to obtain a useful foam, though
with bubble sizes considerably larger than those obtained by the
methods of Examples 6 to 12. This technique is commonly known as
the "Tessari" technique. The inventors have experimented with the
Tessari technique and found that the size and distribution of
bubbles varies widely according to the ratio of gas to air and also
the speed and number of passes of the gas and liquid through the
aperture. The average bubble size for a Tessari foam has been
reported in the literature to be around 300 micron. The best that
the inventors have managed to achieve using the Tessari technique
is a foam with an average bubble size of around 70 micron, though
to do this the ratio of liquid to gas had to be increased to about
40% liquid, 60% gas.
[0336] In this example, the Tessari technique can be adapted to
make a foam of whatever density and bubble size is desired, within
the limitations described above, but using gas with a very low
percentage of nitrogen impurity.
Example 14
[0337] A canister was prepared of the type described in
WO00/72821-A1 having a dip tube and a standard valve assembly
provided with a pair of small air inlet apertures, together with a
mesh stack unit having a 5 micron aperture size. The size of the
apertures in the valve was enlarged slightly compared with the
valve arrangement described in WO00/72821-A1 (which is designed to
produce a foam of density between 1.1 g/ml and 1.6 g/ml). The
purpose of this modification was to increase the proportion of
liquid to gas in the mixture passing through the mash stack.
[0338] The canister was filled with 18 ml of 1% polidocanol
solution and pressurised with a mixture of oxygen, carbon dioxide
and nitrogen. A foam was then dispensed.
[0339] This procedure was repeated for different sizes of valve
aperture and a number of foams produced, all having the appearance
of a white liquid and densities in the range 0.3 to 0.5 g/ml.
Bubble size analysis was performed for each of these foams, which
showed the average bubble size in the region of 50 to 80 micron
diameter.
Example 15
[0340] The above experiment was repeated but with the length and
diameter of the dip tube adjusted rather than the size of the
apertures in the valve unit. It was necessary to increase the
volume of liquid in the canister to ensure that the shortened dip
tube reached the liquid level in the canister. It was possible to
produce the same type of foam as described in Example 6 above.
Example 16
[0341] The inventors envisage reproducing the above experiments
using a pure oxygen or oxygen and carbon dioxide formulation having
nitrogen impurity levels as described above. The same techniques as
those described in Examples 4 and 5 may be followed for producing
very low levels of nitrogen impurity.
Example 17
Pre-Pressurised Container
[0342] A typical apparatus for the generation of therapeutic foam
according to the invention, as disclosed in WO 00/72821-A1, is
shown in FIG. 14.
[0343] The canister has an aluminium wall (1), the inside surface
of which is coated with an epoxy resin. 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 1% vol/vol
polidocanol/20 mmol phosphate buffered saline solution/4% ethanol,
then filled with the required gas mixture.
[0344] A standard 1 inch diameter Ecosol.TM. aerosol valve (5)
(Precision Valve, Peterborough, UK) is crimped into the top of the
canister after sterile part filling with the solution and may be
activated 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 four Nylon 66 meshes
held in high density polyethylene (HDPE) rings (8), all within an
open-ended polypropylene casing. These meshes have diameter of 6 mm
and have a 14% open area made up of 20 .mu.m pores, with the meshes
spaced 3.5 mm apart.
[0345] 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 dip-tube on operation of the actuator (6). These are
conveniently defined by an Ecosol.TM. device provided by Precision
Valve, Peterborough, UK, provided with an insert. Holes (11a, 11b)
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
Example 18
Container with Engaging Means and Mesh Stack Shuttle
[0346] 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. 15. The device comprises a low
pressure container (1) for an aqueous sclerosant liquid and an
unreactive gas atmosphere, a container (2) for a physiologically
acceptable blood-dispersible gas and an engaging means comprising a
connector (3).
[0347] The container (2) for a physiologically acceptable
blood-dispersible gas is charged at 5.8 bar absolute pressure with
the required gas mixture, whereas the container (1) is charged with
an inert gas. Container (2) is used to pressurise container (1) at
the point of use to approx 3.5 bar absolute and is then discarded,
just before the foam is required. The two containers will thus be
referred to hereinafter as the PD [polidocanol] can (1) and the O2
can (2), and the term "bi-can" will be used to refer to the concept
of two containers.
[0348] 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.
[0349] 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.
[0350] 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 O2 can (2) mounting
plate (5) via four locating prongs. The security collar is added at
this point to make an O2 can subassembly.
[0351] The connector (3) includes in its interior a series of
foaming elements comprising 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 .mu.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 (18) 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 (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.
[0352] The mesh stack shuttle (17) is assembled onto the PD can
valve (19) by push-fitting the components together in a aseptic
environment.
[0353] The PD can (1) and attached shuttle (17) are offered up to
the connector (3) and the attached O2 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 O2 can (2) and the point at
which it will form a seal against a female Luer outlet from the
stack.
[0354] When the security collar (16) is 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 O2 can valve
(20).
[0355] 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 O2 can (2) is restricted by a small outlet hole (21) in
the stem valve (20). 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 bar.+-.0.15 bar.
[0356] After the 45 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 O2 can (2) is discarded at this point.
[0357] A standard 1 inch diameter aerosol valve (19) (Precision
Valve, Peterborough, UK) is crimped into the top of the PD can (1)
before or after sterile filling with the solution and may be
activated 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 19
Study to Assess the Effect on Physical Properties of Foam from
Changes to the Mesh Material in the Mesh Stack
[0358] This study outlines the effect on foam properties of
changing the shuttle mesh pore size from 20 microns to 5 microns,
in combination with changes to the gas pressure and gas composition
in the canister. The study dates from before the inventors'
realisation that a nitrogen concentration of 0.8 or below was
desirable. Its main purpose was to test whether use of a 5 micron
instead of a 20 micron mesh will compensate for eliminating the 25%
nitrogen which was previously deliberately incorporated into the
polidocanol canister. The "100%" carbon dioxide and "100%" oxygen
referred to in this and the following examples will in fact
incorporate levels of nitrogen impurity and the final dual canister
product discussed in these examples will probably produce as foam
of about 1-2% nitrogen impurity.
[0359] Two different gas compositions were used. In one, the
canister containing the 1% polidocanol solution and a 75%125%
atmosphere of CO2/N2 is evacuated to 0.5 bar absolute pressure,
whilst the other canister is pressurised to 5.9 bar absolute with
oxygen. In the other, the canister containing the 1% polidocanol
solution is pressurised to 1.2.+-.0.1 bar absolute with 100% CO2,
whilst the other canister is pressurised to 5.8.+-.0.1 bar absolute
with oxygen.
[0360] The objective of the study is to examine and compare results
obtained using 5 micron and 20 micron shuttle meshes, for PD
canister pressures of 0.5 bar absolute with the current gas
atmosphere and for 1.2 bar absolute PD canister pressures with a
100% CO2 as the filling gas.
[0361] Materials and Methods:
[0362] All sample preparation was performed in a laminar flow booth
keeping exposure times to atmosphere to a minimum.
[0363] Shuttle units containing a stack of 4 nylon 6/6 woven meshes
of 6 mm diameter in a class 100K cleanroom moulding facility were
used. They differ in the following aspects shown in Table 3
below.
TABLE-US-00006 TABLE 5 Physical characteristics of the 20 .mu.m and
5 .mu.m meshes compared Mesh Thickness Pore size Open Area (% area
Thread diameter Type (.mu.m) (.mu.m) of pores) (.mu.m) 5 .mu.m 100
5 1 37 20 .mu.m 55 20 14 34
Bioreliance Ltd, Stirling, Scotland, U.K., made the 1% polidocanol
solution for the study under controlled conditions to the formula
in Table 4.
TABLE-US-00007 TABLE 6 Composition of the 1% polidocanol solution
Quantities Material % .sup.w/.sub.w per 1000 g Polidocanol 1.000
10.00 g Ethanol 96% EP 4.200 42.00 g Disodium Hydrogen Phosphate
0.240 2.40 g Dihydrate. EP Potassium Di-hydrogen Phosphate. 0.085
0.85 g EP 0.1M Sodium Hydroxide Solution q.s. q.s. [used for
adjustment of pH: 7.2-7.5] 0.1M Hydrochloric Acid q.s. q.s. Water
for injection. EP [used to approx. 94.475 approx. 944.75 g adjust
to final weight] q.s. to 100.00% q.s. to 1000.00 g TOTAL: 100.00%
1000.00 g
[0364] The polidocanol solution was sterile filtered using a
0.2-micron filter before filling into clean glass screw top
bottles.
[0365] Bi-can assemblies were prepared for testing to the
specifications of gas mix and pressure in the polidocanol canister
detailed in
Table 5.
TABLE-US-00008 [0366] TABLE 7 Summary of PD canister preparation
for each treatment group Canister Sample Gas Gas Pressure Mesh Pore
Size Label Type Composition (bar absolute) (.mu.m) C Control 1 75%
CO.sub.2/25% 0.5 20 N.sub.2 D Test 1 75% CO.sub.2/25% 0.5 5 N.sub.2
A Control 2 100% CO.sub.2 1.2 20 B Test 2 100% CO.sub.2 1.2 5
[0367] The order of testing of the experimental series was
important, in that changes in ambient laboratory temperature affect
the half separation time results. Experiments progressed cyclically
through the sample types rather than test all of one sample type,
followed by all of another sample type. This minimised the effect
of any drift in laboratory temperature throughout the experiments.
The laboratory temperature was maintained as close to 20.degree. C.
as possible.
[0368] It was also essential that the temperature of the half
separation time apparatus be allowed to fully equilibrate to
ambient room temperature following cleaning and drying steps
between successive experimental measurements.
[0369] Summary of Tests:
[0370] The tests and specifications performed on the bi-can units
in this study are summarised in Table 6.
TABLE-US-00009 TABLE 8 Summary of tests and specifications TEST
SPECIFICATION 1 Appearance of Device No corrosion of canisters or
valves. Free from signs of leakage and external damage 2 Gas
Pressure 1.10 to 1.30 bar absolute for Type 2 samples Polidocanol
Canister 0.4 to 0.6 bar absolute for Type 1 samples Oxygen Canister
4.90 to 5.9 bar absolute 3. Appearance of Foam Upon actuation, a
white foam is produced. After the foam has settled, a clear and
colourless liquid is observed. 4. pH of Solution 6.6 to 7.5
(collapsed foam) 5 Foam density 0.10 to 0.16 g/ml. 6 Foam Half
Separation 150 to 240 seconds Time 7 Bubble Size (Diameter
Distribution) <30 .mu.m .ltoreq.20.0% 30 .mu.m to 280 .mu.m
.gtoreq.75.0% 281 .mu.m to 500 .mu.m .ltoreq.5.0% >500 .mu.m
None 8 Particulates (Visible) Complies with Ph. Eur. and
Sub-Visible) 9 Particulates (Sub- The collapsed foam contains not
more Visible) than 1000 particles per ml .gtoreq.10 .mu.m and not
more than 100 particles .gtoreq.25 .mu.m per ml. 10 Polidocanol GC
pattern and retention times to be identification by GC equivalent
to reference preparation method 11 Polidocanol Assay 0.90 to 1.10%
w/w 12 Related Substances No single identified impurity >0.20%
area. No single unidentified impurity >0.10% area. Total
impurities .ltoreq.4.0% area
[0371] Results:
[0372] Results of the tests described in Table 6 on bi-cans
prepared as described in Table 5 are summarised in the following
paragraphs.
[0373] Appear of Device and Foam
[0374] In all cases the appearance of the devices conformed to
specification in that the device showed no corrosion of canisters
or valves and were free from signs of leakage and external damage.
Upon actuation of the charged PD canister a white foam was
produced. After the foam had settled, a clear and colourless liquid
was observed.
[0375] Density, Half Separation Time and pH
[0376] Foam from all devices conformed to density and half
separation time specification. However, one unexpectedly low result
was obtained (C1 canister 1) but an additional two devices were
tested which behaved as expected. In spite of the low result, the
average conformed to specification. In general, foam generated via
the 5 .quadrature.m shuttles had longer half separation times.
Results are summarised in Table 7.
[0377] The average pH of the foam generated conformed to
specification. However, foam produced from the 100% CO2 canister
were close to the lower limit of detection of the specification and
in one instance (C2 canister 4) it was just below specification.
Results summarised in Table 7.
[0378] The gas pressure in the oxygen cans and the polidocanol cans
conformed to specification in all cases. In one instance (C1
canister 6) a slightly lower oxygen canister pressure than expected
was recorded. Results are summarised here in Table 7.
TABLE-US-00010 TABLE 9 Table summarising the foam density, half
separation time, pH and canister gas pressures Gas pressure density
half life (bars abs) Test Condition (g/cm.sup.3) (sec) pH Oxygen PD
Specification 0.10-0.16 150-240 6.6-7.5 4.9-5.9 0.4-0.6 100%
CO.sub.2, 1.2 Bar, 20 .mu.m mesh Canister A1 0.12 164 6.7 5.6 1.1
Canister A2 0.13 150 6.7 5.5 1.1 Canister A3 0.13 153 6.6 5.8 1.1
Canister A4 0.15 154 6.5 5.5 1.1 Canister A5 0.13 154 6.7 5.6 1.1
Canister A6 0.15 154 6.5 5.6 1.1 Average 0.13 155 6.6 5.6 1.1 100%
CO.sub.2, 1.2 Bar, 5 .mu.m mesh Canister B1 0.12 182 6.6 5.4 1.1
Canister B2 0.12 169 6.7 5.6 1.1 Canister B3 0.14 162 6.6 5.4 1.1
Canister B4 0.1 173 6.7 5.7 1.1 Canister B5 0.12 168 6.6 5.6 1.1
Canister B6 0.15 161 6.5 5.4 1.1 Average 0.13 169 6.6 5.5 1.1 75%
CO.sub.2/25% N.sub.2, 0.5 Bar, 20 .mu.m mesh Canister C1 0.14 157#
6.9 5.4 0.6 Canister C2 0.15 182 6.9 5.5 0.6 Canister C3 0.13 193
6.9 5.4 0.6 Canister C4 0.15 183 6.9 5.7 0.6 Canister C5 0.15 192
6.8 5.6 0.5 Canister C6 0.15 191 6.9 5.0 0.6 Canister C11 0.14 189
7.0 5.7 0.6 Canister C12 0.13 179 7.0 5.4 0.6 Average 0.14 183 6.9
5.5 0.6 75% CO.sub.2/25% N.sub.2, 0.5 Bar, 5 .mu.m mesh Canister D1
0.15 203 6.9 5.4 0.6 Canister D2 0.12 209 7.0 5.6 0.6 Canister D3
0.16 198 6.8 5.6 0.6 Canister D4 0.12 205 6.9 5.7 0.6 Canister D5
0.12 208 6.9 5.4 0.6 Canister D6 0.15 205 6.9 5.6 0.6 Average 0.14
205 6.9 5.6 0.6
[0379] Bubble Size Distribution:
[0380] The average bubble size for all conditions was within
specification with the exception of control 1 (C) where the
>5000 m which averaged at one oversized bubble. Results are
summarised here in Table 8.
TABLE-US-00011 TABLE 10 Table to summarise the bubble size
distribution of foam generated Bubble Diameters (.mu.m) <30
30-280 281-500 >500 Specification <=20% >=80% <=5% None
100% CO.sub.2, 1.2 Bar, 20 .mu.m mesh Canister A1 8.2% 89.5% 2.3% 0
Canister A2 8.1% 89.7% 2.2% 0 Canister A3 7.9% 85.3% 6.8% 0
Canister A4 9.0% 88.3% 2.6% 1 Canister A5 7.9% 90.7% 1.5% 0
Canister A6 11.0% 88.1% 0.9% 0 Average 8.7% 88.6% 2.7% 0 100%
CO.sub.2, 1.2 Bar, 5 .mu.m mesh Canister B1 7.8% 91.8% 0.4% 0
Canister B2 5.5% 94.2% 0.3% 0 Canister B3 8.6% 90.7% 0.7% 0
Canister B4 8.8% 91.1% 0.2% 0 Canister B5 7.7% 92.2% 0.0% 0
Canister B6 8.2% 91.3% 0.5% 0 Average 7.8% 91.9% 0.4% 0 75%
CO.sub.2/25% N.sub.2, 0.5 Bar, 20 .mu.m mesh Canister C1 8.9% 87.2%
3.9% 0 Canister C2 10.0% 89.3% 0.6% 0 Canister C3 8.9% 86.5% 4.5% 1
Canister C4 9.7% 87.7% 2.5% 4 Canister C5 10.7% 87.9% 1.5% 0
Canister C6 10.1% 88.0% 1.9% 0 Canister C11 9.6% 89.5% 1.0% 0
Canister C12 11.0% 87.6% 1.4% 0 Average 9.7% 88.1% 2.5% 1.0 75%
CO.sub.2/25% N.sub.2, 0.5 Bar, 5 .mu.m mesh Canister D1 7.8% 92.0%
0.2% 0 Canister D2 8.1% 91.4% 0.6% 0 Canister D3 10.9% 89.0% 0.1% 0
Canister D4 8.5% 91.2% 0.2% 0 Canister D5 8.8% 91.1% 0.1% 0
Canister D6 10.2% 89.8% 0.0% 0 Average 9.0% 90.7% 0.2% 0 # Value
from Control 1, canister 1 are not included in the average
[0381] Particulates (Sub Visible)
[0382] The collapsed foam from all canisters complied to
specification for particulates, in so far as there were no more
than 1,000 particles/ml.gtoreq.10 .mu.m and no more than 100
particles/ml.gtoreq.25 .mu.m. Those which had 100% CO2 gas mixture
gave the lowest numbers of particles overall. There were no visible
particles seen in the collapsed foam. The results are summarised
here in Table 7.
[0383] The appearance of foam from each device conformed to
specification. The appearance of all canisters conformed to
specification.
TABLE-US-00012 TABLE 11 Sub-visible particulates as per in house
method MS14 Counts per ml Counts per container (18 ml) Device No
.gtoreq.10 .mu.m .gtoreq.10-25 .mu.m .gtoreq.25 .mu.m .gtoreq.10
.mu.m .gtoreq.10-25 .mu.m .gtoreq.25 .mu.m Result Ref A Can 7 281.6
271.4 10.2 5,069 4,885 184 Complies Ref A Can 8 235.3 227.9 7.4
4,235 4,102 133 Complies Ref B Can 7 112.8 109.8 3 2,030 1,976 54
Complies Ref B Can 8 123.1 116.3 6.8 2,216 2,093 122 Complies Ref C
Can 7 386.1 370.2 15.9 6,950 6,664 286 Complies Ref C Can 8 369.5
350.6 18.9 6,651 6,311 340 Complies Ref D Can 7 130.2 123.5 6.7
2,344 2,223 121 Complies Ref D Can 8 152.1 141.4 10.7 2,738 2,545
193 Complies
[0384] Polidocanol Identification, Assay and Related Substances
[0385] No significant differences were observed between the results
of the Control and Test preparations. All samples met all
specifications for related substances, assay value and
identity.
[0386] Analysis of the samples using the 25 m column was
undertaken, but no significant peaks were observed relating to
Nylon 6,6 interactions in these samples.
Example 20
Further Study to Assess the Effect on Physical Properties of Foam
from Changes to the Mesh Material in the Mesh Stack
[0387] The study of Example 9 was repeated using a device in which
the shuttle mesh pore size was 20 microns, 11 microns and 5
microns, in combination with changes to the gas pressure and gas
composition in the canister. Bi-can assemblies were prepared for
testing to the specifications of gas mix and pressure in the
polidocanol canister detailed in Table 9.
TABLE-US-00013 TABLE 12 Summary of PD canister preparation for each
treatment group Sample Gas Pressure Mesh Pore Size Type Gas
Composition (bar absolute) (.mu.m) Control 1 75% CO.sub.2/25%
N.sub.2 0.5 20 Control 2 100% CO.sub.2 1.2 20 Test 2 100% CO.sub.2
1.2 5 Test 3 100% CO.sub.2 1.2 11
[0388] Various batches of the foam resulting from the test in which
the shuttle mesh pore size was 11 microns had the following
characteristics:
TABLE-US-00014 TABLE 13 (a) Bubble Diameter (micrometers) <=30
>30-280 >280-500 >500 9.2% 90.2% 0.6% 0.0% 11.8% 88.2%
0.0% 0.0% 10.6% 89.4% 0.0% 0.0% 10.2% 89.8% 0.0% 0.0% 10.6% 89.1%
0.3% 0.0% 10.5% 89.4% 0.1% 0.0%
TABLE-US-00015 TABLE 13 (b) Bubble Diameter (micrometers) excluding
below 30 .mu.m <30-130 >30-280 >280-500 >500 59.1%
99.4% 0.6% 0.0% 71.2% 100.0% 0.0% 0.0% 75.3% 100.0% 0.0% 0.0% 67.3%
100.0% 0.0% 0.0% 66.4% 99.7% 0.3% 0.0% 73.6% 99.9% 0.1% 0.0%
TABLE-US-00016 TABLE 14 Density and Half Life Density (g/cm3) Half
Life (Min) 0.12 180 sec 0.14 171 sec 0.14 175 sec 0.12 175 sec 0.13
177 sec 0.15 177 sec
Example 21
[0389] Experiments were conducted to compare the physical
properties of sclerosing foam made by the methods of Cabrera, using
a range of CO2/O2 gas mixtures as the ambient atmosphere in which a
small brush is rotated at high speed to whip polidocanol (PD)
solution into a foam, as disclosed in EP 0656203.
[0390] All sample preparation was performed under controlled
laboratory conditions at temperatures within the range 18-22
degrees C., using polidocanol solution obtained from Kreussler 1%
Aethoxysclerol. The container was a 100 ml beaker. The beaker and
the 10 ml of solution was placed in a small glass aquarium tank
which was modified to allow the internal space to be sealed from
atmosphere, then flushed and flooded with the test gas mix.
[0391] During the experiments, a small ingress of the test gas mix
was present to ensure that atmospheric nitrogen and oxygen cannot
enter the glass tank and change the known gas mix. A flexible drive
shaft was attached to the micromotor to allow the micromotor to
stay outside of the glass tank, whilst driving the brush inside the
glass tank at the required speed. Where the flexible drive shaft
entered the glass tank, it was sealed to avoid leaks from
atmosphere
[0392] The flushing of the glass tank was performed for 30 seconds
with the gas mix supplied at 0.2 bar above atmospheric pressure to
the glass tank. After the 30 second flush, the regulator was turned
down to allow a trickle of ingressing gas for the rest of the
experiment. The speed of rotation and duration of whipping was
fixed at 11500 rpm and 90 seconds.
[0393] The results in Table 15 show the density and half life of
foams made with 100% CO2, 100% O2, 75% CO2/25% O2 and air. For each
gas, foams were made with plain polidocanol, polidocanol and 5%
glycerol, polidocanol and 25% glycerol and polidocanol and 40%
glycerol. Two runs are reported (1 and 2) for each foam. The
results show that higher percentages of glycerol enable one to make
a CO2 foam with adequate density and half life.
TABLE-US-00017 TABLE 15 Density and Half Separation Time Density
(g/ml) Half Life (Sec) (a) Air Plain PD air 1 0.16 173 Plain PD air
2 0.17 170 5% glycerol 1 0.20 188 5% glycerol 2 0.20 195 25%
glycerol 1 0.30 539 25% glycerol 2 0.27 535 40% glycerol 1 0.44 459
40% glycerol 2 0.45 575 (b) 100% O2 Plain PD O2 1 0.18 122 Plain PD
O2 2 0.17 120 O25GA 0.18 144 O25GB 0.18 140 O225ga 0.30 343 O225gb
0.34 429 O240ga 0.47 432 O240gb 0.44 525 (c) 75% CO2/25% O2 2575
plain PD 1 0.20 72 2575 plain PD 2 0.18 78 2575 5% G A 0.16 81 2576
5% G B 0.19 82 2575 25% G A 0.33 216 2576 25% G B 0.29 229 2575 40%
G A 0.46 399 2576 40% G B 0.47 410 (d) 100& CO2 Plain PD CO2 1
0.19 55 Plain PD CO2 2 0.19 71 CO25GA 0.24 57 CO25GB 0.20 66
CO225ga 0.29 187 CO225gb 0.33 239 co240ga 0.48 227 co240gb 0.51
273
Example 22
Polidocanol, Glycerol and CO2 Foams
[0394] Foams were made with polidocanol, glycerol and CO2 using
various techniques. The technique used to make the foam plays an
important role in the half life and density of the resulting
foam.
Double Syringe Technique
[0395] 500 ml of a buffered solution of 1% polidocanol and 30%
glycerol was made up using the following procedure.
[0396] 100% polidocanol (pd)--a waxy solid--was melted by placing
in a bath of warm water
[0397] 100 ml distilled water was weighed out in a 1000 ml
beaker
[0398] 0.425 g potassium dihydrogen phosphate was added as a
stabiliser
[0399] 5 g of the liquefied pd was weighed out
[0400] 21 g of 96% ethanol was weighed out
[0401] The ethanol and pd were mixed, then added to distilled
water
[0402] 150 g glycerol was added
[0403] Water was added to the 425 ml mark
[0404] pH was adjusted by adding 0.1 M sodium hydroxide to between
7.34 and 7.38 pH.
[0405] Distilled water was added to make up to 500 g on scale
[0406] The solution was filtered through a 0.25 micron filter.
[0407] The same procedure was followed, with an increased amount of
glycerol, to make the 40% glycerol solution.
[0408] Into a 50 ml glass syringe was drawn 10 ml of the
pd/glycerol solution. The nozzle of another 50 ml glass syringe was
connected to a line from a cylinder of carbon dioxide (B.O.C. "CP
grade" having a purity level of 99.995%). The syringe was filled
with carbon dioxide and then removed from the line, the plunger
depressed and the syringe then re-filled to the 50 ml graduation on
the syringe barrel and then detached from the line. A connector
having a female luer at each end and a through bore of diameter
approximately 1 mm was then connected to the line and flushed
through. The two syringes were then each connected to the connector
device.
[0409] The carbon dioxide and pd/glycerol solution were then
manually pumped back and forth between the two syringes as fast as
possible for in excess of 30 cycles. A foam formed in the syringes
during this process. After the final cycle, the foam was quickly
transferred to half-life and density measuring apparatus and the
half life and density of the foam determined.
[0410] The procedure was carried out for a buffered solution of 1%
polidocanol and 30% glycerol and for a buffered solution of 1%
polidocanol and 40% glycerol.
[0411] In each case the resulting foam was observed to be somewhat
runny, though not like a liquid. It would form very flat, gently
rounded "blob" on a surface which decayed and ran away as liquid
within five seconds.
[0412] Double Syringe and Mesh Technique
[0413] The procedure outline above for the double syringe technique
was followed, with the following variations.
[0414] Instead of using a connector with a 1 mm bore, a so called
"mesh stack" device was prepared having a flow path which
incorporated a series of four mesh elements. Each mesh element
measured about 2-3 mm in diameter and had pores with diameter 5
micron. At each end of the device was a luer connection.
[0415] The syringes were again cycled as fast as possible but this
was considerably slower than was possible with the simple connector
having a 1 mm bore. After 10 cycles the pumping of the syringes was
stopped since no further changes in the foam could be observed. Two
operators were necessary to perform this cycling, each operator
depressing the plunger on a respective syringe.
[0416] The procedure was carried out for a buffered solution of 1%
polidocanol and 30% glycerol and for a buffered solution of 1%
polidocanol and 40% glycerol.
[0417] The appearance of the foams made with the double syringe and
mesh stack technique was quite similar to those produced with the
double syringe style technique; however the "blobs" were less flat
and took somewhat longer to decay.
[0418] Canister Technique
[0419] Pressurised canisters with a capacity of approximately 100
ml were made up with about 20 ml of buffered polidocanol/glycerol
solution. The canisters were then pressurised with substantially
pure carbon dioxide to a pressure of 3.5 bar absolute.
[0420] The canisters are each fitted with a valve, with a dip tube
extending from the valve to the base of the canister. On each side
of the valve are apertures which draw in gas as liquid passes up
the dup tube under pressure. Above the valve, each canister is
fitted with a mesh stack unit as described above.
[0421] To dispense foam, the canister valve is opened. The first
portion of foam is discarded and then foam is dispensed directly
into the half life and density measurement apparatus.
[0422] The procedure was carried out with canisters containing a
buffered solution of 1% polidocanol and 30% glycerol and with
canisters containing a buffered solution of 1% polidocanol and 40%
glycerol.
[0423] The foam produced by the 30% glycerol solution was
relatively stiff and formed a compact, rounded blob on a surface.
The blob could be seen to start decaying within a few seconds, but
remained as a blob rather than a liquid puddle for much longer.
Observations were not recorded for the 40% glycerol.
[0424] Results
[0425] Double Syringe Foam
[0426] 1) (100% CO2, 1% polidocanol, 30% glycerol) [0427]
Density=0.231; Half life=99 secs
[0428] 2) (100% CO2, 1% polidocanol, 40% glycerol) [0429] Unable to
make sufficient amount of foam
[0430] Double Syringe and Mesh Technique
[0431] 1) (100% CO2, 1% polidocanol, 30% glycerol) [0432]
Density=0.174; Half life=155 secs
[0433] 2) (100% CO2, 1% polidocanol, 40% glycerol) [0434]
Density=0.186; Half life=166 secs
[0435] Canister
[0436] 1) (100% CO2, 1% polidocanol, 30% glycerol) [0437]
Density=0.094; Half life=121 secs
[0438] 2) (100% CO2, 1% polidocanol, 30% glycerol) [0439]
Density=0.124; Half life=166 secs
[0440] 3) (100% CO2, 1% polidocanol, 30% glycerol) [0441]
Density=0.124; Half life=108 secs
Example 23
Polidocanol, Glycerol and CO2 Foams
[0442] The effects of different viscosity enhancing agents
(glycerol, PVP and ethanol) on the viscosity of the liquid phase
before producing a foam were examined. Viscosity was determined at
23oC using the Brookfield device described above.
[0443] The effects of additional components on the density and half
life of CO2 foams made using the methods of Cabrerra was also
studied. Foams were prepared using the polidocanol (PD) and
different percentages of viscosity enhancing agents (wt/wt) and the
Cabrerra method described above. The half life and density of the
resulting foam was determined as described above. Similar
experiments can be used to determine if a particular combination of
viscosity enhancing agent, sclerosing agent, and gas provide a foam
with a suitable half-life and density. Foams were also produced
using a canister as described above and the results are presented
in Table 16.
TABLE-US-00018 TABLE 16 Canister CO2/glycerol results Composition
(all compositions Viscosity are 100% Average Average of Liquid CO2
& 1% Density Half life Density Half life Component polidocanol)
(g/ml) (seconds) (g/ml) (seconds) (cP) 5% glycerol 0.105 76 0.112
63 1.5 5% glycerol 0.109 58 5% glycerol 0.111 60 5% glycerol 0.117
59 5% glycerol 0.121 61 10% glycerol 0.112 78 0.117 76 1.6 10%
glycerol 0.115 75 10% glycerol 0.118 78 10% glycerol 0.124 73 20%
glycerol 0.113 92 0.115 96 2.2 20% glycerol 0.113 99 20% glycerol
0.113 104 20% glycerol 0.120 95 20% glycerol 0.114 90 25% glycerol
0.105 111 0.109 111 2.6 25% glycerol 0.106 109 25% glycerol 0.108
109 25% glycerol 0.109 118 25% glycerol 0.115 106 30% glycerol
0.094 121 0.114 132 -- 30% glycerol 0.124 166 30% glycerol 0.124
108 40% glycerol 0.083 172 0.118 173 -- 40% glycerol 0.133 174 40%
glycerol 0.137 174 1% PVP C30 0.091 73 0.107 67 1.6 1% PVP C30
0.107 62 1% PVP C30 0.111 69 1% PVP C30 0.119 64 2% PVP C30 0.102
70 0.107 68 2.0 2% PVP C30 0.105 69 2% PVP C30 0.106 69 2% PVP C30
0.114 63 1% PVP K90 0.068 142 0.073 135 5.0 1% PVP K90 0.071 118 1%
PVP K90 0.072 129 1% PVP K90 0.074 159 1% PVP K90 0.078 129
* * * * *