U.S. patent application number 11/574318 was filed with the patent office on 2008-04-24 for container with constrained quality maintenance agent.
Invention is credited to William A. Hagen, Michael R. Mahoney, Muthunadar P. Periasamy.
Application Number | 20080093245 11/574318 |
Document ID | / |
Family ID | 35826592 |
Filed Date | 2008-04-24 |
United States Patent
Application |
20080093245 |
Kind Code |
A1 |
Periasamy; Muthunadar P. ;
et al. |
April 24, 2008 |
CONTAINER WITH CONSTRAINED QUALITY MAINTENANCE AGENT
Abstract
A container (63) having a quality maintenance additive (25, 31,
33, 41, 45, 65) which maintains the quality of a quantity of liquid
(11, 14) or other flowable substance held in the container. The
quality maintenance additive is associated with the container so
that the quality maintenance additive remains with the container
when the liquid or other flowable substance is emptied from the
container.
Inventors: |
Periasamy; Muthunadar P.;
(Chesterfield, MI) ; Hagen; William A.; (OFallon,
MO) ; Mahoney; Michael R.; (Lake St. Louis,
MO) |
Correspondence
Address: |
Mallinckrodt Inc.
675 McDonnell Boulevard
HAZELWOOD
MO
63042
US
|
Family ID: |
35826592 |
Appl. No.: |
11/574318 |
Filed: |
September 28, 2005 |
PCT Filed: |
September 28, 2005 |
PCT NO: |
PCT/US05/35156 |
371 Date: |
February 27, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60613907 |
Sep 28, 2004 |
|
|
|
Current U.S.
Class: |
206/438 |
Current CPC
Class: |
A61M 5/31511 20130101;
A61M 5/007 20130101; A61M 5/3129 20130101 |
Class at
Publication: |
206/438 |
International
Class: |
B65D 81/24 20060101
B65D081/24 |
Claims
1. A container for holding and maintaining quality of a flowable
substance, the container comprising an enclosure for containing the
flowable substance and a quality maintenance additive active to
maintain the quality of the flowable substance, the quality
maintenance additive being disposed relative to the enclosure so
that the quality maintenance additive contacts the flowable
substance when held in the enclosure, the quality maintenance
additive being capable of acting on the flowable substance to
maintain a quality characteristic of the flowable substance when
held in the enclosure, the quality maintenance additive being
associated with the enclosure so that it remains with the enclosure
when the flowable substance is removed from the enclosure.
2. A container as set forth in claim 1 wherein the enclosure
constrains the quality maintenance additive from leaving the
enclosure.
3. A container as set forth in claim 2 wherein the quality
maintenance additive is part of a composition of material forming
the enclosure.
4. A container as set forth in claim 2 wherein the enclosure
includes at least one surface disposed for contact with flowable
substance held in the container, the quality maintenance additive
being disposed on said one surface.
5. A container as set forth in claim 4 wherein the quality
maintenance additive disposed on said one surface is chemically
bonded to the enclosure.
6. A container as set forth in claim 4 further comprising another
material disposed on said one surface of the enclosure, the quality
maintenance additive being in composition with said other
material.
7. A container as set forth in claim 6 wherein said one surface of
the enclosure is etched prior to depositing said other material
thereon.
8. A container as set forth in claim 7 wherein said other material
is a lubricant.
9. A container as set forth in claim 2 wherein the quality
maintenance additive is formed as a piece separate from the
enclosure.
10. A container as set forth in claim 9 wherein the quality
maintenance additive piece is disposed in the enclosure, the
enclosure including an outlet sized for preventing the quality
maintenance additive piece from leaving the enclosure.
11. A container as set forth in claim 10 in combination with
flowable substance contained in the enclosure, the quality
maintenance additive piece being at least partially immersed in the
flowable substance.
12. A container as set forth in claim 9 wherein the quality
maintenance additive piece is attached to the enclosure in a
position for contact with flowable substance contained in the
enclosure.
13. A container as set forth in claim 12 wherein the quality
maintenance additive piece is a film laminated to the
enclosure.
14. A container as set forth in claim 9 wherein the quality
maintenance additive piece comprises a filter adapted to receive
the flowable substance therethrough upon removal of the flowable
substance from the enclosure.
15. A container as set forth in claim 1 wherein the quality
maintenance additive is capable of remediating a quality
characteristic of the flowable substance.
16. A container as set forth in claim 1 wherein the quality
maintenance additive is selected from at least once of an
antimicrobial, an antioxidant, a chelating agent or a buffering
agent.
17. A container as set forth in claim 16 wherein the quality
maintenance additive is a chelating agent.
18. A container as set forth in claim 17 in combination with the
flowable substance, and wherein the flowable substance comprises a
contrast media.
19. A container as set forth in claim 18 wherein the chelating
agent piece is floated in the contrast media.
20. Packaged contrast media comprising: a quantity of imaging
contrast media; a container containing the quantity of the contrast
media therein; a quality maintenance agent in contact with the
quantity of contrast media for maintaining the quality of the
contrast media, the quality maintenance agent being configured to
remain with the container and not being carried by the contrast
media upon removal of the contrast media from the said
container.
21. Packaged contrast media as set forth in claim 20 wherein, the
container is selected from a vial, a bottle, a syringe, a bag or a
pharmacy bulk package.
22. Packaged contrast media comprising: a quantity of imaging
contrast media; a syringe barrel containing the quantity of the
contrast media therein; a plunger head received in the barrel
generally adjacent to one end of the barrel; a chelating agent
element in contact with the quantity of contrast media in the
barrel for capturing free metal ions in the contrast media, the
chelating agent being configured to remain with the syringe and not
be carried by the contrast media upon ejection of the contrast
media from the barrel.
23. Packaged contrast media as set forth in claim 22 wherein the
chelating agent is associated with at least one of the barrel and
the plunger head.
24. Packaged contrast media as set forth in claim 23 wherein the
chelating agent comprises a layer of material attached to one of
the barrel and the plunger head.
25. Packaged contrast media as set forth in claim 24 wherein the
layer of material includes a lubricant.
26. Packaged contrast media as set forth in claim 24 wherein the
layer of material is a film laminated to at least one of the barrel
and plunger head.
27. Packaged contrast media as set forth in claim 23 wherein the
contrast agent is incorporated into material forming at least one
of the barrel and the plunger head.
28. Packaged contrast media as set forth in claim 23 further
comprising a piece made from material including a chelating agent,
the piece being mounted on one of the barrel and the plunger
head.
29. Packaged contrast media as set forth in claim 22 further
comprising a piece made from material including a chelating
agent.
30. Packaged contrast media as set forth in claim 29 wherein the
chelating agent component comprises a filter arranged to receive
contrast media therethrough upon ejection of the contrast media
from the barrel.
31. A method of forming a package of a quantity of flowable
substance, the method comprising: associating a quality maintenance
additive with a container; providing a quantity of flowable
substance; loading the quantity of flowable substance into the
container, the quality maintenance additive being adapted to
maintain the quality of the quantity of flowable substance, the
association of the quality maintenance additive being such that the
quality maintenance additive remains with the container when the
flowable substance is emptied therefrom.
32. A method as set forth in claim 31 wherein the step of
associating a quality maintenance additive comprises formulating
material with a quality maintenance additive and forming the
container from the material.
33. A method as set forth in claim 31 further comprising the step
of depositing a substance including the quality maintenance
additive onto a surface of the container which will be exposed to
the quantity of flowable substance loaded therein.
34. A method as set forth in claim 33 further comprising the step
of etching the surface of the enclosure prior to depositing the
substance including the quality maintenance additive thereon.
35. A method as set forth in claim 34 wherein the step of
depositing the substance comprises one of spraying the substance
onto the container surface, vapor depositing the substance onto the
container surface, and laminating a film including the quality
maintenance additive onto the container surface.
36. A method as set forth in claim 31 further comprising forming a
piece including the quality maintenance additive separately from
the container and operatively connecting the piece to the
container.
37. A method as set forth in claim 36 wherein the step of
associating the quality maintenance additive with the container
comprises fixing the piece to the container.
38. A method as set forth in claim 36 wherein the piece is floated
in the quantity of flowable substance.
39. A method as set forth in claim 36 wherein the piece rests on
the bottom of the container.
40. A container for holding and maintaining quality of a flowable
medical substance for use in medical diagnostics and/or treatment,
the container comprising an enclosure for containing the flowable
medical substance and a quality maintenance additive active to
maintain the quality of the flowable medical substance, the quality
maintenance additive being disposed relative to the enclosure so
that the quality maintenance additive contacts the flowable medical
substance when held in the enclosure, the quality maintenance
additive being capable of acting on the flowable medical substance
to maintain a quality characteristic of the flowable medical
substance when held in the enclosure, the quality maintenance
additive being associated with the enclosure so that it remains
with the enclosure when the flowable medical substance is removed
from the enclosure.
Description
BACKGROUND OF THE INVENTION
[0001] This invention relates generally to storage containers and
the storage of substances, and more particularly to a container for
holding substances and maintaining their quality.
[0002] The present invention has application in the medical field
for medicine and drug storage containers. Particularly, the present
invention can be applied to injectable therapeutic or diagnostic
drug storage containers, including intravenous injectable drug
containers. A more particularly useful application is for
diagnostic contrast media containers.
[0003] Liquids and other substances which are packaged, shipped and
often stored have to be capable of remaining in an efficacious
condition for extended periods of time. Almost always this quality
or "shelf-life" of the substance is facilitated by the packaging
itself, which may protect the substance from contact with air or
exposure to sunlight, for example. In these instances, the
pertinent properties of the packaging pertain to its ability to
form a barrier. The substance being stored may itself contain
quality maintenance components. As an example in the case of
injectable therapeutic or diagnostic drug substances, the
formulation itself may contain components which maintain the
quality of the substance. The maintenance of "quality" or "a
quality characteristic" of a substance may refer to, among other
things, as the maintenance of stability, product attributes and
sterility. For example, quality maintenance additives may fall into
the class of antimicrobials (preservatives), antioxidants,
buffering agents, and/or metal chelating agents (including calcium
sequestering agents). Other examples of quality maintenance
additives are given in JAMES C. BOYLAN ET AL., PARENTERAL PRODUCTS,
in MODERN PHARMACEUTICS (Gilbert S. Banker et al. eds., 3rd ed.,
1996), Chapter 12, pp. 441-460, 470, 471, 473-482, and 486-487,
incorporated herein by reference. Pages 452-458 of MODERN
PHARMACEUTICS particularly discloses added substances for use in
parenteral formulations.
[0004] The addition of quality maintenance additives to the
substance itself requires that the additives not deleteriously
affect the use of the substance. In the case of foods or medical
products, components added must have minimal or no physiological
effect when ingested, injected or otherwise introduced into the
living subject.
[0005] As one example, contrast media used for imaging the body
must be stored while maintaining its efficacy and quality for
extended periods. Contrast media may be used for radiographic
imaging, magnetic resonance imaging, ultrasound imaging, optical
imaging and/or nuclear imaging. Examples of such contrast media are
Optiray.RTM. X-ray contrast media and OptiMARK.RTM. MRI contrast
media available from Tyco Healthcare/Mallinckrodt of St. Louis, Mo.
The contrast media is injected into the patient who is then
subjected to an imaging procedure, the contrast media provides a
greater contrast so that the image produced of the tissue in the
interior of the patient's body is clearer and sharper.
[0006] For instance, magnetic resonance imaging contrast media
frequently includes a chelated paramagnetic metal ion in a complex,
the most common metal ion being gadolinium (Gd.sup.+3) . Free metal
ions are highly undesirable in a living system such as the human
body. The contrast media must not have a concentration of free
gadolinium metal ions that causes a significant physiological
effect on the patient. In addition, it is possible for other metal
ions (e.g., Fe.sup.+3, Pb.sup.+2) to be inadvertently introduced
into the contrast media during the pharmaceutical manufacturing
process.
[0007] Manufacturing techniques are employed to minimize the
introduction of unwanted metal ions. One step that is commonly
taken is to add slight excesses of sodium/calcium salts of
chelating agents (e.g., EDTA, DTPA, DTPA-BMEA, "versetamide") to
the contrast media to bind free ions of any metal ions introduced
in manufacture and metal ions which may come out of their complex.
The chelating agent can in some instances maintain the pH of the
contrast media within an optimal effective range for extended
periods. In some cases, pH of the contrast media may be controlled
by the addition of buffering or stabilizing agents. As an example,
OPTIRAY.RTM. X-ray contrast media contains tromethamine as a
buffer. The effective amount of a buffering or chelating agent
depends upon the particular application.
[0008] In some other cases, the formulation may contain an
antioxidant such as ascorbic acid or bisulfite. Of course, the
additive is somewhat dependent upon the type of liquid being
stored. Whatever the exact consumable or parenteral formulation
being stored, where a quality maintenance additive is added, it is
unavoidable that some (and usually all) of the agent will be
introduced into the body when the product is taken in. It has been
suggested in the case of contrast media that if such additives can
be avoided, the occurrence of side effects in patients is reduced.
See, R. Fattori et al., Iomeprol and Iopamidol in Cardiac
Angiography: a Randomised, Double-blind Parallel-group Comparison,
Eur. J Radiol. 18 Suppl. 1:S1-S12 (1994). However, quality
maintenance additives are important to providing a product which Ls
stable and of a consistent quality. Therefore, there is a need for
a storage and delivery system in which these quality maintenance
additives can still be used, but are prevented from entering the
patient when the formulation is administered to the patient, or is
consumed.
SUMMARY OF THE INVENTION
[0009] In one aspect of the present invention, a container for
holding and maintaining quality of a flowable substance generally
comprises an enclosure for containing the flowable substance and a
quality maintenance additive active to maintain the quality of the
flowable substance. The quality maintenance additive is disposed
relative to the enclosure so that the quality maintenance additive
contacts the flowable substance prior to administration or
consumption, such as when held in the enclosure. The quality
maintenance additive is capable of acting on the flowable substance
to maintain a quality characteristic of the flowable substance
prior to administration or consumption, such as when held in the
enclosure. The quality maintenance additive is associated with the
enclosure so that it remains with the enclosure when the flowable
substance is removed from the enclosure for administration or
consumption.
[0010] In another aspect of the present invention, packaged
contrast media generally comprises a quantity of imaging contrast
media contained in a syringe barrel, and a plunger head received in
the barrel generally adjacent to one end of the barrel. A chelating
agent element, as an example of quality maintenance additive, is in
contact with the quantity of contrast media in the barrel for
capturing free metal ions in the contrast media. The chelating
agent is configured to remain with the syringe and not be carried
by the contrast media upon ejection of the contrast media from the
barrel.
[0011] A method of forming a package of a quantity of flowable
substance generally comprises associating a quality maintenance
additive associated with a container. A quantity of flowable
substance is provided which is loaded into the container. The
quality maintenance additive is adapted to maintain the quality of
the quantity of flowable substance. The association of the quality
maintenance additive is such that the quality maintenance additive
remains with the container when the flowable substance is emptied
therefrom.
[0012] Other features of the present invention will be in part
apparent and in part pointed out hereinafter:.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] FIG. 1 is a longitudinal section of a syringe prepackaged
with a contrast media and with a stem of a syringe plunger
disconnected from a plunger head;
[0014] FIG. 2 is an enlarged, fragmentary section of a barrel of
the syringe taken in the plane including line 2-2 of FIG. 1 and
showing a layer of material applied thereto;
[0015] FIG. 3 is an enlarged, fragmentary section of the plunger
head taken in the plane including line 3-3 of FIG. 1 and showing a
layer of material applied thereto;
[0016] FIG. 4 is an enlarged, fragmentary longitudinal section of a
syringe having chelating agent components mounted thereon;
[0017] FIG. 5 is a bottom elevation of a plunger head of a syringe
showing a chelating agent component mounted thereon;
[0018] FIG. 6 is a section taken in the plane including line 6-6 of
FIG. 5;
[0019] FIG. 7 is an enlarged, fragmentary section of a syringe
similar to FIG. 4 but including a filter at an outlet end of the
syringe;
[0020] FIG. 8 is a section of a bottle containing contrast media
and a floating chelating agent component; and
[0021] FIG. 9 is a section of a vial containing contrast media.
[0022] Corresponding reference characters indicate corresponding
parts throughout the several views of the drawings.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0023] Referring now to the drawings and in particular to FIG. 1, a
prefilled syringe (broadly, "a container") is generally indicated
at 1. The syringe includes a barrel (generally indicated at 3), a
plunger head 5 received in the barrel. The barrel 3 (broadly, "an
enclosure") tapers to a nozzle 7 at a constricted end of the
barrel. The plunger head is located near an open end 8 of the
barrel 3, closing the barrel at that end. The nozzle 7 receives a
cap 9 which sealingly closes the nozzle, but can be removed to open
the nozzle. A liquid, such as a diagnostic contrast media 11 which
may be used for radiographic, magnetic resonance or ultrasound
imaging, is contained in the barrel 3 between the cap 9 and the
plunger head 5. A plunger stem 13, shown separated from the plunger
head 5 in FIG. 1, can be connected in a suitable manner, as by
mating threads (designated 15 and 17, respectively), to the plunger
head. The plunger so formed can be used to drive the plunger head 5
down within the barrel 3 to push the contrast media 11 through the
nozzle 7 and out of the barrel at the time the contrast media is to
be injected. The barrel 3 is formed in a conventional way with a
flange 19 to facilitate driving the plunger down into the barrel.
In the first embodiment illustrated in FIG. 1, the plunger stem 13
would be initially disconnected from the plunger head 5 but
packaged together with the assembled barrel 3, contrast media 11,
plunger head and cap 9. An example of a syringe of the same general
type as described is shown in U.S. Pat. No. 6,648,860, the
disclosure of which is incorporated herein by reference.
[0024] It will be appreciated that, except as described
hereinafter, the construction of the syringe 1 can be conventional.
However, the present invention is not limited to syringes. A
container may be a structure such as a syringe, vial, flask, bottle
or jar, pharmacy bulk package or a flexible structure like a bag.
The container may be made of glass, plastic, metal, a combination
of glass, plastic and/or metal or other suitable materials and
combinations of materials. Moreover, the broader term "container"
may be taken to mean for purposes of this application structures
such as a passage which would contain liquid or other flowable
substance only for an instant as it flows through the structure.
"Flowable substance," as used herein, includes liquids, emulsions,
suspensions and liposomes. The present invention has particular
application to containers holding contrast media, and the
description will be directed to contrast media 11. However, the
present invention is useful with any substance held in a container
that can be beneficially affected by a quality maintenance additive
which is associated with the container and not directly added to
the substance itself in such a way that it is ejected or emptied
with the substance from the container in use.
[0025] Examples of some types of quality maintenance additives to
which the present invention applies are given above in the
Background of the Invention. Chelating agents and buffering agents
are the most common quality maintenance additives used for contrast
media 11, and the embodiments described herein will reference a
chelating agent. It will be understood that although generally
these additives act on the stored substance to maintain the quality
of the stored substance, it is envisioned that a "quality
maintenance additive" could also improve or change the quality of
the stored substance in some predetermined fashion within the scope
of the present invention. Often, the quality maintenance additive
acts on the stored substance to remediate a condition which
deviates from a desired quality characteristic of the stored
substance. A quality characteristic may be, for example and without
limitation, a certain pH range, the absence of microbes, the
absence of positive metal ions, and prevention of oxidation.
Moreover, the present invention is envisioned as having application
outside the medical field.
[0026] The invention is described herein in terms of an embodiment
in which the quality maintenance additive is a chelating agent. In
a first embodiment of the present invention, a
chelating/stabilizing agent (referred to hereafter as a "chelating
agent") is incorporated into a resin that forms the plastic barrel
3 of the syringe 1 using one of the many conventional methods known
in the art. Typically, the syringe barrel 3 is made from a polymer
or resin material such as polyethylene, polypropylene, a copolymer
of polyolefins, polyvinylchloride, polystyrene, polycarbonate,
polyethylene terephthalate, cyclic olefin materials and like
commonly used polymers. The container can also be made of glass or
other suitable materials. One common way of producing the syringe
barrel 3 begins with a polymer produced by a basic polymerization
reaction (e.g., polypropylene) to which is added, for example, an
antioxidant, fiber material (for strength), colorant, nucleators
(to improve stiffness and clarity), and possibly a lubricant.
Optionally a chelating agent may be added to this mixture. The
polymer may take the form of a powder, pellets or other suitable
form. The mixture is fed into an extruder which melts the
components and extrudes the mixture to form pellets which are sent
to a second extruder that injects material into a mold to produce
the barrel 3. The chelating agent could be added at any suitable
location, such as at either extruder, or between extruders. Heat
may be applied to the extruder to facilitate melting. Extrusion
polymerization (or reactive extrusion) can be used to functionalize
the polymer or to modify existing functional groups on the
polymer.
[0027] It is further envisioned that a resin already containing a
chelating moiety or substituents capable of functioning as
chelating agents could be added in place of the chelating agent by
itself. Examples of such resin are suitable ion-exchange resins and
QuadraPure.RTM. chemical and metal scavengers (functionalized
macroporous and microporous resins commercially available from
Sigma-Aldrich Corporation). For additional information on resins
with such substituents, see "Chapter 3. Ion Exchange" in
"Separation and Purification Techniques in Biotechnology" by F. J.
Dechow published in 1989 by Noyes Publications, Park Ridge N.J.,
USA. Other polymers that could be used for this purpose, i.e.
crosslinked copolymers of basic vinyl heterocycles with another
monomer coploymerizable therewith, are described in U.S. Pat. No.
5,094,867, the disclosure of which is incorporated herein by
reference.
[0028] The chelating agent added to the resin mixture should be
able to withstand the various molding process conditions, e.g.
shear forces in the extruder and extrusion temperature. The
chelating agent would be added in an amount which is sufficient to
ensure that in the resin forming the barrel 3, enough of the
chelating agent is exposed on an inner wall 23 of the barrel to the
contrast media 11 to bind free metal ions in the contrast media.
The chelating agent must not affect the strength of the barrel 3 to
the extent that it cannot function for its intended purpose, and
preferably should also not affect the clarity of the barrel.
Moreover other processes for forming the barrel that are known in
the art could be used, such as sintering where the material could
be hot or cold formed, or co-extrusion where only an internal layer
includes the chelating agent and an outer layer(s) maintains
desired mechanical properties.
[0029] Other versions of this form of the present invention are
contemplated. For instance, the head 5 of the plunger, and/or the
cap 9 that closes the nozzle 7 could be made from a material
including a chelating agent. As another option, chelating agents,
such as DTPA or EDTA in the anhydride form, or buffering agents,
such as tromethamine, could be attached (e.g., chemically bonded)
to a suitable functional group, such as amine, primary amide,
carboxylic, hydroxyl or phenolic group already present on the inner
side of the container. Examples of such methods are well known in
the art. The following recent publications are exemplary: Anal.
Chem. 2005, 77, 30-35 and Anal. Chem. 2005, 77, 1096-1105. It is
also envisioned that a chelating agent could be added to a mixture
for making other containers such as a glass container. It will be
appreciated that by associating the chelating agent with the
syringe 1 (or other container such as a vial or bottle), the metal
ions and chelating agents remain in the syringe after the contrast
media 11 has been ejected from the syringe. Thus, neither is
injected into the patient.
[0030] In a second embodiment of the present invention, the quality
maintenance additive can be applied to a surface of the container,
as an example, syringe 1 (that is exposed to the contrast media 11)
after the syringe is formed. It is well known to apply a lubricant,
such as silicone to the barrel 3 and/or plunger head 5 to
facilitate sliding movement of the plunger head 5 along the wall 23
when used to eject the contrast media 11 from the barrel. The
quality maintenance additive, e.g. a chelating agent or a buffering
agent, can be part of the silicone (or other lubricant), such as by
being chemically attached to the silicone molecule or the other
lubricant via a functional group (e.g., an amine, primary amide,
carboxylic, hydroxyl or a phenolic group) in the silicone or the
other lubricant. FIG. 2 illustrates a layer 25 of silicone
including a chelating agent on the inner wall 23 of the barrel 3.
The silicone and chelating agent layer 25 sticks to the plunger
head 5 or the barrel 3 so that as the plunger head moves along the
wall toward the nozzle end of the barrel, the silicone and
chelating agent are not sheared off into the contrast media 11 in
any substantial quantity.
[0031] Although possible, typically the composition containing a
lubricant and a chelating agent does not chemically bond with the
resin material of the barrel 3 when applied thereto. However,
optionally, the lubricant with the quality maintenance additive,
such as a chelating agent or a buffering agent, could be either
chemically or by some other fashion bonded to the surface of the
container such as the syringe barrel and/or the plunger. The Gelest
Catalog 3000-A titled "Silicon Compounds: Silanes & Silicones"
published by Gelest, Inc. in 2004 describes examples of this and
other related methods. For other methods of coating surfaces, see
"Organic Coatings: Science and Technology", second edition 1999,
edited by Z. W. Wicks, Jr., F. N. Jones and S. Peter Pappas and
published by Wiley-Interscience.
[0032] It will be understood that the chelating agent could be
applied without being formulated as part of a lubricant. For
instance, if the material of the barrel 3 and/or the plunger head 5
includes a lubricant as a component it would not require additional
lubricant applied to the plunger head or the barrel. It is also
envisioned that the chelating agent could be attached to a material
applied to the barrel 3 and/or head 5 which is not a lubricant. The
material would not interfere with the normal operation of the
lubricant, but allow the chelating agent to act on the liquid in
the barrel 3. Moreover, if the container is not a syringe and does
not have a plunger head 5 engaging and moving along an inner wall
23 of the barrel 3, no lubricant is needed. The chelating agent can
be formulated in any suitable manner for adhering to the inner wall
of the container. Also, physical roughening or etching can be
employed to increase the surface area of the inner wall 23, so that
the inner wall may then be more readily coated with a material such
as a lubricant that is bonded with desired quality maintenance
additive(s), such as a chelating agent.
[0033] The layer of silicone or other material including a
chelating agent (FIG. 2) can be applied in several ways.
Conventionally, silicone can be applied by spraying, and could be
so applied when formulated with a chelating agent. One type of
silicone elastomer believed to be suitable is used to manufacture
SILICON.RTM. autoclavable silicone tubing, available from NewAge
Industries of Southampton, Pa. In manufacture, the barrels (prior
to insertion of the plunger head 5) may be inverted so that the
large open end 8 faces down and the nozzle 7 is located at the top.
A spray head (not shown) may be inserted into the large open end 8
of the barrel 3 for spraying onto the inner wall 23 of the barrel.
A high pressure spray release using a suitable gas such as air or
nitrogen as a carrier may be employed. As one alternative,
spattering could be used to apply the silicone and chelating agent
composition. Spattering can be carried out by vibrating a membrane
(not shown) so that it will throw off the material to be deposited.
It is also possible to heat the material so that it spatters onto
the barrel 3. More generally, heat, such as applied by a high
voltage arc, may be applied to break down the material for
redepositing on the barrel 3. Still further, the silicone and
chelating agent may be applied by dipping the barrel 3 into a
liquid form of the material so that a layer is deposited in the
barrel. Similarly, the barrel 3 could be tumbled in an emulsion of
the chelating agent (or silicone and chelating agent) suspended in
water or alcohol (or other suitable emulsifier) to deposit a layer
of the chelating agent within the barrel. Other ways of applying
the silicone and chelating agent to the barrel 3 that are known to
those of ordinary skill in the art also may be employed.
[0034] Alternatively, as an example, the chelating agent, as a weak
Ca or other metal ion complex, can be coated on a container surface
in the form of a polymer ink. See Proc. Intl. Soc. Mag. Reson. Med.
13 (2005) page 2142 for a description of the use of a polymer ink.
The following publications describe examples of a methodology for
the formation of stable, derivatized film coating on a silica
surface: Anal. Chem. 2001, 73, 2429-2436 and Anal. Chem. 2003, 75,
3518-3530.
[0035] The chelating agent could also be applied in a conformal
coating (vapor deposition) process. A suitable material in dimer
form (e.g., parylene, polypropylene), including a chelating agent
element is heated to a vapor phase in a vacuum chamber. The barrel
3 of the syringe 1 is also placed in the vacuum chamber. The vapor
flows over and is deposited on the entire exposed surface area of
the barrel 3 in a highly uniform layer. The deposited material on
the barrel 3 attaches to the material of the barrel, forming a
strong connection between the deposited material and the barrel. It
is also envisioned that other techniques for associating the
chelating agent (or other quality maintenance additive) with the
barrel 3 could be used, such as nanocoating technology or a
biologically active coating technique e.g., using an appropriately
derivatized agent of hyaluronan. See, for example, "The chemistry,
biology and medical applications of Hyaluronan and its
derivatives", ed. T. C. Laurent, Wenner-Gren International Series
Vol. 72, Portland Press, London.
[0036] Referring to FIG. 3, the layer of material including the
chelating agent can also be applied to the plunger head 5. The face
of the plunger head does not engage the plunger head 5 of the
barrel 3, so that the chelating agent would not need to be part of
a lubricant and would not be subject to shear forces. The chelating
agent can be applied in the same ways as described above for
application of a layer of material to the inner wall 23 of the
barrel 3. Moreover, the formulation of the material of the plunger
head 5 could include a chelating agent, as described above for the
barrel 3.
[0037] A third embodiment provides a chelating agent that is formed
as a separate component and positioned so as to contact the
contrast media. Ideally (although not exclusively), these
components would be placed in a syringe 1' in areas which are not
subject to wear by action of a plunger head 5' moving in a barrel
3'. Corresponding parts of the third embodiment will be labeled
with the same reference numerals as for the first and second
embodiments, with the addition of a trailing prime. As shown in
FIG. 4, the component could be a ring 31 of material including the
chelating agent. Alternatively, or in addition to the ring 31 as
shown in FIG. 4, a plug 33 of material including a chelating agent
may be mounted in a cap 9' so that it is exposed to the contrast
media (not shown) at the outlet end of a nozzle 7'. The component
material could be porous or nonporous. The advantage of having a
porous material would be in the increase of surface area to which
the contrast media can be exposed. As one example, the ring 31 and
plug 33 could be made of a sintered polypropylene or EPTFE
impregnated with a chelating agent, for example, the ion-exchange
resin or QuadraPure.TM. resin. The barrel 3' and ring 31 are formed
so that the ring fits in the lower end of the barrel above the
nozzle between an inner annular rib 35 and an outer concentric
annular rib 37 that are formed in the bottom of the barrel to
increase the strength of the barrel. In this location, the ring 31
does not interfere with movement of the plunger head (not shown)
and is not subject to wear by engagement with the plunger head.
[0038] A plunger head 5' in a modified form of the embodiment of
FIG. 4 is illustrated in FIGS. 5 and 6. A ring 41 including a
chelating agent is formed so that it can be mounted within the
plunger head 5'. As shown in FIG. 5, the ring 41 faces and is open
to the contrast media. In this embodiment, the ring 41 forms part
of the surface of the plunger head that pushes the contrast media
out of the syringe barrel. The plunger head 5' may be used in
conjunction with the ring 31 and/or plug 33 of FIG. 4, or may be
used by itself. It will be appreciated that other locations of a
chelating component (not shown) within a syringe may be used
without departing from the scope of the present invention.
[0039] In yet another version of this third embodiment shown in
FIG. 7, the chelating agent could be incorporated into filter 45
which is secured to the lower end of a barrel 3'' of a syringe 1'',
where the contrast media passes into a nozzle 7''. A filter (not
shown) having an incorporated chelating agent could be located away
from the barrel 3''. The filter could be positioned at the outlet
of the nozzle 7'' or downstream from the outlet before the contrast
media is injected into the patient. In such cases, the filter would
be sterilized. If the filter (not shown) is away from the syringe,
it is still "associated" with the syringe in the sense that it does
not move with the contrast media into the patient, but remains with
the syringe outside the patient's body. The contrast media from the
barrel 3'' can still flow through the filter to remove metals as
described for the filter 45. Parts corresponding to those of the
syringe 1 are given the same reference numeral, followed by a
double prime. Although shown solid, the filter 45 has small pores
which would permit passage of the contrast media through the
filter. Even further, the chelating agent could be formed as a film
which is laminated to the syringe barrel and/or plunger head. It is
believed that a laminated film layer would add strength to the
barrel, reducing the possibility of syringe cracking during use. If
the chelating agent is laminated to the inner wall of the barrel,
it would need to be smooth enough to allow the plunger head to
slide along the material, and robust enough to avoid being sheared
off by the movement of the plunger head. The laminated film layer
appears similar to the layer 25 illustrated in FIG. 2.
[0040] FIG. 8 illustrates a container in the form of a bottle
(indicated generally at 53) containing a contrast media 11' and
including a lid 55. The bottle 53 may be made of a suitable
material, such as glass or plastic, by conventional processes known
in the art. In this further modification of the embodiment of FIG.
4, the chelating agent component is not attached to or mounted on
any part of the bottle 53. The component takes the form of a disk
57 which may float or rest on the bottom of the bottle in the
contrast media 11'. Moreover, it is envisioned that the disk 57
could be fixed to the bottle (e.g., at the bottom of the bottle).
Still further, the chelating agent component may not have a disk
shape. For example, the chelating agent component could take the
form of microspheres or beads (spherically or otherwise shaped) For
example, the microspheres could be coated with materials containing
a quality maintenance additive or the quality maintenance additive
attached either chemically or by any other conventional method
known in the art. As long as the beads (or other forms of chelating
agent component) are large enough not to be taken into a syringe
through a needle opening, they need not necessarily be larger than
the container opening. Moreover, the beads may float or rest on the
bottom of the container. The disk 57 may be formed in a decorative
manner, or may be marked with information 59 identifying the maker
or type of product. The bottle 53 is formed with a neck 61
optionally having an internal diameter that is smaller than the
disk 57 so that the disk is trapped in the bottle when the contrast
media 11' is poured out.
[0041] The configuration of the bottle 53 and/or disk 57 may be
other than described without departing from the scope of the
present invention. For example, a container (not shown) may
gradually taper in internal diameter from the bottom to the top. As
another example, the chelating agent could be formed as beads that
are contained in a porous container (e.g. a mesh bag) that allows
the beads to be in liquid contact with the contrast media.
[0042] FIG. 9 illustrates a version of the present invention in the
form of a vial generally indicated at 63. The version is similar to
FIG. 8 in that the chelating agent component is a disk 65 that
floats or rests on the bottom of the bottle in the contrast media
11''. The vial 63 may be made of a suitable material, such as glass
or plastic. It will be understood that the chelating agent may be
incorporated into the material of the vial 63. The vial includes a
puncturable seal 67 covered by a cap piece 69.
[0043] When introducing elements of the present invention or the
preferred embodiment(s) thereof, the articles "a", "an", "the" and
"said" are intended to mean that there are one or more of the
elements. The terms "comprising", "including" and "hasting" are
intended to be inclusive and mean that there may be additional
elements other than the listed elements. The use of terms
indicating a particular orientation (e.g., "top", "bottom", "side",
etc.) is for convenience of description and does not require any
particular orientation of the item described.
[0044] As various changes could be made in the above without
departing from the scope of the invention, it is intended that all
matter contained in the above description and shown in the
accompanying drawings shall be interpreted as illustrative and not
in a limiting sense.
* * * * *