U.S. patent application number 13/467301 was filed with the patent office on 2012-10-18 for automatic liquid injection system and method.
This patent application is currently assigned to BRACCO RESEARCH S.A.. Invention is credited to Jean Brochot, Christophe Golay, Laurent Jakob, Christian Mathieu, Michel Schneider, Feng Yan.
Application Number | 20120265065 13/467301 |
Document ID | / |
Family ID | 8230507 |
Filed Date | 2012-10-18 |
United States Patent
Application |
20120265065 |
Kind Code |
A1 |
Schneider; Michel ; et
al. |
October 18, 2012 |
Automatic Liquid Injection System and Method
Abstract
A power assisted method and injector device for controllably
delivering to patients a dispersion medicament or diagnostically
active agent, the homogeneity of which is preserved throughout
delivery. Diagnostically active agents disclosed are gas
microbubble suspensions useful in ultrasonic diagnostic imaging and
liposomal formulations in which liposome vesicles are loaded with
iodinated compounds.
Inventors: |
Schneider; Michel; (Troinex,
CH) ; Golay; Christophe; (Soral, CH) ; Jakob;
Laurent; (Bernex-Suisse, CH) ; Brochot; Jean;
(Feigeres, FR) ; Yan; Feng; (Grand-Lancy, CH)
; Mathieu; Christian; (Remoray, FR) |
Assignee: |
BRACCO RESEARCH S.A.
Plan-les-Ouates (Geneva)
CH
|
Family ID: |
8230507 |
Appl. No.: |
13/467301 |
Filed: |
May 9, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13010044 |
Jan 20, 2011 |
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13467301 |
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12208878 |
Sep 11, 2008 |
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13010044 |
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10769083 |
Jan 30, 2004 |
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12208878 |
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09204067 |
Dec 3, 1998 |
6726650 |
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10769083 |
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Current U.S.
Class: |
600/432 ;
604/506 |
Current CPC
Class: |
A61B 2090/3933 20160201;
B01F 2003/0035 20130101; A61B 2090/3925 20160201; B01F 2015/00636
20130101; A61M 5/1456 20130101; A61M 5/007 20130101; B01F 11/0002
20130101; A61B 2017/22008 20130101; A61M 2205/6072 20130101; B01F
9/0016 20130101 |
Class at
Publication: |
600/432 ;
604/506 |
International
Class: |
A61M 5/20 20060101
A61M005/20; A61B 6/00 20060101 A61B006/00 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 4, 1997 |
EP |
97810947.8 |
Claims
1. A method of administering to patients by injection or infusion a
suspension of microparticles homogeneously distributed in an
aqueous liquid carrier by means of an injector system comprising a
syringe containing said suspension and a power driven piston for
injecting said suspension into a patient, characterised by
subjecting the suspension in the syringe to a rotation or rocking
motion, thereby maintaining said suspension homogeneous by
preventing segregation of the microparticles by gravity or
buoyancy, this being without damaging said particles or disturbing
their distribution.
2. The method of claim 1, in which said motion is provided by
outside means for imparting motion to said particles, which motion
is then transferred to said liquid carrier.
3. The method of claim 1, in which said motion of rocking or
rotation is alternated.
4. The method of claim 3, in which said motion is applied along or
around the syringe longitudinal or transverse axis.
5. The method of claim 4, in which said motion is provided by
subjecting the syringe to continuous or intermittent rotation.
6. The method of claim 5, in which the rotation rate is from 0.5 to
200 rpm.
7. The method of anyone of preceding claims, in which said motion
is alternating rotation the direction of which is reversed every
30.degree., 60.degree., 90.degree., 180.degree., 270.degree. or
360.degree..
8. The method of claim 7, in which the direction is alternated at a
frequency of 0.5 Hz, 1.0, Hz, 1.5 Hz, 2.0 Hz, 2.5 Hz, 3.0 Hz or 3.5
Hz.
9. The method of anyone of preceding claims, in which said motion
is carried out stepwise.
10. An injector system for administering to patients by injection
or infusion a suspension of microparticles in an aqueous liquid
carrier, said system comprising a syringe (22) whose barrel (25)
contains said suspension, and automatic electromechanical power
means (24, 31, 34) controllably acting on the syringe to inject the
suspension into a patient, characterised in that said injector
system further comprises means (30a, 30b) for agitating said
microparticles in said suspension, said agitation keeping said
suspension homogenous by preventing segregation of said particles
by gravity or buoyancy without damaging said particles or
disturbing their distribution.
11. The injector system of claim 10, in which said means (30a, 30b)
for agitating the suspension in the syringe constitute means under
motion for supporting the syringe in the system, the effect of said
motion applied to the syringe being to agitate the liquid in the
syringe barrel.
12. The injector system of claim 11, in which said motion is a
rotation.
13. The injector system of claim 10 in which said injection means
acting on the syringe include a syringe plunger (26) driven into
forward or backward motion by helical screw means (23, 31, 32).
14. The injector system of claim 13, in which the position of the
plunger in the syringe is governed by a number of turns of said
helical screw means as controlled by said automatic power means
(31, 34).
15. The injector system of claim 12, characterized in that said
means under rotation are constituted by wheels (13) in contact with
the syringe barrel for driving it into consecutive rotation.
16. The injector system of claim 12, in which the syringe rotates
alternatively in one and the opposite direction.
17. The injector system of claim 16, in which the angle covered in
each alternate rotation is 30.degree., 60.degree., 90.degree.,
180.degree., 270.degree. or 360.degree..
18. The injector system of claim 11, in which the rotation rate of
the syringe is from 0.5 to 200 rpm.
19. The injector system of claim 11, further comprising a fixed
laser detector for reading identification marks provided on the
syringe.
20. The injector system of claim 10, further comprising safety
means for interrupting the injector operation in case of
emergency.
21. The injector system of claim 20, in which said security means
operate by monitoring the force applied to the syringe during
injection, a sudden increase of that force producing a signal for
stopping the injector operation.
22. The injector system of anyone of claims 10-21, in which the
suspension is a contrast agent for ultrasonic imaging of
patients.
23. The injector system of claim 22, in which the contrast agent
comprises, in suspension in an aqueous liquid carrier, gas filled
microvesicles which are either microbubbles bounded by a gas/liquid
interface made from dissolved surfactants, or microballoons bounded
by a material envelope made of organic polymers, or of di- or
tri-glycerides.
24. The injector system of claim 23, in which the gas is a pure
physiologically acceptable halogenated gas or gas mixture
comprising at least one physiologically acceptable halogenated
gas.
25. The injector system of claim 24, in which the halogenated gas
is selected from CF.sub.4, C.sub.2F.sub.6, C.sub.3F.sub.8,
C.sub.4F.sub.8, C.sub.4F.sub.10, C.sub.5F.sub.12, C.sub.6F.sub.14
or SF.sub.6.
26. The injector system of claim 24, wherein the gas mixture
contains a gas selected from air, oxygen, nitrogen, helium, xenon
or carbon dioxide.
27. The injector system of anyone of claims 23-26, in which at
least one of the surfactants is a saturated phospholipid in a
lamellar or laminar form.
28. The injector system of claim 27, in which at least one of the
phospholipids is a diacylphosphatidyl compound wherein the acyl
group is a C.sub.16 fatty acid residue or a higher homologue
thereof.
29. The injector system of claim 23, in which the polymer of the
membrane is selected from polylactic or polyglycolic acid and their
copolymers, denatured serum albumin, denatured haemoglobin,
polycyanoacrylate, and esters of polyglutamic and polyaspartic
acids.
30. The injector system of claim 29, in which the microballoons are
filled with C.sub.3F.sub.8 and the material envelope is made from
albumin.
31. The injector system of claim 23, in which the microballoons are
bounded by saturated triglycerides, preferably tristearine,
tripalmitine or mixtures of thereof with other glycerides, fatty
acids, and biodegradable polymers.
32. The injector system of anyone of claims 10-31, in which the
suspension is a contrast agent for CT imaging.
33. The injector system of claim 32, in which the contrast agent
comprises as a suspension in a liquid carrier phase liposomes
filled with an iodinated compound selected from iomeprol,
iopamidol, iopentol, iohexyl, metrizamide, iopromide, iogulamide,
iosimide or ioversol.
34. The injector system of claim 33, in which iodine over lipid
ratio I/L is 3 or more.
35. Use of the injector system according to anyone of claims 10-34
in imaging of organs, blood vessels and tissues of a mammalian.
36. Use of claim 33, in which the imaging is ultrasonic imaging and
the organ is the heart, the brain, the kidneys, the liver.
37. Use of the injector system according to anyone of claims 10-34
in imaging of organs, blood vessels and tissue of a mammalian.
38. Use according to claim 37, in which the imaging is CT imaging
and the organ is the liver.
Description
FIELD OF THE INVENTION
[0001] The present invention concerns the administration by
injection to patients of liquid compositions for therapeutic or
diagnostic purposes. It more particularly concerns a power assisted
method and device for controllably dispensing a liquid medicament
or diagnostically active contrast agent, the homogeneity of which
is preserved throughout delivery. Typically, the contrast agent is
an aqueous suspension of gas filled microvesicles, namely
microbubbles bounded by a surfactant stabilized gas/liquid
interface, or microballoons bounded by a tangible material
envelope.
BACKGROUND ART
[0002] Power injectors and mechanically assisted infusion systems
for controllably dispensing therapeutically active medications are
well known in the art. Typically, such devices include an automatic
injector for syringes containing an injectable liquid and a plunger
or piston movable within the barrel of the syringe to expel said
liquid through a tip thereof and injecting into a patient via a
tubing connected to an injecting needle or catheter. For
controlling the injections parameters, the plunger is driven by
means of an electromechanical arrangement organised to push the
plunger at a desired rate, continuously or at chosen intervals, so
that the amount of medication is delivered to the patient's body
under strictly determined conditions. For instance, in the case of
intravenous dispensing contrast agent formulations for diagnostic
purposes (X-ray, MRI or ultrasound), the rate and the mode of
injection can be accurately controlled to match the requirements of
the imaging methods and detector systems used to investigate the
circulation or a specific organ in the body. Typical automated
injection devices are illustrated and described in U.S. Pat. No.
5,176,646 incorporated herein by reference.
[0003] Although the automated injectors known are highly
sophisticated instruments capable of mastering most injection
problems experienced in practice, there remains at least one
variable factor not yet under control. Indeed the known power
injectors have no control of the homogeneity of the liquid stored
within the syringe barrel during the course of its application.
This kind of problem is of course non-existent with "true
solutions" (i.e. solutions to the molecular level) since in this
case no concentration change can occur in the course of time; it
however may become important when the injectable formulation is a
suspension or dispersion of active particles which tend to settle,
coalesce or segregate with time in the syringe. Indeed, even some
modest separation of the particles by gravity or otherwise from the
carrier liquid in the course of administration of the formulation
may have very important influence on reproducibility and
reliability of the tests. Hence, in this case, a method and means
to keep the syringe content homogeneous during injection is highly
desirable. The present method and device constitute a very
effective solution to the aforediscussed problem.
SUMMARY OF THE INVENTION
[0004] Briefly stated, in order to secure homogeneity of a liquid
suspension of particles within the barrel of an injector device,
the invention provides a method and means whereby the particles are
kept under sufficient agitation so as not to settle, segregate or
agglomerate in the carrier liquid. This may involve acting on the
carrier liquid itself, i.e. on the bulk of the suspension, or may
involve acting only on the particles (in this case, one would
expect the moving particles to impart motion to the carrier liquid
by viscous friction). The agitation means may be provided within
the syringe or in some cases outside thereof; for instance with
magnetic particles, the particles can be subjected to an external
variable magnetic field, the oscillation or rotation of which will
set them into motion, the moving particles then acting on the
carrier liquid and keeping the suspension homogeneous.
[0005] In the case of particles not sensitive to external fields,
mechanical agitation is provided to the extent that it is
sufficient to keep the suspension homogeneous but insufficient to
break or damage the particles or disturb their distribution. For
this, the syringe barrel may be subjected to motion, said motion
being continuous or discontinuous, regular or irregular; the motion
can possibly have a shaking, rocking or oscillating effect on the
syringe. The frequency, intensity and rate of the motion is such
that it will not interfere with the control of delivery parameters
of the suspension.
[0006] The embodiments disclosed below in connection with the
annexed drawings provides very effective means to keep the syringe
content under sufficient agitation to secure injection of a
homogeneous therapeutic or diagnostic liquid compositions into a
patient.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] FIG. 1 is a schematic view in perspective of a device for
agitating a liquid within the syringe of a power driven automatic
injector system of the invention.
[0008] FIG. 2 is a graph illustrating the homogeneity variations in
a suspension of microbubbles contained in a syringe, the latter
being either still or subjected to motion according to the
invention.
[0009] FIG. 3 is a graph illustrating the gas volume and in vitro
intensity of samples with and without treatment according to the
invention.
[0010] FIG. 4a is a schematic view in perspective of another device
for agitating a liquid within the syringe of a power driven
automatic injector system of the invention. In this embodiment, the
syringe is held by a supporting bracket, the latter being driven
into motion by a motor.
[0011] FIG. 4b is a schematical sectional view of the motor driving
means of the embodiment of FIG. 4a.
DETAILED DESCRIPTION OF THE INVENTION
[0012] The device represented schematically in FIG. 1 comprises a
series of co-operating elements mounted on a board 1. Such
schematic representation of the present device is only for clarity
and better understanding of the device's operation. Obviously, in
its actual commercial construction, the device is in the form of a
much more compact and sophisticated apparatus, for instance in the
form of an instrument like the Perfusor.RTM. fm of the Firm BRAUN
Meslungen AG, D-34209, Meslungen, Germany (displayed in Publication
B.03.01.95 No 0879 0744), or like the apparatuses disclosed in U.S.
Pat. No. 4,652,260 and U.S. Pat. No. 5,176,502, both being
incorporated herein by reference.
[0013] The present device comprises the following working
components: a syringe 2 shown in an uplifted position, an automatic
power driving unit 3 for acting on the syringe, a pair of syringe
motioning units 4 for liquid agitation, and a control box 14 for
controlling operation of the units 4.
[0014] The syringe 2 has a barrel 5, a plunger 6 sliding in the
barrel and a tip connector 7 linked to a tubing 8, the latter
leading to an injection needle 9. The needle 9 is for injecting an
administrable liquid into the tissues or the circulation of a
patient.
[0015] The power driving unit 3 has an electromechanically
controlled pusher rod 10 for acting on the rear end 11 of the
syringe plunger, and a control knob 12 for setting the automatic
driving parameters that will rule the action of the rod 10.
[0016] Each unit 4 is equipped with two rollers 13, themselves
driven into rotation by electric motors within the units and not
represented in the drawing. The rotation of the rollers 13 is
governed by means of a box 14 via lead wires 15 connected to said
motors.
[0017] In operation, an injectable carrier liquid with particles
(e.g. gas-filled microballoons) in suspension is introduced into
the barrel 5 of the syringe 2 through the tip 7, this being
consecutive to the retraction (manual or mechanical) of the plunger
6, so that an adequate pumping action is provided. Then the syringe
is placed on the rollers 13, so that the flange 16 thereof abuts
the roller's edge 17, this being for retaining the syringe in its
relative position against unwanted longitudinal translation. In
this situation, the pushing rod 10 of the driving unit 3 couples
with the plunger's end 11, so that any forward displacement of the
rod 10 is transferred to the plunger with consequent expelling of
the liquid toward the needle 9 for injection.
[0018] During injection, the rollers will alternately rotate the
syringe a certain angle in one direction, say 30.degree.,
60.degree., 90.degree., 180.degree., 270.degree. or 360.degree. and
then, reciprocably, in the opposite direction. This balancing
motion, which may be carried out in a stepwise manner, will move
the liquid carrier to such an extent that any separation or
segregation of the particles is hindered. This is very efficient
for instance in the case of suspensions of gas-filled microbubbles
used in echography since there is always a bubble size distribution
in such suspensions, the larger bubbles tending to rise faster than
the smaller ones by buoyancy. In a variant, the syringe can be made
to rotate in one direction only, provided that the connector tip 7
thereof is made to freely rotate in order to prevent distortion of
the tubing 8. Normally, the rate of rotation impressed by the
rollers 13 is from about 0.5 to 200 rpm depending upon the
suspension viscosity. This rate should be sufficient to keep the
particles in homogeneous suspension but insufficient to break the
particles or disturb their distribution in the carrier liquid. If
necessary, in the case of more viscous suspensions, an additional
vibrational motion of a few Hz to a few hundreds of Hz can be
applied to the syringe by means of a pitch-fork or pitch-pipe. It
should be mentioned that at very high rotation rates (e.g. 1,000
rpm or more) the radial speed may become dominant which will result
in axial concentration of the microbubbles in the middle of the
syringe. Rotational speeds at which the radial component becomes
important are to be avoided as under such conditions the suspension
will become non-homogeneous again. This is clearly undesired.
[0019] In a variant, the unit 4 can have the form of a closable
housing equipped with fixed syringe retaining means, i.e. other
than the rollers edges 17 and, possibly if required, pressure
resisting means (like a pressure mantle or jacket) in case the
suspension is viscous and exerts undue pressure efforts to the
syringe barrel. Also the syringe components can be made of moulded
plastic (disposable syringes) and the barrel external surface
provided with an integrally moulded relief pattern mating with
corresponding pattern on the roller's surface, so that positive
grip drive of the syringe is ensured.
[0020] Also, the rod 10 and the plunger 6 can be made integral with
each other so that filling of the syringe can be controlled by the
power unit 3, the pumping action then resulting from a backward
displacement of rod 10.
[0021] The power unit per se is standard and its nature and
operation well known to the skilled person. Embodiments thereof are
disclosed in the cited references and also in U.S. Pat. No.
5,456,670. The power unit usually contains an electrically powered
and controlled helical screw means for mechanically advancing or
retracting rod 10 continuously or intermittently, so that the
liquid in the syringe can be dispensed continuously or by
increments. The various parameters ruling said motions of the
syringe piston can be monitored and adjusted by the control 12 and
possible other control means not represented in the drawing. Means
of unit 3 also ensure that such delivery parameters can be
monitored and recorded for display. An instant stop switch (not
shown) may also exist, in case the operation of the system should
be suddenly interrupted due to a problem with the patient or
otherwise.
[0022] It should be incidentally noted that although the present
embodiment involves rocking the syringe only, one may also consider
a modification involving a back and forth rotation of the pumping
ensemble, this being achieved by well known mechanical means
adapted to support said pumping ensemble and to impart motion
thereto.
[0023] Furthermore, although the present embodiment involves motion
around the longitudinal axis, a variant may include rocking the
syringe about a transversal axis.
[0024] A second device embodiment illustrated schematically in
FIGS. 4a and 4b comprises a syringe 22 with a barrel 25 supported
in a rotatable fashion by a bracket 30a-30b and a plunger 26
sliding in the barrel whose displacement therein is controlled by a
power driven unit 23 capable of moving forward and backward in
engagement with the back pusher end of the plunger 26. The device
also comprises a motor driven unit 24 encompassing a portion 30b of
the supporting bracket, the latter being rotated through gears 31,
as better shown on FIG. 4b, for agitation of a liquid suspension in
the syringe barrel. The longitudinal forward or backward
displacement of the unit 23 (acting on the plunger 26) is effected
via a motor 31 which rotates a screw-bar 32, the latter engaging
with a matching threaded portion (not shown) within the unit 23.
The device further comprises an electronically computerized control
box 34 for controlling operation of the units 23 (via motor 31) and
24, and for processing the signals from a laser detector 35
designed to read an identifying mark 36 on the syringe; this mark
is for preventing errors in the selection of the syringe,
especially if the syringe is of the prefilled type. The code of the
mark can be according to standard bar codes. Note in this regard
that since the syringe barrel is set into rotation in the present
device, one can use a fixed detector instead of a mobile one which
is advantageous designwise. By counting and recording via box 24
the number of turns of the screw bar 32, the position of the unit
23 (and consequently of the plunger 26) can be monitored and
regulated at will. The control box 34 can of course comprise
further monitoring and visualizing means (not shown) to optically
display and appropriately regulate the various parameters involved
in operation of the device. As in the previous embodiment, the
syringe has a tip 27 for connecting to a liquid dispensing tubing
28, the latter leading to means for injecting an administrable
liquid into a patient.
[0025] The operation of the present device is very similar to that
of the earlier embodiment and hence needs not be discussed further
at length. Suffice to say that it may also comprise security means
intended to automatically interrupt the operation in case troubles
develop with the patient or otherwise during injection. For
instance, the pressure in the syringe barrel can be monitored by
registering the force required to push the plunger, this being via
the power absorbed by the driving motor 31. A sudden surge, for
instance a rapid increase of current in said motor can trigger via
the control unit 34 an emergency stop of the device. Alternatively,
this effect could also be detected according to usual means by a
strain gauge installed in the drive 23.
[0026] As already said, the particles of the suspensions in this
invention may be of various kinds and involve for instance
microspheres containing entrapped air or other gases used in
echography. These microspheres may be bounded by a liquid/gas
interface (microbubbles), or they may have a tangible membrane
envelope of for instance synthetic polylactides or natural polymer
like denatured protein such as albumin (microballoons). The carrier
liquid for the microbubble suspensions comprises surfactants,
preferably saturated phospholipids in laminar or lamellar form such
as diacylphosphatidyl derivatives in which the acyl group is a
C.sub.16 or higher fatty acid residue.
[0027] The gases used in the microbubbles or microballoons are pure
gases or gas mixtures including at least one physiologically
acceptable halogenated gas. This halogenated gas is preferably
selected among CF.sub.4, C.sub.2F.sub.6, C.sub.3F.sub.8,
C.sub.4F.sub.8, C.sub.4F.sub.10, C.sub.5F.sub.12, C.sub.6F.sub.14
or SF.sub.6. The gas mixtures can also contain gases such as air,
oxygen, nitrogen, helium, xenon or carbon dioxide. In fact in a
number of cases microbubbles or microballoons will contain mixtures
of nitrogen or air with at least one perfluorinated gas in
proportions which may vary between 1 and 99%.
[0028] In the microballoons the membrane is made from a
biodegradable material such as biodegradable polymers, solid
triglycerides or proteins and are preferably selected from the
polymers of polylactic or polyglycolic acid and their copolymers,
denatured serum albumin, denatured haemoglobin, lower alkyl
polycyanoacrylates, and esters of polyglutamic and polyaspartic
acid, tripalmitin or tristearin, etc. In an embodiment, the
microballoons are filled with C.sub.3F.sub.8 and the material
envelope is made of albumin.
[0029] Homogeneity of suspensions of microballoons whose membrane
is made of saturated triglycerides such as tripalmitin, trimyristin
or tristearin and their mixtures with other tri- or di-glycerides,
fatty acids or polymers is particularly interesting as those are
used for delivering active ingredients to specific sites within the
body. Homogeneity of suspensions of such microballoons has been
effectively maintained using the method and the device of the
invention.
[0030] Other particles whose density is different from that of the
carrier liquid may include liposomes filled with iodinated X-ray
opacifiers such as iomeprol, iopamidol, iopentol, iohexyl,
metrizamide, iopromide, iogulamide, iosimide or ioversol or, for
instance, coated and uncoated magnetic particles which tend to
precipitate in saline or other carriers.
[0031] The present injector system can be used in imaging organs,
blood vessels and tissues of mammalians, e.g. the ultrasonic
imaging of the heart, the liver or spleen, the brain, the kidneys,
the blood vessels, etc.
[0032] The invention is further illustrated by the following
Examples.
Example 1
[0033] A solution of gas filled microbubbles stabilised by a
phospholipids interface was prepared according to Example 1 of U.S.
Pat. No. 5,445,813. The dry matter concentration was 5 mg/ml in a
saline solution (0.9% NaCl). Typically, the bubble size
distribution extended from 0.2 to 15 .mu.m. The concentration of
bubbles between 2 and 5 .mu.m was 5.times.10.sup.7
microbubble/ml.
[0034] The solution was transferred in a 50 ml plastic syringe and
samples were taken in time intervals for analysis. This represent
the starting 100% of the bubble concentration. The syringe was
mounted in the infusion unit and the elution started. The elution
flow was fixed at 1.6 ml/min.
[0035] Aliquots of the eluted solution were analysed by Coulter
measurement (bubbles distribution; size and concentration) and
imaging.
TABLE-US-00001 TABLE 1 Radius Va 1.0 0.131 1.5 0.294 2.0 0.523 2.5
0.817 3.0 1.177 3.5 1.602 4.0 2.092 4.5 2.648 5.0 3.269 5.5 3.955
6.0 4.707 6.5 5.524 7.0 6.407 7.5 7.355 8.0 8.368 8.5 9.446 9.0
10.590 9.5 11.800 10.0 13.075 10.5 14.415 11.0 15.820 11.5 17.291
12.0 18.828 12.5 20.429 13.0 22.096 13.5 23.829 14.0 25.626 14.5
27.489
[0036] In water, the rate of rise (Va) by buoyancy of air filled
microbubbles of radius (a) can be obtained from the following
Stokes relation
Va = 2 gr 9 h .times. a 2 ##EQU00001##
where g is the gravitation constant (9.81 ms.sup.-2), r is the
density of water (1000 g/l) and h is the viscosity (10.sup.-3
Kg[sm]). Table 1 shows a range of such rates (in mm/min) in
function to the bubble radius in .mu.m. The tangential speed
(V.sub.r=2pnR) of a syringe barrel of 28 mm diameter (R=14 mm) in
function to the rotation rpm (n) is given in the next Table 2.
TABLE-US-00002 TABLE 2 n V.sub.r (rpm) (mm/min) 0.5 2539 1 5278 2
10556 3 15834 4 21112 5 26389 10 52779
[0037] It is seen from the foregoing figures that in the case of a
suspension of microbubbles of size in the range of 1-10 .mu.m, very
low rates of rotation of the syringe are sufficient to prevent
segregation of the bubbles by buoyancy. This means that even at low
rates of rotation the tangential speed of the microbubbles in
suspension is much larger than buoyancy and that the microbubbles
will move together with the rotating liquid and will not rise to
the top of the syringe.
[0038] In a comparative study, the syringe was rotated along its
axis in an alternative mode at a speed of 60 rpm. The results were
compared with an experiment where the syringe was not rotated
(under otherwise same experimental conditions).
[0039] FIG. 2 shows the evolution of the concentration of the total
microbubble population and, separately, microbubbles above 8 .mu.m
along the elution while FIG. 3 shows the evolution of imaging
intensity and the total bubble volume in the course of elution. In
the case of no-agitation, the concentration decreases rapidly due
to decantation. At the end of the infusion, the concentration rises
sharply (not shown) because all the bubbles accumulate in the upper
part of the barrel.
[0040] When the syringe is rotated, the bubble concentration
remains constant throughout the entire infusion.
[0041] The same type of experiments were carried out under
different experimental conditions including different microbubbles
sizes and concentrations, different elution rates, different
rotation types and speed, different syringe types and different
particles such as heavy magnetite particles or other microbubble
structures including phospholipid, tripalmitin or albumin
encapsulated microbubbles. All experiments invariably showed that
the method of infusion disclosed delivers homogeneous suspensions
of active agents.
Example 2
Preparation of Contrast Agents for Infusion
[0042] To test the efficiency of the present invention (a system of
rotary syringe pump), different contrast agents for ultrasound
echography were prepared.
[0043] Microbubble Suspensions
[0044] Phospholipid stabilised microbubbles were, obtained in the
following manner. 500 mg DAPC and 50 mg DPPA (Avanti Polar Lipids,
Inc.) were dissolved in hexane/iso-propanol 8/2 (v/v) and dried in
a round-bottomed flask using a rotary evaporator and, further, in a
vacuum dessicator. After addition of water (100 ml), the suspension
of lipids was heated at 75.degree. C. for 1 hour under agitation
and then extruded through a 0.8 .mu.m polycarbonate filter
(Nuclepore.RTM.). The resulting suspension and 10 g of
poly-ethyleneglycol (M.sub.W4000) were mixed and lyophilised. 2 g
of the lyophilisate was introduced into a glass vial and sealed
under SF.sub.6 or an air/C.sub.4F.sub.10 mixture. After
reconstitution with 25 ml NaCl 0.9%, the resulting suspensions
contained about 6.times.10.sup.8 (SF.sub.6) or 1.times.10.sup.9
(C.sub.4F.sub.10) bubbles per ml with a mean diameter in number of
2 .mu.m (Coulter Multisizer).
[0045] Microballoon Suspensions
[0046] Gas filled albumin microspheres were prepared as described
by Porter T. R. (J. Am. Coll. Cardio. 23 (1994) 1440 and PCT/WO
96/38180). 16 ml of human serum albumin (HSA) diluted 1:3 with
dextrose (5%) was introduced into a 20 ml syringe and sonicated
(sonifier 250 Branson) for 80 seconds in the presence of a flux of
C.sub.3F.sub.8 gas (octafluoropropane) at liquid/air interface. The
sonicator tip was immersed at about 1 cm below the surface of the
solution, the ultrasound energy level was set at output -40 and the
temperature of the solution was monitored at 75.degree. C. After
removing the foam phase by decantation, the final suspension
contained 8.times.10.sup.8 gas microspheres per millilitre with a
mean diameter in number of 2 .mu.m (9 .mu.m in volume) determined
by Coulter.RTM.. The suspensions are stored at 4.degree. C. until
use.
Example 3
Determination of the Limit of Rotation Rate for the Syringe Used
for Infusion
[0047] The effect of syringe rotation on stability of gas
microbubble suspensions in the syringe used for infusion has been
tested using a 50 ml syringe which was mounted on a rotation system
which allows very low rotation speeds (about 1 rpm). Prior to its
mounting the syringe was filled with 30 ml of phospholipid
stabilised microbubble suspension. The mounted syringe was then
rotated at different speeds: 0 (no rotation) 1.3, 2 and 60 rpm (1
Hz) and the suspension monitored taking one sample every 5 minutes.
The samples were then analysed using Coulter counter. Table 3A
shows the results obtained with a suspension of 3.1.times.10.sup.8
microbubbles/ml having a mean diameter of 2.1 .mu.m.
TABLE-US-00003 TABLE 3A Homogeneity of microbubble suspensions in
the syringe as a function of the rotation rate and time
(microbubble concentration 3.1 .times. 10.sup.8 bubbles/ml) Syringe
rotation rates rpm 0 1.3 2 60 0 1.3 2 60 0 1.3 2 60 Vr 0 114 176
5278 0 114 176 5278 0 114 276 5278 t(min) Nb total (%) Nb >
8.mu. (%) Volume (%) 0 100 100 100 100 100 100 100 100 100 100 100
100 5 68.7 77.6 90.4 97.4 23.5 48.0 73.3 95.4 37.5 55.6 80.4 97.7
10 53.7 77.3 88.8 100.6 1.1 43.9 70.9 98.9 19.8 44.8 73.3 99.4 15
48.2 72.8 89.5 96.2 1.9 38.0 74.1 96.5 14.5 44.0 75.7 98.1 20 43.5
73.8 86.6 99.0 0.8 37.2 77.9 97.3 10.8 42.5 73.6 98.6 25 39.9 76.4
88.5 100.3 0.5 36.9 84.6 99.5 9.6 43.0 81.6 99.7 Nb total (%):
percentage of the total bubble concentration as compared to value
at t = 0. Nb > 8.mu. (%): percentage of the bubbles above 8
.mu.m as compared to value at t = 0. Volume (%): percentage of
total bubble volume per ml of solution as compared to value at t =
0 rpm: rotation per minute; Vr (mm/min) = tangential speed of the
syringe (radius = 14 mm) Gas microbubbles: air/C.sub.4F.sub.10
(50:50).
[0048] The above results clearly indicate that even at very low
rotation rates (1.3 and 2 rpm), the buoyancy rise of the
microbubbles is prevented. This is because even at low rotation
rates, the tangential velocity of the microbubble is far greater
than that of buoyancy. As previously shown, microbubbles of 3 and
10 .mu.m have the respective rising rates of 0.29 and 3.3 mm/min.
At 1.3 rpm rotation, the tangential speed is 114 mm/min
(Vr=2p.times.rpm.times.R.sub.syringe) which makes the tangential
component of the 3 .mu.m microbubble 390 times greater than the
buoyancy. For 10 .mu.m microbubble the tangential component is 35
times greater than the ascension rate. It should be mentioned that
at very high rotation rates (e.g. 1,000 rpm) the microbubbles will
concentrate in the middle of the syringe (as the radial component
becomes dominant). Rotational speeds at which the radial component
becomes important are not of interest as under such conditions the
suspension becomes non-homogeneous again. The rotational speed at
which the radial force is becoming significant depends on the
syringe size (diameter, size of microbubbles and viscosity of the
suspension) hence the exact value of the rotational speed at which
the radial component becomes important is to be established for
each individual case. However, as already pointed out such
rotational speeds are to be avoided.
TABLE-US-00004 TABLE 3B Homogeneity of microbubble suspensions in
the syringe as a function of the rotation rate and time
(microbubble concentration 1.3 .times. 10.sup.9 bubbles/ml) Syringe
rotation rates rpm 0 3 12 60 0 3 12 60 0 3 12 60 Vr 0 264 1056 5278
0 264 1056 5278 0 264 1056 5278 t(min) Nb total (%) Nb > 8.mu.
(%) Volume (%) 0 100 100 100 100 100 100 100 100 100 100 100 100 5
6.0 26.0 76.8 81.3 0.5 16.0 73.1 83.4 1.5 17.2 81.4 87.7 10 3.2
26.3 78.8 81.3 0.2 19.1 71.5 79.9 1.0 20.0 81.9 79.4 15 3.9 27.3
81.5 82.2 0.6 16.8 78.0 80.5 1.1 20.3 84.9 90.8 20 4.3 32.0 76.6
95.0 0.2 19.2 79.6 85.9 1.8 21.5 92.3 92.6 25 0 31.7 78.9 95.3 0
16.9 78.6 85.5 0 18.4 83.4 91.1 Nb total (%): percentage of the
total bubble concentration as compared to value at t = 0. Nb >
8.mu. (%): percentage of the bubbles above 8 .mu.m as compared to
value at t = 0. Volume (%): percentage of total bubble volume per
ml of solution as compared to value at t = 0 rpm: rotation per
minute; Vr (mm/min) = tangential speed of the syringe (radius = 14
mm) Gas microbubbles: air/C.sub.4F.sub.10
[0049] For more concentrated suspensions (e.g. 1.3.times.10.sup.9
bubbles/ml) the microbubble ascension rate increases in the
syringe. This is probably due to microbubble interactions
(associations, dragg etc.) indicating that higher rotation speeds
are required for prevention of microbubble ascension in the
suspensions with higher microbubble concentrations. However, the
lower limit of the syringe rotation is not easy to determine as the
microbubble ascention rate is also a function of viscosity and
density of the suspension, the nature of the gas used, the
microbubble diameter and size distribution as well as the type of
the microparticles (i.e. microbubbles having just a layer of a
surfactant stabilising the gas, microballoon with a tangible
membrane or microemulsion).
Example 4
Evaluation of the Efficiency of the Rotary Pump
[0050] A. Infusion of Gas Microbubble Suspensions at Low Bubble
Concentration and "Fast" Infusion Rate (3.3 ml/min)
[0051] In this study, the phospholipid stabilised gas microbubbles
were prepared with a gas mixture (air/perfluorobutane 50:50) as gas
phase.
[0052] The efficacy of the rotary pump of the present invention was
evaluated by checking the homogeneity and stability of the bubble
suspensions during the infusion. During a continuous infusion, the
bubble suspensions were successively sampled at different infusion
times with an interval of about every 5 minutes. The syringe used
for infusion had a effective volume of 60 ml with a diameter of 28
mm (Braun Perfusor, Germany). The rotation rate of the syringe was
fixed at 60 rpm or 1 Hz (in order to compare different suspensions)
and the direction of rotation was reversed for each turn. Infusion
was stopped after 15 minutes while maintaining syringe rotation and
then restored at the same rate during one minute after 30 minutes
and 60 minutes. The bubble concentration, sizes and size
distribution were assessed with Coulter.RTM. Multisizer II and the
echo contrast effect of the suspensions was simultaneously examined
with an echographic imaging device (Acuson 128XP10, USA). For
Coulter.RTM. and echo evaluation, the native samples taken from the
syringe were further diluted 1000 and 3000 folds (in some
experiences 1/750). For in vitro imaging evaluation, an acoustic
phantom ATS (Peripheral Vascular Doppler Flow Phantom, ATS
Laboratories Inc., USA) was used and the image was visualised in
B-mode with a 3.5 MHz ultrasound probe. The acoustic energy was set
to minimum (-9 dB) in order to prevent bubble destruction. The
results are summarised in the Table 4.
TABLE-US-00005 TABLE 4 Evaluation of the efficacy of the rotary
pump (Coulter and Echo imaging) Gas microbubbles:
air/C.sub.4F.sub.10 Pump flow rate: 3.3 ml/min Coulter measurement
Imaging Diam VI t (min) Nbtot/ml .times. 10.sup.8 Nb > 8 .mu./ml
.times. 10.sup.6 (.mu.m) Vol/ml (pixels) 0 3.26 4.90 2.09 7.33 62 2
2.97 4.90 2.15 7.12 59 8 3.31 4.50 2.06 7.15 59 15 3.06 3.55 2.09
5.82 59 30 3.12 4.82 2.15 6.96 59 60 3.15 4.66 2.10 7.03 59 Nb >
8 .mu./ml: number of bubbles above 8 .mu.m. Nb total/ml: total
bubble concentration. Volume (.mu.l/ml): total bubble volume per ml
of solution Diameter (.mu.m): mean diameter in number. VI: video
intensity(dilution 1:3000).
[0053] These results show that even at a small rotation rate (1
Hz), the bubble suspension was fairly stable and homogeneous: both
the total bubble count and bubbles >8 .mu.m remain constant
during the entire infusion.
[0054] B. Infusion of Gas Microbubble Suspensions at High Bubble
Concentration and "Slow" Infusion Rate (1.2 ml/min)
[0055] The example A was repeated at a "slow." infusion rate and a
higher concentration of the microbubbles. One can note from the
Table 5 that even at very slow infusion rate (corresponding to
0.017 ml/kg/min for a 70 kg person) and a very high bubble
concentration (Nb/ml >10.sup.9/ml), the present rotary infusion
pump is capable to ensure the stability and the imaging performance
of the bubble suspensions during the entire infusion (24 min).
TABLE-US-00006 TABLE 5 Evaluation of the efficacy of the rotary
pump (Coulter and Echo imaging) Gas microbubbles:
air/C.sub.4F.sub.10 Pump flow rate: 1.2 ml/min Coulter measurement
Imaging Nb > 8 .mu./ Diameter Volume/ VI t (min) Nb/ml .times.
10.sup.9 ml .times. 10.sup.7 (.mu.m) ml (pixels) 0 1.10 2.2 2.09
32.5 60 5 1.03 2.2 2.15 30.9 60 13 1.01 2.1 2.06 30.5 55 18 1.03
2.1 2.09 30.0 58 24 1.04 2.1 2.15 30.5 57 Nb > 8 .mu./ml: number
of bubbles above 8 .mu.m. Nb total/ml: total bubble concentration.
Volume (.mu.l/ml): total bubble volume per ml of solution Diameter
(.mu.m): mean diameter in number. VI: video intensity(dilution
1:3000)
Example 5
Evaluation of the Efficacy of the Rotary Pump Comparative Tests
with and without Syringe Rotation
[0056] The procedure of Example 4 was repeated except that the
phospholipid stabilised microbubbles were prepared with gas
SF.sub.6 instead of air/C.sub.4F.sub.10. Moreover, the stability of
the gas bubble suspensions during infusion was compared using the
same pump in the presence and absence of rotation of the syringe
(R=28 mm, rotation rate=60 rpm and 0 rpm). The experimental results
of a concentrated bubble suspension (Nb>10.sup.9/ml) infused at
an infusion rate of 1.1 ml/min are shown in Table 6. Without
syringe rotation, the amount of microbubbles delivered from the
syringe decrease rapidly during infusion, especially for the large
bubbles (see Nb>8 .mu.m and the volume). After 5 minutes of
infusion, the total bubble concentration decreased by 83%, >99%
for the bubbles larger than 8 .mu.m and 90% for the bubble volume.
After 10 minutes, the video intensity had decreased by a factor 3
and the contrast effect of the microbubbles was almost non
detectable (IV=6.+-.3 pixels for the background) at 10 minutes of
the infusion. In contrast, in the presence of rotation the bubble
suspension remained stable during the entire infusion (30 min).
TABLE-US-00007 TABLE 6 Evaluation of the efficacy of the rotary
pump: comparative test Gas microbubbles: SF.sub.6 Pump flow rate:
1.1 ml/min Coulter measurement Nb/ Nb > 8 .mu./ Diameter Imaging
t(min) ml .times. 10.sup.9 ml .times. 10.sup.7 (.mu.m) Volume/ml VI
(pixels) rot with w/out with w/out with w/out with w/out with w/out
0 1.2 1.1 1.58 1.32 2.09 2.22 24.3 20.4 32 54 5 1.16 0.19 1.41
0.008 2.09 2.14 22.6 2.0 30 16 10 1.06 0.15 1.37 0.012 2.13 1.96
21.4 1.2 30 10 15 1.15 0.13 1.38 0.00 2.11 1.92 22.5 0.9 30 8 20
1.38 0.12 1.81 0.00 2.13 1.83 28.5 0.7 31 7 30 1.25 0.11 1.53 0.00
2.11 1.79 24.4 0.6 32 6 Nb > 8 .mu./ml: number of bubbles above
8 .mu.m. Nb total/ml: total bubble concentration. Volume
(.mu.l/ml): total bubble volume per ml of solution Diameter
(.mu.m): mean diameter in number. VI: video intensity(dilution
1:3000)
TABLE-US-00008 TABLE 7 Evaluation of the efficacy of the rotary
pump: comparative tests Gas microbubbles: SF.sub.6 Pump flow rate:
3.3 ml/min Coulter measurements Nb tot/ Nb > 8 .mu./ Diam.
t(min) ml .times. 10.sup.6 ml .times. 10.sup.6 (.mu.m) Vol./ml Vol
% rotat with w/out with w/out with w/out with w/out with w/out 0
2.73 2.48 3.14 2.99 2.22 2.09 5.5 4.9 100.0 89.4 5 2.57 2.05 3.21
0.5.4 2.23 1.94 5.3 2.1 96.7 39.1 10 2.53 1.71 3.42 0.01 2.27 1.81
5.8 1.1 105.7 20.6 15 2.48 1.41 3.28 0.00 2.28 1.64 5.2 0.6 96.1
10.8 20 2.35 1.16 1.33 0.00 2.21 1.54 4.6 0.5 83.6 8.3 Nb > 8
.mu./ml: number of bubbles above 8 .mu.m. Nb total/ml: total bubble
concentration. Volume (.mu.l/ml): total bubble volume per ml of
solution Diameter (.mu.m): mean diameter in number. VI: video
intensity(dilution 1:3000)
[0057] In Table 7, the comparative infusion was conducted at a
lower bubble concentration (2.7 10.sup.8/ml) and an infusion rate
of 3.3 ml/min. Again, these results show a very good efficacy of
the rotary infusion system to maintain the homogeneity and
stability of the microbubble suspensions during infusion. In
contrast, the syringe pump without rotation was completely
inadequate for microbubble infusion.
Example 6
Evaluation of the Efficiency of the Rotary Pump
[0058] Application to as Microspheres (Comparative Tests)
[0059] The Example 5 was repeated with the gas albumin microspheres
prepared as described in Example 2. For the infusion, the bubble
concentration was adjusted to 6.times.10/ml by diluting the
suspension with HSA/dextrose (1:3). In the present experience, the
in vitro characteristics of the microspheres during infusion (2.7
ml/min) with and without the syringe rotation were compared to
assess the homogeneity of the suspensions delivered from the
syringe. The results are gathered in Table 8.
TABLE-US-00009 TABLE 8 Evaluation of the efficacy of the rotary
infusion pump with gas albumin microspheres Gas microbubbles:
C.sub.3F.sub.8 Pump flow rate: 2.7 ml/min Coulter measurements
Nbtot/ Nb > 8 .mu./ Diam t(min) ml .times. 10.sup.8 ml .times.
10.sup.6 (.mu.m) Vol/ml VI (pixels) rot with w/out with w/out with
w/out with w/out with w/out 0 6.64 6.7 9.6 7.6 2.03 1.97 15.4 12.3
47 46 5 6.4 6.6 8.0 4.5 1.96 1.93 13.1 8.8 47 38 10 6.4 6.3 6.0 2.6
1.91 1.8 10.3 5.0 45 23 15 6.4 6.0 6.5 0.38 1.92 1.65 10.5 3.5 45
19 20 6.25 5.2 6.15 0.15 1.92 1.61 9.9 3.8 43 26 Nb > 8 .mu./ml:
number of bubbles above 8 .mu.m. Nb total/ml: total bubble
concentration. Volume (.mu.l/ml): total bubble volume per ml of
solution Diameter (.mu.m): mean diameter in number. VI: video
intensity(dilution 1:3000) Background: VI = 9 pixels
[0060] The albumin microspheres appear to be more homogeneous in
the syringe than phospholipid microbubbles in the absence of
rotation. This is likely to be due to the higher viscosity of the
albumin/dextrose solution (5%) and possibly to the thicker wall of
the microspheres (about 15 times thicker than a phospholipid
monolayer). Nevertheless, large microspheres (>8 .mu.m) still
decanted in the syringe and their concentration decreased
progressively during infusion. After 10 minutes, the volume of
microspheres and the video intensity decreased to half of the
initial values. It was been reported that the myocardial perfusion
with a similar agent--FSO69 (Optison.RTM., HSA-C.sub.3F.sub.8
microsphere suspensions) was attributed essentially to a small
number of large microspheres (10-15 .mu.m) entrapped in the tissue
(Skyba et al., J. Am. Coll. Cardio. 28 (1996) 1292-1300).
Therefore, on can speculate that for such clinical application this
kind of contrast agents could hardly be infused by a classic
infusion pump as demonstrated in the present example.
Example 7
[0061] Tetracaine filled tripalmitin microcapsules made according
to Example 6 of WO96/15815 were suspended in 50 ml of saline
solution (0.9% NaCl). The suspension with a concentration of
tetracaine of 0.06 mg/ml was placed into a 50 ml syringe. The
syringe was placed on the rotational pump of the invention and the
exit concentration of tetracaine measured using UV
spectrophotometer (in THF/water 60/40% at 307 nm). The syringe was
rotated at a rate of 1 Hz (alternating direction of rotation every
180.degree.). The rate of infusion was 1.5 ml/min. The UV analysis
showed constant concentration of tetracaine over the entire period
of infusion. In the parallel experiment in which the tetracaine
filled syringe was kept stationary the exit concentration of the
medicament varied with time.
Example 8
[0062] Fifty milligrams of Amphotericin B in the deoxycholate form
(Fungizone.RTM. Bristol Mayers Squibb) were dispersed in 50 ml of
Intralipid.RTM. 20% (Pharmacia) and the emulsion obtained
(Chavanet, P, Rev. Med. Interne 18 (1997) 153-165) introduced into
a 50 ml syringe. The syringe was placed on the rotational pump and
infused at 1 ml/min rate and rotation of 1-Hz (alternating
direction of rotation every 360.degree.. Exit concentration of
Amphotericin B was followed by HPLC (detection UV/visible at 405
nm). The HPLC analysis confirmed constant concentration of the
medicament during the entire infusion. The experiment clearly
showed that the separation of Amphotericin B reported by several
research groups (Trissel, L. A., Am. J. Health Syst. Pharm. 52
(1995) 1463; Owens, D., Am. J. Health Syst. Pharm. 54 (1997) 683)
was successfully suppressed using the method disclosed.
Example 9
[0063] A liposome solution was prepared from 9/1 molar ratio of
hydrogenated soy lecithin (DPPC) and dipalmitoylphosphatidic acid
disodium salt (DPPA) in chloroform according to a well known
procedure (e.g. EP 0 514 523). After extrusion and cooling of MLV
suspension the same was concentrated to 30 mg/ml by
microfiltration. To 1 l of the concentrated liposome solution, 1 l
of an aqueous solution containing 1040 g of
(S)--N,N'-bis[2-hydroxy-1-(hydroxymethyl)-ethyl]-2,4,6-triiodo--
5-lactamido-isophthalamide (Iopamidol.RTM., an X-ray contrast agent
of BRACCO S.p.A.) was added and the resulting mixture having an
iodine concentration of 260 g/l was incubated. The density of the
Iopamidol.RTM. solution was 1.29 g/cm.sup.3.
[0064] An aliquot of the liposome preparation was dialyzed against
saline (NaCl 0.9% in water) until all iopamidol outside the
liposomes vesicles was removed. The iodine-to-lipid ratio of the
preparation obtained (I/L) was between 3 and 5 mg of entrapped
iodine per mg lipid.
[0065] Part of the preparation of contrast agent-loaded liposomes
was introduced into a syringe which was placed on the rotational
pump of the invention and the exit concentration of the contrast
agent measured using HPLC. The syringe was rotated at a rate of 1
Hz (alternating direction of rotation every 180.degree.). The rate
of infusion was 1.5 ml/min. The HPLC analysis showed constant
concentration of the iodinated contrast agent over the entire
period of infusion.
[0066] When, in the foregoing example, the Iopamidol was replaced
by Iomeprol
(N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-5-glycolamido-isoph-
tal-imide), another iodinated contrast agent from BRACCO S.p.A.,
similar results were experienced.
* * * * *