U.S. patent application number 10/887647 was filed with the patent office on 2004-12-23 for suspension device and method.
This patent application is currently assigned to MALLINCKRODT INC.. Invention is credited to Doty, Brian, Hagen, William, Hughes, Michael Scott, Persaud, Gordon.
Application Number | 20040260242 10/887647 |
Document ID | / |
Family ID | 26980358 |
Filed Date | 2004-12-23 |
United States Patent
Application |
20040260242 |
Kind Code |
A1 |
Hughes, Michael Scott ; et
al. |
December 23, 2004 |
Suspension device and method
Abstract
A device and method for providing a suspended agent such as a
contrast agent without mechanical resuspension. A volume of agent
is divided into sub-volumes in a network configured to suspend and
deliver the sub-volumes of agent to a patient when a propellant
fluid flows through the network. The invention reduces
sedimentation of agents into one or a few aggregates and eliminates
a mechanical mixing step. The invention thus provides a uniformly
suspended agent, improving patient health and safety and increasing
cost and time savings.
Inventors: |
Hughes, Michael Scott;
(Glencose, MO) ; Hagen, William; (Simpsonville,
SC) ; Doty, Brian; (St. Peters, MO) ; Persaud,
Gordon; (Lee's Summit, MO) |
Correspondence
Address: |
WOOD, HERRON &EVANS, L.L.P.
2700 Carew Tower
441 Vine St.
Cincinnati
OH
45202
US
|
Assignee: |
MALLINCKRODT INC.
St. Louis
MO
|
Family ID: |
26980358 |
Appl. No.: |
10/887647 |
Filed: |
July 9, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10887647 |
Jul 9, 2004 |
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09918240 |
Jul 30, 2001 |
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6770051 |
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09918240 |
Jul 30, 2001 |
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09513087 |
Feb 25, 2000 |
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09513087 |
Feb 25, 2000 |
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09316315 |
May 21, 1999 |
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6554792 |
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Current U.S.
Class: |
604/140 ; 222/1;
604/82 |
Current CPC
Class: |
A61M 5/007 20130101;
A61M 5/1452 20130101; A61M 5/1409 20130101 |
Class at
Publication: |
604/140 ;
604/082; 222/001 |
International
Class: |
A61M 037/00 |
Foreign Application Data
Date |
Code |
Application Number |
May 19, 2000 |
WO |
PCT/US00/13905 |
Claims
What is claimed is:
1. A method for providing a volume of a suspendable agent using a
propellant fluid, the method comprising: operably engaging a
charging container containing a pressurized propellant fluid to the
inlet of the tubular network having a plurality of helices
containing a plurality of sub-volumes of a suspendable contrast
agent with at least two helices compressibly secured and fastened
together, an inlet to the tubular network, and an outlet from the
tubular network; and depressurizing the charging container and
providing propellant pressure to the tubular network effective to
suspend and deliver the plurality of sub-volumes of the suspendable
agent through the outlet.
2. The method of claim 1 wherein the pressurized fluid is a
gas.
3. The method of claim 2 wherein the gas is selected from the group
consisting of helium, neon, argon, hydrogen, octafluoropropane,
air, carbon dioxide, oxygen, and combinations thereof
4. The method of claim 1 wherein the tubular network is positioned
inside a syringe.
5. The method of claim 1 wherein the suspendable agent is selected
from the group consisting of a colloid, a microbubble preparation,
an imaging contrast agent.
6. The method of claim 1 wherein the suspendable agent is a
contrast agent having a microbubble formulation in which
microbubbles are formed by the method.
7. A suspension device for a suspendable agent, comprising: a
tubular network for containing a plurality of sub-volumes of the
agent, said tubular network including inflow and outflow ports for
flow of a fluid to suspend and propel the agent from said tubular
network, said tubular network having a first cross-sectional
internal geometrical configuration along a first length and a
second cross-sectional internal geometrical configuration along a
second length, the second cross-sectional internal geometrical
configuration differing from the first cross-sectional internal
geometrical configuration.
8. The suspension device of claim 7 wherein said first
cross-sectional internal geometrical configuration is circular, and
said second cross-sectional internal geometrical configuration is
selected from the group consisting of circular, square, elliptical,
triangular, rectangular, and wedge-shaped.
9. The suspension device of claim 7 wherein at least one of said
first cross-sectional internal geometrical configuration or said
second cross-sectional internal geometrical configuration includes
a plurality of lumens.
10. The suspension device of claim 7 wherein said first internal
cross-sectional geometrical configuration and said second internal
cross-sectional geometrical configuration are each selected from
the group consisting of circular, square, elliptical, triangular,
rectangular, and wedge-shaped.
11. The suspension device of claim 7 wherein at least one of said
first internal cross-sectional geometrical configuration or said
second internal cross-sectional geometrical configuration is
non-circular.
12. The suspension device of claim 7 wherein said first and second
geometrical configurations are contiguous along said network
path.
13. The suspension device of claim 7 wherein said first and second
geometrical configurations are non-contiguous along said network
path.
14. The suspension device of claim 7 wherein said first and second
geometrical configurations are symmetrical along said network
path.
15. A suspension device for a suspendable agent, comprising: a
helical tubular network for containing a plurality of sub-volumes
of the agent, said helical tubular network having a non-uniform
radius of curvature, a columnar arrangement, a non-uniform network
density, or a combination thereof; and inflow and outflow ports in
said helical tubular network for flow of a fluid to suspend the
suspendable agent and propel the suspended agent from said helical
tubular network.
16. The suspension device of claim 15 wherein said tubular network
has a radius of curvature that varies symmetrically.
17. The suspension device of claim 15 wherein said tubular network
has a radius of curvature that varies non-symmetrically.
18. The suspension device of claim 15 wherein said tubular network
includes at least two parallel columns, each of said at least two
parallel columns being independently operatively connected in said
suspension device.
19. A method of decreasing escape of a gaseous agent contained
within a device for suspending a volume of said agent, the network
comprising a network to contain a plurality of sub-volumes of said
agent and ports for an inflow and an outflow of a fluid to propel
said agent from said network, said method comprising: providing
said device within a container comprising a material having a
permeability to said gaseous agent that is less than a permeability
of said network to said gaseous agent.
20. The method of claim 19 wherein a plurality of said devices are
provided within said container.
21. An apparatus to decrease escape of a gaseous agent contained
within a suspension device for a volume of said agent, the device
comprising a network to contain a plurality of sub-volumes of said
agent and ports operatively connected to said network at an inflow
site and an outflow site for a fluid to propel said agent from said
network, said apparatus comprising: a container made of a material
that is less permeable to said gaseous agent than the permeability
of said network and containing at least one of said device.
22. The apparatus of claim 21 wherein said material is selected
from the group consisting of glass and thick walled plastic.
23. The apparatus of claim 22 wherein said thick walled plastic is
selected from the group consisting of polypropylene and polyvinyl
chloride.
24. A method of manufacturing a device for delivering a suspendable
agent, comprising: forming a tubular network having a plurality of
helices, an inlet adapted to receive a pressurized propellant fluid
and an outlet; compressibly securing and fastening together at
least two helices; and filling the tubular network with a plurality
of sub-volumes of a suspendable agent.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of application Ser. No.
09/918,240, filed Jul. 30, 2001, now pending, which is a
continuation-in-part of application Ser. No. 09/513,087, filed Feb.
25, 2000, now pending, which is a continuation-in-part of
application Ser. No. 09/316,315 filed May 21, 1999, now U.S. Pat.
No. 6,554,792.
FIELD OF THE INVENTION
[0002] The invention relates to a device and method of using the
device for providing a suspended volume of an agent without
additional mixing.
BACKGROUND
[0003] Agents that do not persist in a suspended state and sediment
must be resuspended prior to use. One example of an agent that must
be resuspended prior to use is a pharmaceutical colloid, such as a
contrast agent that is injected into a patient to enhance an
imaging procedure. Contrast agents are used in various types of
imaging including x-ray, magnetic resonance imaging (MRI), computed
tomography (CT) and ultrasound (US). A contrast agent that comes
out of suspension must be resuspended before placing the desired
volume to be dosed into a delivery container such as a syringe. If
there is a delay before the dose is injected into a patient, for
example while preparing the patient or equipment, or if the
infusion is extended, the agent must again be suspended before or
during administration.
[0004] Resuspension of contrast agent requires mechanical
manipulations, for example, removing a filled syringe positioned in
an injector and remixing its contents. Additional remixing steps
may delay a critical infusion time or, if remixing is omitted, the
entire imaging procedure may have to be repeated due to suboptimal
contrast obtained. Duplicate procedures not only put patients at
increased risk and inconvenience, but are also cost- and
time-inefficient. Even if the need to resuspend a single bolus
injection is not prohibitive for a given procedure, repeated bolus
injections or long term continuous infusions can become problematic
due to the agent coming out of suspension during
administration.
[0005] The loss of suspension for a contrast agent at any point in
a delivery system to a patient, such as in a syringe and/or in the
connecting tubing, severely limits the duration of continuous
infusions or the time between intermittent injections. The need to
initially resuspend the colloid or other type of agent, and to
further suspend if the agent is not used shortly after
resuspension, requires either time-consuming effort and vigilance
by the user or the use of mechanical mixing devices. In any case,
the need to resuspend an agent poses an additional step and a
possible source of error in an imaging procedure.
SUMMARY OF THE INVENTION
[0006] The invention is directed to a method to control the rate at
which a volume of an agent suspended in a fluid is delivered to a
patient. The agent, provided in a device having a tubular network
and inflow and outflow ports for a fluid to propel the agent, is
divided into sub-volumes within the tubular network. By altering
the flow to which the agent is exposed, for example, a laminar or
non-laminar flow, the rate at which the fluid is delivered is
controlled. For example, laminar flow may be altered by changing
the density, cross-sectional diameter, length, and/or pitch of the
tubular network, and/or by symmetrically or randomly altering the
radius of curvature. For example, the radius of curvature and/or
density from the inflow port to the center of the device may
progressively decrease, and the radius of curvature and/or density
from the center of the device to the outflow port may progressively
increase. Non-laminar flow may be altered by replacing a circular
cross-sectional internal geometrical configuration of the tubular
network with a non-circular internal geometrical configuration, in
a symmetric or random manner and along part of or along the entire
network path.
[0007] The invention is also directed to a method to control the
rate at which a volume of an agent suspended in a fluid is
delivered to a patient by providing the agent in a device having a
tubular network containing sub-volumes of the agent. The device
also contains inflow and outflow ports for fluid to propel agent
from the network. The rate is controlled by altering a laminar flow
of agent through the network by altering the network density, or by
altering a non-laminar flow of agent through the network by
replacing a circular internal cross-sectional geometrical
configuration of a network path with a non-circular cross-sectional
geometrical configuration.
[0008] The invention is also directed to a suspension device that
contains a tubular network providing at least one network path and
containing sub-volumes of the agent, and has inflow and outflow
ports for a fluid to propel agent from the network. The device has
a cross-sectional internal geometrical configuration that may be of
geometric shape and may be contiguous, non-contiguous, symmetrical
or non-symmetrical along the length of the network. The tubular
network may have a symmetrically altered radius of curvature, for
example, the radius of curvature may increase from an inflow port
to the center of the device and may decrease from the center of the
device to an outflow port. The tubular network may be a
compressible helix, either housed within a container such as a
syringe or a network support, or placed in-line. The device may
control the rate of agent delivery to a patient, and/or may enhance
mixing of the agent.
[0009] The invention is also directed to a method and apparatus of
decreasing escape of a gaseous agent contained within a suspension
device, where the device is a network to contain sub-volumes of the
agent and has inflow and outflow ports for a fluid to propel the
agent from the network. In the method, one or more devices is
provided within a container that is less permeable to the gaseous
agent than the network. The apparatus is a container made of a
material such as glass or a thick walled plastic such as polyvinyl
chloride (PVC) or polypropylene that is less permeable to the
gaseous agent than the network.
[0010] The invention is also directed to a suspension device for a
volume of an agent that is a tubular network arranged in at least
two parallel columns, where each column is independently
operatively connected and contains sub-volumes of the agent, and
inflow and outflow ports for a fluid to propel agent from the
network. This embodiment of the device permits the user to adjust
the network volume.
[0011] The invention is also directed to a method to deliver an
agent that contains microbubbles of a pre-determined size. The
agent is contained in a suspension device having a tubular network
that contains sub-volumes of the agent, and inflow and outflow
ports for a fluid to propel agent from the network. In the method,
a force exerted on the microbubble-containing agent is altered by
exposing the agent to a non-circular internal network geometrical
configuration.
[0012] The invention is also directed to a method to alter a size
distribution of microbubbles in a contrast agent injected into a
patient by altering a flow rate of the agent between the agent
source and an inflow line into the patient.
[0013] The invention is also directed to a suspension device for a
volume of a contrast imaging agent, such as a
microbubble-containing agent. The device is a compressible helical
network, for example 2 foot to fifty feet in an uncompressed state,
containing sub-volumes of the agent and with inflow and outflow
ports for a fluid to propel agent from the network.
[0014] The invention is also directed to a method of providing a
volume of a suspended agent to a patient by dividing the volume
into sub-volumes, storing the sub-volumes in a network,
mechanically mixing the agent in the network either before, during
or after releasing the agent sub-volumes into a patient through a
patient connector by providing a fluid under pressure through the
network to propel the suspended agent.
[0015] These and other embodiments will become apparent in light of
the following figures and detailed description.
BRIEF DESCRIPTION OF THE FIGURES
[0016] FIG. 1 is a cross-sectional view of a syringe container with
an internal tubular network.
[0017] FIG. 1A is a view similar to FIG. 1 of an alternate
embodiment of the invention.
[0018] FIG. 2 is a cross-sectional view of a syringe container with
an external tubular network operably attached to a propellant fluid
container exit port.
[0019] FIG. 3 is an elevational view of an in-line device.
[0020] FIGS. 4A, 4B and 4C are various network embodiments and
configurations.
[0021] FIG. 5 is a cross-sectional view of a syringe container
having an integral network.
[0022] FIG. 6 is a cross-sectional view of an integral network with
channels.
[0023] FIGS. 7A, 7B, 7C, 7D, 7E, 7F, 7G, 7H and 7I are embodiments
of network cross-sectional geometries.
[0024] FIGS. 8A and 8B are schematics of in-line devices with
tubular networks in parallel arrangements of columns.
[0025] FIG. 9 is a single column removed from a device.
[0026] FIG. 10 is an in-line device with a helical tubular
network.
[0027] FIG. 11 is a device having a symmetrically variable tubular
network.
[0028] FIGS. 12A, 12B, and 12C show a self-activation and discharge
device.
[0029] FIGS. 13A, 13B, and 13C show a self-activation and discharge
syringe.
[0030] FIGS. 14A, 14B, and 14C show devices to minimize tangling of
a network in a coiled helix embodiment.
DETAILED DESCRIPTION
[0031] The device of the invention sub-divides a desired volume of
an agent to suspend the agent without mechanical mixing. As used
herein, the device is comprised of a network of structures for
containing sub-volumes of the agent, with the entire volume of
agent contained in the network component sub-volumes. Resuspension
is caused by viscous fluid flow through the network of sub-volumes,
turbulence promoted interlaminar mixing, and mixing caused by
varying the gravitational orientation of agent sub-volumes. As will
be described, the device may be located in the same container that
contains propellant fluid to eject the agent from the network
(container package embodiment). Alternatively, the device may be
located adjacent an exit port of a propellant fluid container
(add-on embodiment), or may be positioned in-line at any point in a
fluid path between the propellant fluid container and the ultimate
deposit site such as a patient (in-line embodiment). As used
herein, a propellant fluid is one that is used to eject the agent
from the network of tubes, cells, etc. As used herein, a network is
defined as a collection of structures which contain the entire
desired volume of agent in sub-volumes, and hence increase the
surface area of the agent over which the propellant fluid must
flow, in the device. In one embodiment, the network has a common
exit port, and agent sub-volumes are ejected from the network at a
substantially equal rate. The network may encompass tubes, cells,
sponges, etc. and is not limited by volume or configuration.
[0032] The device sub-divides a volume of an agent to prevent it
from settling or sedimenting into one or a few dense aggregates
without the need for mechanical mixing or suspending prior to use,
and thus reduces or eliminates the problem of remixing or
resuspending an agent that has come out of suspension prior to use.
Use may be either preparing an injection dose by transferring the
desired volume of agent from a package to a dosing container such
as syringe, or injecting the dosing volume of agent into a patient.
This problem may occur with contrast agents, either while in their
package or portioned in a container such as a syringe for injecting
into a patient about to undergo an imaging procedure. The invention
solves the problem by sub-dividing the volume of the agent to
prevent separation or aggregation of the agent from the suspending
liquid and by turbulence or gravitationally promoted interlaminar
mixing. While mechanical mixing is not required, it may be used
with the inventive device either before, during, or after mixing in
the device, to supplement mixing achieved by the device.
[0033] Dividing a uniformly suspended contrast agent or other agent
into a network of sub-volumes rather than a single large volume
inhibits the particles from either floating or precipitating into
one or more larger masses or aggregates. The invention thus reduces
or obviates the need for mixing before or during a process, such as
an infusion process. This increases the quality, safety, and cost-
and time-efficiencies of the process.
[0034] With reference to FIG. 1, a network 8a containing divided
sub-volumes of an agent 12 is internal to a container 10 for
propellant fluid 16. The container 10 may be a syringe 14 or other
types of containers which include but are not limited to vials,
bags having flexible or semi-flexible walls, bottles of either
glass or plastic, etc. The agent 12 contained in the network 8a is
ejected from the container 10 as propellant fluid 16 flows through
the network 8a and displaces the agent 12. The propellant fluid 16
is any viscous fluid (liquid or gas) that is biocompatible. The
propellant fluid may be a diluent for the agent 12 such as normal
saline, water, buffer, etc. The propellant fluid 16 may also be a
contrast agent that is different from the agent 12 injected for the
imminent imaging procedure.
[0035] The network 8a may be any structure that serves to contain a
sub-volume of the desired total volume of an agent 12 in a unit
area. The network 8a may be contained in a network holder 22 (FIGS.
2 and 3). The network 8a may be tubes 18 which, as used herein,
encompass tubules, microtubules, channels, or other types of hollow
cylinders that convey a fluid or that function as a passageway,
whereby a volume of agent 12 is divided into sub-volumes of any
size. There are numerous configurations of the tubes 18 that can be
used to sub-divide the volume of agent 12. These include, but are
not limited to, a single long tube 18 as best shown in FIG. 1 or a
collection of tubes 18a as shown in FIG. 1A. The tubes 18 may be in
any configuration, such as one or more coils or helices, an angular
or stairstep configuration, and/or even random configurations. A
collection of tubes 18 may similarly be one or more coils or
helices, an angular or stairstep configuration, and/or even random
configurations, or may be arranged in a parallel configuration
(FIG. 1A). The geometries and configurations of the network 8 may
be combined in either regular or random configurations. While FIGS.
1 and 1A show tubes 18 positioned in a syringe 14 without any
accompanying support, other configurations are contemplated. For
example, the tubes 18 may be positioned within a network holder 22
(FIGS. 2 and 3), or may be supported or held in a syringe 14 or
network holder 22 by a fixture such as 24 (shown in phantom lines
in FIG. 1) which may extend for part of or all of the length of the
network 8.
[0036] With reference to FIG. 2, a dose delivery container 10 that
is a syringe 14 is shown with a network holder 22 containing the
network 8 external to the syringe 14. The network 8c is packaged
within a network holder 22, which may be any container in which the
network is housed or retained and may be made of any biocompatible
material. The network holder 22 containing the network 8c may be
separable from the syringe 14 or other container 10 and attached to
an exit port 24 of the syringe 14 or container 10. The network
holder 22 for the network 8c may also be manufactured as part of
the container 10, which may be useful as a pre-packaged embodiment
of the invention. In a non-pre-packaged embodiment, the network
holder 22 may be attached to an exit port 24 using, for example,
connectors 26 such as luer fittings. The exit port 24 of the
syringe 14 may be fitted with luer fittings, such as Luer-Lok.RTM.
caps (Becton-Dickinson), or may have luer fittings such as metal,
brass or glass luer tips attached. As previously described, a
support or fixture 30 for the tubes 28 may be used, and the support
30 and tubes 28 may be contained in a network holder 22. As one
alternative, the support 30 and tubes 28 may be contained directly
in the container 10. As another alternative, the tubes 28 in a
network holder 22 may be unsupported as shown in FIG. 2.
[0037] While FIG. 2 illustrates a network holder 22 which is
attached to a syringe 14, other embodiments are contemplated. With
reference to FIG. 3, the network (not shown) contained in a network
holder 22 is shown in an in-line embodiment. The network holder 22
is fashioned with connectors 26 at both an inflow port 32 and an
outflow port 34. Tubing is connected to connectors 26 to carry
propellant fluid 16 from a syringe to holder 22 and from holder 22
to a patient. The connectors 26 may be the same or different at the
inflow 32 and outflow 34 ports and may be any type such as luer
fittings, as previously described. Network holder 22 and the
network inside may be configured symmetrically, so that the
orientation of the network holder 22 in an in-flow embodiment need
not be a concern; i.e., there is no back-to-front or front-to-back
limitation. Agent 12 can be removed from the network within the
network holder 22 upon pressure from a propellant fluid 16.
[0038] A network 8 that is internal to a container 10 such as a
syringe 14 need not be housed in a network holder 22. As seen in
FIGS. 1 and 1A, the network 8a, 8b of tubes 18 or other structures
may be positioned directly within the barrel 36 of the syringe 14.
In an alternative embodiment, the network 8 that is internal to a
syringe 14 or other container 10 may also be housed in a network
holder 22. In either embodiment, the barrel 36 of the syringe 14
may contain a propellant fluid 16 that, upon initiation of flow,
provides pressure to release or eject the agent 12 from the network
8. The propellant fluid 16 need not be pre-filled in the barrel 36
of the syringe 14, but instead may be added to the barrel 36 of the
syringe 14.
[0039] In one embodiment and with reference to FIGS. 12A-C, a fluid
92 that is used to propel the agent through the network (not shown)
may be contained within the same container 10 as that which
contains the network 8. Thus, the embodiment would be a
self-contained, combined storage container 10 and delivery device.
This would eliminate the need for transferring the agent 12 into a
separate delivery device, such as a syringe 14. Use of this
embodiment would permit delivery of a uniformly suspended agent 12,
without the need for either manual or mechanical mixing, from the
same container 10 in which the agent 12 was stored. The embodiment
thus provides activation and delivery, in the case where the agent
is a microsphere or microbubble formulation of the agent and
activation is required to form the microspheres or microbubbles, or
delivery of a stable, uniformly suspended agent 12 from its
original storage container 10 using a simple hand-held one-step
device.
[0040] Contrast agents, as used for ultrasound and other imaging
modalities, may be comprised of microbubbles or microspheres that
contain air or an inert gas or liquid emulsion. These gases or
liquids provide echogenicity and a means for visualization of
anatomical regions. The size of the bubbles or spheres formed is an
important parameter in the efficacy and safety of the product. The
bubble or sphere size is dependent upon formulation components,
methods of manufacture, stability, etc.
[0041] Formulations are prone to stability problems when packaged
into vials due to destabilization of the bubbles or spheres or
breakdown of key components, making it difficult to generate
bubbles or spheres by hand agitation. Often, hand agitation may not
be significant enough to produce consistent and efficacious bubbles
or spheres. The invention provides for one step hand activation
without the need for an instrument (such as a shaker or agitator),
as the resulting product is ready to use after activation.
[0042] Among the advantages to the above-described apparatus are
that the dispersion is generated immediately before use.
Particularly with respect to contrast agents, where persistence
size of bubbles are limiting factors and provide a diagnostic
advantage, increasing bubble persistence and uniform desired size
as near to the time and site of infusion as possible is desirable.
The above-described system also limits the exposure time of the
components, allowing components that are less than optimally
compatible to be used. It also enhances stability of the agent due
to the package design, for example, transfer to a separate
container is not necessary. Ingredients which otherwise would be
incompatible for an extended time prior to administration may be
mixed, as only short-term exposure exists prior to use. The method
facilitates high pressure in situ mixing, and affords flexibility
in the formulation design, since only a limited stability is
needed.
[0043] The bubbles or spheres generated are microfine and
monodispersed. Bubble aggregation, which may be problematic, is
thereby minimized. The bubbles generated using the inventive device
and method are of a uniform, small size, providing for enhanced
imaging. In one embodiment, one or more screening devices, such as
filters or wire mesh screens, may additionally be incorporated
within the device to select bubbles within a certain size range for
administration. Furthermore, the inventive method accomplishes all
of this without resorting to extra processing steps, as occurs with
lyophilization.
[0044] A storage container 10, such as a vial, containing the agent
12 to be delivered is adapted to receive a charging container 90 to
generate an aerosol formulation 100 on FIG. 12A of the agent 12,
similar to shaving cream. For example, a storage container 10 has a
receiving port 94 for an engaging member 96 on the charging
container 90. The charging container 90 contains a pressurized
fluid 92 such as an inert gas (including, but not limited to,
hydrogen, nitrogen, helium, and argon), or another type of
formulation (for example, octafluoropropane (C.sub.3F.sub.8),
oxygen, carbon dioxide, etc.). The fluid 92 is activated and
depressurized when the engaging member 96 is connected with the
receiving port 94 (e.g., by breaking a seal). The apparatus also
contains a compartment into which the charged agent mixes with the
agent to be delivered (expansion container).
[0045] Activation is achieved by operatively attaching the charging
container 90 to the storage container 10 via the receiving port 94
(e.g., applying pressure sufficient to break a seal FIG. 12B). The
gas or other formulation 92 contained in the charging container 90
is thereby discharged into the storage container 10 FIG. 12C, the
agent 12 contained in the network (not shown) is propelled and
mixed with the gas in the expansion chamber, and a uniform
suspension of stabilized bubbles are available for infusion.
[0046] With reference to FIGS. 13A-C showing a syringe 14 delivery
container 90, the charging container 90 is incorporated within the
plunger 58 of the syringe 14. Application of pressure to the
plunger 58 propels the agent contained therein. Advancement of the
plunger 58 discharges the inert gas or other formulation 92
contained within the charging container 90 into the barrel 36 of
the syringe 14 via contact with a means to pierce a receiving port
(e.g., moving the container 90 past a piercing needle 98). A
uniform dispersion thereby forms in the barrel of the syringe.
[0047] The sub-dividing volume structure of tubes 18 in the network
8 may assume a variety of geometries and configurations. As shown
in FIGS. 1A, 2, 4A, 4B and 4C, the tubes 18 may be straight,
coiled, helical, in random filaments 38, in an angular or stairstep
(not shown) configuration, or may have other configurations. All of
these alternatives are appropriate for use in any of the
illustrated embodiments. The sub-dividing network 8 need not
encompass tubes 18 at all; all shown in FIGS. 4A, 4B and 4C, the
network 8d, 8e and 8f respectively, may be a series of discrete
cells 42 (see FIG. 4B), or may have a sponge 44 type of structure
(see FIG. 4A). In a cell 42 structure, the agent 12 is retained in
or on discreet cells 42. In a sponge 44 structure, the agent 12 is
either absorbed in or adsorbed on the sponge 44, rather than
contained within tubes 18 or cells 42. A cell 42 or sponge 44
structure may also be used effectively in a network holder 22
separate from a syringe 14. In any embodiment, the network 8 may be
configured so that there is a non-uniform direction for all
sub-volumes, that is, there is no single upward, downward or
lateral direction for all sub-volumes.
[0048] With reference to FIG. 5, a network 8g that is integral with
the container 10 is shown. In this embodiment, the network 8g is
fabricated as grooves or channels 48 that are etched or otherwise
manufactured within the container 10 itself. For example, a syringe
14 may have a cylindrical plug 46 disposed in the barrel 36, where
the plug 46 has parallel or spiral grooves 48 in its outer surface.
The grooves 48 contain the agent 12 between the syringe 14 inner
wall 50 and barrel 36. As shown in FIG. 6, the grooves 48 may
contain substantially perpendicular channels 60 at one or more
regularly spaced intervals. The channels 60 permit rapid and
uniform filling of the network 8 with agent 12 added into one side
of a container 10 when the other side of the container 10 is
sealed. In another embodiment, the syringe 14 has a cylindrical
plug 46 disposed in the barrel 36 as previously described, where
the inner wall 50 of the syringe 14 has parallel or spiral grooves
in its structure. The grooved structures 48 may also be used in a
separate network holder 22. In these embodiments, the grooved
structure 48 comprises the network 8 which sub-divides the volume
of agent 12. It will thus be appreciated that the network 8 may
assume a variety of forms and configurations whereby a volume of
agent 12 can be sub-divided into smaller volumes with increased
surface area of the agent 12 over which the propellant fluid 16
flows to reduce sedimentation.
[0049] The network 8, whether in the form of tubes 18, cells 42 or
sponges 44, may be made of any biocompatible material that can
withstand sterilization and is inert with respect to the agent 12,
the propellant fluid 16, and the container 10. Examples of such
materials for a tubular 18 network include biocompatible tubing
such as polyethylene, polypropylene, silicon, rubber, etc., for
example, Tygon.RTM. tubing (halogenated vinyl plastic, Norton
Plastics). Tubes 18 used in kidney dialysis devices, such as
cellulose tubes 18 having a nominal diameter of 200 .mu.m, may also
be used in the invention. In a network 8e having cells or voids,
the cells 42 may be produced by incomplete fusion of pieces of
fusible material such as thermoplastics or metals. The cells 42 may
be made of Delrin.TM., polycarbonate such as Lexan.TM.,
polyethylene, polypropylene, silicon, rubber, etc. In a network 8d
having a sponge 44 structure, the sponge 44 may be made of porous
Delrin.TM., porous polycarbonate such as Lexan.TM., porous
polyethylene, porous polypropylene, porous silicon, porous rubber,
etc.
[0050] The size and volume of the network 8, container 10, and
network holder 22 may vary, depending upon a number of factors.
These factors include the volume of agent 12, the size of the
container 10, the duration of the imaging or other procedure to be
performed, etc. There is neither a maximum nor a minimum volume for
the network 8, container 10, or network holder 22, and an
exponential range of volumes is contemplated by the invention. For
embodiments in which the network 8 is internal or integral with the
container 10, however, the volume of agent 12 contained within the
network 8 is at most one-half the volume of propellant fluid 16 in
the container 10. This ensures that substantially all the agent 12
will be released from the network 8 by the flow of propellant fluid
16. For example, volumes of contrast agent 12 injected for enhanced
ultrasound imaging may range from 1 ml to about 10 ml. As an
example, a 3 ml volume of agent would require using about a 10 ml
syringe 14, with the tubular 18 or other structure of the network 8
containing 3 ml agent 12 and the remaining volume of the syringe 14
containing at least 3 ml, and more typically 4-5 ml, of propellant
fluid 16. A 3 ml volume of agent 12 may be sub-divided in a syringe
14 having ten threads or grooves 48 per inch, with the threads or
grooves 48 one millimeter deep, each thread or groove 48 containing
about 0.3 ml agent 12.
[0051] The container 10 and/or network holder 22 may be
manufactured having the network 8 preloaded with a uniformly mixed
suspension of agent 12 such as a pharmaceutical colloid. The
container 10 and/or network holder 22 may have both an entry port
54 and an exit port 56 with appropriate fittings 26 such as luer
locks for connection to standard tubing or catheters, as is known
to one skilled in the art (FIG. 3). To eject the agent 12 in the
network 8 from the exit port 56 of the container 10 or network
holder 22 and into the patient through a patient connector line,
propellant fluid 16 may be injected into the entry port 54 or,
alternatively, pressure may be applied to the propellant fluid 16
already in the container 10. The container 10 may also have a
single exit port 56 and a plunger 58, with liquid 60 in the
opposite end, to permit use as a prefilled syringe (FIG. 1).
[0052] The specific location, position and configuration of the
network 8 may depend upon an intended use. For example, an agent
containing a gas other than air should be housed in a container 10
that has been purged of air. A container 10 made of glass may be
rendered air-tight more easily than a plastic syringe, and thus is
preferable for this agent. Likewise, a network 8 that is internal
rather than external is preferred for use with an agent that
contains a gas other than air. This allows the propellant fluid 16
to be purged of air and become saturated with the agent-containing
gas, maintaining a substantially anaerobic environment prior to
injection.
[0053] One advantage of the invention is that it eliminates the
need for resuspension of agents 12 that may come out of suspension,
either in their original container 10 or in a dose delivery
container such as a syringe 14. Conventional containers 10 require
mechanical devices or manipulations to maintain colloids such as a
contrast agent 12 in suspension. By eliminating the need for prior
resuspension of the agent 12 for single-bolus injection, the device
and method of the present invention provides a competitive
advantage for injectable agents 12. In accordance with the
principles of the present invention, a syringe 14 having a network
8 containing agent 12 can remain resuspendable for more than five
months.
[0054] Maintaining the agent 12 in a substantially fully
resuspendable state assures consistent quality and reduced
sensitivity to user technique. The agent 12 may be shipped already
prepackaged in the network 8. This arrangement has the potential to
reduce susceptibility of agents, such as microbubble preparations,
to mechanical vibration and shock which may decrease the integrity
of the agent 12. Dividing the volume of agent 12 into sub-volumes
also allows it to be more quickly preheated to a desired
temperature, facilitating the efficiency of the entire imaging
procedure.
[0055] Another advantage of the invention is that the colloid or
other agent 12 may be released, ejected or expelled from the exit
port 56 of the container 10 by injecting a propellant fluid 16.
This precludes the need to draw the pharmaceutical or contrast
agent 12 into a syringe 14 for injection, and provides similar
advantages as enjoyed by pre-filled syringes.
[0056] Still another advantage of the invention is that, in those
embodiments such as FIGS. 2 and 3 where network 8 is external to
the syringe 14, the exit port 56 of the dose delivery container 10
or network holder 22 may be connected to a short angiocatheter (not
shown) that is very close to a venous or arterial puncture site in
a patient. This arrangement prevents loss of suspension of agent 12
that would occur inside a longer catheter, and permits use of a
manual or power syringe located a substantial distance away from
the patient, while preventing the need for the agent 12 to maintain
resuspendable in the manual or power syringe 14 and connecting
tubing. Instead, the manual or power syringe and tubing need only
contain a non-colloidal fluid that does not require mixing or
resuspending during long injection times.
[0057] A further advantage of the invention is realized with an
optional built-in plunger 58 in the syringe 14. A built-in plunger
58 permits use of the device as a manual syringe 14 or with a
small, battery-operated power injector at the end of a very short
angiocatheter. In either case, the filled syringe 14 could be
located very close to a venous or arterial puncture site,
precluding the need to maintain the agent 12 resuspended in a long
catheter for infusion into a patient. This embodiment also
precludes the need for a fluid-filled syringe 14 connected to the
entry port 54 of the dose delivery container 10 in order to eject
the agent 12 from the exit port 56 of the dose delivery container
10.
[0058] Mixing of the agent 12 flowing through a network 8 having a
tubular structure 18a-b, also called a tubular network 18, may be
achieved by varying the intrinsic and/or extrinsic geometries of
the tubes 18a-b. The effectiveness of mixing increases or decreases
with alterations in the network cross-sectional geometrical
configuration. Any change which increases flow velocity or
turbulence will improve mixing. Since mixing of agent 12 can be
accomplished by either turbulent flow (defined as the motion of a
fluid having local velocities and pressures that fluctuate
randomly) or non-turbulent (also called laminar) flow, providing
configurations of tubes 18a-b that enhance either or both types of
flow will promote mixing.
[0059] Interlaminar mixing may be promoted by altering the
gravitational orientation of the agent 12 suspended as sub-volumes
in the tubular network 18, or by altering turbulent flow. In an
agent containing microbubbles, the agent may be thought of as being
divided into sub-volumes which each contain a subset of the total
number of microbubbles. Over short time intervals most of the
microbubbles in a given sub-volume will tend to remain in the same
sub-volume as agent flows through the network. As the various
sub-volumes of agent flow through the network, the orientation will
continuously vary between up and down as the sub-volume flows
through the network. In effect, this results in the sub-volume
being turned upside down, then downside up, then back to upside
down, and so on. This mechanism promotes mixing of the microbubbles
within a given sub-volume.
[0060] Turbulent flow may occur by exposing the agent 12 to one or
a number of intrinsic geometries within the internal surface of the
network. For example, and with reference to FIGS. 7A, 7B, 7C, 7D
7E, 7F, 7G, 7H, and 71 the geometrical configuration of the
internal network path or channel 62 through which the agent 12 must
pass in a tubular network 18 may be altered. The channel geometries
62 may be altered symmetrically at various points along the total
length of the network 18a-b, or may be altered in a continuously
variable or even random manner. The internal geometries 62 to which
agent 12 is exposed may include, but are not limited to, single
lumen channels that are circular FIG. 7A, square, FIG. 7B,
rectangular FIG. 7C, elliptical FIG. 7D, triangular FIG. 7E, or
other geometric shapes, multi-lumen channels that have a plurality
of either the same or different geometric shapes such as a four
lumen tube having circular channels FIG. 7F, a two lumen tube
having circular FIG. 7G or square 7H channels, a five lumen tube
having one inner circular lumen with four peripheral wedge-shaped
lumens FIG. 7I, any combination or combinations of the above, or
even random shapes, to promote the degree of mixing desired. For
example, exposure to a channel geometry 62 that is square or
rectangular creates increased mixing of the agent 12, compared to
exposure to a channel geometry 62 that is circular or elliptical
because a square channel exposes the flowing agent 12 to blunt
edges, which in turn promotes turbulence. It will be appreciated
that any geometric configuration and arrangement that will result
in agitation or turbulence of the agent 12 as it flows through a
channel 62 in a tubular network 18 is possible. The geometric type
and/or length of tubes 18a-b containing a particular geometric type
of channel will promote mixing of the agent 12 to different
degrees, and may be selected according to the degree of mixing
required. Single-lumen circular channels 62 have an internal
channel diameter in the range of 0.005-0.1 inch. In one embodiment
the circular internal diameter is 0.030 inch. In an alternate
embodiment the circular internal diameter is 0.034 inch.
Multi-lumen circular channels 62 have an internal channel 62
diameter in the range of 0.020-0.044 inch. Multi-lumen channels 62
may be arranged in any configuration and provide an advantage in
being easier to fill with sub-volumes of agent, since a particular
volume of agent 12 is divided into more than one tube. This also
allows for a proportionally shorter tubular network 18 needed to
contain the same volume of agent 12.
[0061] With reference to FIGS. 8A and 8B, other embodiments of an
in-line network 8 are shown. The network 8 is arranged so that the
tubular structures 18 are in a parallel configuration of columns
70. This arrangement allows the liquid flow path to continue,
albeit in a changed direction, at regular intervals, which results
in mixing of the agent 12. In one embodiment, the network 18
contains a total volume of about 4 ml of agent contained in about
12 columns. The tubular structures 18 may be contained with a
network holder 22. The network holder 22 is a rectangle of about 3
inches long by about 2 inches wide, and may be manufactured from
any machined substance that is biocompatible and may be rendered
sterile. In some embodiments the network holder 22 may be
manufactured of cyclic olefin polymers (e.g., Zeonex.RTM., Nippon
Zeon), cyclic olefin copolymers (e.g., Zeonor.RTM.), Nippon Zeon),
polymethylpentene (e.g., TPX.RTM.), Mitsui Corp.), urethane,
polyvinyl chloride (PVC), propylene, a polystyrene resin (e.g.,
styrene butadiene (NK-11.RTM., Phillips Plastics)), or a random
copolymer (e.g., polypropylene copolymer nucleated with NA-11.RTM.,
Huntsman Corp.). In additional embodiments, and with reference to
FIG. 9, each column 70 may be separately added or removed from the
container 10 so that the network 8 may be configured to contain an
adjustable volume of fluid. In this embodiment, the volume of the
tubular network 18 is adjustable to accommodate either a larger or
smaller volume of agent. Volume adjustment occurs easily by
removing a single column 70, as shown in FIG. 9, or a plurality of
columns (not shown). The tubular network 18 in a column 70
terminates in an opening 75 which connects to an opening 75 in the
tubular network 18 in an adjacent column 70 via a luer fitting or
connector (not shown). The columns 70 are stacked with an
alternating order to produce a single network path for the agent
12.
[0062] A first configuration, shown in FIG. 8A, shows the tubular
network 18 in each column 70 arranged in a zigzag configuration. At
sites in the network 18 where the directional flow of liquid
changes (upward to downward or downward to upward), the last
tubular structure 18 in a column 70 joins with a first tubular
structure 18 in an adjacent column 70 that is about twice the
length as the last tubular structure 18 in the preceding
column.
[0063] A second configuration, shown in FIG. 8B, also shows the
tubular network 18 in each column 70 arranged in a zigzag
configuration. The change in directional flow in this embodiment,
however, is accomplished by a U-shaped tubular connector 71 at one
end of the column 70 and a tandem arrangement of two tubes joined
to form an angle of about 1600 at the other end of the column 70.
Comparing the tubular network of FIGS. 8A and 8B, the pitch of the
network is greater in FIG. 8A versus FIG. 8B, the diameter of
tubing is greater in FIG. 8A than in FIG. 8B, and the
cross-sectional area is greater in the network of FIG. 8A than FIG.
8B. Thus, it will be appreciated that numerous variations of the
size, symmetry, shape and configuration of the tubular network 18
are possible to achieve the degree of mixing desired.
[0064] With reference to FIG. 10, an additional embodiment of a
tubular network 18 is shown. The tubular structure 18 is arranged
in a compressible coiled helix configuration 72, resembling a
telephone handset cord. The tube may be polyvinyl chloride (PVC) or
any tubing composition that is biocompatible, can be sterilized,
and can be conformed to this desired coiled configuration. As will
be appreciated, any length of network 18 can be configured for the
desired application, but most often the network 18 in a
noncompressed state is in the range of 1/2 foot to 50 feet,
preferably 6-12 inches. While FIG. 10 illustrates a freestanding
(that is, not within a network holder 22) network 18, this coiled
configuration may be used within a network holder 22, or may be
included within a container 10 such as a syringe.
[0065] As occurs with a telephone handset cord, the compressible
coiled helix configuration (hereinafter referred to as a coiled
helix 72) may become tangled or snagged. For example, the coiled
helix 72 may become tangled upon itself, or tangled or snagged on
equipment, furniture, or people in its vicinity. Problems of
tangling or snagging may be minimized in a number of ways.
[0066] As shown in FIG. 14A, in one embodiment, a portion of the
coiled helix 72 is secured to another portion of the coiled helix
72. With reference to the portion adjacent the inflow port 32 as a
proximal terminus, and the portion adjacent the outflow port 34 as
a distal terminus, one or more portions of the coiled helix 72
between the proximal and distal termini may be secured. For
example, the middle one-third portion of the coiled helix 72 may be
secured, leaving the proximal one-third and distal one-third
unsecured. For another example, using arbitrary numbers, in a
network having ten helices, the proximal two helices and the distal
two helices may be unsecured, with the middle six helices secured.
As will be appreciated by one skilled in this art, any combinations
are possible to secure the desired portion or portions of the
coiled helix.
[0067] The desired portion of the coiled helix 72 may be secured
using mechanical fasteners 101, such as clips, pins, clamps, bands,
ties, etc. that may be made of any number of materials (plastic,
fabric, metal, rubber, etc.). As shown in FIG. 14C, an adhesive
fastener 102 (for example, any type of adhesive bandage, tape or
glue) may also be used. The desired portion of the coiled helix 72
may also be secured in a containment device 104, such as a
protective cylinder-shaped device or sleeve or by encasing all or a
part in a wrap (for example, plastic wrap).
[0068] In one embodiment, the desired number of helices 106 in the
center portion of the coiled helix 72 are secured using an
adhesive. For example, glue is applied to at least part of a facing
helix 106 which is maintained in contact with an adjacent helix 106
until a secure attachment is achieved. Preferably, a non-permanent
type of glue is applied so that the user may detach, and possibly
even reattach, the desired number of helices 106. In use, the
desired length of coiled helix 72 is determined, and the number of
helices 106 required to be compressed to achieve the desired length
is estimated. Glue is then applied to at least part of the adjacent
helical surfaces to form a secure attachment. The user is then free
to detach helices 106 as needed to provide additional length, if
desired, or to secure additional helices 106 to minimize slack.
[0069] In an alternative embodiment, the coiled helix is secured
using clamps 101 that are plastic. The clamps 101 may be adjustable
or rigid, either in whole or in part. As one example, the terminal
portions of the clamps 101 may be made of a rigid plastic, with the
middle portions made of a resilient plastic to provide a
spring-like action, akin to a spring-like toy. The user then
adjusts the portion of the coiled helix 72 to be secured throughout
use with the clamp 101 that is adjustable. As another example, the
entire clamp 101 may be rigid, and the user would pre-select the
portion of the coiled helix 72 to be either secured to unsecured
during use.
[0070] FIG. 11 shows a further embodiment of a device with densely
packed tubes 18 which have a systematically varied radius of
curvature, which is mathematically defined as 1/radius with a
perfect circle, or 1/radius of a best fit circle at any point of a
curve. For example, a circle having a diameter of one inch has a
higher radius of curvature than a circle having a diameter of one
foot. The tubes 18 may or may not be wound around a fixture 30
shown in phantom. The tubular network 18, whereby the first half 77
of the network 8 is paralleled in the second half 79 of the network
8. In the first half 77 of the network 18, the radius of curvature
of the tubes 18 has a density which increases from the inflow
portion 32 to the center. In the second half 79 of the network, the
radius of curvature of the tubes 18 has a density which decreases
from the center to the outflow portion 34. An advantage of this
arrangement is that irregularities in the network promote
turbulence induced interlaminar mixing.
[0071] The network may be configured to be of a relatively low or
high density, depending upon the outcome to be attained. A low
density network is one having a relatively smaller network volume
of contained agent per defined area, in contrast to a high density
network, which is one having a relatively greater network volume of
contained agent in the same defined area. For example, in a tubular
network, tubes that are of identical sizes may be configured to
have a smaller radius of curvature (for example, a radius of
curvature of 1/8 inch) around a fixture. This would result in
greater mixing of a contained agent than tubes 18 configured to
have a larger radius of curvature (for example, a radius of
curvature of one inch) around a fixture having the same internal
channel geometrical configuration. This is because the agent
flowing through a 1/8 inch tubular network is exposed to a greater
centrifugal force in negotiating a greater number of curves than an
agent flowing through a one inch tubular network.
[0072] Enhanced mixing may also be achieved by other means, for
example, by altering the diameter of the channels through which the
agent flows in the network, altering the pitch of grooves (that is,
the distance between repairing turns on a line drawn parallel to a
helical axis) in a symmetrical or partially symmetrical network
configuration, and/or altering the length of the tubular network. A
longer, thinner tubular network has a higher ambient pressure than
a shorter wider network having the same total area. If an agent
contains microbubbles suspended in a liquid, this configuration
impacts the hydrostatic pressure to which the microbubbles are
exposed, which in turn affects the microbubble size distribution
infused into a patient. The following example, not shown in the
figures, illustrates this concept.
[0073] A total volume of 1.5 ml of a microbubble-containing agent
is contained in a tube having a cross-section of 0.015 inch, and
wound as tightly as possible (that is, at relatively high density)
around a 1/8 inch diameter rod-shaped fixture that is two feet long
(that is, a total of two feet of wound tubing). If the agent is
viscous, the agent will have to be subjected to increased pressure
(overpressured) to flow through the tubular network. However,
overpressurization collapses microbubbles of all sizes in the
agent, and once the smallest sized microbubbles collapse, there is
no nucleation site for exchange of the gas contained within the
microbubbles. Since these smallest sized microbubbles cannot be
regenerated, they are permanently removed from the agent under
these conditions.
[0074] In comparison, a total volume of 6 ml of a
microbubble-containing agent is contained in a tubular network
having a cross-section of 0.034 inch, and wound as tightly as
possible (that is, at relatively high density) around a {fraction
(3/16)} inch diameter rod-shaped fixture that is two feet long
(that is, a total of two feet of wound tubing). Under these
conditions, even if the agent is viscous, the agent will not have
to be subjected to increased pressure (overpressured) to flow
through this network. Thus, no microbubbles will be collapsed and
an agent containing microbubbles of all sizes will be delivered and
infused into the patient.
[0075] There is, however, a trade-off between the length of the
network and the cross section of the network that is independent of
the volume contained. While one can obtain any volume desired if
the cross-section of the network is increased sufficiently, once
the cross-section is increased above a certain point, the
microbubbles become trapped or hung up in the network and hence do
not reach the patient.
[0076] In other embodiments, the composition of the tubular network
18 and/or network holder 22 may be altered to achieve a desired
effect. For example, the network 18 and/or network holder 22 may be
made of a material that protects a gaseous agent 12 contained in
the network 18 from a gaseous exchange, and hence protects the
integrity of the agent 12. An example of this would be a network 18
composed of a material that is less permeable or even impermeable
to gas, thus decreasing gas exchange. As an alternate example, the
network 18, either of a typical material or a material that is less
permeable or impermeable to gas exchange, may be packaged in a
secondary container 74, as shown in phantom in FIG. 8B, that is
less permeable or impermeable to gas exchange, to achieve the same
or similar effect. This would increase protection for agents which
are sensitive to air. The secondary container 74 may be glass or a
thick walled (greater than 1/4 inch) plastic such as polyvinyl
chloride (PVC), polypropylene, or other material that may be
sterilized using gamma irradiation. Alternatively, one secondary
container 74 may contain a plurality of less expensive but gas
permeable containers (multi-unit packaging). This advantageously
provides a secondary container 74 that is less permeable or
impermeable to gas exchange, but reduces the expense of providing
such a container 74 for each network 18 or network holder 22. In
still another embodiment, a secondary container 74 may itself
contain a gas that is the same as, or compatible with, the gas
contained in the microbubbles to further decrease gas exchange and
to maintain integrity of a gaseous agent, such as a
microbubble-containing agent 12.
[0077] Another embodiment of the invention is the use of an
inventive resuspension device in combination with a mechanical
resuspension device such as a mixing apparatus (not shown). This
may be advantageously used when a tubular network is being filled
with an agent, for example, when a non-prefilled network embodiment
is used. This embodiment may also be used when filling must occur
over a period of time, during which the agent may come out of
suspension, and the user desires to maintain the agent in a
suspended state throughout the filling process. Additionally, this
embodiment may be used when a very large volume of agent is to be
delivered to a patient and the volume of agent exceeds the capacity
of the network, necessitating a volume greater than the network
capacity. In this case, a mechanical suspension device may be used
that is small enough to be proximal to an infusion site in a
patient, for example, that is taped to a patient's arm or leg, to
maintain suspension of agent.
[0078] The device may be used to control the rate of delivery of
sedimenting agents such as pharmaceutical colloids to a patient.
Heretofore, it was not appreciated that altering the flow rate of a
microbubble-containing agent would alter the normal
size-distribution curve of the microbubbles in the volume of agent,
and hence would alter the size distribution of the contained
microbubbles that are delivered into a patient. If the agent is
comprised of a plurality of microbubbles, such as a contrast agent
containing a plurality of microbubbles suspended in a liquid, the
rate at which the agent is delivered may be used to control the
size of microbubbles that are injected into the patient. This
advantageously excludes microbubbles that are above a set threshold
size, which may have deleterious effects if they are injected into
a patient. Also, depending upon the type of imaging procedure that
a patient is to undergo and the particular organ or tissue to be
imaged, infusion of microbubbles limited to a certain size range is
desirable. As one example, in renal, hepatic and ocular imaging,
only relatively small microbubbles in the range of about 2 .mu.m to
4 .mu.m should be administered, due to the small microvascular
network in the kidney, liver, and eye, respectively. As another
example, the clinician or technician is able to alter the
microbubble size and distribution to achieve, for example, an
altered backscatter or an altered attenuation. This permits the
technician or clinician to make fine adjustments to the image in
real time, that is, as the imaging is in progress and during
infusion of the agent into the patient. As the image is being
displayed and evaluated, alteration of the image quality by
alteration of the delivery rate will result in images of higher
diagnostic significance, and hence the imaging procedure will be of
a higher diagnostic value and be more cost- and time-efficient.
[0079] This would be applicable for use in a single bolus injection
of a microbubble-containing agent, as well as a continuous infusion
of agent.
[0080] Control of the rate at which the agent is delivered,
resulting in control of the particle size of microbubbles in an
agent, is accomplished by altering the cross sectional geometrical
configuration of the tubular network. Using the inventive device,
the technician or clinician thus controls the profile of shear
forces and mixing turbulence of the agent within the network. This
impacts the hydrostatic pressure on the microbubbles, which in turn
alters the flow rate of the agent through the network and in turn
affects the size distribution of microbubbles reaching the infusion
site and being injected into the patient.
[0081] The pressure at which the agent containing microbubbles
flows through the network may also be controlled to achieve altered
size distribution. Since microbubbles flow through the network at a
defined hydrostatic pressure, alteration of the ambient hydrostatic
pressure, either by constant or variable alteration, exposes the
microbubbles to a different hydrostatic pressure at any given
time.
[0082] It should be understood that the embodiments of the present
invention shown and described in the specification are exemplary
embodiments contemplated by the inventor and are not limiting in
any way. For example, the invention is not limited to use in the
clinical area and may be used in research applications, as well as
in other industries where uniformly suspended agents are needed,
such as the food and beverage industries. In such cases, for
example, the propellant fluids 16 may also include oils, epoxy
resins, sugars, etc., depending upon the application. Therefore,
various changes, modifications or alterations to these embodiments
may be made or resorted to without departing from the spirit of the
invention and the scope of the following claims.
* * * * *