U.S. patent application number 09/989821 was filed with the patent office on 2002-05-16 for containers and methods for storing and admixing medical solutions.
Invention is credited to Becker, Michael, Desbrosses, Freddy, Masterson, Michael.
Application Number | 20020058927 09/989821 |
Document ID | / |
Family ID | 24861048 |
Filed Date | 2002-05-16 |
United States Patent
Application |
20020058927 |
Kind Code |
A1 |
Becker, Michael ; et
al. |
May 16, 2002 |
Containers and methods for storing and admixing medical
solutions
Abstract
Containers and methods for storing medical solutions are
provided. More specifically, containers and methods for storing
components that are to be admixed together to create a final
solution, one of the components comprising a lipid. In an
embodiment, a container including an interior defining at least two
chambers. The first chamber includes a lipid containing liquid. The
second chamber includes a liquid that does not include a lipid. The
first and second chambers are separated by an openable seal.
Inventors: |
Becker, Michael; (Palatine,
IL) ; Masterson, Michael; (Gurnee, IL) ;
Desbrosses, Freddy; (Thuin Belgium, BE) |
Correspondence
Address: |
Jeffrey Nichols, Esq.
Baxter International, Inc.
One Baxter Parkway
Deerfield
IL
60015-4633
US
|
Family ID: |
24861048 |
Appl. No.: |
09/989821 |
Filed: |
November 20, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09989821 |
Nov 20, 2001 |
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09015475 |
Jan 29, 1998 |
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6319243 |
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09989821 |
Nov 20, 2001 |
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08712174 |
Sep 11, 1996 |
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Current U.S.
Class: |
604/518 ;
977/700 |
Current CPC
Class: |
A61P 3/02 20180101; A61J
1/2024 20150501; A61J 1/2093 20130101; A61P 7/08 20180101; Y10S
977/713 20130101; A61J 1/10 20130101; B32B 27/08 20130101 |
Class at
Publication: |
604/518 |
International
Class: |
A61M 031/00 |
Claims
We claim:
1. A container including an interior defining at least two
chambers: a first chamber including a liquid that includes a lipid;
a second chamber including a liquid that does not include a lipid;
the first and second chambers being separated by an openable
seal.
2. The container of claim 1 wherein the openable seal is a peelable
seal.
3. The container of claim 1 wherein the second chamber includes at
least one component selected from the group consisting of dextrose,
amino acids, water, vitamins, and electrolytes.
4. The container of claim 1 including three separate chambers
separated by two openable seals.
5. The container of claim 1 wherein each of the first and second
chambers includes an access port to allow selective fluid
communication with the chamber.
6. The container of claim 1 wherein the container is constructed
from a plastic film including an RF responsive layer and a non RF
responsive layer.
7. The container of claim 4 wherein the liquid in the second
chamber includes amino acids and the third chamber includes in an
interior thereof a liquid including dextrose.
8. The container of claim 5 wherein the access ports are
constructed from a material not including polyvinyl chloride.
9. The container of claim 1 wherein the openable seal includes
portions thereof that are permanent and do not open.
10. The container of claim 1 wherein the liquid in the first
chamber is a lipid emulsion.
11. A container comprising a body constructed from a flexible
plastic material that does not include polyvinyl chloride, the body
defining a chamber that includes a lipid containing liquid.
12. A container comprising: a body constructed from a flexible
plastic material that does not include polyvinyl chloride, the body
defining at least a first and second chamber; the first chamber
including a lipid containing liquid; a second chamber including a
liquid that includes at least one component selected from the group
consisting of: amino acids; dextrose; vitamins; and electrolytes;
and an openable seal located between the first and the second
chambers.
13. The container of claim 12 wherein the openable seal is a
peelable seal.
14. The container of claim 12 including three separate chambers
separated by two openable seals.
15. The container of claim 12 wherein each of the first and second
chambers includes an access port to allow selective fluid
communication with the chamber.
16. A method for providing nutrition to a patient comprising the
steps of: providing a container including at least two chambers, a
first chamber including a first lipid containing liquid and a
second chamber including a second liquid that does not include a
lipid, the chambers being separated by an openable seal; opening
the seal between the first and second chambers; mixing the first
and second liquids within an interior of the container; and
administering a resultant liquid to a patient.
17. The method of claim 16 wherein the container includes three
chambers and a third liquid in a third chamber.
18. The method of claim 16 wherein the resultant liquid is,
administered parenterally to the patient.
19. A method for providing hyperalimentation to a patient
comprising the steps of: providing a multi-chambered container
including a lipid component, a dextrose component, and an amino
acid component, each of the components being housed in a separate
chamber of the multi-chambered container; mixing the components in
an interior of the container; and administering a resultant fluid
to a patient.
20. The method of claim 19 wherein the resultant fluid is
administered parenterally to a patient.
21. A method for providing hyperalimentation solutions to a
healthcare facility comprising the steps of: providing a
multi-chambered container; filling one of the chambers with a
liquid including a lipid; filling a separate of the chambers with a
liquid including amino acids; filling a different of the chambers
with a liquid including dextrose; and providing the multi-chambered
container to a healthcare facility.
22. The method of claim 21 wherein the chambers are filled
substantially simultaneously.
23. The method of claim 21 wherein the amino acids are first filled
into the container.
24. The method of claim 21 wherein the dextrose is first filled
into the container.
25. The method of claim 21 including the step of sterilizing a
filled container.
26. The method of claim 25 wherein the filled container is
autoclaved.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates generally to medical products
and procedures. More specifically the present invention relates to
containers for storing medical solutions and methods of sterile
admixing such solutions before they are administered to a
patient.
[0002] It is of course known to store medical solutions in
containers. A variety of such solutions are housed and stored in
such containers. Such medical solutions can include, for example,
parenteral, enteral, dialysis solutions, nutrients and
pharmacologic agents, including gene therapy and chemotherapy
agents.
[0003] These containers can be either constructed from glass or
plastic. Plastic containers can either be rigid or flexible.
Flexible containers are constructed from plastic films.
[0004] Although there are a great variety of solutions that are
used in medical treatments today, there are however, a number of
issues that can limit the ability to store at least certain medical
solutions. For example, due to stability, compatibility or other
concerns a number of medical solutions can not be premixed. Rather,
the individual components must be stored separately. Typically
these components are either stored in separate containers and
admixed before use, or are stored in separate compartments of a
flexible container and then mixed prior to use. For example, amino
acids and dextrose solutions require storage in separate containers
or compartments.
[0005] One of the disadvantages of storing components in separate
containers and then mixing them together is that the mixing process
can compromise sterility of the system and/or process.
Additionally, such a mixing process creates a labor intensive
process. Still further, it is possible for mistakes to occur during
the admixing process due to the amount of solution to be added from
the separate containers into the final container for the
patient.
[0006] To deal with the disadvantages of separate containers, it is
known to provide flexible containers that include multiple
chambers. To this end, such containers have an interior that
defines two or more chambers. One way to create such a container is
with a heat seal that divides the interior into two chambers. Such
containers are disclosed, for example, in U.S. Pat. Nos.:
4,396,488; 4,770,295; 3,950,158; 4,000,996; and 4,226,330.
[0007] It is also known to use frangible valves between the heat
seal to allow for the selective communication and mixing of the two
components stored in the separate chambers. See, for example, U.S.
Pat. No. 4,396,488.
[0008] However, such a structure-frangible valves--may not be
desirable for a number of reasons, including, inter alia, mixing
time, particulate matter generation, difficulty in opening,
difficulty in achieving a homogenous mixture, and cost, An
alternative to frangible valves is disclosed in U.S. Pat. Nos:
3,950,158; 4,000,996; and 4,226,330. In these patents multiple
chamber containers are disclosed with a line of weakness, such as a
score line, which breaks upon the application of pressure.
[0009] U.S. Pat. No. 4,770,295 discloses a selectively openable
seal line positioned between two sheets of flexible thermoplastic
material. The seal line is resistant to unintentional opening
forces but opens upon the application of a specific force.
[0010] Additionally, it is known to use tear tabs or tear strips
for plastic containers. See U.S. Pat. Nos.: 2,991,000; and
3,983,994. A disadvantage of these systems is they involve the use
of relatively complicated seal structures.
[0011] A number of other issues must also be addressed in
constructing containers for use in the medical industry. For
example, it is typically necessary to sterilize the container and
solution after manufacturing the container and solution. Typically
the products are sterilized by steam sterilization or autoclaving.
Autoclaving sterilization can alter the thermal properties of the
film used to form the container as well as the seal between the
chambers in the container. Still further heat sterilization can
adversely effect the solutions contained therein unless they are
maintained at certain conditions, an example of such a composition
is dextrose.
[0012] Of course, it is necessary that the seal between any
multiple chamber container is able to withstand external stresses.
Such stresses can include pressure that may be applied to one or
more of the chambers from, for example, squeezing thereof or
accidentally dropping the bag. Therefore the seal must be
sufficiently strong. But, on the other hand, the seal must not be
too strong so that it is not possible to mix the solutions
contained therein before one intends that they be mixed.
[0013] Still further, a problem that one faces, especially with
respect to parenteral nutritional solutions, is that the components
that comprise the solutions may not only not be compatible with
each other but, also may not be compatible with the materials from
which the container is constructed. For example, lipids cannot be
housed in typical plastic materials used to make containers. Lipids
can leach certain materials out of the plastic; if a lipid is
housed in a polyvinyl chloride material it will leach out the
plasticizers. Leaching of the plasticizer causes toxicity issues.
Additionally, when the plasticizers are leached out, the plastic
becomes rigid. Therefore, heretofore commercially available lipid
products only have been housed in glass containers.
[0014] One form of potentially life supporting therapy is total
parenteral nutrition or hyperalimentation. Typically, parenteral
nutrition solutions that provide total nutritional requirements to
a patient include a lipid component, a carbohydrate component, a
protein component, and vitamins and minerals.
[0015] Because of a number of stability and related issues, total
parenteral nutrition solutions can not be stored in a ready to use
state. Thus, it is necessary to admix the solutions prior to
use.
[0016] Heretofore, due to the inability to store all the base
components that may be necessary for a parenteral nutritional
solution in a single container, it is known to use automated
compounders for admixing parenteral nutritional solutions. In such
compounders, solution containers are hung on the compounder, and
through the use of pumps or valves the solutions therein are
compounded to create a final solution including all of the
necessary components, e.g. lipids, carbohydrates and amino acids.
U.S. Pat. Nos. 4,653,010, and 4,467,944 disclose embodiments of
such automated compounders.
SUMMARY OF THE INVENTION
[0017] The present invention provides containers and methods for
storing medical solutions. More specifically, the present invention
provides containers and methods for storing components that are to
be admixed together to create a final solution, one of the
components comprising a lipid.
[0018] To this end, the present invention provides a container
including an interior defining at least two chambers. The first
chamber includes a lipid containing liquid. The second chamber
includes a liquid that does not include a lipid. The first and
second chambers are separated by an openable seal.
[0019] In an embodiment the openable seal is a peelable seal.
[0020] In an embodiment the second chamber includes at least one
component selected from the group consisting of dextrose, amino
acids, water, vitamins, and electrolytes.
[0021] In an embodiment three separate chambers are provided that
are separated by two openable seals.
[0022] In an embodiment each of the first and second chambers
includes an access port to allow selective fluid communication with
the chamber.
[0023] In an embodiment the liquid in the second chamber includes
amino acids and the third chamber includes in an interior thereof a
liquid including dextrose.
[0024] In an embodiment the access ports are constructed from a
material not including polyvinyl chloride.
[0025] In another embodiment of the present invention, a container
is provided having a body constructed from a flexible plastic
material that does not include polyvinyl chloride. The body defines
at least a first and second chamber. The first chamber includes a
lipid containing liquid and the second chamber includes a liquid
including at least one component selected from the group consisting
of: amino acids; dextrose; vitamins; and electrolytes. An openable
seal is located between the first and the second chamber.
[0026] The present invention also provides a method for providing
nutrition to a patient comprising the steps of: providing a
container including at least two chambers, a first chamber
including a lipid containing liquid and a second chamber including
a second liquid that does not include a lipid, the chambers being
separated by an openable seal; opening the seal between the first
and second chambers; mixing the first and second liquids within an
interior of the container; and administering a resultant liquid to
a patient.
[0027] In an embodiment, the resultant liquid is administered
parenterally to the patient.
[0028] In another embodiment of the present invention, a method for
providing hyperalimentation to a patient is provided comprising the
steps of: providing a container including a lipid component, a
dextrose component, and an amino acid component, each of the
components being housed in a separate chamber; mixing the
components in an interior of the container; and administering a
resultant fluid to a patient.
[0029] Furthermore, in an embodiment of the present invention a
flexible plastic container is provided that includes a liquid that
contains a lipid. Still further, the present invention provides a
method for providing hyperalimentation solutions to a healthcare
facility comprising the steps of: providing a multi-chambered
container; filling one of the chambers with a liquid including a
lipid; filling a separate of the chambers with a liquid including
amino acids; filling a different of the chambers with a liquid
including dextrose; and providing the multi-chambered container to
a healthcare facility.
[0030] In an embodiment, the chambers are filled substantially
simultaneously.
[0031] In an embodiment, the amino acids are first filled into the
container.
[0032] In an embodiment, the dextrose is first filled into the
container.
[0033] In an embodiment, the method includes the step of
sterilizing a filled container.
[0034] In an embodiment, the filled container is autoclaved.
[0035] An advantage of the present invention is that it provides a
container for storing all of the base components for a total
parenteral nutrition solution.
[0036] Additionally, an advantage of the present invention is that
it provides a container that includes, in an embodiment,
electrolytes in amino acids, calcium in dextrose, and trace
elements in dextrose.
[0037] Still further, an advantage of the present invention is to
provide a container for storing medical solutions that include a
lipid.
[0038] Furthermore, an advantage of the present invention is to
provide a method for improving the safety of compounding medical
solutions.
[0039] Further, an advantage of the present invention is to provide
a container and method for preparing parenteral nutrition solutions
that does not require an automated compounder.
[0040] Another advantage of the present invention is to provide a
method and container for decreasing waste of unused customized
total parenteral nutrition solutions.
[0041] Moreover, an advantage of the present invention is to
provide a method and container for decreasing the turn around time
between ordering and administering medical solutions such as
nutritional solutions to patients.
[0042] Furthermore, an advantage of the present invention is to
provide a safer method for providing total parenteral nutrition to
patients.
[0043] Still further, an advantage of the present invention is to
reduce pharmacy labor in compounding nutritional solutions.
[0044] Still, an advantage of the present invention is to help
simplify the ordering of total parenteral nutrition solutions.
[0045] Moreover, an advantage of the present invention is it
reduces the risk of contamination during the preparation of medical
solutions by minimizing pharmacy manipulations.
[0046] Additional features and advantages of the present invention
are described in, and will be apparent from, the detailed
description of the presently preferred embodiments and from the
drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0047] FIG. 1 illustrates a perspective view of an embodiment of
the container of the present invention.
[0048] FIG. 2 illustrates a perspective view of another embodiment
of the container of-the present invention.
[0049] FIG. 3 illustrates a cross sectional view of an embodiment
of the film used to construct the container of the present
invention.
[0050] FIG. 4 illustrates an end view of an embodiment of a die
used to create the seal of the container of FIG. 1.
[0051] FIG. 5 illustrates total ion chromagrams generated from
sample extracts pursuant to Example No. 1.
[0052] FIG. 6 illustrates a mass spectrum of peak B of FIG. 5.
DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENTS
[0053] The present invention preferably provides a multiple chamber
container that can be used to house multiple liquid components of a
product that are to be stored separately prior to use. Due to the
unique structure of the present invention, the components can be
mixed prior to use and the container, as well as the method, allows
the storage of lipids in the same structure with other components.
Thus, in an embodiment, the present invention allows for the
storage of at least three base solutions of a hyperalimentation
solution in a single container prior to use. It should be noted
that although in a preferred embodiment the present invention
provides multi-chambered containers, pursuant to the present
invention a container having a single chamber containing a lipid
containing liquid is contemplated.
[0054] Referring now to FIG. 1, an embodiment of the present
invention is illustrated. Preferably, the container 10 includes, at
least three chambers 12, 14, and 16. The chambers 12, 14, and 16
are designed for the separate storage of liquids and/or solutions.
It should be noted that although three chambers 12, 14, and 16 are
present in the embodiment of the invention illustrated in FIG. 1,
more or less chambers can be used.
[0055] Preferably, peelable seals 18 and 20 are provided between
the chambers 12 and 14 and 14 and 16 respectively. Such a peelable
seal is disclosed in U.S. patent application Ser. No.
08/033,233,filed on Mar. 16, 1993 entitled "PEELABLE SEAL AND
CONTAINER HAVING SAME". The disclosure of that application is
hereby incorporated herein by reference. The peelable seals allow
for the selective opening of the chambers to allow for the
selective mixing of the liquids contained therein.
[0056] Pursuant to the present invention, at least one of the
chambers 16 can store a liquid that includes lipids. In a preferred
embodiment the container 10 includes in the first chamber 12
dextrose, in the second chamber amino acids 14, and in the third
chamber lipids 16.
[0057] Referring now to FIG. 2, another embodiment of the present
invention is illustrated. Similar to the embodiment illustrated in
FIG. 1 preferably, the container 110 includes, at least three
chambers 112, 114, and 116. The chambers 112, 114, and 116 are
designed for the separate storage of liquids and/or solutions. It
should be noted that although three chambers 112, 114, and 116 are
present in the embodiment of the invention illustrated in FIG. 2,
more or less chambers can be used. As in the embodiments of FIG. 1,
preferably peelable seals 118 and 120 are provided between the
chambers 112 and 114 and 114 and 116 respectively.
[0058] Referring now to FIG. 3 a cross sectional view of an
embodiment of the film 21 used to construct the containers 10 and
110 of the present invention is illustrated. In the preferred
embodiment illustrated, the film 21 includes, a four layer 22, 24,
26, and 28 structure.
[0059] In this regard, in the illustrated embodiment, the outer, or
first layer 22 is constructed from a polyester material such as
PCCE copolyester. If desired, other high melting temperature
flexible materials can be used. A PCCE copolyester material can be
purchased from Eastman Kodak under the designation Ecdel 9965. A
typical thickness of outer layer 22 may be, for example, from 0.39
mil to 0.71 mil, e.g., 0.55 mil.
[0060] A tie layer 24 is provided to secure the first layer 22 to a
third layer 26. Preferably the tie layer is a highly reactive
polymer adhesive such as EVA copolymer chemically modified with
maleic acid. Such a material is available from DuPont under the
name Bynel E-361. The tie layer 24 may have a varied thickness for
example from 0.20 mils to 0.60 mils, e.g., 0.40 mils.
[0061] The third layer 26 preferably is a RF responsive polymer,
such as EVA copolymer. Such a material is available from DuPont
under the name Elvax 3182-2. Preferably the third layer has a
thickness of about 5.56 mils to about 6.84 mils, e.g., 6.20
mils.
[0062] This film also includes a sealant layer 28 constructed of 1)
a bulk polyolefin that is thermally stable at sterilization
temperatures, yet melts below the outside layer melting
temperature; such polymers are preferably polypropylene-ethylene
copolymers, such as Z9450 from Fina Oil and Chemical; and 2) a
thermoplastic elastomer which produces a more flexible and free
radical resistant sealant layer and gives the sealant layer two
melt points with the elastomer having the lower value; such
polymers preferably are styrene-ethylene-butene-styrene block
copolymers such as Kraton G-1652 from Shell Oil and Chemical. Thee
sealant layer preferably has a thickness of from about 1.28 mils to
about 1.92 mils, e.g., 1.60 mils.
[0063] The sealant layer 28 is adjacent the solution side of the
container 10 such that when the seal is ruptured, communication is
provided between the chambers, e.g. 12 and 14.
[0064] As constructed the four-layer film illustrated in FIG. 3 has
at least one RF-responsive layer 26 and one non-RF responsive layer
28. To create the seals a RF field heats a seal bar (described
hereinafter with reference to FIG. 4) which heats the RF-responsive
layer 26 which, in turn, heats the non-RF responsive layer 28 to
soften the layer, but not liquify same. A resulting cohesive bond
develops from contact between the non-RF responsive layer 28 of the
sheet 30 and a corresponding non-RF responsive layer 28 of the
sheet 30a, but fusion between the layers, which can cause permanent
bonding, does not occur.
[0065] To form the peelable seal using radio frequency welding or
other forms of heating sealing technology in a preferred embodiment
a die 40, illustrated in FIG. 4, is used. The die 40 includes the
seal bar 42 which is formed to project substantially
perpendicularly to a base 44 on which the seal bar 42 is integrally
mounted. The base 44 can be further secured to manufacturing
components (not shown) by fasteners (not shown) inserted through
holes in the base 44. The seal bar 44 of the die 40 is used to form
the peelable seal wherein the seal bar 42 can be energized using RF
energy.
[0066] The seal bar 42, as illustrated, has a substantially equal
width, designated as "x" in FIG. 4, of, in the preferred
embodiment, approximately 3/8 inches. The seal bar 42 further
includes radiused corners 48 and grooves 49 to control activation
forces and increase consistency of the seal. During sterilization
temperatures, the inside layer, in intimate contact with itself,
will weld together due to fusion of the lower melting point
material. This phenomenon allows the die 42 to have a lower surface
area, thus giving more control of pressure parameters and reducing
the risk of fusing the higher melting point material which would
result in actual heat seals. In the preferred embodiment
illustrated, the radial dimension is {fraction (1/16)}". The
peelable seal formed using the seal bar 42 of the present invention
results in a bond which is less likely to break due to external
forces exerted thereon.
[0067] By way of example, and not limitation, an example of how the
peel seal is created will be given. In a preferred embodiment, the
inner layer includes SEBS and ethylene polypropylene. SEBS has a
melting point of approximately 127.degree. C. and ethylene
polypropylene approximately 140.degree. C. The die, illustrated in
FIG. 4, is initially heated to a temperature of 50.degree. C. and
urged against the container in a position to create the desired
seal. The die is then energized with sufficient RF energy to reach
a temperature of between 128.degree. C. and 131.degree. C. This
creates the peel seal.
[0068] In a preferred embodiment, the peel seals are created so
that they are permanent seals for the length of the container
10.
[0069] Pursuant to the present invention, and in view of the
structure of the container 10, the container can house lipids. In
this regard, the lipids will not leach any components from the film
used to construct the container 10. The present invention also
allows the lipids to be filled into the container 10 and the
container retorted (sterilized). Heretofore, commercially available
lipids could not be stored in plastic containers and were always
retorted in glass.
[0070] As illustrated in FIG. 1, preferably, each chamber 12, 14,
and 16 can include an access or tubular port 31, 32, and 34. In the
illustrated embodiment, port 31 is an injection site and port 32 is
an administration port. The ports 31 and 32 can be constructed from
any number of methods. For example, in an embodiment the ports 31
and 32, for chambers 12 and 14, are constructed from a clear PVC
membrane plasticized with DEHP. To maintain sterility of the
interior of the ports 31 and 32, an injection cap can be secured
over the port.
[0071] However, with respect to chamber 18, that is designed to
house a lipid, the access port 34 is constructed from a non-PVC
containing material. For example, a blend, preferably of
polypropylene, SEBS, and EVA can be used. In a preferred embodiment
the port 34 is a three layer co-extrusion with the following
formulation:
[0072] External layer (125.mu.):
[0073] 35% PP Fortilene 4265
[0074] 25% Tafmer A4085
[0075] 10% Kraton FG1924
[0076] 10% Macromelt TPX16-159
[0077] 20% EVA Escorene UL00328 (28% VA)
[0078] Medium layer (580.mu.)
[0079] 35% PP Fortilene 4265
[0080] 25% Tafmer A4085
[0081] 10% Kraton FG1924
[0082] 10% Macromelt TPX16-159
[0083] 20% EVA Escorene UL00328 (28% VA)
[0084] Internal layer (125.mu.)
[0085] 50% EVA Escorene UL00119 (19%; VA)
[0086] 50% EVA Escorene UL00328 (28% VA)
[0087] In a preferred embodiment, all of the access ports 31, 32,
and 34 are constructed from a non-PVC material such as that set
forth above.
[0088] The tubular ports 31, 32, and 34 are mounted in the
container to allow fluid communication with the container 10 and
specifically the chambers 12, 14, and 16. To this end the ports 31,
32, and 34 can include a membrane that is pierced by, for example,
a cannula or a spike of an administration set for delivery of the
contents of the container through the administration set to the
patient. Of course, more or less than three ports can be used.
[0089] In an embodiment, an additive port (not shown) is located at
an end of the container 10 opposite the access ports 31, 32, and
34. The additive port allows the addition to the container of micro
ingredients or micro nutrients.
[0090] Preferably, all the ports are located on one end of the
container. This may allow for more efficient manufacturing and
allows filling of all chambers at one time.
[0091] In an embodiment the container 10 is a 3 liter unit with
three chambers separated by two peel seals. The chambers of the
container, in an embodiment, are designed to contain dextrose
(10-70%), amino acids (5.5-20%, with or without electrolytes) and a
lipid (10%-30%). The filled container is designed to be placed in
an oxygen barrier overpouch and autoclaved. Prior to use, the user
will open the seals and mix the solutions. It is believed that such
a container 10 will have a shelf life of at least twelve
months.
[0092] It should also be noted that the container 10 may be
prepackaged with trace elements, vitamins, and/or electrolytes. For
example trace elements could be packaged in the same chamber with
dextrose.
[0093] By way of example and not limitation examples of containers
for providing total parenteral nutrition to patients will now be
given.
1 Chamber sizes (mL) Corresponding formulas 800/225/800 Acute 1,
Acute 1E, Acute 2E, Acute 3, Acute 3E and Non-acute 1E 800/400/800
Acute 4E (High lipid) and Peripheral formula 1 Acute 1 = the
formula below without electrolytes 800/225/800 config. Acute 1E =
the formula below with electrolytes chamber final % NPC conc. conc.
vol grams g/kg.sup.1 kcal NPC NPC/kg kcal kcal/kg as lipid AA 15.0%
6.6% 800 120 1.7 480 lipid 20.0% 2.5% 225 45 405 dextrose 50.0%
21.9% 800 400 1,360 1,765 25 2,245 32 23% 1825 Acute 2E (with
electrolytes) 800/225/800 config. chamber final % NPC conc. conc.
vol grams g/kg kcal NPC NPC/kg kcal kcal/kg as lipid AA 13.0% 5.7%
800 104 1.5 416 lipid 20.0% 2.5% 225 45 405 dextrose 50.0% 21.9%
800 400 1,360 1,765 25 2,181 31 23% 1825 Acute 3 = the formula
below without electrolytes 800/225/800 config. Acute 3E = the
formula below with electrolytes chamber final % NPC conc. conc. vol
grams g/kg.sup.1 kcal NPC NPC/kg kcal kcal/kg as lipid AA 10.0%
4.4% 800 80 1.1 320 lipid 20.0% 2.5% 225 45 405 dextrose 50.0%
21.9% 800 400 1,360 1,765 25 2,085 30 23% 1825 Acute 4E (with
electrolytes) 800/400/800 config. High lipid formula chamber final
% NPC conc. conc. vol grams g/kg.sup.1 kcal NPC NPC/kg kcal kcal/kg
as lipid AA 13.0% 5.2% 800 104 1.5 416 lipid 20.0% 4.0% 400 80 720
dextrose 30.0% 12.0% 800 240 816 1,536 22 1,952 28 47% 2000
Non-acute 1E (with electrolytes) 800/225/800 config. chamber final
% NPC conc. conc. vol grams g/kg.sup.1 kcal NPC NPC/kg kcal kcal/kg
as lipid AA 8.5% 3.7% 800 68 1.0 272 lipid 20.0% 2.5% 225 45 405
dextrose 50.0% 21.9% 800 400 1,360 1,765 25 2,037 29 23% 1825
Peripheral 1E (with electrolytes) 800/400/800 config. chamber final
% NPC conc. conc. vol grams g/kg.sup.1 kcal NPC NPC/kg kcal kcal/kg
as lipid AA 8.5% 3.4% 800 68 1.0 272 lipid 10.0% 2.0% 400 40 360
dextrose 10.0% 4.0% 800 80 272 632 9 904 13 57% 2000 .sup.1Assumes
a 70 kg patient. Osmolarity: approx. 670 mOsm/L
[0094] It is believed that these eight containers could meet 80-90%
of all adult patients.
[0095] By way of example and not limitation examples of the present
invention will now be given:
EXAMPLE NO. 1
[0096] The purpose of this study was to provide preliminary
extractive information regarding an embodiment of the container of
the present invention for the long-term storage of retorted lipid
emulsions.
[0097] In this study, the test articles were 500-ml units prepared
from the film set forth previously in the specification with two
non-PVC port tubes. The units were filled with,20% lipid emulsion,
placed in a foil overpouch, purged with nitrogen and steam
sterilized for either 30, 40 or 50 minutes. Aliquots of the 20%
lipid emulsion stored in the test articles, 20% lipid emulsion
stored in glass bottles, and 20% lipid emulsion stored in glass
bottles spiked with target extractives were analyzed for target
extractives.
[0098] Irganox.RTM. 1076, 2-ethylhexanoic acid, and 25-Crown-5 in
the lipid emulsion samples were at levels below the estimated
detection limits of the method, 0.57 .mu.g/mL, 0.44 .mu.g/mL and
0.24 .mu.g/mL, respectively. 1,2-Bis (sec-butoxycarboxy) ethane
(SBCE) and 2,6-di-t-butyle-4-methylphenol (BHT) were detected in
the samples at levels near the estimated detection limits of 0.28
.mu.g/mL and 0.095 .mu.g/mL, respectively. There were no apparent
differences in the extractive levels due to the length of
sterilization. Additionally, no non-targeted extractives were seen
in a total ion chromatogram of an extract of 200 lipid emulsion
stored in a test article.
[0099] To enhance the sensitivity for the target extractives, the
lipid emulsion extracts were analyzed using selective ion
monitoring mass spectral detection, while the total ion monitoring
mass spectrometry was used to screen the extracts for additional
non-targeted compounds. In both analyses, the factor limiting the
sensitivity of this method is concentrating the 20t lipid emulsion.
In principle, the sensitivity of this methodology will be greater
in the three-chambered container system due to the lower lipid
emulsion concentration in the-final solution.
[0100] In other studies, the levels of target extractives were
determined. The extractive levels in the lipid emulsion solutions
were determined by extracting the lipid emulsion and analyzing by
gas chromatography with selected ion mass spectrometry. The intent
of this study was to provide preliminary information on the
accumulation of 2-ethylhexanoic acid, 1,2-bis (sec-butoxycarboxy)
ethane (SBCE), 2,6-di-t-butyle-4-methylphenol (BHT), 25-crown-5
ether and Irganox.RTM. 1076 in 20% lipid emulsion retorted in
containers. Additionally, a sample extract was analyzed by gas
chromatography with total ion mass spectrometry.
[0101] These units had two non-PVC port tubes which were sealed
with aluminum crimps. The film is co-extruded, with the following
configuration: polypropylene-Kraton.RTM. (solution
contact)/poly(ethylene vinyl acetate) (EVA)/maleic anhydride
modified EVA (tie layer)/PCCE. The PCCE is
poly(cyclohexylenedimethylene cyclohexanedicarboxylate) copolymer
with tetramethylene glycol. The test articles were filled with 20%
lipid emulsion, placed in a foil overpouch, purged with nitrogen
and sealed. The units were then steam sterilized for either 30, 40
or 50 minutes and analyzed.
[0102] The following sample extraction methodology was developed as
part of the study. 1.0-mL aliquot of the 20% lipid emulsion sample
and of the 20t lipid emulsion stored in glass were transferred into
125-mL separatory funnels containing 15 mL of 0.9% sodium chloride.
A 1.0-mL, volumetrically pipetted, aliquot of a 31.3 .mu.g/mL
di-n-octyl phthalate (DOP) internal standard solution, 20 mL of
methanol and 40 mL of methylene chloride were added. The samples
were extracted and the methylene chloride was collected in a 200-mL
Zymark TurboVap.RTM. collection tube. The samples were then
extracted with a second 40-mL portion of methylene chloride. The
methylene-chloride fractions were pooled, concentrated to
approximately 1 mL under a stream of N.sub.2 and analyzed.
[0103] The GC standard was prepared as follows: into 125-mL
separatory funnels containing 1 mL of the 20% lipid emulsion which
was stored in glass and 15 mL of 0.9% sodium chloride, 1.0-mL
aliquots of each standard solution were added. The standards were
extracted and analyzed. Additionally, the extract of the STD-H
spiked lipid emulsion was analyzed.
2 Concentration of Standards, (.mu.g/mL) Standard 2-EHA SBCE BHT
Irganox .RTM. 1076 25-Crown-5 STD-H 268 66.8 83.2 99.6 79.2 STD-MH
66.9 16.7 20.8 24.9 19.8 STD-ML 40.1 10.0 12.5 14.9 11.9 STD-L 8.03
2.00 2.50 2.99 2.38
[0104] Gas chromatography with selected ion monitoring mass
spectral detection (GC/MS-SIM) was used. The instrument conditions
were as follows:
3 Gas Chromatograph: HP5890 Detector: Mass Selective Detector
HP5790 Column: DB-5, 30 m .times. 0.32 mm .times. 0.25 .mu.m (film)
Program: 40.degree. for 1 min, 5.degree. C./min to 210.degree. C.,
20.degree. C./min to 300.degree. C. held for 25 min. Injection
port: 250.degree. C., with a glass wool plug. Transfer Line:
310.degree. C. Injection volume: 2 .mu.L, splitless for 30 sec.
Mode: EI+ Ions monitored (m/z): Time on (mm): 5.00 (2-EHA) 73, 88
and 116 20.00 (BHT) 57, 205 and 220 27.00 (SBCE) 45, 89 and 151
30.00 (25-Crown-5) 71, 72 and 100 42.30 (DEHP) 149, 167 and 279
46.00 (Irganox .RTM. 1076) 219, 515 and 530 Dwell Time: 100
msec.
[0105] Gas chromatography with total ion mass spectral detection
(GC/MS):
4 Gas Chromatograph: HP5890 Detector: Mass Selective Detector
HP5790 Column: DB-5, 30 m .times. 0.32 mm .times. 0.25 .mu.m (film)
Program: 40.degree. for 1 mm, 5.degree. C. min to 210.degree. C.,
20.degree. C./min to 300.degree. C. held for 25 min. Injection
port: 250.degree. C., with a glass wool plug. Transfer Line:
310.degree. C. Injection volume: 2 .mu.L, splitless for 30 sec.
Mode: EI+ Scan Range (m/z): 35-650
[0106] The levels of 2-EHA, Irganox.RTM. 1076 and 25-Crown-5 in the
lipid emulsion samples were below the estimated detection limits of
the methodology. The detection limits were calculated at three
times the signal to noise ratio of the spiked standard (STD-L).
[0107] At the GC retention time of BHT, small peaks were observed
in the extracts of the sample and control lipid emulsion. At the GC
retention time of SBCE, small peaks were observed in the extracts
of the samples. The concentrations of BHT and SBCE in the lipid
emulsion were then determined from the relative response of the
analyte to the internal standard in the spiked lipid standard
(STD-L).
[0108] These BHT and SBCE levels were near the estimated detection
limits of the method. The spike recovery for the individual target
extractives were not calculated. The level of each target
extractive in the 20% lipid emulsion samples is listed in Table 1.
The estimated detection limit for each extractive in 20% lipid
emulsion is listed in Table 2.
5TABLE 1 Levels of Target Extractives in 20% Lipid Emulsion Samples
and Control, .mu.g/mL. Sample 2-EHA SBCE BHT Irganox .RTM. 1076
25-Crown-5 149014.30 <d.l. 0.30 0.14 <d.l. <d.l. 149014.40
<d.l. 0.23 0.09 <d.l. <d.l. 149014.50 <d.l. 0.22 0.08
<d.l. <d.l. Control <d.l. <d.l. 0.03 <d.l. <d.l.
Where: <d.l. is less than the detection limit listed in Table
2.
[0109]
6TABLE 2 Estimated Detection Limit for Target Extractives in 20%
Lipid Emulsion, .mu.g/mL. Analyte Detection Limit 2-EHA 0.44
.mu.g/mL SBCE 0.28 .mu.g/mL BHT 0.095 .mu.g/mL Irganox .RTM. 1076
0.57 .mu.g/mL 25-Crown-5 0.24 .mu.g/mL
[0110] No additional extractives were observed in the total ion
monitoring GC/MS analysis of the extracted lipid emulsion
sample.
[0111] The study provided preliminary data on the accumulation of
target extractives in retorted 20% lipid emulsion. 2-EHA,
Irganox.RTM. 1076 and 25-Crown-5 in the lipid emulsion samples were
at levels below the detection limit of the methodology. SBCE and
BHT were detected in the samples at levels near the detection
limits. There were no apparent differences in the extractive levels
due to the length of sterilization. Additionally, no non-targeted
extractives were seen in the total ion chromatograms of the
extracts of the 20% lipid emulsion.
[0112] To enhance the sensitivity for the target extractives, the
lipid emulsion extracts were analyzed using selective ion
monitoring mass spectral detection, while the total ion monitoring
mass spectrometry was used to screen the extracts for additional
non-targeted compounds. In both analyses, the factor limiting the
sensitivity of the method is the inability to concentrate the oil
extracted from the 20% lipid emulsion. In principle, the
sensitivity of this methodology will be greater in the
three-chambered RTU container system due to the lower lipid
emulsion concentration in the mixed solution.
EXAMPLE NO. 2
[0113] This example analyzed an embodiment of the container system
of the present invention for the long-term storage and intravenous
administration of dextrose, amino acids and lipid emulsion. An
embodiment of the container is a 2-L non-poly(vinylchloride)(PVC)
unit with three chambers separated by two peelable seals. One
chamber will contain 800 mL of a dextrose solution (10-70%), the
second chamber will contain 800 mL of an amino acid solution
(5.5-10%, with or without electrolytes) and the third chamber will
contain up to 400 mL of lipid emulsion (10 or 30%). The filled
container will be placed in a foil overpouch, purged with nitrogen
and steam sterilized. Prior to use, the customer will break the
peel seals and mix the three solutions. The maximal lipid emulsion
concentration in the resulting total parenteral nutrition (TPN)
solution is 4%.
[0114] The container is constructed from a co-extruded film with
the following configuration: polypropylene-Kraton.RTM. (solution
contact)/poly(ethylene vinyl acetate)(EVA)/maleic anhydride
modified EVA (tie layer)/PCCE. The PCCE is
poly(cyclohexylene-dimethylenecyclohexanedi- carboxylate) copolymer
with tetramethylene glycol. The container is fitted with PVC
containing port and membrane tube assemblies on the chambers
containing the dextrose and amino acid solutions and a non-PVC port
and plug assembly on the chamber containing the lipid emulsion
solution.
[0115] The test articles were filled as follows: 1) the chamber of
the container to be used for the dextrose solution was filled with
800 mL of water for injection, 2) the chamber of the container to
be used for the amino acid solution was filled with 800 mL of water
for injection, and 3) the chamber of the container to be used for
the lipid emulsion was filled with 400 mL of 20% lipid emulsion.
The filled units were placed in foil overpouches and autoclaved. A
total of twelve units were produced for the study.
[0116] The study design follows previously developed methodologies
for: 2,6-di-t-butyl-4-methylphenol (BHT),
2,6-di-t-butyl-4-ethylphenol 1,2-bis(sec-butoxycarboxy)ethane,
25-crown-5 ether, isopropyl myristate, 2-ethylhexanoic acid,
Irganox.RTM. 1010, Irganox.RTM. 1076, AO330,
1,2-bis(2-ethylhexyl)phthalate (DEHP), aluminum, volatile organic
compounds and propylene and ethylene vinyl acetate oligomers in
lipid containing solutions. To access the extractable burden of the
container, the peel seals of the three chambered test articles were
opened and the three solutions were mixed prior to all analyses
except for cyclohexanone. Due to an expected loss of cyclohexanone
during the lipid extraction procedure, only the peel seal
separating the water-filled chambers was opened, mixed and assayed
for cyclohexanone.
[0117] The volatile organic compounds, semi-volatile compounds,
aluminum, antioxidants, and oligomeric propylene and ethylene vinyl
acetate assays were performed on unit numbers 601, 602, and 604.
Immediately after sampling the test articles for volatile organic
compounds, the units were allowed to stand at ambient temperature
for an additional 48 hours to mimic the potential interaction of
the lipid solution with the entire container system expected from
product handling and administration. The solutions from the three
test articles were then sampled for aluminum, transferred into
separate glass containers, and stored under refrigeration until
required for analyses. The cyclohexanone assay was performed on a
sample of the pooled water from the amino acid and dextrose
chambers of unit numbers.
[0118] Lipid emulsion control solutions diluted with NANOpure water
to a nominal concentration of 4%, along with diluted lipid emulsion
solutions spiked with known targeted compounds were analyzed as
appropriate.
[0119] Two aliquots from the three containers and the control lipid
emulsion were analyzed for volatile organic compounds by purge and
trap gas chromatography with mass spectrometric detection (GC/MS)
using the method listed in Table 3 below.
[0120] The major volatile organic compound observed in the total
ion chromatograms was cyclohexanone. The levels of cyclohexanone in
the water-filled chambers were determined in three containers. In
addition to the cyclohexanone, 4-methyl-2-pentanone and toluene
were detected as compounds unique to the lipid emulsion stored in
the container system. The r-methyl-2-pentanone and toluene detected
in the sample solutions had the same GC retention time and mass
spectra as that of the authentic standard materials.
[0121] In an earlier study, 4-methyl-2-pentanone and toluene were
identified as materials which may accumulate in solution from the
hot stamp foil used to print the container. The levels of the
4-methyl-2-pentanone and toluene in the lipid solution stored in
the container were determined from the response of the
d.sub.5-chlorobenzene internal standard. The levels of
4-methyl-2-pentanone and toluene in the lipid solution stored
containers are as follows:
7 Unit Sample 4-methyl-2-pentanone, .mu.g/mL toluene, .mu.g/mL
601-1 0.028 0.033 601-2 0.029 0.032 602-1 0.034 0.036 602-2 0.034
0.035 604-1 0.032 0.034 604-2 0.034 0.036
[0122] The levels of the targeted semivolatile compounds
2,6-di-t-butyl-4-methyl-phenol (BHT), 2,6-di-t-butyl-4-ethylphenol
(DtBEP) 1,2-bis(sec-butoxycarboxy)ethane (SBCE), 25-crown-5 ether
(25-C-5), isopropyl myristate (IPM), 2-ethylhexanoic acid (2-EHA),
and 1,2-bis(2-ethylehexyl)phthalate (DEHP) were determined in two
aliquots from each of three units, the control lipid and emulsion
spiked with the known targets extractives.
[0123] A 5.0-mL aliquot of the lipid emulsion sample and of the 4%
lipid emulsion control were transferred into 125-mL separatory
funnels containing 15 mL of 0.9t sodium chloride. A 1.0-mL,
volumetrically pipetted, aliquot of a 30.3 mg/mL di-n-octyl
phthalate (DOP) internal standard solution, 20 mL of methanol and
40 mL of methylene chloride were added. The samples were extracted
and the methylene chloride was collected in a 200-mL Zymar Turbo
Vap.RTM. collection tube. The samples were then extracted with a
second 40-mL portion of methylene chloride. The methylene chloride
fractions were pooled, concentrated to approximately 1 mL under a
stream of N.sub.2 and analyzed by the GC/MS-SIM system listed in
Table 4.
[0124] Spiked lipid controls were prepared by adding the target
extractive compounds into the 4% control lipid emulsion resulting
in the following concentrations (.mu.g/mL):
8 Spike 2-EHA BHT DtBEP IPM SBCE 25-C-5 DEHP Irganox .RTM. 1076
Spike-L 0.58 0.16 0.17 0.17 0.17 0.18 0.20 0.20 Spike-M 2.9 0.82
0.84 0.85 0.84 0.88 1.0 0.98 Spike-H 5.8 1.6 1.7 1.7 1.7 1.8 2.0
2.0
[0125] The spiked lipid controls were then extracted, concentrated
and analyzed in the same manner as that used for the samples.
[0126] To screen for potential non-targeted extractives, an extract
from each of the three units and the control lipid was analyzed in
a total ion scanning GC/MS mode using the instrument conditions
listed in Table 5.
[0127] Responses for the target extractives were detected at each
spike level with the exception of the 0.58 .mu.g/mL 2-EHA spike and
the Irganox.RTM. 1076. The lower sensitivity for 2-EHA results in a
corresponding higher detection limit for 2-EHA. No Irganox.RTM.
1076 was observed in the GC/MS analysis of the spiked lipid control
solutions of the standard solutions which were used to spike the
control lipid emulsion. This result indicates that the GC/MS
conditions which were utilized may have not been suitable for
detecting Irganox.RTM. 1076. In an earlier study, Irganox.RTM. 1076
was not detected in samples of 20% lipid emulsion stored and
retorted in containers prepared from the film at a detection limit
of 0.57 .mu.g/mL.
[0128] With the exception of DEHP, the concentration of the target
extractives in the extracts from the container were either not
detected or observed at a level significantly less than that of the
lowest level spiked. The DEHP levels in the sample extracts were
near the lowest level spiked with the exception of a single
replicate at 2.1 .mu.g/mL.
[0129] For each target extractive, detection limits were calculated
at three times the signal to noise ratio in the chromatogram of the
lowest spike concentration for which a response was observed. In
samples where the response for a target extractives was observed
above this detection limit, the concentration of the extractive was
determined from the linear regression analysis of the response of
the spiked lipid extracts at the three levels analyzed.
[0130] Since the detection limit and quantitation calculations were
conducted using the responses from the spiked lipid controls, no
corrections for spike recovery were required or performed. The
level of the target extractives observed in duplicate aliquots from
the three containers and calculated detection limits, in .mu.g/mL,
are as follows:
9 Unit- sample 2-EHA BHT DtBEP IPM SBCE 25-C-5 DEHP Irganox .RTM.
1076 601-1 <dl (a) 0.029 <dl <dl 0.084 <dl 0.11 N/A (b)
601-2 <dl 0.045 <dl <dl 0.097 <dl 0.11 N/A 602-1 <dl
0.047 <dl <dl 0.10 <dl 2.1 N/A 602-2 <dl 0.049 <dl
<dl 0.11 <dl 0.086 N/A 604-1 <dl 0.050 <dl <dl 0.11
<dl 0.10 N/A 604-2 <dl 0.049 <dl <dl 0.11 <dl 0.27
N/A Detection 0.17 0.012 0.011 0.018 0.015 0.010 0.010 N/A Limit
(a) Where, dl indicates a level less than the detection limit (b)
Where N/A indicates that no values could be determined.
[0131] To screen for potential non-targeted extractives, the total
ion chromatograms generated for the sample extracts were compared
to that of the control (See FIG. 5). Four peaks (labeled A, B, C
and D in FIG. 5) unique to the samples were observed in the sample
chromatograms. Since these peaks were only observed in the lipid
solutions stored in the containers, these compounds appear to be
non-targeted extractives related to the c container system. The
mass spectrum of peak B, the largest peak observed in the sample is
in FIG. 6.
[0132] Cyclohexanone
[0133] The levels of cyclohexanone in duplicate aliquots of the
pooled water-filled chambers from three RTU containers were
determined using the direct aqueous injection gas chromatography
with flame ionization detection (GC/FID). To quantitate the level
of cyclohexanone in the samples, cyclohexanone standards in water
were prepared at concentrations of 0.034 .mu.g/mL, 0.135 .mu.g/mL,
3.37 .mu.g/mL and 6.74 .mu.g/mL. A 10-.mu.g/mL aliquot of a 356
.mu.g/mL cyclopentanone standard solution was added to 1-mL
aliquots of each standard and sample for use as an internal
standard. The GC/FID instrument conditions are listed in Table
6.
[0134] The levels of cyclohexanone in the water-filled chambers of
the three containers were determined from the linear regression
line constructed from the responses of the cyclohexanone standards.
The results of the cyclohexanone analysis are as follows:
10 Unit Number Cyclohexanone, .mu.g/mL 591 2.05 605 2.81 613
3.16
[0135] Aluminum
[0136] Samples of the lipid emulsion mixtures which were stored in
the container for 48 hours at room temperature and transferred to
Teflon.RTM. bottles, the 4% lipid emulsion control solution and the
water control were analyzed for aluminum by graphite furnace atomic
absorption spectroscopy.
[0137] No aluminum was detected in the water control at a level
greater than the detection limit of 0.0009 .mu.g/mL. The aluminum
levels observed in the lipid emulsion solution stored in unit
number 601 was slightly higher than that in the 4% lipid emulsion
control article, while the aluminum levels in the lipid emulsion
solutions stored in the unit numbers 602 and 604 were approximately
the same as that observed for the 4i lipid emulsion control
article. The aluminum concentrations in the sample and control
articles are as follows:
11 Sample/Unit Number Aluminum, .mu.g/mL Water Control <0.0009
4% Lipid control 0.012 601 0.023 602 0.017 604 0.015
[0138] Antioxidants and Oligomeric Propylene and Ethylene Vinyl
Acetate
[0139] A 50-mL aliquot of three lipid emulsion samples, in
duplicate, and of the 4% lipid emulsion control were transferred
into separatory funnels containing 25 mL of 0.9% sodium chloride
and 60 mL of methanol. The mixture was extracted with two 90-mL
portions of methylene chloride. The organic fractions were
collected in 200-mL Zymark TurboVap.RTM. evaporation tubes and
concentrated to remove the organic solvent. The resulting oil was
transferred into 10-mL volumetric flasks and combined with
tetrahydrofuran (THF) rinsings of the TurboVap.RTM. tube. The 10-mL
volumetric flasks were then diluted to volume with THF.
[0140] A 3-mL aliquot of the extract was applied to a
Chromatotron.RTM. thin layer chromatography system which uses a
rapidly rotating silica gel plate (4 mm) to effect the separation.
The samples and eluting solvent are applied to the center of the
rotating plate that is at a displacement of about 45.degree. from
horizontal. As the plate spins, the solvent front advances outward
and the components are separated in concentric circular bands. When
the band reaches the outer edge of the plate, the eluate leaves the
plate and drains through a small spout at the bottom edge of the
Chromatotron.RTM. housing.
[0141] The eluate is collected by the analyst for analysis. The
first three 45 mL of eluent were collected. These fractions
contained the desired antioxidant and oligomeric materials. The
eluent was concentrated to 1 mL under a stream of nitrogen prior to
analyses.
[0142] Spiked lipid controls were prepared by adding extractive
materials into the 50-mL aliquots of a 4t control lipid emulsion
solution. The target extractive compounds for the antioxidant assay
consisted of Irganox.RTM. 1010, Irganox.RTM. 1076 and A0330
standard materials. The antioxidants were analyzed at approximate
concentrations of 0.5 .mu.g/mL, 0.9 .mu.g/mL and 1.8 .mu.g/mL in
the lipid emulsion. The target extractive material for the
oligomeric propylene and ethylene vinyl acetate assay, consisted of
an organic solvent extract of the film.
[0143] The film extracts were prepared by weighing approximately 10
grams film, cut into small pieces, into two separate Erlenmeyer
flasks. A 75-mL aliquot of pentane was added to each flask and
placed into a sonicator for 15 minutes. The pentane extracts were
then decanted into separate round-bottom flasks. The same film was
extracted two additional times with pentane. Each additional
pentane extract was combined with the previous extracts in the
respective flask. The pentane extracts were then evaporated to
dryness under a stream of nitrogen. The residue, 73.4 mg, was
dissolved in 50mL of THF to prepare a stock standard. Dilutions of
this stock standard resulted in the analysis of pentane extractable
material at concentrations of 7.34 .mu.g/mL, 14.7 .mu.g/mL and 29.4
.mu.g/mL in the lipid emulsion. These spiked lipid solutions were
then extracted, purified on the Chromatotron.RTM. and analyzed as
described for the test and control articles.
[0144] The purified extracts from the lipid emulsion mixture from
the containers, control article and spiked controls were assayed
for Irganox.RTM. 1010, Irganox.RTM. 1076 and A0330 antioxidants by
high temperature GC and for oligomeric propylene and ethylene vinyl
acetate by gel permeation chromatography (GPC) with ultraviolet
(UV) and refractive. index (RI) detection. The high temperature GC
and gel permeation chromatography conditions are described in
Tables 7 and 8, respectively.
[0145] The levels of the Irganox.RTM. 1010, Irganox.RTM. 1076 and
A0330 antioxidants in the product could not be determined in
aliquots from the containers units due to the presence of residual
lipid emulsion in the extracts interfering with the detection. In
the extracts of the samples, no oligomeric propylene or ethylene
vinyl acetate was observed. A detection limit for the, oligomeric
propylene or ethylene vinyl acetate was calculated at three times
the signal to noise ration in the GPC/RI chromatogram. The
detection limit determined for the oligomeric propylene and
ethylene vinyl acetate is 5.6 .mu.g/mL.
[0146] CONCLUSION
[0147] Three units of the lipid emulsion mixture from a 2-L
container were analyzed for volatile -organic compounds, targeted
and non-targeted semivolatile organic compounds, aluminum,
antioxidants and oligomeric propylene and ethylene vinyl acetate.
The targeted semi-volatile organic extractives included
2,6-di-t-butyl-4-methyl-phenol (BHT), 2,6-di-t-butyl-4-ethylphenol
(DtBEP) 1,2-bis(sec-butoxycarboxy)ethane (SBCE), 25-crown-5 ether
(25-C-5), isopropyl myristate (IPM), 2-ethylhexanoic acid (2-EHA),
and 1,2-bis(2-ethylhexyl)phthalate (DEHP). The selected ion
monitoring GC/MS analysis of the extracts provide enhanced
sensitivity for the targeted extractives, with detection limits of
typically less than 0.02 .mu.g/mL. The amounts of volatile and
targeted semivolatile compounds observed in the lipid emulsion
stored in the proposed container system were present at low
levels.
[0148] Of the extractives which were quantitated, chclohexanone was
present in the container at the highest concentrations.
Cyclohexanone is not a container system extractive, but rather a
processing residual from the sealing of the port and membrane tube
assemblies. These cyclohexanone levels were determined in the
water-filled chambers of the three containers. The following table
summarizes the concentration ranges and detection limits for the
extractives in the container system.
12 Concentration Detection Compound Range, .mu.g/mL limit, .mu.g/mL
4-methyl-2-pentanone 0.028-0.034 n.d(a) toluene 0.032-0.036 n.d
2,6-di-t-butyl-4-methyl- 0.029-0.050 0.012 phenol 2,6-di-t-butyl-4-
<d.l.(b) 0.011 ethylphenol 1,2-bis(sec- 0.08-0.11 0.015
butoxycarboxy) ethane 25-crown-5 ether <d.l. 0.010 isopropyl
myristate <d.l. 0.018 2-ethylhexanoic acid <d.1. 0.17
1,2-bis(2- 0.1-2.1 0.010 ethylhexyl) phthalate cyclohexanone
2.05-3.16 n.d. aluminum 0.015-0.023 0.0009 Antioxidants n/a(c) n/a
(Irganox .RTM. 1010, Irganox .RTM. 1076 and AO330) Oligomeric
propylene <d.l. <5.6 and ethylene vinyl acetate (a)n.d.
indicates not determined. (b)<d.l. indicates less than the
detection limit. (c)n/a indicates not available due to an
analytical interference of the compounds of interest with residual
lipid emulsion.
[0149] To screen for potential non-targeted extractive materials in
the container system, the extracts from the semi-volatile analysis
were analyzed by GC/MS in a total ion scanning mode. In the total
ion chromatograms from the container extracts four unknown peaks
were observed. Based on the mass spectral fragmentation patterns,
the four compounds appear to be structurally similar. The apparent
odd molecular weights, along with the presence of several even mass
to charge fragment ions, suggests that the unknowns contain an odd
number of nitrogen atoms.
13TABLE 3 Instrumental Conditions for the Purge and Trap GC/MS
Analysis Purge and Trap: Instrument: Tekmar LSC 200 Purge and Trap.
Trap: Carbopack B and Carbosieve (S III) Sparge Vessel: 5 mL,
Fritless Standby temperature: 32.degree. C. Purge Time: 8 Min.
Desorb Preheat Temp.: 65.degree. C. Desorb Program: 4.00 min. at
220.degree. C. Bake Program: 8.00 min. at 260.degree. C. Valve
Temp.: 200.degree. C. Mount Temp.: 75.degree. C. Transfer line
Temp.: 220.degree. C. Instrument: Tekmar ALS 2050 Autosampler
Prepurge time: 30 sec. Sample pressurize time: 30 sec. Sample
Transfer time: 30 sec. Internal Standard Transfer: 75 sec. Sample
Loop: 5 mL Internal Standard Loop: 10 .mu.L GC/MS: Instrument:
HP5890 Gas Chromatograph with VG Trio-1 Mass Spectrometer Column:
Quadrex 007-624 Cyano- Propyl Methyl Phenyl siloxane fused silica
capillary, 50 m .times. 0.53 mm ID .times. 3.0 mm (film) Program:
30.degree. C. for 6.00 min., 10.degree. C./min. to 180.degree. C.,
held for 3.00 min. Carrier: Heat approximately 3 mL/min with an
open split interface. Mass Range: m/z 25-400
[0150]
14TABLE 4 Instrument Conditions for Gas Chromatography with
Selected Ion Monitoring Mass Spectral Detection (GC/MS-SIM) Gas
Chromatograph: HP5890 Detector: Mass Selective Detector EP5790
Column: DB-5, 30 m .times. 0.25 mm .times. 0.1 .mu.m (film)
Program: 40.degree. C. for 1 min, 5.degree. C./min to 250.degree.
C., 20.degree. C./min to 310.degree. C. held for 25 min. Injection
port: 300.degree. C., with a glass wool plug. Transfer Line:
315.degree. C. Injection volume: 2 .mu.L, splitless for 30 sec.
Mode: EI+ Ions monitored (m/z): Time on (min): 5.00 (2-EHA) 73, 88
and 116 16.00 (BHT) 57, 205 and 220 20.50 (DtBEP) 57, 219 and 234
21.60 (SBCE) 45, 89 and 151 25.00 (IPM) 60, 102 and 228 31.00
(25-Crown-5/DEHP) 71 and 100/149 and 279 41.00 (DOP, I STD) 149,
167 and 279 45.00 (Irganox .RTM. 1076) 219, 515 and 530 Dwell Time:
100 msec.
[0151]
15TABLE 5 Instrument Conditions for Gas Chromatography with Total
Ion Scanning Mass Spectral Detection (GC/MS) Gas Chromatograph:
HP5890 Detector: Mass Selective Detector HP5790 Column: DB-5, 30 m
.times. 0.25 mm .times. 0.1 .mu.m (film) Program: 40.degree. C. for
1 min, 5.degree. C./min to 250.degree. C., 20.degree. C./min to
310.degree. C. held for 25 min. Injection port: 280.degree. C.,
with a glass wool plug Transfer Line: 315.degree. C. Injection
volume: 2 .mu.L, splitless for 30 sec. Mode: EI+ Scan Range (m/z):
35-600
[0152]
16TABLE 6 Instrument Conditions for Direct Aqueous Injection Gas
Chromatography with Flame Ionization Detection (GC/FID) Gas
Chromatograph: HP5890A Detector: Flame ionization Column: DB-624 30
m .times. 0.53 mm .times. 3.0 .mu.m (film) Program: 40.degree. C.
for 0 min, 15.degree. C./min to 190.degree. C. held for 1 min.
Injection port: 140.degree. C., with a cyclosplitter .RTM. injector
liner Detector: 200.degree. C. Injection volume: 1 .mu.L, split
Data Acquisition System: Multichrom .RTM.
[0153]
17TABLE 7 Instrument Conditions for Antioxidant Determination by
High Temperature Gas Chromatography with Flame Ionization Detection
(GC/FID) Gas Chromatograph: HP5890A Detector: Flame ionization
Column: HP-1, A1-Clad, 10 m .times. 0.53 mm .times. 0.9 .mu.m
(film) Program: 70.degree. C. for 1 min, 25.degree. C./min to
400.degree. C. held for 5 min. Injection port: 310.degree. C.
Detector: 400.degree. C. Injection volume: 1 .mu.L, splitless for
0.5 min. Data Acquisition System: Multichrom .RTM.
[0154]
18TABLE 8 Instrument Conditions for Gel Permeation Chromatography
with Ultraviolet (UV) and Refractive Index (RI) Detection HPLC
Pump: Applied Biosystems, Model 400 Injector: Rheodyne, Model 7125
UV Detector: Spectraflow, Model 757 at 254 nm, filter rise time 1
sec RI Detector: Erma Model ERC-7510 at 30.degree. C., Polarity (+)
Data System: Multichrom Mobile Phase: Tetrahydrofuran Flow Rate:
0.7 mL/min. Injection volume: 20 .mu.L Guard Column: TosoHaas
TSK-GEL .RTM. H.sub.XL, 4 cm .times. 6 mm I.D. Analytical column,
(in 1) TosoHaas TSK-GEL .RTM. series): G3000H.sub.XL, 30 cm .times.
7.8 mm I.D. 2) TosoHaas TSK-GEL .RTM. G2500H.sub.XL, 30 cm .times.
7.8 mm I.D. Column Temperature: 30.degree. C.
[0155] It should be understood that various changes and
modifications to the preferred embodiments described herein will be
apparent to those skilled in the art. Such changes and
modifications can be made without departing from the spirit and
scope of the present invention and without diminishing its
attendant advantages. It is, therefore, intended that such changes
and modifications be covered by the appended claims.
* * * * *