U.S. patent application number 14/107233 was filed with the patent office on 2014-04-17 for generation of therapeutic microfoam.
This patent application is currently assigned to BTG International Limited. The applicant listed for this patent is BTG International Limited. Invention is credited to Timothy David BOORMAN, Anthony David HARMAN, David Dakin IORWERTH, Tariq OSMAN, Sheila Bronwen SHILTON-BROWN.
Application Number | 20140107224 14/107233 |
Document ID | / |
Family ID | 10854273 |
Filed Date | 2014-04-17 |
United States Patent
Application |
20140107224 |
Kind Code |
A1 |
OSMAN; Tariq ; et
al. |
April 17, 2014 |
GENERATION OF THERAPEUTIC MICROFOAM
Abstract
Improved therapeutic sclerosing microfoams and methods and
devices for making them are provided that have advantage in
producing a consistent profile injectable foam with minimal input
by the physician yet using high volume percentages of blood
dispersible gases, thus avoiding use of potentially hazardous
amounts of nitrogen.
Inventors: |
OSMAN; Tariq; (London,
GB) ; SHILTON-BROWN; Sheila Bronwen; (Essex, GB)
; IORWERTH; David Dakin; (High Wycombe, GB) ;
HARMAN; Anthony David; (Henley-on-Thames, GB) ;
BOORMAN; Timothy David; (Essex, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BTG International Limited |
London |
|
GB |
|
|
Assignee: |
BTG International Limited
London
GB
|
Family ID: |
10854273 |
Appl. No.: |
14/107233 |
Filed: |
December 16, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13315445 |
Dec 9, 2011 |
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14107233 |
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12487387 |
Jun 18, 2009 |
8091801 |
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13315445 |
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12039341 |
Feb 28, 2008 |
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12487387 |
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11171293 |
Jul 1, 2005 |
7357336 |
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12039341 |
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09979655 |
Apr 12, 2002 |
6942165 |
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PCT/GB00/02045 |
May 26, 2000 |
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11171293 |
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Current U.S.
Class: |
514/723 ;
222/190 |
Current CPC
Class: |
B65D 83/20 20130101;
B65D 83/60 20130101; B65D 83/62 20130101; A61K 9/122 20130101; B65D
83/14 20130101; B05B 7/0037 20130101; A61K 9/0019 20130101; B65D
83/48 20130101; A61K 31/08 20130101; B05B 11/02 20130101; A61P 9/14
20180101; A61P 9/00 20180101; Y10S 514/945 20130101 |
Class at
Publication: |
514/723 ;
222/190 |
International
Class: |
A61K 9/12 20060101
A61K009/12; A61K 31/08 20060101 A61K031/08 |
Foreign Application Data
Date |
Code |
Application Number |
May 26, 1999 |
GB |
9912356.4 |
Claims
1-81. (canceled)
82. A microfoam comprising a gas component and an aqueous
sclerosant liquid wherein the microfoam is obtained by mixing the
components by passing the gas component and the aqueous sclerosant
liquid through at least one passage at least one time, wherein: the
gas component comprises a physiologically acceptable blood
dispersible gas comprising 10 to 100% vol/vol carbon dioxide or a
mixture of 10 to 100% vol/vol carbon dioxide with the remaining gas
oxygen, and the aqueous sclerosant liquid comprises a sclerosing
agent suitable for use in sclerotherapy of blood vessels, and the
at least one passage has a diameter ranging from about 5 .mu.m to
about 25 .mu.m.
83. The microfoam of claim 82, wherein the physiologically
acceptable blood dispersible gas comprises 10 to 40% vol/vol carbon
dioxide or a mixture of 10 to 40% carbon dioxide vol/vol and 60 to
90% vol/vol oxygen.
84. The microfoam of claim 82, wherein the physiologically
acceptable blood dispersible gas comprises 20 to 30% vol/vol carbon
dioxide or a mixture of 20 to 30% carbon dioxide vol/vol and 70 to
80% vol/vol oxygen.
85. The microfoam of claim 82, wherein the aqueous sclerosant
liquid comprises 1% vol/vol polidocanol in an aqueous carrier.
86. The microfoam of claim 82, wherein a density of the microfoam
ranges from 0.07 g/ml to 0.19 g/ml.
87. The microfoam of claim 86, wherein the density of the microfoam
ranges from 0.11 g/ml to 0.14 g/ml.
88. The microfoam of claim 82, wherein the microfoam has a
half-life of at least 2 minutes.
89. The microfoam of claim 82, wherein the aqueous sclerosant
liquid is a solution of polidocanol in an aqueous carrier or sodium
tetradecylsulfate (STS) in an aqueous carrier.
90. The microfoam of claim 89, wherein the concentration of
polidocanol ranges from 0.5 to 4% vol/vol in the liquid.
91. A microfoam obtained by passing a gas component and a
sclerosant liquid at least one time through at least one passage
having a diameter ranging from about 5 .mu.m to about 25 .mu.m,
comprising: the gas component comprising about 20 to about 99.99%
vol/vol carbon dioxide or a mixture of about 20 to about 99.99%
vol/vol carbon dioxide and about 0.01 to about 80% vol/vol oxygen;
and the sclerosant liquid comprising polidocanol or sodium
tetradecylsulfate (STS).
92. The microfoam of claim 91, wherein the sclerosant liquid
comprises polidocanol in an aqueous carrier or sodium
tetradecylsulfate (STS) in an aqueous carrier.
93. The microfoam of claim 92, wherein the sclerosant liquid
comprises about 1% vol/vol polidocanol.
94. The microfoam of claim 92, wherein the sclerosant liquid
comprises about 0.5 to about 4% vol/veal polidocanol.
95. The microfoam of claim 91, wherein a density of the microfoam
ranges from about 0.09 g/ml to about 0.16 g/ml.
96. The microfoam of claim 91, wherein the microfoam has a
half-life of at least 3 minutes.
97. A device for producing a microfoam for use in sclerotherapy of
blood vessels, comprising: a chamber fixedly coupled to a support,
wherein the chamber has at least one outlet; a pathway in fluid
communication with the at least one outlet, wherein the pathway
includes at least one passage having a diameter ranging from about
5 .mu.m to about 25 .mu.m that is moveably coupled to the support;
and a pressurization mechanism configured to apply a pressure to a
fluid within the chamber to force the fluid through the pathway to
form a microfoam.
98. The device of claim 97, wherein the fluid comprises a
physiologically acceptable blood dispersible gas comprising 10 to
100% vol/vol carbon dioxide or a mixture of 10 to 100% vol/vol
carbon dioxide with the remaining gas oxygen.
99. The device of claim 97, wherein the at least one passage
includes at least one of a porous membrane, a mesh, a screen, and a
sintered material.
100. The device of claim 97, wherein the pathway comprises a
plurality of passages arranged in parallel.
101. The device of claim 97, further including a valve in
communication with the at least one outlet and configured to direct
the microfoam to a first outlet conduit and a second outlet
conduit.
102. A method for producing a microfoam suitable for use in
sclerotherapy of blood vessels, comprising: passing a mixture of a
blood dispersible gas and an aqueous sclerosant liquid through one
or more passages having a diameter ranging from about 5 .mu.m to
about 25 .mu.m, wherein the blood dispersible gas comprises 10 to
100% vol/vol carbon dioxide or a mixture of 10 to 100% vol/vol
carbon dioxide with the remaining gas oxygen.
103. The method of claim 102, wherein the gas comprises at least
about 90% vol/vol carbon dioxide.
104. The method of claim 103, wherein the gas comprises at least
about 99.99% vol/vol carbon dioxide.
105. The method of claim 104. wherein the gas and liquid are passed
through the at least one passage between 2 and 2,000 times.
106. The method of claim 105, wherein the gas and liquid are passed
through the at least one passage between 4 and 200 times.
107. The method of claim 102, wherein the gas and liquid are passed
through at least one of a porous membrane, a mesh, a screen, and a
sintered material.
Description
[0001] The present invention relates to the generation of microfoam
comprising a sclerosing material, particularly a sclerosing liquid,
which is suitable for use in the treatment of various medical
conditions involving blood vessels, particularly varicose veins and
other disorders involving venous malformation.
[0002] Sclerosis of varicose veins is based on the injection into
the veins of liquid sclerosant substances which, by inter alia
causing a localised inflammatory reaction, favour the elimination
of these abnormal veins. When a sclerosing substance is injected in
liquid form, it is mixed with the blood contained in the vein and
is diluted in an unknown proportion. The results are uncertain,
owing to over- or under-dosage, and are limited to short varicose
segments. As the size of the varicose veins to be injected
decreases, this dilution is less and the results obtained are more
predictable.
[0003] Until recently, sclerosis was a technique selected in cases
of small and medium varicose veins, those with diameters equal to
or greater than 7 mm being treated by surgery. Sclerosis and
surgery complemented one another but sclerosis treatment continued
not to be applicable to large varicose veins. In these large
varicose veins, if a sclerosing substance was injected, its
concentration in the vein, its homogeneous distribution in the
blood, and the time for which it is in contact with the internal
walls of the vessel treated were not known.
[0004] In 1946, Orbach injected a few cubic centimetres of air into
small varicose veins and confirmed a displacement of the blood
inside the vessel which was occupied by the injected air. A
sclerosing solution introduced immediately afterwards was more
effective than if it had been injected into the blood. However, in
thick varicose veins, when air is injected the phenomenon described
of the displacement of the blood by the injected air does not occur
but the air forms a bubble inside the vein which makes the method
ineffective in these vessels.
[0005] The same author had the idea, a few years later, of
injecting foam obtained by agitation of a container containing
sodium tetradecyl sulphate, which is an anionic sclerosing
detergent with a good foaming capability. The method was of little
use owing to the large size of the bubbles formed and was dangerous
owing to the side effects of atmospheric nitrogen which is only
slightly soluble in blood. Both methods had limited practical
repercussion being used only in small varicose veins.
[0006] An injectable microfoam suitable for therapeutic uses has
now been developed and is described in EP 0656203 and U.S. Pat. No.
5,676,962 (incorporated herein by reference). These patents
describe a microfoam produced with a sclerosing substance which,
when injected into a vein, displaces blood and ensures that the
sclerosing agent contacts the endothelium of the vessel in a known
concentration and for a controllable time, achieving sclerosis of
the entire segment occupied.
[0007] The advantages of use of this foam are that it allows the
concentration of the sclerosing agent in the blood vessel to be
known, since the microfoam displaces the blood and is not diluted
therein in to the same extent as a simple liquid would be.
Furthermore it allows homogeneous distribution of the sclerosis
product in the vein to be ensured and the time for which it is kept
in contact with the internal walls of the vein to be controlled.
None of which factors is known precisely or is controllable with
the use of sclerosing agents in simple liquid form.
[0008] The preparation of such a microfoam may be carried out with
a solution of any sclerosing substance, particularly polidocanol,
alkali metal tetradecyl sulphate eg. sodium salt, hypertonic
glucose or gluco-saline solutions, chromic glycerol, ethanolamine
oleate, sodium morrhuato or iodic solutions.
[0009] However, this known method requires production of microfoam
by the physician, pharmacist or an assistant immediately prior to
administration to the patient. Such procedure allows for variation
of agent depending upon the person preparing it, with content of
gas, bubble size and stability all needing attention with respect
to the condition being treated. It also requires a high degree of
care and knowledge that may be difficult to replicate under
pressure, ie. when time available to prepare the foam is short.
[0010] The method particularly described in the aforesaid patents
uses a high speed beating action with a brush to generate a foam of
correct property. Other reported techniques in use do not produce
such uniform, stable or injectable microfoam and notably include
those where gas is bubbled, eg sparged into the sclerosant, eg. by
leakage into a sclerosant filled syringe from around the side of
the syringe plunger.
[0011] Furthermore, a problem in using air as the gas for producing
the foam is the perception that large volumes of nitrogen should
not unnecessarily be introduced into patients, particularly where
large vessels are being filled with foam and eliminated. Gas
embolism with nitrogen remains a possibility.
[0012] The solubility of physiological gases in aqueous fluids,
such as blood, varies considerably. Thus while nitrogen is almost
twice as insoluble in water as oxygen at STP, carbon dioxide is
over fifty times as soluble in aqueous liquids as nitrogen and over
twenty five times as soluble as oxygen.
TABLE-US-00001 TABLE 1 Solubility of Gases in water at STP Gas Mole
Fraction Solubility 10.sup.-5 Helium 0.7 Nitrogen 1.18 Oxygen 2.3
Xenon 7.9 Nitrous oxide 43.7 Carbon dioxide 61.5
[0013] At the present time it is perceived that production of such
microfoam with gases incorporating high proportions of gas that is
readily dispersed in blood, such as carbon dioxide, would be
desirable for the purposes of minimising the prospect of the
treatment producing a gas embolism. However, it is also perceived
by practitioners that this is difficult task due to its high
solubility in water.
[0014] It would also be desirable to provide a relatively stable
microfoam of uniform character that is readily producible by use of
a relatively simple and reliable mechanism, rather than one
involving use of high speed mixing or beating, the time of
performance of which may affect foam property.
[0015] It is particularly desirable that the microfoam so produced
may be passed through a needle of gauge suitable for injecting into
blood vessels without being significantly converted back to its
separate gas and liquid components and/or changing characteristics
such as significantly increasing bubble sizes.
[0016] Such a needle may be of very small diameter, eg a 30 gauge
needle (0.14 mm interior diameter). More typically it will be
larger eg. an 18 to 22 gauge needle (interior diameter 0.838 to
0.394 mm), more preferably 19 to 21 gauge (interior diameter. 0.686
mm).
[0017] The rate at which the foam is passed down the needle can be
such that any foam might be broken down, but it is desirable that a
foam is produced that does not break down under normal injection
conditions, ie. at rates compatible with control of entry of foam
into a vein. For example, it should withstand injection at rates of
0.1 to 0.5ml/second, more preferably 0.3 to 1 ml/second for a 19 to
21 gauge needle.
[0018] It is still further desirable to provide a device that is of
sterile type with regard to the foam it generates particularly with
regard to micro-organisms and pyrogens.
[0019] It is particularly desirable to provide a sealed device that
operates to produce foam of set property suitable for a given
medical procedure without technical input from the physician who
will perform the procedure, or assistants thereof.
[0020] One form of device that could potentially provide these
desired properties would be an aerosol dispenser of a type that
produces foams. However, for the purposes of generating a microfoam
to be injected into a human or animal body, it is undesirable to
have a propellant gas of the type usually employed in aerosol
canisters, eg such as isopropane. This determines that the gas from
which the foam is to be made must itself be pressurised to allow
production of foam.
[0021] Water soluble gases such as carbon dioxide have been found
by the inventors to be incapable of producing a stable foam when
generated by merely being passed through a standard aerosol valve
under pressure, such as might be expected to convert a detergent
solution such as one of polidocanol or sodium tetradecylsulphate to
a foam. They have determined that when this gas is used under
pressure to propel a sclerosing agent solution through a
conventional aerosol valve the foam produced, while initially
containing at least some microfoam structure, is not sufficiently
stable to be applied to the treatment of blood vessels as described
in EP 0656203 and U.S. Pat. No. 5,676,962. Such foam is furthermore
incapable of being passed through a syringe needle without
significant reversion to liquid and gas phases. It will be realised
by those skilled in the art that the microfoam technique exploits
the ability of the gas to deliver the sclerosant solution to the
wall of the vessel to be treated, rather than to allow its dilution
in blood as in the liquid phase.
[0022] Aerosol units that are capable of producing foam have been
described in the prior art. U.S. Pat. No. 3,471,064 describes a
device wherein air is drawn into a foamable liquid through a series
of small holes in the dip tube of the unit. Such a device is not
sterile in operation as it relies on its contents being open to the
air. Foam so produced would appear to vary in properties dependent
upon how much air is drawn in. A further device is described in
U.S. Pat. No. 3,428,222 and utilises a wicking and foaming element
in a compressible container that again draws in air to produce
foam.
[0023] U.S. Pat. No. 3,970,219 describes sealed aerosol devices
which are capable of using pharmacologically inert gases to foam
and expel liquid compositions, It describes devices which produce
foam by passage of the propellant through a material having pores
of 0.01 to 3 mm diameter from a lower propellant gas holding
chamber to an upper foam holding chamber. The liquid to be foamed
sits in the upper chamber or is absorbed onto the porous material
by shaking the container or is wicked up from a lower chamber. This
patent teaches that liquid from foam in the upper chamber drains
down into the lower chamber, such that the thinnest walled bubbles
are expelled, and teaches that the propellant gas should be `less
soluble`, such as nitrogen, fluorocarbon or hydrocarbon, where
aqueous liquids are to be foamed.
[0024] Similar bubbler devices are used in accessories for use with
`environmentally friendly` aerosol devices that operate using air
under low pressure, ie. hand pump conditions. Two such devices are
supplied by Airspray International as the `Airspray.RTM. Finger
Pump Foamer` and `Airspray Mini-Foamer`. The former is said to be
suitable for simple water based formulations while the latter is
suggested for cosmetics, hair or skin care preparations. A second
such device is provided as an optional extra in the
Swedspray/Eurospray.RTM. hand pump device as a foaming nozzle. This
device is marketed as being suitable for use to `make you own
cleansing foam or shaving lather`.
[0025] However, the present inventors have found that use of the
available hand-pump devices themselves, which in any case are not
sterile, cannot produce good microfoam with high loadings of carbon
dioxide due to outgassing, nor with inclusion of significant
amounts of glycerol which otherwise stabilises microfoam.
Furthermore, when significant back-pressure is applied to the
outlet of such device, such as when attached to a syringe to be
loaded for injecting the foam, stuttering occurs. Use of low
ejection velocity with this device can cause wetting at the nozzle
which results in large bubbles caused by air entrapment. In any
case the foams so produced, whether with oxygen or carbon dioxide,
tend to be very dry, with resultant nccd for high concentration of
sclerosant to be included, and tendency to break up on passage down
a needle.
[0026] It is preferred not to unnecessarily use high concentrations
of sclerosant in the solution as this could result in overdosage
should a dispensing device fail and deliver a more dense microfoam,
ie. including a higher proportion of liquid than intended.
[0027] Thus there is a need to provide a method and device that are
capable of producing a uniform injectable microfoam made with a
relatively low concentration of a sclerosing agent and a
significant amount of a blood dispersible gas in sterile fashion
without volatile liquid propellants or the need for the operator to
directly be concerned in control of its parameters.
[0028] The present applicants have now provided a method and
devices capable of addressing at least some of the aforesaid needs
and have produced a novel stable injectable sclerosing microfoam
with that method and devices.
[0029] For the purpose of this application terms have the following
definitions: Physiologically acceptable blood dispersible gas is a
gas that is capable of being substantially completely dissolved in
or absorbed by blood. A sclerosant liquid is a liquid that is
capable of sclerosing blood vessels when injected into the vessel
lumen. Scleropathy or scelrotherapy 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 microfoam is the time taken for
half the liquid in the microfoam to revert to unfoamed liquid
phase.
[0030] In a first aspect of the present invention there is provided
a method for producing a microfoam suitable for use in scleropathy
of blood vessels, particularly veins, characterised in that it
comprises passing a mixture of a physiologically acceptable blood
dispersible gas and an aqueous sclerosant liquid through one or
more passages having at least one cross-sectional dimension of from
0.1 to 30 .mu.m, the ratio of gas to liquid being controlled such
that a microfoam is produced having a density of between 0.07 g/ml
to 0.19 g/ml and a half-life of at least 2 minutes.
[0031] Preferably the microfoam is such that 50% or more by number
of its gas bubbles of 25 .mu.m diameter and over are no more than
200 .mu.m diameter.
[0032] Preferably the gas/liquid ratio in the mix is controlled
such that the density of the microfoam is 0.09 g/ml to 0.16 g/ml,
more preferably 0.11 g/ml to 0.14 g/ml.
[0033] Preferably the microfoam has a half-life of at least 2.5
minutes, more preferably at least 3 minutes. The half-life may be
as high as 1 or 2 hours or more, but is preferably less than 60
minutes, more preferably less than 15 minutes and most preferably
less than 10 minutes.
[0034] Half-life is conveniently measured by filling vessel with a
known volume and weight of foam and allowing liquid from this to
drain into a graduated vessel, the amount drained in a given time
allowing calculation of half-life ie. of conversion of microfoam
back into its component liquid and gas phases. This is preferably
carried out at standard temperature and pressure, but in practice
ambient clinic or laboratory conditions will suffice.
[0035] Advantageously and 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.
[0036] Preferably 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, eg. approximately 1
mm and over, and over such as can be produced by lightly agitating
the two phases by shaking. Preferably the gas and liquid are in
provided in the form of an aerosol where a source of pressurised
gas and a means for mixing the two is provided to the point of use.
It may be preferred that a macrofoam is first produced where the
liquid and gas are brought together only at the point of use.
[0037] The ratio of gas to liquid used in the mixture is important
in order to control the structure of the microfoam produced such
that its stability is optimised for the procedure and the
circumstances in which it is being carried out. For optimum foams
it is preferred to mix 1 gram sclerosant liquid with from
approximately 6.25 to 14.3 volumes (STP), more preferably 7 to 12
volumes (STP), of gas.
[0038] Preferably the physiologically acceptable blood dispersible
gas comprises a major proportion of carbon dioxide and/or oxygen.
Conveniently it may comprise a minor proportion of nitrogen or
other physiologically acceptable gas. 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.
[0039] In one preferred form the gas used is a mixture of carbon
dioxide and other physiological gases, particularly containing 3%
or more carbon dioxide, more preferably from 10 to 90% carbon
dioxide, most preferably 30 to 50% carbon dioxide. The other
components of this gas are preferably oxygen with a minor
proportion only of nitrogen being preferred. Most preferably the
other component is oxygen.
[0040] A further preferred 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 preferred gas is 60 to 90% vol/vol oxygen and 40 to 10%
vol/vol carbon dioxide, more preferably 70 to 80% vol/vol oxygen
and 30 to 20% vol/vol carbon dioxide. More preferred is 99% or more
oxygen.
[0041] It is found that passing a stream of the sclerosant liquid
and the gas under pressure through one or more passages of 0.1
.mu.m to 30 .mu.m as described provides a stable blood dispersible
gas based sclerosant injectable microfoam that was previously
though to be only producible by supply of high amounts of energy
using high speed brushes and blenders.
[0042] Preferably the sclerosing agent is a solution of polidocanol
or sodium tetradecylsulphate in an aqueous carrier, eg 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, eg. 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.
[0043] Polidocanol is a mixture of monolaurylethers of macrogols of
formula C.sub.12C.sub.25(OCH.sub.2CH.sub.2).sub.nOH with an average
value of n of 9. It will be realised that mixtures with other alkyl
chains, oxyalkyl repeat units and/or average values of n might also
be used, eg. 7 to 11, but that 9 is most conveniently obtainable,
eg. from Kreussler, Germany, eg as Aethoxysklerol.
[0044] Most preferably the concentration of sclerosant in the
aqueous liquid is a 1-3% vol/vol solution, preferably of
polidocanol, in water or saline, more preferably about 2% vol/vol.
The water or saline also, in some cases at least, preferably
contain 2-4% vol/vol physiologically acceptable alcohol, eg
ethanol. Preferred saline is buffered. Preferred buffered saline is
phosphate buffered saline. The pH of the buffer is preferably
adjusted to be physiological, eg from pH6.0 to pH8.0, more
preferably about pH7.0.
[0045] The sclerosant may also contain additional components, such
as stabilising agents, eg foam stabilising agents, eg such as
glycerol. Further components may include alcohols such as
ethanol.
[0046] 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.
[0047] The interface device may however be very simple, such as a
single chamber or passage of millimetre dimensions, ie. 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.
[0048] 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 pressurised 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.
[0049] The one or more passages through which the aerosol or
macrofoam so produced are passed to produce the stable microfoam
preferably have diameter of from 5 .mu.m to 25 .mu.m, more
preferably from 10 .mu.m to 20 .mu.m where simple passages arc
provided, such as provided by openings in a mesh or screen, eg. of
metal or plastics, placed perpendicular to the flow of gas/liquid
mixture. The passage is conveniently of circular or eliptical cross
section, but is not necessarily so limited. A number of such meshes
or screens may be employed along the direction of flow.
[0050] 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, eg 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, eg. 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.
[0051] Where several elements are used in series these are
prefereably spaced 1 to 5 mm apart, more preferably 2 to 4 mm apart
eg. 3 to 3.5 mm apart.
[0052] 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.
[0053] Alternatively the method provides for passing the mixture of
gas and liquid through the same set of passages, eg as provided by
one or more such porous bodies, a number of times, eg. from 2 to
2,000, more preferably 4 to 200 times, or as many times as
conveniently results in a microfoam of the required density set out
above. It will be realised that the more times the microfoam passes
through the meshes, the more uniform it becomes.
[0054] 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 pressurised
chamber, 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, eg 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.
[0055] In one preferred form of the invention the passages are in
the form of a membrane, eg of polymer such as
polytetrafluoroeythylene, 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 biaxilally oriented PTFE
film provided by Tetratec.TM. USA under the trademark
Tetratex.RTM., 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.
[0056] 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, eg. pores in a mesh, screen,
membrane or sinter provides energy sufficient to produce a stable
aqueous liquid soluble gas, eg carbon dioxide and/or oxygen, based
sclerosant microfoam that was previously though to be only
producible by supply of high amounts of energy using high speed
brushes and blenders as described in the prior art.
[0057] Preferably the method of the invention provides a microfoam
having at least 50% by number of its gas bubbles of 25 .mu.m
diameter or over being no more than 120 .mu.m diameter. Preferably
at least 95% of its gas bubbles of 25 .mu.m diameter or over are of
no more than 250 .mu.m diameter. Diameter of such bubbles may be
determined by the method set out in the Example 6 set out
herein.
[0058] 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 pressurised,
fluid will be forced along the pathway and through one or more
outlet orifices.
[0059] The method is particularly characterised in that the housing
incorporates one or more of (a) a pressurised 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.
[0060] 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, eg flow through, the passages the solution and gas
form a the micro foam.
[0061] 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, eg. by shaking of the device, eg, by hand, or mechanical
shaking device.
[0062] In a second aspect of the present invention there is
provided a device for producing a microfoam suitable for use in
scleropathy of blood vessels, particularly veins, comprising a
housing in which is situated a pressurisable chamber containing a
solution of the sclerosing agent in a physiologically acceptable
solvent referred to in the first aspect; a pathway with one or more
outlet orifices by which the solution may pass from the
pressurisable chamber to exterior of the device through said one or
more outlet orifices and a mechanism by which the pathway from the
chamber to the exterior can be opened or closed such that, when the
container is pressurised and the pathway is open, fluid will be
forced along the pathway and through the one or more outlet
orifices
said housing incorporating one or more of (a) a pressurised 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
[0063] 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 30 .mu.m, through
which the solution and gas mixture is passed to reach the exterior
of the device, said passing of said mixture through the passages
forming a microfoam of from 0.07 to 0.19 g/ml density and of
half-life at least 2 minutes.
[0064] Preferably the microfoam has 50% or more by number of its
gas bubbles of 25 .mu.m diameter and over of no more than 200 .mu.m
diameter.
[0065] More preferably the microfoam is from 0.09 to 0.16 g/ml
density and most preferably of 0.11 g/ml to 0.14 g/ml.
[0066] Preferably the microfoam has a half-life of at least 2.5
minutes, more preferably at least 3 minutes.
[0067] Advantageously and preferably this device provides a
microfoam 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 or less, more preferably at least 95% by number of these
gas bubbles are of diameter 280 .mu.m or less. Still more
preferably at least 50% by number of these gas bubbles are of no
more than 120 .mu.m diameter and still more preferably at least 95%
of these gas bubbles are of no more than 250 .mu.m diameter.
[0068] Preferably the apparatus includes a chamber, eg such as in a
sealed canister, charged with the blood dispersible gas and the
sclerosant liquid, eg. 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.
[0069] 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, ie.
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.
[0070] 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. 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.
[0071] A preferred device of this aspect of the invention is of the
`bag-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 microfoam. A suitable one-way valve is a duck-bill
type valve, eg 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.
[0072] Conveniently the one way valve is located at the top of the
dip-tube between that and the gas liquid interface junction, ie. an
Ecosol device. This allows filling of the bag before application of
the one way valve, followed by sterilisation of the contents,
whether in the canister or otherwise.
[0073] 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, eg. during sterilisation
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 microfoam 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.
[0074] 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 pressurised chamber, ie.
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 pressurised chamber this is
preferably higher.
[0075] A third aspect of the invention provides a device for
producing a microfoam 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 tillable
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 pressurised
such that its contents pass to the exterior along the pathway and
through one or more outlet orifices
said pathway to the exterior of the housing or the chamber
including one or more elements defining one or more passages of
cross sectional dimension, preferably diameter, 0.1 .mu.m to 30
.mu.m through which the contents of the chamber may be passed,
whereby on passing through the passages the solution and gas form a
microfoam of from 0.07 to 0.19 g/ml density and having a half-life
of at least 2 minutes.
[0076] Preferably the microfoam is such that 50% or more by number
of its gas bubbles of 25 .mu.m or more diameter are of no more than
200 .mu.m diameter.
[0077] Preferably the microfoam is of density 0.09 to 0.16 g/ml and
more preferably of 0.11 g/ml to 0.14 g/ml. The preferred limits on
bubble size are also as for the first and second aspects.
[0078] Preferably the microfoam has a half-life of at least 2.5
minutes, more preferably at least 3 minutes
[0079] 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.
[0080] Such device may be conveniently constructed in the form of a
syringe device, comprising a syringe barrel and a functionally
co-operating syringe plunger defining a chamber, the plunger being
the means for pressurising the chamber, that chamber containing the
gas and liquid in use, but which is particularly characterised by
being formed with the passages of aforesaid dimension adjacent or
at the needle affixing end of the syringe body, eg at a luer
connection opening.
[0081] In use such a device is partially charged with the required
sclerosant liquid and then charged with the physiologically
acceptable gas, or vice versa, by withdrawing the syringe plunger
while connecting the luer opening to a source of each in turn.
Alternatively these may be mixed beforehand as a macrofoam, or even
as a microfoam which by its nature will be breaking down. Where the
gas and liquid are charged as separate phases the syringe contents
may be agitated such as to produce a foam. The plunger is then
pushed into the syringe body whereby this foam passes through the
passages and is converted to a microfoam having the required
stability for the procedure concerned. Where the gas and liquid are
charged together as a foam, operation of the plunger will provide
the microfoam.
[0082] In a preferred embodiment of this device two chambers are
provided and are linked to each other through a passage, eg
including the syringe body luer connector orifice, via the one or
more passages of 0.1 .mu.m-30 .mu.m dimension. In this manner
reciprocation of a plunger in one or both of the chambers results
in the gas and liquid being passed through the passages of defined
dimension a desired number of times to produce the desired
foam.
[0083] In an alternative embodiment an element defining a number of
the passages of said dimension is provided within the chamber such
that it can be moved in either direction to pass chamber contents
through its passages. Conveniently this element may be mounted on a
support, such as a support plunger rod coaxial to the syringe
plunger rod. The element may incorporate any of the porous
passageway defining items referred to above, but conveniently
includes meshes or a porous membrane mounted with major surfaces
perpendicular to the syringe barrel/chamber longitudinal axis such
that movement of the support rod in either direction longitudinally
results in a sweeping action by the element such that chamber
contents, gas and liquid, are passed through the passages together.
It will be realised that once such a device is charged with a
suitable ratio of gas and liquid, it may also be shaken to give a
loose macrofoam as a first step.
[0084] 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.
[0085] 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.
[0086] 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-30
.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.
[0087] Preferably the canister or syringe device is sized such that
it contains sufficient gas and solution to form up to 500 ml of
microfoam, more preferably from 1 ml up to 200 ml and most
preferably from 10 to 60 ml of microfoam. Particularly the amount
of gas under pressure in such canisters should be sufficient to
produce enough foam to treat, ie. 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.
[0088] 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.
[0089] In order to ensure that the micro foam delivered from
devices of the invention is not `outside` specification, ie. falls
within the desired density, bubble size and half life parameters
set out above, the present invention provides a further, fourth,
aspect which provides a device which is positioned to receive
microfoam emitted from the device of the second and third aspects
of the invention, which device allows venting of the first portion
of microfoam to waste and passage of a second portion of microfoam
to a delivery device, such as a syringe, in sterile fashion.
[0090] A device of the fourth aspect comprises an inlet conduit
being adapted to engage the outlet of a microfoam producing device
of the second or third aspect in a microfoam tight fashion, the
conduit being connected to and leading through a multipath tap
capable of being set to direct microfoam passing down the conduit
to one or both of first and second contiguous outlet conduits or to
close the inlet conduit, at least one of the first and second
outlet conduits being adapted to receive the luer connector of a
syringe. Preferably the device also comprises one or more elements
for engaging the device of the second or third aspect other than by
its outlet nozzle to hold it securely, eg upright in the case of a
canister with a dip-tube.
[0091] Preferably the device of the fourth aspect comprises a
three-way tap. More preferably the device of the fourth aspect
comprises a base element, sufficiently stable to mount a microfoam
producing device of the second or third aspects when engaged
thereby. Preferably the microfoam producing device is engaged by
resilient elements which locate it securely adjacent the three-way
tap whereby the inlet conduit can be attached to the micro foam
producing device outlet conduit.
[0092] Particularly preferred the device of the fourth aspect
comprises a base element adapted mount the microfoam dispensing
device and an activating element which operates to cause the
pathway to be opened the to the inlet conduit. In this manner when
the multi-way tap is shut, the dispensing device contents remain
therein, but when the multi-way tap is opened to either of its
outlet conduits it immediately causes release of foam generated by
the device.
[0093] A further aspect of the present invention provides improved
microfoams for use in the elimination of blood vessels and vascular
malformations that are made available by the method and devices of
the invention characterised in that they comprise a physiologically
acceptable gas that is readily dispersible in blood together with
an aqueous sclerosant liquid characterised in that the microfoam
has a density of from 0.07 to 0.19 g/cm and is capable of being
passed down a 21 gauge needle without reverting back to gas and
liquid by more than 10%, based on liquid content reverting back to
unfoamed liquid phase.
[0094] Preferably the microfoam, 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%.
[0095] Preferably the microfoam 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.
[0096] Preferably at least 50% by number of said gas bubbles remain
at no more than 150 .mu.m diameter and at least 95% of these
bubbles at no more than 280 .mu.m diameter. Preferably the
microfoam has a half-life as measured by drainage through a funnel
of 2cm neck diameter and drainage path 10 cm of at least 2 minutes,
more preferably 2.5 minutes and most preferably 3 minutes. This may
be carried out at ambient temperature or STP. 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 microfoam filled syringe upside down, without its plunger, above
the funnel leading into a graduated receptacle allows convenient
measurement of this parameter.
[0097] Preferably the gas includes less than 40% v/v nitrogen.
Preferably the density of the microfoam is from 0.09 to 0.16 g/ml,
more preferably 0.11 g/ml to 0.14 g/ml.
[0098] Advantageously and preferably at least 50% by number of the
gas bubbles of 25 .mu.m diameter or more are of no more than 120
.mu.m diameter and still more preferably at least 95% of these gas
bubbles are of diameter 250 .mu.m or less.
[0099] Preferably 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.
[0100] Preferably 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, eg
substantially 100% oxygen or carbon dioxide. Preferably the oxygen
or carbon dioxide is medical grade.
[0101] Preferably the sclerosant is aqueous polidocanol or sodium
tetradecyl sulphate.
[0102] When the sclerosant is aqueous polidocanol the concentration
of polidocanol is from 0.5 to 4% vol/vol in the liquid, preferably
being 1 to 3% vol/vol polidocanol and most preferably being 2%
vol/vol in the liquid.
[0103] Advantageously the sclerosant is made up in water, but more
advantageously is made up in a saline solution, particularly 10 to
70 mM phosphate buffered saline, eg. 50 mM phosphate buffered
saline, and preferably of pH6 to pH8.0 eg. about pH 7.0.
Advantageously the aqueous solution contains a minor amount of an
alcohol, preferably 96% ethanol, eg at between 2 and 6% vol/vol,
more preferably at about 4% vol/vol of 96% ethanol.
[0104] Addition of glycerol to the aforesaid sclerosant imparts a
longer half-life to the resultant foam. However, glycerol 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.
[0105] 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.
FIGURES
[0106] FIG. 1: Shows a cross-sectional view of a canister device of
the second aspect of the invention as further described in Example
2 below.
[0107] FIG. 2: Shows a cross-sectional view of a canister device of
the second aspect incorporating a bag-on-valve reservoir for the
sclerosant with the gas being in the outer chamber and separated
therefrom by a one way duck-bill valve.
[0108] FIG. 3: Shows a cross-sectional view of a syringe-like
device of the third aspect incorporating a set of meshes across its
dispensing chamber.
[0109] FIG. 4: Shows a cross-sectional view of a syringe-like
device of the third aspect incorporating a porous membrane
supported on an inner plunger rod such that it can be reciprocated
within the syringe chamber contents.
[0110] FIG. 5: Is a bar chart and graph illustrating distribution
of gas bubble diameter in a preferred 0.13 g/ml
oxygen/air/polidocanol microfoam of the fourth aspect.
[0111] FIG. 6: Is a bar chart and graph illustrating distribution
of gas bubble diameter in microfoams of 0.09 g/ml and 0.16 g/ml of
the fourth aspect.
[0112] FIG. 7: Is a graph showing the effect of passing a preferred
foam of the fourth aspect down a 21 gauge needle as compared to
control fresh and similarly aged microfoams.
[0113] FIG. 8: Is a graph showing the effect of passing a 2% vol
polidocanol solution dry microfoam of 0.045 g/ml , such as
producible by use of a prior art bubbler device (Swedspray valve,
Ecosol insert and head), down a 21 gauge needle.
[0114] FIG. 9: Is a graph showing the effect of passing a 1% vol
polidocanol dry microfoam of 0.045 g/ml such as producible by use
of the prior art bubbler device (Swedspray valve, Ecosol insert and
head), down a 21 gauge needle.
[0115] FIG. 10: is an elevation view of a syringe filling device of
the fourth aspect.
[0116] FIG. 11: Is a plan view of the device of FIG. 10.
EXAMPLES
Example 1
[0117] A standard aerosol canister with a one way depressible
action valve is charged half full with a 3% v/v solution of
polidocanol in sterile water and pressurised to 3 atmospheres with
a 50:50 mix of carbon dioxide and oxygen. On the valve stem is
mounted an actuator and delivery head which carries four plastics
screens, just under 0.5 mm thick, perforated with 20 .mu.m diameter
passages, these screens being of the general type provided in the
Swedspray-Eurospray foaming actuator cap ApRisC.RTM. device. The
valve is fed through an Ecosol gas liquid interface insert from a
dip-tube and the surrounding chamber. Gas inlet sizes (x2) into the
insert are 0.006''.times.0.01'' while the single liquid inlet is
0.024'', as controlled by selecting Ecosol insert size. On
depression of the head the aerosol valve releases pre-mixed
solution and gas onto the screens whereupon a microfoam suitable
for scleropathy and that is dimensionally stable for at least 2
minutes, preferably 5 minutes using glycerol in the is
produced.
Example 2
[0118] FIG. 1 illustrates a further canister design of the
invention wherein the passages through which the gas liquid mixture
must travel are placed within the pressurised chamber, thus
increasing hygiene of the device.
[0119] The canister is of standard 500 ml design with an aluminium
wall (1), the inside surface of which is coated with an epoxy resin
resistant to action of polidocanol and oxygen (eg Hoba 7940-Holden
UK)) . The bottom of the canister (2) is domed inward. The canister
inner chamber (4) is pre-purged with 100% oxygen for 1 minute,
containing 15 ml of a 2% vol/vol polidocanol/20 mmol phosphate
buffered saline solution (3) then filled with the oxygen at 2.7 bar
gauge (1.7 bar over atmospheric). This is provided by
overpressuring the polidocanol part filled can with 1.7 bar
oxygen.
[0120] The dome provides a perimeter area around the bottom of the
inner chamber in which a level of polidocanol solution is retained
sufficient for the bottom open end of a dip tube to be submerged
therein when the top of the dome is no longer covered with the
solution. In this manner, by use of an indicia on the outside of
the canister to indicate the position of the dip tube, the canister
can be oriented to extract the last fraction of solution if
desired. In practice a vertical orientation is sufficient.
[0121] A standard 1'' diameter aerosol valve (5) (Precision Valves,
Peterborough) is crimped into the top of the canister after sterile
part filling with the solution and is activatable by depressing an
actuator cap (6) to release content via an outlet nozzle (13) sized
to engage a luer fitting of a syringe or multi-way connector (not
shown). A further connector (7) locates on the bottom of the
standard valve and mounts, preferably by interference fit, four
Nylon 66 meshes held in high density polyethylene (HDPE) rings (8)
all within an open ended polypropylene casing. These meshes have
diameter of 8 mm and have a 15% open area made up of 20 .mu.m
pores, with the meshes spaced 3.5 mm apart by the HDPE rings.
[0122] A further connector (9) locates on the bottom of the
connector holding the meshes and receives a housing (10) which
mounts the dip tube (12) and includes gas receiving holes (11a,
11b) which admit gas from chamber (4) into the flow of liquid which
rises up the diptube on operation of the actuator (6). These are
conveniently defined by an Ecosol device with insert as before.
Holes (11a,11b) have cross-sectional area such that the sum total
ratio of this to the cross-sectional area of the diptube is
controlled to provide the required gas/liquid ratio. This is for
example 0.010''.times.0.013'' each hole (11a, 11b) to 0.040''
liquid receiving hole.
Example 3
[0123] A further canister embodiment of the present invention is
shown in FIG. 2, which is broadly as shown in FIG. 1, but for the
inclusion of a modified `bag-on-valve` arrangement. In this
embodiment the polidocanol sclerosing solution (3) is enclosed in a
foil bag (22), comprising an aluminium foil/plastics laminate
(Coster Aerosols Stevenage UK) sealed in gas tight fashion to
dip-tube (12). At the top end of the dip-tube is a one-way
duck-bill valve (Vernay Labs Inc Ohio USA) that serves to prevent
contact of polidocanol with the contents of the dip-tube (12) and
chamber (4) until the valve (5) is operated. On said operation the
valve (21) opens and polidocanol solution (3) is caused to rise up
the dip-tube (12), whereby it becomes mixed with the air/oxygen gas
mixture entering through holes (11a, 11b). In this manner the can
may be safely sterilised with ionising radiatons which may
otherwise cause interactions between radical species in the gas and
the organic component of the polidocanol solution. Such arrangement
can also improve the operation of the canister with regard to start
up of foam delivery. The bag (22) preferably substantially only
contains the liquid (3), with no head-space gas above it.
Example 4
[0124] The device of this example is identical with that of Example
3, save that the polidocanol in the liquid is replaced with a
sodium tetradecylsulphate at 1% vol/vol, all other ingredients
being the same.
Example 5
[0125] FIG. 3 shows a syringe device that is specifically designed
to produce microfoam according to the invention using the method of
the invention. Syringe body (13) has a luer opening (14) and
locating flanges (15) and cooperates with a plunger (16) to define
a chamber (19). Chamber (19) is prefilled, or filled in use, with
sclerosing solution (18), in this case polidocanol as above. The
plunger has a sealing face (17) that is inert with respect to the
polidocanol solution and which ensures that said solution does not
escape around the sides of the plunger when that is depressed to
pressurise the contents of chamber (19).
[0126] Located between the plunger sealing face (17) and luer
opening (14) is a series of three spaced meshes (20) of the type
and configuration referred to in Example 2. In this example the
meshes are located such as to leave a space between them and the
luer opening such that a physician can see the foam produced by
passage of gas/liquid mixture through the meshes.
[0127] In operation such a syringe is preferably provided with the
plunger pushed in such as to define a reduced chamber (19) volume
filled with sclerosing solution with the luer opening sealed in a
sterile fashion, eg. by a foil seal cap attached to its exterior.
The cap is peeled off, the luer attached to a source of required
blood dispersible gas and the plunger withdrawn to admit a required
amount of gas to give a ratio of gas to liquid suitable such that
when agitated, eg. by shaking the syringe, a macrofoam is produced
containing a 7:1 to 12:1 ratio gas to liquid. For production of
foam the plunger is depressed with an even pressure, such as to
depress at 1 ml/second, and the macrofoam is converted to
microfoam.
[0128] It will be realised that the microfoam could be directly
applied to a patient, but more conveniently would be transferred
directly to a chamber, eg a second syringe, where viewing of a
large volume of foam such as would be required to eliminate a large
saphenous vein, would be more readily performed. In this manner,
should it be desired, the microfoam could be passed between the two
chambers via the meshes in order to render it still more uniform in
nature.
Example 6
[0129] FIG. 4 shows a further syringe device embodiment of the
invention designed to produce microfoam according to the invention
using the method of the invention. Syringe body (13) has a luer
opening (14) and locating flanges (15) and cooperates with a
plunger (16) to define a chamber (19). Chamber (19) is prefilled,
or filled in use, with sclerosing solution (18), in this case
polidocanol as above. The plunger has a sealing face (17) that is
inert with respect to the polidocanol solution and which ensures
that said solution does not escape around the sides of the plunger
when that is depressed to pressurise the contents of chamber
(19).
[0130] Passing down the central longitudinal axis of the plunger is
a rod (21) mounting a porous Tetratex membrane (22) of effective
pore size about 5 .mu.m in a double ring mounting. The rod (21) has
a handle (23) located outside the syringe chamber which allows the
membrane to be moved independently of the plunger such as to force
the contents of chamber (19) to pass through its pores.
[0131] In operation such a syringe is preferably provided with the
plunger pushed in such as to define a reduced chamber (19) volume
filled with sclerosing solution with the luer opening sealed in a
sterile fashion, eg. by a foil seal cap attached to its exterior.
The cap is peeled off, the luer attached to a source of required
blood dispersible gas and the plunger withdrawn to admit a required
amount of gas to give a ratio of gas to liquid. Eg. a 7:1 to 12:1
ratio gas to liquid. For production of foam the handle (23) on rod
(21) is operated to pass the membrane up and down the chamber a
number of times, eg 2 to 10 times, causing the gas and liquid to
mix and produce foam. For dispensing of foam directly to a patient,
or to another syringe or container, the rod (21) is withdrawn such
that membrane mounting (22) abuts the plunger sealing face and the
plunger is such depressed with an even pressure, eg. at 1
ml/second. Obviously when the foam is passed directly into a
patient a suitable needle is affixed to the luer connection.
Example 6
[0132] A microfoam of the invention is produced in a device as
described in Example 1, having critical passage and gas mixing
dimensions as set out in Example 2 but differing therefrom in that
mesh is located in the dispensing cap, downstream of the valve,
while gas/liquid mixing occurs in an Precision Valves Ecosol insert
device upstream of the valve. The chamber (500 ml) is charged with
15 ml of an aqueous solution containing per 100 ml polidocanol
(Kreussler-Germany) (2 ml), 96% ethanol (4 ml) and 55 mmol
Phosphate Buffer (pH7.0) (94 ml) with gas being air overpressured
with 1.5 bar 100% oxygen. The characteristics of the microfoam
produced on operation of the valve are shown in FIGS. 5 and 6. FIG.
5 shows bubble size distribution immediately after microfoam
generation; foam density being 0.138 g/ml. FIG. 6 shows bubble size
produced with varying ratio of gas to liquid, provided by altering
the gas/liquid interface hole size (11a, 11b) to give foams of 0.09
g/ml (closed diamonds) and 0.16 g/ml (open circles). FIG. 7 shows
the effect on bubble size distribution of a preferred micro foam
(0.13 g/ml) after passage through a 21 G needle: Open circles show
fresh foam, crosses control foam aged to match injection time and
closed diamonds show after passage through the needle. FIG. 8 shows
the effect of passing a microfoam made using a Swedspray device
density 0.045 g/ml through the needle. Closed diamonds are control
aged while open circles are after needle passage.
[0133] Note, when 5% glycerol is added to the formulation, half
life was increased to approximately 4 minutes.
[0134] Bubble sizes are calculated by taking up foam into a syringe
through its luer opening, optionally attaching a 21 G needle, and
injecting foam between two glass slides that are separated using
23.25 micron diameter beads (eg. available as microspheres from
Park Labs USA). Maxtascan/Global Lab Image technique was used to
analyse bubble size. Diameters of uncompressed bubbles (Dr) were
calculated from diameters of bubbles between slides (Df) using the
equation Dr=3 3Df.sup.2x/2 where x is the distance between the
slides. These measurements thus are made at ambient temperature and
pressure.
[0135] It will be realised that bubbles much smaller than 25 .mu.m
diameter may be present but not counted. The % figures given with
respect to bubble thus relate to bubbles in the range 25 .mu.m and
above.
Example 7
[0136] For filling of a syringe with microfoam of the invention the
bottom of a canister of Example 1, 2 or 3 is placed into a
receiving recess in the base of a syringe filling device as shown
in elevation in FIG. 10 and plan (FIG. 11). Canister (24) is
inserted into a 1 cm deep recess (25) in a plastics base element
(26), the recess being approximately 1 mm in diameter more than the
canister such that a snug fit is provided. The canister is further
supported by two resilient fixed arms (27a, 27b), fixed on vertical
support rod (28) that deform to receive the canister diameter. Just
above the top of the position of the canister cap in use, the
support rod (28) mounts an actuator arm that is lockable between a
first actuating position (full lines) an and an off position
(dotted lines). In the actuating position the arm depresses the
canister actuator cap (30), thus opening the canister valve and
causing microfoam to be released.
[0137] Also on the base (26) is a recess (32) sized to snugly
receive a syringe (34) with its plunger. A stop element (33) is
provided that is positioned such that on filling the plunger is
limited in its range of longitudinal movement such that the syringe
cannot be overfilled.
[0138] A flexible transparent plastics tube (35), inert to the
sclerosant foam, is attached to the canister outlet nozzle (31) in
use and is fixed to a three way valve (36) affixed to the base
(26). The valve is operated by turning a tap (37) to one of three
positions: (a) valve shut-no microfoam passage (b) valve open to
waste (38) whereby any microfoam that by visual inspection of the
contents of tube (35) appears unsuitable, is vented and (c) valve
open to syringe, whereby a set amount of microfoam passes through
the syringe luer and fills it until the syringe plunger abuts the
stop (33)
Example 8
[0139] 20 mls microfoam of Example 6 is loaded into a 20 ml syringe
using the device of Example 7 and the syringe disengaged from the
device. A 19 gauge needle is attached either directly to the
syringe luer fitting or via a catheter. The microfoam is
administered into to a varicose vein while its advance and final
position is monitored using a hand held ultrasound scanner such
that the fresh foam is restricted in location to the vein being
treated. After between 1 and 5 minutes the vein contracts and
subsequently becomes fibrosed.
* * * * *