U.S. patent application number 15/935894 was filed with the patent office on 2019-09-26 for kit and method of reducing human error during implanted infusion pump refilling.
This patent application is currently assigned to SAOL INTERNATIONAL LIMITED. The applicant listed for this patent is SAOL INTERNATIONAL LIMITED. Invention is credited to Sharon HAMM, David Allen PENAKE, Martin REYNELL.
Application Number | 20190290839 15/935894 |
Document ID | / |
Family ID | 67983970 |
Filed Date | 2019-09-26 |
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United States Patent
Application |
20190290839 |
Kind Code |
A1 |
PENAKE; David Allen ; et
al. |
September 26, 2019 |
KIT AND METHOD OF REDUCING HUMAN ERROR DURING IMPLANTED INFUSION
PUMP REFILLING
Abstract
Protein detection kit usable with implanted infusion pumps. The
kit includes at least one container containing a protein-detecting
composition and having an interface for allowing fluid to be
introduced and a visual indicating mechanism for providing a visual
indicator indicative of protein detection.
Inventors: |
PENAKE; David Allen;
(Atlanta, GA) ; HAMM; Sharon; (Odessa, FL)
; REYNELL; Martin; (Dublin, IE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SAOL INTERNATIONAL LIMITED |
Hamilton |
|
BM |
|
|
Assignee: |
SAOL INTERNATIONAL LIMITED
HAMILTON
BM
|
Family ID: |
67983970 |
Appl. No.: |
15/935894 |
Filed: |
March 26, 2018 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61M 5/14276 20130101;
A61M 2039/0238 20130101; A61M 2005/14284 20130101; A61M 5/427
20130101; A61M 39/0208 20130101 |
International
Class: |
A61M 5/142 20060101
A61M005/142; A61M 5/42 20060101 A61M005/42; A61M 39/02 20060101
A61M039/02 |
Claims
1-22. (canceled)
23. A method of safely refilling an implanted infusion pump, the
method comprising: locating a reservoir refill septum of the
implanted infusion pump; preventing inadvertent injection into an
area overlying the implanted infusion pump; and filling or
refilling the implanted infusion pump, wherein the preventing
comprises: withdrawing fluid from said area while attempting to
fill or refill a reservoir of the implanted infusion pump; and
after the withdrawing, contacting the fluid with a
protein-detecting composition to determine whether the
protein-detecting composition experiences a reaction.
24. The method of claim 23, wherein the method further comprises:
accessing a container containing the protein-detecting composition;
injecting the withdrawn fluid into the container; determining
whether or not the protein-detecting composition experiences a
color change.
25. The method of claim 24, wherein the method further comprises:
filling or refilling the implanted infusion pump only after the
determining.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
[0001] This invention relates to a kit or system for more safely
filling an implanted infusion pump, for example, by determining or
detecting whether "pocket fill" has occurred. The invention also
includes a method of determining or detecting whether pocket-fill
has occurred and/or of more safely filling an implanted infusion
pump. The implanted infusion pump may be of the type that dispenses
baclofen.
2. Discussion of Background Information
[0002] Implantable infusion pumps are generally safe and effective
forms of treatment for approved uses. An example of the same is
described in U.S. Pat. No. 7,044,932 to BORCHARD et al., the entire
disclosure of which is herein expressly incorporated by reference,
However, one of the safety concerns of implantable infusion pumps
is human error during the pump refill process.
[0003] One type of error that can occur in a refill process is that
the health care professional fails to inject the medicine into the
designated reservoir of the infusion pump, and instead, injects the
medicine into the human tissues surrounding the infusion pump. This
can result in a number of safety concerns for the patient depending
on the type of medicine used for injection.
[0004] Errors in the context of the invention include those
associated with underdose, overdose, and adverse events. In
addition, such errors can likely lead to either an overdose
(injection of too much medicine directly into the body) or
under-dose, leading potentially to withdrawal reactions (from the
lack of medication reaching the pump and resultant delivery target,
resulting in a complete withdrawal of medication from the patient
when the reservoir becomes empty). These errors are referred to as
"pocket fills" referring to the injection of some or all of the
prescribed drug into the patient's subcutaneous tissue, which
includes the pump pocket or area under the skin where the pump is
placed, which may include a pocket of fluid that often surrounds
foreign objects implanted into the body. This can lead to a series
of serious medical events, which could include death. One should
also appreciate that, for some pumps, one cannot readily determine
(or directly measure) the volume of fluid that actually makes it
into the pump reservoir.
[0005] Implantable infusion pumps have been designed to ensure the
highest level of safety when delivering medicine within the human
body. In order to maintain that safety, the pumps have been
engineered to ensure that exposure to foreign materials (anything
other than medicine which was specifically developed for this use)
is minimized to prevent pump malfunction or infection. These
efforts have led to pump systems that are highly effective in
preventing unintended exposure to protein inside the pump
reservoir.
[0006] Foreign objects, such as implantable infusion pumps, can be
disruptive to the human body. In an effort to protect the body from
the foreign object, the immune system may respond by surrounding
the foreign object with fat, collagen, and/or vasculature in an
effort to create a barrier between the foreign object and the body.
In doing so, the body may create fluid pockets that directly
surround the pump and these fluids are filled with a variety of
things, including proteins.
[0007] Post implantation, the infusion pump requires periodic
refilling of the drug product intended for targeted delivery via
the infusion pump.
[0008] The infusion pump refill procedure is typically broken into
five sub-procedures as follows: [0009] 1. Patient prep--this
involves getting the patient into a good position to conduct the
procedure. Cleaning the site overlaying the infusion pump in
preparation for a subcutaneous injection, and preparing the sterile
field with the instruments (syringes, needles, medicine, etc.) that
will be used in the procedure (generally described in the infusion
pump refill kit instructions--which can be provided or otherwise
available such as from a website). [0010] 2. Placing a needle into
the pump reservoir--this is the procedure in which the health care
professional attempts to secure a direct line with a needle into
the designated septum of the infusion pump reservoir, which occurs
via subcutaneous injection. This process is often challenging and
the health care professional may supplement their own training and
skill with other detection techniques, including but not limited to
the use of ultrasound. [0011] 3. Withdrawing the remaining drug in
the reservoir--before refilling the pump, the pump must be
completely empty as the refills are typically designated to fill
the full volume of the pump reservoir. This is also an opportunity
for physicians to identify how much medication was left in the pump
and compare it to what was expected to be leftover (based on
information available in the pump and in some devices, extractable
through a handheld, wireless programming device). This is the
primary method of physicians identifying if they have hit a
"pocket" or if they have been able to access the pump reservoir. If
a physician were to hit a "pocket" they may extract a clear fluid
as well, potentially due to the lack of vasculature directly
surrounding the pump. [0012] 4. Refilling the pump--this is when
the health care professional injects the new medication into the
pump via subcutaneous injection through the designated pump septum.
This is also the place where a health care professional might
inject the medication instead into a "pocket", delivering the
medication inadvertently directly into the patient subcutaneously.
[0013] 5. Removal, cleanup, reprogramming--after the pump is
filled, the pump is reprogrammed for administration of the newly
placed drug, typically using the same hand-held device and the
patient is cleaned for discharge.
[0014] At each time in which the pump is filled or refilled, there
is a risk that the pump will not be filled correctly, as explained
above. There remains a need in the field to improve the safety at
the filling and refilling stage.
SUMMARY OF THE INVENTION
[0015] The invention aims to improve the safety of treating with
implantable infusion pump technology by providing an embodiment
that would allow health care practitioners or trained assistants,
when performing the withdrawing stage (as related to pump filling
or refilling), to access the fluid that they are extracting from
the body and to prevent the filling or refilling stage until there
is assurance that the pump reservoir has been correctly
located.
[0016] Embodiments of the invention include methods of testing the
fluid that has been removed from the body with a color-changing
composition that, upon contact with the withdrawn fluid, can detect
the existence of proteins. If no color change occurs, the health
care professional will have an indication that they have correctly
accessed the pump reservoir. This method can be employed as part of
the pump refill kit and can be performed by physicians, hospital
personnel, ancillary healthcare practitioners or trained staff.
[0017] Non-limiting embodiments of the invention include: [0018] A
fluid-withdrawing device such as a syringe for withdrawing fluid.
[0019] A bag or container containing a color-changing composition
such as biuret and having a connecting interface allowing the
syringe to connect thereto and to receive therein the withdrawn
fluid. If the introduced withdrawn fluid contains protein, it will
cause the color changing composition to change color upon contact
therewith. If the introduced fluid does not contain protein (or
contains protein in an amount below the detection threshold), no
color change will be detected.
[0020] Non-limiting embodiments of the invention include: [0021] A
fluid-withdrawing device such as a syringe for withdrawing fluid.
[0022] A bag or container containing a color-changing composition
such as biuret and having a connecting interface allowing the
syringe to connect thereto and to receive therein the withdrawn
fluid. A label or tag is arranged on or associated with the bag or
container to provide a visual indicator to the user. If the
introduced withdrawn fluid contains protein, it will cause the
color changing composition to change color upon contact therewith.
This color may be configured to match a color on the adjoining
label or tag that visually indicates to a user that the fluid has
tested positive for containing protein. If the introduced fluid
does not contain protein (or contains protein in an amount below
the detection threshold), no color change will be detected. The tag
may contain another color indicator associated with a negative test
result, i.e., if the color of the fluid matches the color on the
tag, the tested withdrawn fluid does not contain protein (or
contains protein in an amount below the detection threshold),
[0023] Non-limiting embodiments of the invention include: [0024] A
fluid-withdrawing device such as a syringe for withdrawing fluid.
[0025] A needle, medical tubing for accessing the pump reservoir,
and a valve device for selectively stopping flow through the
tubing. [0026] A bag or container containing a color-changing
composition such as biuret and having a connecting interface
allowing the syringe to connect thereto and to receive therein the
withdrawn fluid. If the introduced withdrawn fluid contains
protein, it will cause the color changing composition to change
color upon contact therewith. If the introduced fluid does not
contain protein (or contains protein in an amount below the
detection threshold), no color change will be detected. [0027] A
package or container for containing and storing the above-noted
items.
[0028] Non-limiting embodiments of the invention include: [0029] A
fluid-withdrawing device such as a syringe for withdrawing fluid.
[0030] A needle, medical tubing for accessing the pump reservoir,
and a valve device for selectively stopping flow through the
tubing. [0031] A bag or container containing a color-changing
composition such as biuret and having a connecting interface
allowing the syringe to connect thereto and to receive therein the
withdrawn fluid. A label or tag is arranged on or associated with
the bag to provide a visual indicator to the user. If the
introduced withdrawn fluid contains protein, it will cause the
color changing composition to change color upon contact therewith.
This color will generally match a color on the tag that visually
indicates to a user that the fluid has tested positive for
containing protein. If the introduced fluid does not contain
protein (or contains protein in an amount below the detection
threshold), no color change will be detected. The tag may contain
another color indicator associated with a negative test result,
i.e., if the color of the fluid matches the color on the tag, the
tested withdrawn fluid does not contain protein (or contains
protein in an amount below the detection threshold). [0032] A
package or container for containing and storing the above-noted
items which can include instructions or information for obtaining
instructions elsewhere such as from a website.
[0033] Non-limiting embodiments of the invention include: [0034] A
fluid-withdrawing device such as a syringe for withdrawing fluid.
[0035] A needle, medical tubing for accessing the pump reservoir,
and a valve device for selectively stopping flow through the
tubing. [0036] A bag or container containing a color-changing
composition such as biuret and having a connecting interface with
integral one-way valve (or device containing the same) allowing the
syringe to connect thereto and to receive therein the withdrawn
fluid. If the introduced withdrawn fluid contains protein, it will
cause the color changing composition to change color upon contact
therewith. If the introduced fluid does not contain protein (or
contains protein in an amount below the detection threshold), no
color change will be detected. [0037] A package or container for
containing and storing the above-noted items.
[0038] Non-limiting embodiments of the invention include: [0039] A
fluid-withdrawing device such as a syringe for withdrawing fluid.
[0040] A needle, medical tubing for accessing the pump reservoir,
and a valve device for selectively stopping flow through the
tubing. [0041] A bag or container containing a color-changing
composition such as biuret and having a connecting interface with
integral one-way valve allowing the syringe to connect thereto and
to receive therein the withdrawn fluid. A label or tag is arranged
on or associated with the bag to provide a visual indicator to the
user. If the introduced withdrawn fluid contains protein, it will
cause the color changing composition to change color upon contact
therewith. This color will generally match a color on the label,
tag or instructions that visually indicates to a user that the
fluid has tested positive for containing protein. If the introduced
fluid does not contain protein (or contains protein in an amount
below the detection threshold), no color change will be detected.
The tag may contain another color indicator associated with a
negative test result, i.e., if the color of the fluid matches the
color on the tag, the tested withdrawn fluid does not contain
protein (or contains protein in an amount below the detection
threshold). [0042] A package or container for containing and
storing the above-noted items.
[0043] Non-limiting embodiments of the invention include, among
other things: [0044] A fluid-withdrawing device such as a
non-needle or non-luer-lock type syringe for withdrawing fluid;
[0045] A one-way valve for connecting the injection device to a
container or bag; and [0046] A bag or container containing a color
changing composition such as biuret in either liquid form or as a
coating disposed inside the container or bag. If the introduced
withdrawn fluid contains protein, it will cause the color changing
composition to change color upon contact therewith. If the
introduced fluid does not contain protein (or contains protein in
an amount below the detection threshold), no color change will be
detected.
[0047] Non-limiting embodiments of the invention include: [0048] A
fluid-withdrawing device such as a needle or needle-luer-lock type
syringe for withdrawing fluid; and [0049] A vial, bottle, bag or
container containing a color changing composition such as biuret in
either liquid form or as a coating disposed inside the container or
bag. A portion of the container, such as the container wall or a
pierceable cap, allows for the needle to pass there-through to
introduce the withdrawn fluid. If the introduced withdrawn fluid
contains protein, it will cause the color changing composition to
change color upon contact therewith. If the introduced fluid does
not contain protein (or contains protein in an amount below the
detection threshold), no color change will be detected.
[0050] Non-limiting embodiments of the invention include: [0051] A
fluid-withdrawing device having a needle for withdrawing fluid; and
[0052] A vial containing a color changing composition such as
biuret in either liquid form or as a coating disposed inside the
vial. A portion of the vial such as a pierceable cap allows for the
needle to pass there-through to introduce between 2 to 6
milliliters the withdrawn fluid. If the introduced withdrawn fluid
contains protein, it will cause the color changing composition to
change color upon contact therewith. If the introduced fluid does
not contain protein (or contains protein in an amount below the
detection threshold), no color change will be detected.
[0053] Non-limiting embodiments of the invention include: [0054] A
fluid-withdrawing device having a needle for withdrawing fluid. The
fluid-withdrawing device contains therein a color changing
composition such as biuret in either powder form, liquid form or as
a coating disposed inside and can receive therein between 1 and 10
milliliters the withdrawn fluid. If the introduced withdrawn fluid
contains protein, it will cause the color changing composition to
change color upon contact therewith. If the introduced fluid does
not contain protein (or contains protein in an amount below the
detection threshold), no color change will be detected.
BRIEF DESCRIPTION OF THE DRAWINGS
[0055] The present invention is further described in the detailed
description which follows, in reference to the noted plurality of
drawings by way of non-limiting examples of exemplary embodiments
of the present invention, in which like reference numerals
represent similar parts throughout the several views of the
drawings, and wherein:
[0056] The figures are intended to show basic features, functioning
and aid in understanding and may or may not show features or
details which are utilized in commercial embodiments.
[0057] FIG. 1 shows an exemplary container or hag containing a
protein-detecting composition and a connecting interface having an
integral one-way valve in accordance with the invention;
[0058] FIG. 2 shows a top view of FIG. 1;
[0059] FIG. 3 shows a bottom view of FIG. 1;
[0060] FIG. 4 shows how an injection device can be aligned with the
connecting interface of the container or bag containing the
protein-detecting composition;
[0061] FIG. 5 shows the injection device connected to the
connecting interface of the container or bag and injecting the
withdrawn fluid into the container or bag so that it can contact
the protein-detecting composition;
[0062] FIG. 6 shows a partial cross-section of an exemplary
connecting interface system that can he used with the invention.
The connecting interface is sealingly connected to a wall of the
container or bag and includes a male luer-lock that can be
connected with a standard luer-lock connector of an injection
device such as a syringe;
[0063] FIG. 7 shows an enlarged view of the connecting interface
having an integral one-way valve in accordance with the
invention;
[0064] FIG. 8 shows a top view of FIG. 7;
[0065] FIG. 9 shows a bottom view of FIG. 7;
[0066] FIG. 10 shows an exemplary container or bag containing a
protein-detecting composition and a connecting interface having an
integral one-way valve in accordance with another embodiment of the
invention. This embodiment includes a label having two distinct
color regions at least one of which is indicative of the
protein-detecting composition color change;
[0067] FIG. 11 shows a bottom view of FIG. 10;
[0068] FIG. 12 shows an exemplary container or bag containing a
protein-detecting composition and a connecting interface having an
integral one-way valve in accordance with another embodiment of the
invention. This embodiment includes a label having multiple, e.g.,
three, distinct color regions at least one of which is indicative
of the protein-detecting composition color change;
[0069] FIG. 13 shows a bottom view of FIG. 12;
[0070] FIG. 14 shows an exemplary container or bag containing a
protein-detecting composition and a connecting interface having an
integral one-way valve in accordance with another embodiment of the
invention. This embodiment includes a tag having at least one color
region which is indicative of the protein-detecting composition
color change;
[0071] FIG. 15 shows a bottom view of FIG. 14;
[0072] FIG. 16 shows an exemplary container or bag containing a
protein-detecting composition and a connecting interface having an
integral one-way valve in accordance with another embodiment of the
invention. This embodiment includes a tag having plural color
regions, e.g., two, at least one of which is indicative of the
protein-detecting composition color change;
[0073] FIG. 17 shows a bottom view of FIG. 16;
[0074] FIG. 18 shows how a non-needle or non-luer-lock type
injection device can be aligned with the connecting interface of a
one-way valve and how the one-way valve can be aligned with an
inlet tube of a container or bag containing the protein-detecting
composition;
[0075] FIG. 19 shows the injection device connected to the one-way
valve which in turn is connected to the container or bag and
injecting the withdrawn fluid into the container or hag so that it
can contact the protein-detecting composition, which in this
embodiment has the form of a liquid composition disposed inside the
bag;
[0076] FIG. 20 shows how a non-needle injection device can be
aligned with the connecting interface of a one-way valve and how
the one-way valve can be aligned with an inlet tube of a container
or bag containing the protein-detecting composition;
[0077] FIG. 21 shows the injection device connected to the one-way
valve which in turn is connected to the container or bag and
injecting the withdrawn fluid into the container or bag so that it
can contact the protein-detecting composition, which in this
embodiment has the form of a coating disposed on inner surfaces of
the container or bag;
[0078] FIG. 22 shows what can happen when the injected withdrawn
fluid contacts the coating--with the shaded area representing a
reaction zone whereby the coating exhibits a color change;
[0079] FIG. 23 shows an injection device using a needle that can be
injected into a pierceable portion of a bag or container to
introduce the withdrawn fluid without the need for a one-way valve.
The container contains therein a protein detecting composition that
can change color when contacted by protein;
[0080] FIG. 24 shows an injection device using a needle that can be
injected into a pierceable cap of a bottle or vial to introduce the
withdrawn fluid without the need for a one-way valve. The bottle or
vial contains a protein detecting composition that can change color
when contacted by protein;
[0081] FIG. 25 shows an injection device using a needle that can
receive therein the withdrawn fluid. The injection device contains
therein a protein detecting composition that can change color when
contacted by protein;
[0082] FIG. 26 is a flow chart describing an exemplary method in
accordance with the invention;
[0083] FIG. 27 shows an exemplary way in which one can access an
implanted infusion pump and attempt to locate the pump reservoir
for filling the same;
[0084] FIG. 28 shows a typical arrangement used for accessing and
filling an implanted infusion pump;
[0085] FIG. 29 is a table illustrating Gornall biuret solution;
[0086] FIG. 30 is a table illustrating Weichselbaum biuret
solution;
[0087] FIG. 31 is a table illustrating a Modified biuret
solution;
[0088] FIG. 32 is a table illustrating test results;
[0089] FIG. 33 is a graph illustrating a BSA calibration curve;
[0090] FIGS. 34 and 35 are tables illustrating Weichselbaum
solution performance;
[0091] FIG. 36 a graph comparing biuret solutions;
[0092] FIG. 37 shows tables illustrating Modified biuret
solution;
[0093] FIG. 38 shows graphs comparing biuret solutions;
[0094] FIG. 39 is a table illustrating biuret reagent solution
performance;
[0095] FIG. 40 a graph comparing different ratios of modified
biuret solution reagents;
[0096] FIG. 41 are tables illustrating BSA/biuret solutions;
[0097] FIG. 42 are tables illustrating BSA/biuret solutions;
[0098] FIG. 43 are tables illustrating NBCL-VWR biuret
solutions;
[0099] FIG. 44 is a graph illustrating calibration lines;
[0100] FIG. 45 is a table illustrating concentrations; and
[0101] FIG. 46 is a table illustrating Weichselbaum solution
performance,
DETAILED DESCRIPTION OF THE INVENTION
[0102] The present invention is further described in the detailed
description which follows, in reference to exemplary
embodiments.
[0103] FIGS. 27 and 28 show an exemplary implanted infusion pump IP
disposed beneath skin while a user or medical professional utilizes
an access template T and shows some of the devices used to perform
this function. These devices include a syringe, a needle as well as
other components associated with these devices such as connectors,
connecting ports, pinch clamp valves, needles and medical tubing.
The invention, in embodiments, utilizes a number of these devices
(see e.g., FIG. 28) such as a syringe having a luer-lock interface,
a section of medical tubing having one end with a luer-lock
connector for connecting to the syringe and an opposite end
connected to a needle which will access the reservoir of the pump.
A hose-pinch type valve can be arranged on the tubing to
selectively stop the flow through the tubing.
[0104] As shown in FIGS. 1-3, the invention also utilizes an
exemplary container or bag 10 which is sized and configured to
contain a predetermined amount of protein-detecting composition 30.
In accordance with non-limiting aspects of the invention, this
composition 30 is a biuret solution which changes color when
contacted by a fluid containing protein. The container or bag 10
can have a variety of forms which include vials, bottles and bags
that resemble IV solution bags which can assume a generally flat
configuration when empty. At least a portion (e.g., a window area)
or all, or nearly all, of the container 10 can be transparent or
translucent in order that a color change can be detected from
outside the container. When having the form of a bag, the container
10 can have a thickness "t" (see FIG. 3) of only one to a few
millimeters when in the empty state. Non-limiting exemplary volumes
for the bag 10 include from about 15 ml (milliliters) to 100 ml or
more. Non-limiting exemplary volumes for the composition 30 include
from about a few ml to 30 ml or more with 5 ml being appropriate.
The volume of the container 10 can also be determined in the range
of, e.g., about 3 to 4 times, that of the volume of composition 30
contained therein.
[0105] As is shown in FIGS. 1-6, the container or bag 10 includes a
connecting interface 20 that allows one to connect an injection
device or syringe 40 thereto. In the exemplary embodiment, the
interface 20 includes a luer-lock connector 21 which can he
connected to a luer-lock connector 41 of the syringe 40. As is
shown in FIGS. 6-9, the interface 20 also includes an insertion end
22, a container attaching groove 23 and an integral one-way valve.
The groove 23 is configured to sealing connect the interface to a
wall 11 of the container 10 and can be sealingly connected using a
number of techniques such as, e.g., adhesive bonding or ultrasonic
welding. The one-way valve 24 can have the form of a slit which
elastically spreads apart when fluid is forced through the
interface 20 but which then elastically returns to a closed
position when fluid is no longer forced through the interface 20.
The invention also contemplates utilizing an interface 20 of the
type disclosed in U.S. Pat. No. 9,227,048, the disclosure of which
is herein expressly incorporated by reference, as well as one that
does not include an integral one-way valve which is instead
separately employed. In the case where the interface 20 is of the
type disclosed in U.S. Pat. No. 9,227,048, the withdrawn fluid can
be injected via a needle of the syringe 40 into the interface
without the syringe 40 being connected to the interface 20.
[0106] A user will typically connect the syringe 40 to the
interface 20 as shown in FIGS. 4 and 5 after fluid is withdrawn in
an attempt to re-fill an implanted pump in a manner similar to that
shown in FIGS. 19 and 20. Since the user will want to ensure that
the withdrawn fluid is from the pump reservoir and not a pocket
fill injection, the user can inject the withdrawn fluid WF into the
container 10 as shown in FIG. 5. When this happens, the injected
withdrawn fluid WF will come into contact with the
protein-detecting composition 30. After contact, the composition 30
can react (or not react) in a number of ways which include: [0107]
A. No color change (or a change below a threshold value); [0108] B.
A color change indicative of protein detection. Examples include a
change from clear or translucent to violet, or a change from blue
or light blue to violet (hut the actual color is not critical, and
can be any color whose appearance may be observed, either through
the naked eye or with machine assistance); [0109] C. A color change
indicative of a medicine contained in the infusion pump; and [0110]
D. A color change indicative of a medicine and a protein contained
in the infusion pump.
[0111] In the case of A, where no color change occurs, this can
provide a visual indication that no protein was detected in the
fluid WF. The user can thus be assured that the withdrawn fluid is
from the pump reservoir and not from a pocket fill injection. If
the pump reservoir has not yet been emptied, this can now be
completed and the infusion pump refilled. Note that while "no color
change" is referred to here, this of course encompasses a situation
in which a color change occurs but is minor and is considered to be
below a threshold value.
[0112] In the case of B, where a color change indicates protein
detection has occurred, this will provide a visual indication that
protein was detected in the fluid WF. The user can thus be informed
that an error was made in that the withdrawn fluid is likely from a
pocket fill location rather than from the pump reservoir. The user
thus knows not to attempt refilling of the infusion pump and to
instead attempt again to correctly locate the pump reservoir. This
can occur by the obtaining another needle, locating the pump
reservoir and injecting the needle in that location. The withdrawn
fluid from this new location can be tested using a new syringe 40
and a new container 10 containing the protein-detecting composition
30. In this case, the original syringe 40, container 10, tubing and
needle can be safely discarded.
[0113] In the case of C, where a color change occurs detecting only
a medicine, this can provide a visual indication that no protein
was detected in the fluid WF. The user can thus be assured that the
withdrawn fluid is from the pump reservoir and not from a pocket
fill infection. If the pump reservoir has not yet been emptied,
this can now be completed and the infusion pump refilled.
[0114] In the case of D, where a color change indicates protein
detection and medicine detection has occurred, this will provide a
visual indication that both medicine and protein was detected in
the fluid WF. The user can thus be informed that something is wrong
with the implanted pump. The area of tissue around the pump should
not contain any significant amount of medicine and the pump
reservoir should not contain any protein. The user thus knows not
to attempt refilling of the infusion pump and to instead take
corrective action(s).
[0115] FIGS. 10 and 11 show another embodiment of a container or
bag 10 which is sized and configured to contain a predetermined
amount of protein-detecting composition 30. In accordance with
non-limiting aspects of the invention, this composition 30 is a
biuret solution which changes color when contacted by a fluid
containing protein. Examples of the biuret solution can be found in
Table 1 below. As with the embodiment of FIG. 1, the container or
bag 10 can have a variety of forms which include vials, bottles and
bags that resemble IV solution bags which can assume a generally
flat configuration when empty. Non-limiting exemplary volumes for
the bag 10 include from about 15 ml (milliliters) to 100 ml or
more, if necessary. Non-limiting exemplary volumes for the
composition 30 include from about a few ml to 30 ml or more with 5
ml being appropriate. The volume of the container 10 can also be
determined in the range of, e.g., about 3 to 4 times, that of the
volume of composition 30 contained therein. In this embodiment, the
container 10 need not be transparent or translucent except for the
first indicator FI. The second indicator area SI can be the same or
substantially the same as the composition 30 after detecting
protein and undergoing a color change. Thus, if the area FI assumes
a color that sufficiently matches the color of the area SI, the
user will be informed that the tested withdrawn fluid contains
protein and appropriate action can be taken as described above. In
the embodiment of FIG. 10, the areas FI and SI can have the form of
a label 50. Non-limiting examples include printing the label 50
directly onto the container 10 or separately providing a label 50
that is adhesively attached to the container 10.
[0116] Alternatively, in the embodiment of FIGS. 10 and 11, the
container or bag 10 is substantially transparent or translucent and
the label 50 contains a first indicator area FI and a second
indicator area SI. Either one of these areas can be the same or
substantially the same as the composition 30 after detecting
protein and undergoing a color change while the other area is that
of the original non-color changed composition. Thus, if the area FI
that will change color assumes a color that sufficiently matches
the color of the area SI (or vice versa), the user will be informed
that the tested withdrawn fluid contains protein and appropriate
action can be taken as described above.
[0117] FIGS. 12 and 13 show another embodiment of a container or
bag 10 which is sized and configured to contain a predetermined
amount of protein-detecting composition 30. In this embodiment, the
container 10 need not be transparent or translucent except for the
first indicator FI. The second indicator area SI can be the same or
substantially the same as the composition 30 after detecting
protein and undergoing a color change. The third indicator area TI
can be the same or substantially the same as the composition 30
after detecting only medicine and undergoing a color change. Thus,
if the area FI assumes a color that sufficiently matches the color
of the area SI, the user will be informed that the tested withdrawn
fluid contains protein and appropriate action can be taken as
described above. On the other hand, if the area FI assumes a color
that sufficiently matches the color of the area TI, the user will
be informed that the tested withdrawn fluid contains only medicine
and appropriate action can be taken as described above. In the
embodiment of FIG. 12, the areas FI, SI and TI can have the form of
a label 50', Non-limiting examples include printing the label 50'
directly onto the container 10 or separately providing a label 50'
that is adhesively attached to the container 10.
[0118] FIGS. 14 and 15 show another embodiment of a container or
bag 10 which is sized and configured to contain a predetermined
amount of protein-detecting composition 30. In this embodiment, the
container 10 is preferably transparent or translucent and includes
at attached tag 50'' forming a first indicator FI. Thus, if the
composition 30 changes color to sufficiently match the color of the
area FI of the tag 50'', the user will be informed that the tested
withdrawn fluid contains protein and appropriate action can be
taken as described above. On the other hand, if the composition 30
does not change to a color matching area FI, the user will know
that no protein was detected. Non-limiting examples include
integrally forming the tag 50'' with the container 10 or separately
providing the tag 50'' and attaching the same to the container 10
via, e.g., adhesive bonding or ultrasonic welding.
[0119] FIGS. 16 and 17 show another embodiment of a container or
bag 10 which is sized and configured to contain a predetermined
amount of protein-detecting composition 30. In this embodiment, the
container 10 is preferably transparent or translucent and includes
at attached tag 50''' forming a first indicator FI and a second
indicator SI. Thus, if the composition 30 changes color to
sufficiently match the color of the area FI of the tag 50''', the
user will be informed that the tested withdrawn fluid contains
protein and appropriate action can be taken as described above. On
the other hand, if the composition 30 does not change to a color
matching area FI and has a color sufficiently matching area SI, the
user will know that no protein was detected. Non-limiting examples
include integrally forming the tag 50''' with the container 10 or
separately providing the tag 50'' and attaching the same to the
container 10 via, e.g., adhesive bonding or ultrasonic welding.
[0120] Alternatively, the embodiment of FIGS. 16 and 17, can
utilize a tag 50''' forming a first indicator FI and a second
indicator SI wherein if the composition 30 changes color to
sufficiently match the color of the area FI of the tag 50''', the
user will be informed that the tested withdrawn fluid contains
protein and appropriate action can be taken as described above. On
the other hand, if the composition 30 changes to a color matching
area SI, the user will know that only medicine was detected.
Non-limiting examples include integrally forming the tag 50''' with
the container 10 or separately providing the tag 50'' and attaching
the same to the container 10 via, e.g., adhesive bonding or
ultrasonic welding.
[0121] In further embodiments, the areas FI, SI and TI can include
indicia providing further indication or positive or negative test
results such as a plus "+" sign and a minus "-" sign, a check
indicator, etc., or other indicators for better or more clearly
providing an indication to the user.
[0122] As shown in FIGS. 18 and 19, the invention can also utilize
an exemplary container or bag 100 which is sized and configured to
contain a predetermined amount of protein-detecting composition 30.
In accordance with non-limiting aspects of the invention, this
composition 30 is a liquid biuret solution which changes color when
contacted by a fluid containing protein. The container can ideally
be a bag 100 that has one or more inlet tubes to which one can
connect a one-way valve 200. The valve 200 has an inlet side that
can be connected to a non-needle injection device 400 and allows
for fluid movement only in one direction so that a use can inject
fluid into the bag 100 when the valve 200 is used but cannot
accidentally withdraw fluid from the bag 100 back into the
injection device 400. As in previous embodiments, the bag 100 can
have a portion (e.g., a window area) or all, or nearly all, of the
bag 100 can be transparent or translucent in order that a color
change can be detected from outside the container. Non-limiting
exemplary volumes for the bag 10 include from about 15 ml
(milliliters) to 100 ml or more. Non-limiting exemplary volumes for
the composition 30 include from about a few ml to 30 ml or more
with 5 ml being appropriate. The volume of the bag 100 can also be
determined in the range of, e.g., about 3 to 4 times, that of the
volume of composition 30 contained therein.
[0123] In the exemplary embodiment of FIGS. 18 and 19, the valve
200 is separate from the injection device 400 and bag 100 and
includes a non-luer-lock type inlet end or connector 210 which can
be connected to a non-luer-lock type connector 410 of the injection
device 400. The valve 200 also includes an outlet end 220 which can
be connected to the tube 110 of the bag 100. Although not shown, it
may be desirable to make the connection between the interface 220
and the tube 110 non-removable. This can prevent the user from
reusing the bag 100 a second time and also prevent the contents of
the bag 100 from spilling out after use. The operation of the
system shown in FIGS. 18 and 19 can otherwise take place in a
manner similar to that of the other embodiments described
above.
[0124] As shown in FIGS. 20-22, the invention can also utilize an
exemplary container or bag 100' which is sized and configured to
contain a predetermined amount of protein-detecting composition
30'. In accordance with non-limiting aspects of the invention, this
composition 30' is a coating of biuret solution which is coated on
inside surfaces of the bag 100' and which changes color when
contacted by a fluid containing protein. The operation of the
system shown in FIGS. 20-22 can otherwise take place in a manner
similar to that of the other embodiments described above except
that when a coating is used, the area or zone of the coating that
is contacted by the injected fluid will be more visually apparent,
as shown in FIG. 22.
[0125] As shown in FIG. 23, the invention can also utilize an
exemplary container or bag 100'' which is sized and configured to
contain a predetermined amount of protein-detecting composition
(not shown). In accordance with non-limiting aspects of the
invention, this composition can be either a liquid or a coating of
biuret solution which is coated on inside surfaces of the bag 100''
and which changes color when contacted by a fluid containing
protein. The operation of the system shown in FIG. 23 can take
place as follows. A user uses a needle type injection device 40' to
extract the withdrawn fluid and then injects the needle N into a
portion 110'' of the container or bag 100''. If the injected fluid
contains protein, this will be indicated by a color change in the
protein-detecting composition as in other embodiments described
herein. However, unlike other embodiments described herein, no
valve is needed in this embodiment as the injection device can be
directly injected into the container or bag containing the
protein-detecting composition. Variations of this embodiment
include injecting the withdrawn fluid into and through a pierceable
sidewall of the container or bag 100'' or through a dedicated
pierceable member arranged on the container 100''. This embodiment
can also utilize a tag or other visual indicator devices such as
those used in the embodiments shown in FIGS. 10-16.
[0126] As shown in FIG. 24, the invention can also utilize an
exemplary bottle or vial 100''' which is sized and configured to
contain a predetermined amount of protein-detecting composition
(not shown). In accordance with non-limiting aspects of the
invention, this composition can be either a liquid or a coating of
biuret solution which is coated on inside surfaces of the bottle or
vial 100''' and which changes color when contacted by a fluid
containing protein. The operation of the system shown in FIG. 24
can take place like the previous embodiment as follows. A user uses
a needle type injection device 40' to extract the withdrawn fluid
and then injects the needle N into a cap 110''' of the bottle or
vial 100'''. If the injected fluid contains protein, this will be
indicated by a color change in the protein-detecting composition as
in other embodiments described herein. Again, unlike other
embodiments described herein, no valve is needed in this embodiment
as the injection device can be directly injected into the container
or bag containing the protein-detecting composition. This
embodiment can also utilize a tag 50.sup.IV or other visual
indicator devices such as those used in the embodiments shown in
FIGS. 10-16. In a non-limiting alternative to this embodiment, the
vial can be an ampule such as a synthetic resin ampule. This ampule
can be either sterilized or non-sterilized.
[0127] As shown in FIG. 25, the invention can also utilize an
exemplary injection device 40'' which is sized and configured to
contain a predetermined amount of protein-detecting composition
30''. In accordance with non-limiting aspects of the invention,
this composition can be a powder, a liquid or a coating of biuret
solution which is coated on an inside surface and which changes
color when contacted by a fluid containing protein. The operation
of the system shown in FIG. 25 can take place as follows. A user
uses a needle type injection device 40'' to extract the withdrawn
fluid. If the injected fluid contains protein, this will be
indicated by a color change in the protein-detecting composition as
in other embodiments described herein. This embodiment can also
utilize a tag 50.sup.V or other visual indicator devices such as
those used in the embodiments shown in FIGS. 10-16.
[0128] With reference to FIG. 26, there is shown on non-limiting
way in which one can implement a method in accordance with the
invention. In stage 100, a user attempts to withdrawn fluid from
the implanted pump. This typically occurs with the use injecting a
needle into an area of skin overlying the implanted pump and then
withdrawing the fluid using a syringe connected to the needle. This
can occurs in the manner described with respect to FIGS. 27 and
28.
[0129] In stage 200, a user accesses a test kit having a container
10 similar to that shown in FIGS. 1-22.
[0130] In stages 300 and 400, a user connects the syringe
containing the withdrawn fluid to the container 10 and injects the
withdrawn fluid similar to that shown in FIGS. 4 and 5.
[0131] In stages 500-700, a user visually detects whether the
composition 30 experiences a color change and takes action
consistent therewith such as performing a refilling procedure as in
stage 600 or starting over in stage 700.
Non-Limiting Examples of Protein-Detecting Composition
[0132] Protein-sensing dyes (Biuret test for example) were
developed and have been used to identify a number of
protein-related disorders and are commonly used to identify protein
in urine. Some tests have become complex and are sensitive to
certain types of protein, others provide more general recognition
of the presence of protein. Protein-detecting compositions
generally produce a visually observable reaction on reacting with
protein. Examples include, but are not limited to, the Bradford
protein assay, which is based on Coomassie Brilliant Blue G-250,
and the use of which results in an observable color shift.
Preferably, the composition includes a Biuret solution.
[0133] Biuret protein test is a well-established test to
qualitatively detect this presence of proteins. It generally
includes a reagent made up of potassium iodide, potassium sodium
tartrate, copper sulfate, and sodium hydroxide. It is based on the
cupric ions in the alkaline solution reacting with the peptide
bonds of the protein and polypeptides to produce a violet colored
complex.
C.sup.+++Protein.fwdarw.OH.sup.- Cu-Protein Complex
[0134] Numerous examples of protein-sensing dyes and tests are
known in the art, and are not set forth herein for the sake of
brevity. However, the inventors do not believe the choice of dye or
test is a limiting aspect of the invention, as any type could be
used according to the invention. Particular types of biuret
reaction tests are described, for example, by Gornall et al., in
The Journal of Biological Chemistry, Vol. 177, pages 751-766, Feb.
1, 1949, and Weichselbaum, in American Journal of Clinical
Pathology, Vol. 10, pages 40-49, Mar. 1946, the entire disclosures
of both of which are incorporated by reference herein. Commercially
available products are also available. There are various advantages
and disadvantages to different tests, relating for example, to the
speed and sensitivity of the reaction, and color of the reaction
product, but the choice of particular test method is not
critical.
[0135] The invention contemplates various protein-detecting
compositions which can change color upon contact with protein. This
includes a change from clear or light blue to violet as well as
other changes. Although acceptable results can be obtained when a
certain volume or amount of withdrawn fluid is placed into contact
with a certain volume or amount of the protein-detecting
composition and ratio ranges of between 1 to 1 (withdrawn fluid to
protein-changing composition) and 1 to 2 (withdrawn fluid to
protein-changing composition) can provide acceptable results, the
invention contemplates other ratio ranges. In addition, the
invention can be implemented with a certain or threshold amount of
withdrawn fluid such as 1 milliliter and with a predetermined range
or amount of protein-detecting composition such as between 2 and 6
milliliters. A preferred embodiment of the present invention
includes the use of at least 4 milliliters, with 4 milliliters of
withdrawn fluid mixed therewith.
[0136] The protein-detecting compositions used in the present
invention may be in dry form such as powder form or in liquid form.
For example, in dry form, the separate dry elements of the reaction
mixture can be included, and then rely on the liquid from the
biological fluid to dissolve the elements for the reaction to
occur. Alternatively, for example, a liquid composition may be
dried (after dissolving the various components in a solvent), and
the dried composition may be mixed and re-dissolved in biological
fluid. Or the protein-detecting composition may be in liquid form,
which can be mixed with the biological fluid to be tested for
protein. Various combinations and modifications will be readily
apparent to skilled persons after reviewing the present
specification.
[0137] Note that the protein-detecting compositions are intended to
provide a basis for determining whether a composition includes a
sufficient amount of protein to be a cause for concern. The
inventors of course recognize the any injection into human tissue
will almost necessarily introduce some protein into or onto a
needle tip, which can be detected by the protein-detecting
compositions. Thus, the inventors contemplate that some protein in
a sample may be unavoidable, and contemplate that a threshold color
change may determined through a standard concentration curve to
determine what level of protein is considered to be a cause for
concern. While not wishing to be bound to any particular
concentration, a concentration of protein of about 30 mg/ml or
higher in the withdrawn fluid will generally be considered as
evidence that the needle has been inserted into human fluid, i.e.,
outside the pump reservoir.
[0138] The inventors certainly also recognize that certain human
conditions might result in a normally higher or lower concentration
of protein in serum. For example, liver disease, acute infection,
or immunodeficiency can result in low serum albumin concentration;
and other diseases such as paraproteinemia (caused by certain
leukemias and lymphomas), Hodgkin's lymphoma, and leukemia can
result in an increase in immunoglobulins. The presence of such
conditions can be taken into account by the practitioner in
determining whether a color change in the protein-detecting test
should be considered cause for concern.
EXAMPLES
[0139] Development of a qualitative colour test for proteins in
abdominal body fluid.
[0140] Sensitivity to be reached 0.03 g/mL=30 mg/mL.
[0141] The value of 30 mg/ml was determined as the target value
based on reported levels of total protein in peritoneal fluid
(normally exudate material is>3.0 g/dl with transudate<3.0
g/dl).
Objectives
[0142] (1) Develop formulation for peritoneal fluid
[0143] (2) Define appropriate Biuret solution to protein fluid
ratio
[0144] (3) Define protein operating range and limit of detection
for the Biuret solution
[0145] (5) Verify stability of the solution
[0146] (6) Use of control samples with the Biuret solutions
Technical Summary
[0147] (1) Biuret reagent development
[0148] Three different Biuret solutions were tested--with all
solutions sensitive enough to visualize 30 mg/mL, of protein.
Gornall and Weichselbaum refer to the sources of biuret found in a
literature search.
[0149] (1.1) Biuret Formulations
[0150] Gornall biuret solution. See FIG. 29.
[0151] Weichselbaum biuret solution. See FIG. 30.
[0152] Modified biuret test solution. See FIG. 31.
[0153] (1.2) Formulation performance
[0154] For this the various Biuret solutions above were evaluated
against visual colour and spectrophotometrically.
[0155] Gornall. See FIGS. 32 and 33.
[0156] Conclusion: The BSA calibration curve is linear until about
2.5 mg/ml. For this reason, only the 0-2.5 mg/ml curve was used to
calculate concentrations. The total protein concentration found is
77 mg/ml (120% recovery). The target concentration of 30 mg/ml is
clearly visible.
[0157] The Weichselbaum solution performance was compared again
against the Gornall See FIGS. 34-36.
[0158] Conclusion: The Weichselbaum Biuret solution reaches a
higher OD value than the Gornall solution. Also the Weichselbaum
signal develops in time more than the Gornall signal.
Solution
[0159] The solution performance was tested and compared against the
two previous solution types. See FIGS. 37 and 38.
[0160] Conclusion: the biuret solution results in a good
performance. A very low background and good colour intensity @ (10
mg/ml, OD 0.710).
[0161] (2) Evaluation of the performance of different ratios of
biuret reagent solutions with BSA calibrators in different
protein:biuret ratios: 1:3, 1:2, 1:1, 2:1, 3:1. See FIGS.
39-42.
[0162] Conclusion: There is a wide range of color changing ratios
versus the typically specified 1:1 preferred biuret ratio. This
allows for a single volume of biuret fill with a range of potential
pump aspiration volumes and still provide valid results
[0163] (3) Protein operating range and limit of detection
determination
[0164] (3.1) From the above section 1.2 an operational range of 1.0
to 10.0 mg/ml was established for all Biuret solutions. However,
the % CV was best for the solution with a relatively low background
and hence less variability.
[0165] Further linearity studies were carried out listed below
these confirmed the linear range. See FIGS. 43-45.
[0166] Conclusion Linearity and hence range was demonstrated from
1.0 mg/ml to 10.0 mg/ml. LOD of 0.1 mg/ml was determined.
[0167] (3.2) Also a visual study was conducted with laboratory
personnel to determine when an end point (color change) could he
visually detecLcu and to see what concentration of protein this
corresponded to. The spectrophotometric method was used a
reference.
[0168] Conclusion (without showing all data): At the concentration
of 1 mg/ml, all laboratory personnel (n=6) could visually detect
the colour change.
[0169] (4) Stability
[0170] Stability was initially carried out on Gornall and
Weichelbaum solutions. After this initial study and evaluation, the
Weichelbaum reagent was not as stable and further stability was not
continued for this solution.
[0171] Stability studies were carried out on the solutions at
various conditions.
[0172] Conclusion (data not shown): The solutions all demonstrate
acceptable stability.
[0173] (5) Control samples (including drug)
[0174] (5.1) Baclofen as a negative control
[0175] Lioresal (baclofen(2.0 mg/ml)) was used as a negative
control to determine if the use influenced a false positive result.
See FIG. 46.
[0176] Conclusion: Baclofen solution alone (ie. Aspirate in a real
world setting) does not create a color change and therefore a
false-positive.
[0177] Conclusion from all examples:
[0178] Each of the various biuret solutions exhibited acceptable
performance.
* * * * *