U.S. patent application number 13/057089 was filed with the patent office on 2011-08-11 for method and device for transferring a substance between closed systems.
Invention is credited to Walter Pobitschka.
Application Number | 20110192489 13/057089 |
Document ID | / |
Family ID | 41396102 |
Filed Date | 2011-08-11 |
United States Patent
Application |
20110192489 |
Kind Code |
A1 |
Pobitschka; Walter |
August 11, 2011 |
METHOD AND DEVICE FOR TRANSFERRING A SUBSTANCE BETWEEN CLOSED
SYSTEMS
Abstract
The invention relates to a method and to a device for
transferring a substance between closed systems (G1 G/Z, Z, G+G/Z),
which prior to the transfer are connected in a sterile manner and
can be disconnected from each other in a sterile manner, and
wherein means for transferring the substance are provided. The goal
is to enable a contamination-free transfer of the substance without
gas inclusions between closed systems. This is achieved with
respect to the method in that the pressure differences occurring
during the transfer of the substance are compensated for within the
system. This is achieved with respect to the device in that a
pressure compensating unit (1) is provided, which has a sterile
flow connection to at least one system (G, G/Z, Z, G+G/Z).
Inventors: |
Pobitschka; Walter; (Bad
Homburg, DE) |
Family ID: |
41396102 |
Appl. No.: |
13/057089 |
Filed: |
July 30, 2009 |
PCT Filed: |
July 30, 2009 |
PCT NO: |
PCT/DE2009/001062 |
371 Date: |
April 27, 2011 |
Current U.S.
Class: |
141/1 ;
141/85 |
Current CPC
Class: |
A61J 1/2096 20130101;
A61J 1/22 20130101; A61J 1/2093 20130101 |
Class at
Publication: |
141/1 ;
141/85 |
International
Class: |
B65B 1/04 20060101
B65B001/04 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 2, 2008 |
DE |
10 2008 035 835.5 |
Claims
1.-58. (canceled)
59. A method for transfer of a substance between closed systems,
said method comprising: providing closed systems, namely at least
one source system and at least one target system, which are simply
connected in sterile fashion before transfer, in which the
substance reaches the target system and in which after transfer of
the substance the target system and the source system can be
separated from each other in sterile fashion, wherein pressure
differences occurring during transfer of the substance are
compensated within the system.
60. The method according to claim 59, wherein pressure compensation
occurs where volume changes of the substance occur.
61. The method according to claim 59, wherein the substance is
transferred in metered fashion.
62. The method according to claim 59, wherein the substance is
transferred active from the source system, especially by a
calibrated syringe or carpule, to the target system or wherein the
substance is actively removed from the source system, especially by
a calibrated syringe or that the substance reaches the target
system under the influence of gravity.
63. The method according to claim 59, wherein the source system is
connected in sterile fashion to several other source systems.
64. The method according to claim 59, wherein the target system
becomes the source system when the received substance is conveyed
to another target system.
65. The method according to claim 59, wherein the substance is
introduced to the source system in sterile fashion under cleanroom
conditions, which is closed in sterile fashion.
66. A device for transfer of a substance between closed systems,
said device comprising: closed systems configured to be connected
in sterile fashion to each other and configured to be separated in
sterile fashion from each other and which have means for transfer
of the substance, wherein a pressure compensation device is
provided, which is in flow connection in sterile fashion to at
least one system.
67. The device according to claim 66, wherein the pressure
compensation device is bonded to one system.
68. The device according to claim 66, wherein the means for
transfer includes at least one connector for sterile connection to
at least one additional system.
69. The device according to claim 68, wherein a container is
provided and wherein the connector is bonded in sterile fashion to
the container of system.
70. The device according to claim 69, wherein the container
includes a base plate or a cover plate or at least one holding
device.
71. The device according to claim 69, wherein at least part of the
wall of the container is designed flexible so that means to
transfer the substance can be operated at least partially from
outside via the flexible wall, especially via a bellows.
72. The device according to claim 66, wherein one system is a
component of an overall system and a sterile connection also exists
within the overall system.
73. The device according to claim 69, wherein the substance can be
transferred from one system, especially under the influence of
gravity, into the other closed system, the connector facing the
floor in the operating position.
74. The device according to claim 73, wherein the connector of one
system with one end opens into the container and preferably extends
minimally into the substance and has a snap-in closure of sealing
material with a fastening bridge which can be operated via the
flexible wall of the container.
75. The device according to claim 73, wherein the container has a
preferably collapsible bed with a volume between 30 mL and 1000 mL
or 10 mL to 30 mL.
76. The device according to claim 66, wherein at least two
connectors are provided, which include an inlet and an outlet
facing the floor in the operating position.
77. The device according to claim 76, wherein a calibrated drip
chamber is provided as container, in which the substance is at
least temporarily contained.
78. The device according to claim 77, wherein the calibrated drip
chamber forms a closed system with connectors in the sense of a
gravity-operated metering device and is both source and target
system.
79. The device according to claim 77, wherein the inlet and the
outlet open in sealed fashion into the drip chamber.
80. The device according to claim 76, wherein a metering device is
assigned to the connector.
81. The device according to claim 69, wherein a receptacle is
contained in the container of the system in the form of a bottle or
ampule within which the substance is situated and whose closure
faces the floor in the operating position.
82. The device according to claim 81, wherein the means for
transfer of the substance includes a short cannula for transfer of
the substance, especially a liquid, and a long cannula for air or
inert gas supply, in which the cannulas puncture the closure of the
receptacle in the operating position and extend into the receptacle
and in which the short cannula is in flow connection with the
connection.
83. The device according to claim 82, wherein the long cannula
opens into the container.
84. The device according to claim 82, wherein the short cannula and
the long cannula in the rest position are arranged in a holding
device in the form of a slotted sleeve, which is supported on one
side against the base plate of the container, and against the
receptacle on the other side and which encloses the receptacle in
the operating position, whereas the cannulas puncture the closure
of the receptacle.
85. The device according to claim 82, wherein the volume of the
receptacle is predetermined so that the amount removed can be
estimated and the closure preferably includes a metering valve.
86. The device according to claim 81, wherein the container
includes a calibrated drip chamber into which at least a short
cannula extends via a connection piece and on which the connection
facing the floor in the operating position is provided.
87. The device according to claim 86, wherein the long cannula
opens into the pressure compensation device, which ensures pressure
compensation in container and in the receptacle as well as the
calibrated drip chamber of the overall system.
88. The device according to claim 66, wherein the means to transfer
substance includes at least one calibrated syringe with an ampule
plunger and an ampule barrel.
89. The device according to claim 88, wherein the syringe is
arranged within a container and can be operated from the outside
via an at least partially flexible wall of the container especially
via a bellows.
90. The device according to claim 88, wherein the ampule barrel
simultaneously forms an at least temporary receptacle for the
substance.
91. The device according to claim 88, wherein the system has an
overlapping source and target function if filling with substance
and release of substance occur in the same system.
92. The device according to claim 88, wherein a connection piece in
flow connection with the connector is provided for connection to
the syringe within the container.
93. The device according to claim 92, wherein the connection piece
is present in the form of an internal line.
94. The device according to claim 90, wherein a receptacle with
substance in the form of an ampule with a puncture stopper is
provided in the container.
95. The device according to claim 88, wherein the ampule barrel
includes a cannula with a cannula closure, which can be manipulated
from the outside via the flexible wall of the container.
96. The device according to claim 95, wherein the container
includes two chambers, both of which are in flow connection with
the pressure compensation device.
97. The device according to claim 96, wherein the first chamber
contains the ampule plunger and wherein the second chamber contains
the ampule barrel with the cannula.
98. The device according to claim 96, wherein the second chamber of
the container forms the connector for sterile connection to the
connector of the source system or the connector of the target
system on the end facing away from the first chamber.
99. The device according to claim 88, wherein the system has a
container in the form of a plastic enclosure and that an ampule
containing the substance is arranged within the plastic enclosure
with a puncture stopper made of elastomer.
100. The device according to claim 88, wherein the ampule plunger
is in flow connection with the ampule barrel.
101. The device according to claim 100, wherein the ampule plunger
can be connected in sterile fashion to a closed system via a
connector equipped with a metering valve and wherein the connection
extends into the ampule plunger and opens from there into the
ampule barrel.
102. The device according to claim 101, wherein the ampule barrel
has a connector for sterile connection to a closed system equipped
with a metering valve facing away from the ampule plunger.
103. The device according to claim 102, wherein for suction of
substance from the closed system the metering valve adjacent to the
ampule barrel is closed and the metering valve adjacent to the
ampule plunger is opened.
104. The device according to claim 103, wherein for transfer of the
substance drawn into the ampule barrel to the target system the
metering valve adjacent to the ampule barrel is opened and the
metering valve adjacent to the ampule plunger is closed.
105. The device according to claim 100, wherein the container
includes a bellows in the area of the ampule plunger and wherein
the bellows is connected in sealed fashion to the ampule
barrel.
106. The device according to claim 100, wherein the closed system
includes a short cannula for transfer of the substance, especially
a liquid, and a long cannula for air or inert gas supply, in which
the cannulas puncture the closure of the receptacle in the
operating position and extend into the receptacle and in which the
short cannula is in flow connection with the connection, and
wherein the long cannula opens into the container.
107. The device according to claim 106, wherein the source system
is in sterile connection with the ampule plunger via a connection
piece of the short cannula and wherein the source system and the
closed system comprising the syringe form an overall system.
108. The device according to claim 88, wherein the syringe can be
tightened in a syringe pump so the transfer of substance can be
accomplished automatically at pre-established times or over a
determined period with precise volume.
109. The device according to claim 66, wherein the means for
transfer of substance includes a carpule with a carpule plunger and
a carpule barrel containing the substance.
110. The device according to claim 109, wherein the container
includes two chambers.
111. The device according to claim 110, wherein the first chamber
includes a cannula, which faces the carpule barrel with its tip and
extends into the connector with its opposite end.
112. The device according to claim 110, wherein the second chamber
comprises a cylindrical section and a bellows, in which the carpule
barrel is contained within the cylindrical section as well as part
of the carpule plunger and in which the rest of the carpule plunger
is contained within the bellows.
113. The device according to claim 110, wherein the second chamber
and a coupling tube of the first chamber are movable relative to
each other and can preferably be fastened to each other in a
predetermined position.
114. The device according to claim 66, wherein the connection is
connected in sterile fashion to a closed system, which contains an
internal line and wherein the system containing the internal line
transfers the substance to the next closed system.
115. The device according to claim 66, wherein the components of
the device or the closed system are arranged within a sterile
package before sterile connection to the other closed system.
116. The device according to claim 115, wherein the package has a
smooth surface on which a disinfectant, especially 70% ethanol, can
be applied.
Description
[0001] The invention concerns a method for transfer of a substance
between closed systems, in which the closed systems, namely at
least one source system and at least one target system are at least
simply connected in sterile fashion before transfer, in which case
the substance enters the target system and, after transfer of the
substance, the target system and the source system can be separated
from each other in sterile fashion.
[0002] The present invention also concerns a device for transfer of
a substance between closed systems, especially for performance of
the method in which the systems can be connected in sterile fashion
to each other and can be separated in sterile fashion from each
other and have means to transfer the substance.
[0003] Operating free of contamination in closed systems under
conditions of cleanroom technology is known per se in many areas of
technology, especially medical technology. A system is considered
closed, if it at least cannot exchange matter with the
surroundings.
[0004] There is often the requirement precisely in medical
technology to introduce matter into the closed system so that any
contamination is ruled out and processing or investigation can
occur there. This includes for example preparations of cell
populations, their cryopreservation and removal of samples for
laboratory studies from these preparations, while guaranteeing a
closed state of the system.
[0005] Sterile connection techniques like "sterile docking" and
"sterile welding" are already known from the U.S. Pat. No.
6,022,344 with which thermoplastic tubes of two closed systems
could be connected in sterile fashion to each other and also
separated in sterile fashion again. "DOCKING" involves the making
of cuts under the influence of temperature and direct sealing of
both ends of two plastic tubes. "WELDING" involves separation of
the connection with compression under temperature to form a
homogeneous cross-sectional surface and cutting so that two closed
interfaces are formed. Sterile connection, however, can also be
produced independently of the aforementioned connection techniques,
like sterile docking and sterile welding by mounting and sealing
plastic vessels and tubes under cleanroom conditions and
sterilization measures in known fashion.
[0006] Removal of substance under a sterile bench in the clean room
by means of syringes is also known from practice, which has
shortcomings because a closed state of the system is abandoned.
[0007] A specific application from matter or substance that is to
be introduced to the closed system pertains to stem cells, which
are recovered from patient blood during apheresis treatment. Before
a cancer patient is subjected to chemotherapy, stem cells are taken
from him. Only then does the patient receive chemotherapy. Since
stem cells are broken down during this chemotherapy, the removed
stem cells are later supplied to the patient.
[0008] Apheresis treatment proceeds by taking blood from the
patient and transferring it in a closed system. Centrifugal forces
act in the closed system during which the blood is broken down into
components. Cell populations that contain stem cells are separated
to initially secure them. The remaining blood is returned directly
to the patient. The separated cell populations, depending on their
purpose, are provided with additives, for example, for the
patient's own plasma and foreign plasma.
[0009] This substance present as a cell suspension must be made
storable in order to be later supplied to the patient. Making it
storable can only occur using the chemical compound dimethyl
sulfoxide, subsequently called DMSO, in a freezing bag for
cryopreservation. The chemical compound DMSO serves to concentrate
the cell fluid in the preparation in order to compensate for
differences there between different osmotic pressures. The stem
cell substance is protected from destruction/bursting of the cells
by this. The freezing bag consists of ethylene vinyl acetate, a
plastic which is also abbreviated EVA.
[0010] While the stem cell preparation can be further treated under
sterile conditions, addition of the chemical compound DMSO
represents the weak link with respect to maintaining a closed
system. Even addition of DMSO through a filter, as is known from DE
101 24 487 A, cannot prevent contaminants, like viruses or toxic
gases, from entering the closed system. Because of its
aggressiveness relative to plastics DMSO also cannot be positioned
in the bag system by the producer and subjected there to
sterilizing pretreatment. Storage of the chemical compound DMSO in
any case must be conducted over the long term in chemically inert
vessels, for example, made of borosilicate glass with a
solvent-resistant closure.
[0011] DE 101 51 343 A1 deals with a bag system for
cryopreservation of body fluids. There the substance is transferred
to another closed system from a glass ampule, which is situated
within a closed system. Transfer occurs via a sterile connection,
which is accomplished before transfer during production of a closed
system. After transfer, sterile separation occurs with disposal of
the emptied source systems filled beforehand under sterile
conditions. A shortcoming in this bag system with respect to
transfer is that volume-precise metering is not possible and air
inclusions cannot be avoided in defined fashion within the
substance being transferred but depend on the skill of the person
handling the flexible bag. Air inclusions in the substance cannot
be ruled out and can adversely influence the effects and results of
later applications, for example, mixing processes. Continuity of
transfer is also not guaranteed. A further shortcoming is that the
only solution to compensate pressure differences in the system is
seen in releasing excess air via filters into the surroundings. As
already stated in conjunction with DE 101 24 487 A1, however, even
a filter cannot prevent contaminants like viruses or toxic gases
from entering the closed system.
[0012] Starting from the already known prior art the underlying
task of the invention is to provide a method and device in which
contamination-free transfer of the substance is made possible
without gas inclusions between closed systems.
[0013] The aforementioned task is solved with reference to the
method by the features of claim 1. The method of the type in
question is characterized by the fact that pressure differences
occurring during transfer of the substance are compensated within
the system.
[0014] The aforementioned task is solved with respect to the device
by the features of claim 8. A device of the type in question is
characterized by the fact that a pressure compensation device is
provided which is in sterile flow connection with at least one
system.
[0015] Starting from DE 101 51 343 A1, it was initially known
relative to the method that compensation of pressure differences
there occurs by discharging air from the bag system into the
environment, in which case it is tolerated that contaminated
surrounding air enters the closed system, despite filters. It was
recognized according to the invention that the sterility of the
closed system need not be abandoned in any way when the pressure
differences are compensated exclusively within the system. This
finding is implemented by means of the device according to the
invention in that a pressure compensation device is provided which
is in sterile flow connection with at least one system. In other
words: displaced air advantageously is not released to the
surrounding air but trapped in a pressure compensation device and
available there in conjunction with substance removal processes so
that no vacuum is formed. The device according to the invention can
be used as a disposable article at the location of preparation, for
example, in the blood bank or transplantation laboratory.
Standardized industrially produced disposable articles according to
the invention enormously expand sterile work and widen the use
possibility of substances.
[0016] Pressure compensation can occur anywhere volume changes of
the substance occur. Generally this could occur both in the source
system and in the target system. In one application in which the
source system consists merely of a sterile, sheathed ampule with
transfer device that can be connected in sterile fashion, pressure
compensation could also be fully switched to the target system and
the partial vacuum developing in the source system tolerated, since
the empty ampule after sterile separation from the target system is
disposed of.
[0017] Implementation of volume-precise transfer of the substance
is of essential importance to the invention, since this achieves a
situation in which the substance is transferred in metered fashion.
This includes semiquantitative metering processes or metering with
calibrated metering devices.
[0018] In principle, the substance could be actively transferred
from the source system to the target system or actively removed
from the source system. With respect to desired metering,
calibrated syringes or carpules could then be used. As an
alternative, the substance could reach the target system under the
influence of gravity. Metering could occur here via a calibrated
drip chamber. Transfer devices, like syringes, carpules, drip
chambers, could in turn form closed systems or be components of
closed systems.
[0019] In implementation of the method the source system could be
connected to several different target systems. Multiple connection
of the source system to one or more target systems could be
possible in succession or simultaneously. Partial amount transfer
of the substance is made possible by this.
[0020] During the method it could happen that the target system
becomes the source system when the received substance is conveyed
to another target system. This could either happen after a first
sterile connection and separation or the device is set up so that a
function change occurs by opening and closing of metering valves. A
metering valve between the source and target system initially
opened to receive the substance is closed after filling of the
target system. If substance is transferred to another target system
from the filled target system by opening another metering valve,
the filled target system now has a source function.
[0021] In a source system that is marketed in the form of a blister
package and then directly available for use the substance could
preferably be introduced under sterile conditions to the source
system under cleanroom conditions, which is then closed in sterile
fashion to form a blister package. In a simple practical example a
container could be filled in the plant under cleanroom conditions
and closed, then go to the laboratory physician who produces
sterile connection to a target system and can thus transfer the
prepared substance. A differently configured but likewise simple
practical example proposes to produce a container at the plant
without substance, which contain means to transfer the
substance--here to remove it from a source system available in the
laboratory or delivered at the same time.
[0022] According to a preferred variant of the device according to
the invention, the closed system, which can be a source system, a
target system or also a system with source and target function,
could have a container for the substance. The container separates
the surroundings from the internal space of the closed system in
which the substance could already be contained. The pressure
compensation device could be bonded to the container and be present
as a rubber bag. The connector of the pressure compensation device
could be welded into the container so that the closed state of the
system is not interrupted. As an alternative, the pressure
compensation device could also be an integral component of the
container via a special shaping method.
[0023] The means for transfer of the substance could include at
least one connector for sterile connection to at least one
connection of another closed system. The connector could be
designed as a thermoplastic tube. Like the pressure compensation
device, the connector to the container of the system could also be
bonded in sterile fashion. The connector or plastic tube could have
a length that permits repeated sterile connection and separation.
Going further, several connectors or plastic tubes could be
provided for multiple connection to another closed system or
several other closed systems.
[0024] In terms of design, the container of a device according to
the invention could include a base plate. This base plate could
consist of a rigid plastic and have holding devices and/or
connection sites that concern the connection. In order for the
objects contained in the container to be examinable, the container
could be transparent at least in the flexible areas of the wall.
Transparency, for example, permits metered substance removal or
filling and in a special practical example positioning or mounting
of the transfer device within the container. Otherwise, at least a
view of the amount of substance available is furnished by
transparency. In addition, the container could also have a cover
plate. The flexible wall, especially the bellows, or also an
enclosure could extend between the cover plate and base plate. A
stabilization element could be arranged on the bottom of the cover
plate, which contributes to fastening of a receptacle for the
substance arranged within the container during transport. The
holding devices could be assigned to the base plate and/or cover
plate and also have the function of spacers or stabilizers in
addition to the holding function.
[0025] A particularly easy-to-handle variant of the at least
partially flexible container consists of designing the flexible
wall in the form of a bellows. This bellows could be strongly
deformed in all directions based on an extremely tear-proof thin
material, which could also be stretchable. This deformation is
reversible. Because of the limited material thickness objects
situated in the interior of the container could be grasped, joined
to each other or positioned or otherwise manipulated. For the
gripping movement it is particularly important that the wall
include at least two opposite flexible areas. With respect to
production of the container the bellows could be welded or glued in
sealed fashion to the base plate and cover plate.
[0026] A further variant of the device according to the invention
proposes sterile connection of the closed systems already at the
plant. In particular, this concerns the combination of a source
system and a source and target system into an overall system.
Specifically, the source system could be connected in sterile
fashion to a closed source and target system in the sense of a
metering device and form an overall system. It is understood that
an overall system can also contain more than two closed systems.
The possibility exists after emptying of the source system to
separate this in sterile fashion and dispose of it or to use it
elsewhere for partial amount removal. Successive separation can
occur in any system with a source function, if the previous source
system is completely emptied or emptied as desired.
[0027] Gravity-operated devices according to the invention without
metering function are generally pure source systems. The substance
is transferred to the other closed system from the source system
under the influence of gravity. The source system could then have a
container in which the substance is contained and whose connection
in the operating position points toward the floor.
[0028] According to a first very simple practical example of the
device according to the invention the container itself could form
the receptacle for the substance and be present, for example, as a
collapsible, flexible bag. This practical example permits
cost-effective production and storage of substances, like
preparation solutions, at the location of use, while maintaining a
closed condition of the systems.
[0029] In the first practical example the connection could open
into the container, on the one hand, especially extend minimally
into the substance and be provided there with a reclosable closure.
On the other hand, the connection could emerge from the container
and be welded with its free end in sterile fashion to the other
system or already be welded.
[0030] Reclosability of the end of the connection extending into
the substance permits partial removal of substances, like
preparation solutions, naturally heeding sterile connection and
disconnection. Formation of the closure as a snap closure made of
sealing material, which is equipped with fastening bridges and can
be operated through the flexible wall of the container, is of
special significance for the first practical example. The fastening
bridge serves for nonclosability of the closure. The closure
ensures that the substance does not reach the connection before
sterile connection has occurred and is possibly contaminated. The
material of the container present as a bag is soft, but strong
enough not to be damaged during manipulation of the closure.
[0031] In terms of design, the container could also include in its
bag form a base plate through which the connection is passed
through in sealed fashion. A pressure compensation device can be
arranged so that it opens into the area of the container filled
with air or inert gas, which always points up in the operating
position.
[0032] According to the simple and particularly cost-effective
modification of the first practical example of the device according
to the invention, a metering valve that could be advantageously
operated from the outside could be provided so that at least
estimated partial amounts can be removed.
[0033] A variant of the first practical example suitable for
volume-precise transfer consists of the fact that the source system
present there as a bag is already connected in a sterile fashion at
the plant to a source/target system in the form of a calibrated
drip chamber and forms an overall system. In this way the metering
device is contained in the overall system as an intrinsic closed
system which is also gravity-operated. Here again a metering valve
can be assigned to the source system. An overall system that also
contains additional closed systems in addition to the source system
and the metering device with combined source and target function is
also conceivable. In each case, however, sterile connection at the
plant between the systems applies in each case as a method step
prior to substance transfer.
[0034] The container in larger package sizes could have a volume
between 30 mL and 1000 mL. With small amounts so-called "minibags"
reach a volume between 10 mL and 30 mL. These "minibags" are
prescribed for individual use and can each contain the maximum
required amount of substance for the intended preparation.
[0035] A special second practical example of the device according
to the invention consists of the fact that it is formed as a
gravity-operated metering device. For this purpose at least two
connections can be provided for the system, which include an inlet
and an outlet pointing toward the floor in the operating position.
A calibrated drip chamber can be provided as container of the
system, in which the substance is at least temporarily contained.
The substance is fed via the inlet from a source system and
discharge through the outlet to a target system. A metering valve
can be assigned to the inlet and/or outlet. For the closed
condition of the system it is important that the inlet and outlet
are arranged sealed on the drip chamber. For example, the drip
chamber could include a base plate, cover plate and transparent
plastic jacket between the cover and base plate. With this
container design the connector of the pressure compensation device,
especially via the cover plate, could open in sealed fashion into
the drip chamber.
[0036] The calibrated drip chamber with the two connectors that can
be connected in sterile fashion in the second practical example
forms a closed system in the sense of the gravity-operated metering
device, which is both a source and target system. The thing to do
is have the source system for the aforementioned gravity-operated
metering device also release the substance by gravity into the
calibrated drip chamber after sterile connection of the connectors.
The amount of substance arriving from the source system could be
regulated via the metering valve with the inlet.
[0037] A third practical example of the device according to the
invention, which is also based on the gravity principle, proposes
to arrange a receptacle in the form of a bottle or ampule in the
container of the source system, within which the substance is
situated and whose closure points toward the floor in the operating
position. According to a preferred design the receptacle could be
fastened to a cover plate in the container. An eye could be
provided on the outside of the cover plate so the container can be
suspended like a drop. The connector could be welded into the base
plate opposite the cover plate.
[0038] In the third practical example in question the means for
transfer of the substance could include a short cannula for outlet
of the substance, especially a liquid, and a long cannula for air
or inert gas supply. The cannulas could puncture the closure of a
receptacle in the operating position and extend into the
receptacle.
[0039] In a simple variant of the third practical example only the
short cannula could be in a flow connection with the
sterile-connectable connector in the operating position. A
connection piece connected to the short cannula could then extend
in the form of a plastic tube into a plastic tube of the connector
that is larger in terms of cross section. The connector is welded
onto the base plate of the container and plastic tube connected to
the short cannula passes through a passage opening in the base
plate in sealed fashion. The long cannula opens into the container
equipped with a bellows to which the pressure compensation device
is connected. In the rest position a bellows is deployed and
accommodates the two cannulas. The cannulas are prevented from
puncturing the closure of the receptacle by a holding device. The
shaping of the receptacle can be utilized to fix the holding device
and the holding device can also be supported on the base plate. The
holding device according to a preferred design variant that is
particularly easy to handle could be present in the form of a
flexible slit sleeve. As long as the cannulas are not in use, they
are arranged in the holding device which protects the flexible wall
of the container, bellows from puncturing. The sleeve is supported
in the rest state, on the one hand, against the base plate of the
container and on the other hand against the shoulders of the
receptacle. In the operating position the sleeve is manipulated
from the outside via the bellows, positioned around the ampule
barrel and the cannulas puncture the closure. The bellows of the
container is then collapsed.
[0040] In this variant the volume of the receptacle could be
predetermined so that the removed amount can be estimated. The
arrangement of a metering valve on a connection improves volume-
and time-precise metering of the amount intended for the other
closed system.
[0041] A somewhat more demanding variant of the third practical
example with more precise metering capability proposes that the
container include a calibrated drip chamber. This drip chamber
could be directly welded to the base plate of the container and
with appropriate sealing and sterility of all connectors and
connection pieces be a component of the source system. Both
cannulas (both long and short cannulas) are in flow connection with
the drip chamber via connection pieces. The short cannula within
the container could be assigned a metering valve which can be
operated via the bellows of the container. The connector for
connection to another system can start from the calibrated drip
chamber, which expediently points toward the floor in the operating
position.
[0042] As an alternative to a welded-on drip chamber, however, an
overall system prepared sterile at the plant could also be formed,
consisting of a source system and metering device in the sense of a
combination of a source and target system. The large cannula could
then also open directly into the pressure compensation device. In
this alternative only one pressure compensation device is
advantageously provided, which ensures pressure compensation in the
container and in the receptacle of the source system, as well as in
the calibrated drip chamber of the target and source system--in
short, in all components of the closed overall system.
[0043] Finally, there is also the possibility of connecting the
connector of the source system according to the third practical
example subsequently in sterile fashion to a gravity-operated
metering device according to the second practical example. Here
again the source system could be assigned a metering valve.
[0044] As an alternative to a gravity-operated device according to
the invention according to the first three practical examples, the
fourth practical example deals with a variety of uses of a
calibrated syringe with an ampule plunger and ampule barrel as
means for active metered transfer of the substance.
[0045] Force application can occur manually by the user. However,
the syringe can also be introduced into an electric motor pump
system known per se, in which metering can be programmed precisely
in terms of time and volume.
[0046] On the one hand, the syringe could be filled within a
container from a receptacle containing the substance or on the
other hand the ampule barrel of the syringe could already be filled
with substance or finally be filled by filling the syringe with
substance from another source system. The ampule barrel of the
syringe simultaneously forms a generally temporary receptacle for
the substance, since transfer occurs via the syringe. The syringe
could be operated from the outside via the at least partially
flexible wall of the container, especially via its bellows.
[0047] The system including the syringe could have superimposed
source and target function, if filling with substance and delivery
of substance occur in the same system.
[0048] According to one variant of the fourth practical example the
syringe could be arranged within the container and be operable from
the outside via an at least partially flexible wall of the
container, especially via its bellows. In addition to the syringe,
a cannula could also be contained, which can also be handled via
the bellows. The syringe would be initially packed with the
cannula. The stopper of the receptacle would then be punctured and
the syringe filled, i.e., filled with substance within the system.
The cannula would then be removed and the filled syringe connected
to the connector oriented toward the target system with a
connection piece in the form of a tubular connector. Finally, the
ampule plunger would be forced into the ampule barrel so that the
substance flows into the connector and into the target system
connected in sterile fashion.
[0049] The connection piece could also be present in the form of an
internal line. The internal line in the rest state could extend
through a passage opening of the container into the connector and
be wound in a spiral within the container. The internal line then
initially extends into the plastic tube only far enough so that it
can be connected without hindrance to the connector of the other
closed system. The internal line could have a smaller cross section
than the connection with a plastic tube of the connection leading
to the other closed system and consist of a rigid, flexible
material with a sliding surface. Polypropylene, for example, could
be considered as material. The free end of the internal line
extending into the container could be connected to the syringe in
order to be operated.
[0050] This variant with internal line permits precise positioning
of the free end of the internal line in the other system and can
serve both to deliver the substance and to receive the substance.
Advance of the internal line through the connector connected in
sterile fashion to a specific withdrawal site in the other closed
system could be accomplished via the flexible wall of the
container. In the case of substance removal the removed substance
could be blood or umbilical cord samples that are to be furnished
to the laboratory. The status of the preparation and its
compatibility for the patient must be determined in the laboratory.
Via the syringe on the internal line the sample is removed from the
other system and introduced in the first sterile system to the
receptacle, here via the suction and ejection movements of the
syringe through a cannula and the stopper of a preferably evacuated
ampule. After "retrieval" of the internal line via the bellows into
the first system, separation of the withdrawal system can be
carried out. During transfer of a substance situated in the
receptacle of the container into the other closed system the
connection between the syringe and cannula is initially produced,
the substance taken up with it, the cannula then removed and the
syringe connected to the internal line, whose free end was already
positioned in the target system. The substance is conveyed through
the internal line to the destination with the plunger movement.
After transfer, the internal line is retracted into the first
system via the connected plastic tubes of both systems and the
systems are separated in sterile fashion.
[0051] As already mentioned, the ampule barrel of a syringe
according to another modification of the first practical example of
the device according to the invention could simultaneously form the
receptacle for the substance, the ampule barrel according to
another variant of the fourth practical example could then be
positioned in a holding device on the base plate and have a
connection in the form of a plastic tube, which passes through the
base plate in sealed fashion and serves for sterile connection to
another system. The ampule barrel could already be filled in
advance with the substance in this case.
[0052] Another modification of the fourth practical example of the
device according to the invention proposes to provide the ampule
barrel with a cannula with a cannula closure, which can be opened
and closed via the flexible wall of the container. More rapid
emptying and filling of the pressure compensation device is
achieved according to the variable gas volume in the container, if
the container includes two chambers with two connection pieces for
preferably one pressure compensation device or also two smaller
separate pressure compensation devices. The first chamber could
then contain the ampule plunger and the second chamber could
contain the ampule barrel with the cannula and the closure.
Deviating from other practical examples in which the connector is
welded into a base plate, here the second chamber of the container
could itself form the connector for sterile connection to the
connector of another closed system on the end facing away from the
first chamber for the ampule plunger.
[0053] The other closed system, here the source system, could be
present in the practical example in question in the form of an
ampule containing the substance. This ampule could in turn have a
plastic enclosure with a connector for sterile connection of the
connection of the container or second chamber, in short the
connector of the first closed system. The enclosed ampule with a
connector connectable in sterile fashion in itself forms a closed
system and with respect to aggressive substances could consist of
borosilicate glass and be equipped with an elastomer puncture
stopper. Finally, the cannula of the device according to the
invention is moved through the connections to the ampule, the
ampule plunger is forced into the ampule barrel and air or inert
gas is injected into the ampule after puncturing of the elastomer
stopper. The ampule contents are then under pressure and fine
metering is then possible during removal of the substance. The
ampule plunger is now withdrawn from the ampule barrel during
drawing in of the substance and the two systems are separated in
sterile fashion. The now filled closed system is available as
source system for sterile connection again to a target system.
[0054] In another variant of the fourth practical example the
ampule plunger and the ampule barrel could be in a flow connection.
The ampule barrel can have a connector that can be connected in
sterile fashion to another closed source system. In addition, a
metering valve could be provided. The connector could be present as
a plastic tube that extends into the ampule plunger. The ampule
barrel could have a connection that can be connected in sterile
fashion in a closed target system away from the ampule plunger,
which is also provided with a metering valve.
[0055] To draw in substance from the source system the connection
of the ampule barrel is closed, that of the ampule plunger opened
and the latter moved out of the ampule barrel. The substance then
flows from the source system into the target system, which is
represented in this situation by the syringe. To convey the
drawn-in substance to the target system, the metering valve is
closed on the side of the ampule plunger and opened on the side of
the ampule barrel. The ampule plunger is introduced to the ampule
barrel and the substance thus transferred to the target system. In
this situation the syringe is the source system. Another
advantageous application is obtained, if the ampule barrel is from
both directions to the mixing container or target system. This can
be done, if filling occurs only partially via the ampule plunger,
i.e., the ampule plunger is not placed in the maximum introduction
position. If the metering valve on the side of the ampule plunger
is then closed and the metering valve on the side of the ampule
barrel opened and the now only half introduced ampule plunger
withdrawn, suction of substance occurs from the source system
connected in a sterile fashion on the side of the ampule barrel.
Two different substances are then situated proportionately in the
syringe, which were transferred in sterile fashion from both
directions and can then be introduced to another target system as a
mixture. The device according to the invention just described
represents a particularly elegant solution for laboratory work,
which gets by without additional mixing containers on this
account.
[0056] A special advantage in this variant of the fourth practical
example is also the space-saving design of the container, which
consists of a combination of an enclosure in the area of the ampule
barrel and a bellows in the area of the ampule plunger. The device
according to the invention because of this can be tightened better
in a known syringe pump, since the container is reduced to a
minimum. Advance of the substance is continuously guaranteed by the
alternation of suction and ejection. The effective connection of
the syringe to a syringe pump makes it possible to accomplish
transfer of substance automatically at pre-established times.
[0057] A modification of the variant of the fourth practical
example just described consists of the fact that an overall system
is formed with a source system according to the second practical
example. The source system here has a receptacle in the form of an
ampule facing the floor with its opening in the operating state.
During filling of the ampule plunger of the syringe, substance is
drawn in from the source system and the ampule barrel filled. The
syringe is the target system here. When substance is conveyed to
another target system, the syringe is then the source system. The
overall system could already be produced at the plant and the
source and combined source/target system could be connected in
sterile fashion via a connection piece that extends to the tip of
the ampule plunger.
[0058] The overall system could also be formed by the fact that two
source systems are connected to a syringe and substance is removed
by means of the syringe, on the one hand, from a source system via
the ampule plunger and, on the other hand, substance is removed
from the other source system via the ampule barrel. Mixing could
then occur in the syringe and the new substance could be
transferred to another target system after sterile separation and
reconnection.
[0059] Regardless of how the syringe is accommodated in the
container in the closed system, the syringe together with the
container could be incorporated in an ordinary syringe pump.
Transfer of substance can therefore be accomplished automatically
at pre-established times.
[0060] Another variant of the fourth practical example proposes the
syringe again as mixing vessel. Substances are drawn into the
ampule barrel from closed source systems via a multipath closure.
This naturally does not occur to complete filling of the ampule
barrel. After the substances (for example, plasma and a mixture of
white blood cells and plasma) have entered the ampule barrel, this
branch is closed and the branch that concerns introduction of DMSO
is opened. Several DMSO-source systems can then be coupled and
contain rupture ampules within sterile containers. The DMSO branch
is also closed and a third branch opened, via which any air drawn
into the system is released into the container that contains the
syringe. Finally the third branch (corresponding to the pressure
compensation device) is closed and a fourth branch of the multipath
closure opened, to which at least one freezing bag or also several
series-connected and separately closable freezing bags are
connected in sterile fashion. The mixture is now ejected into the
freezing bags by means of ampule plungers. The container in this
variant is a foil enclosure dimensioned so that it has sufficient
free volume for the system's gas/air. The generously dimensioned
foil enclosure is provided here with reference to the mixing
syringe and DMSO rupture ampules whose future openings point
downward. If the rupture ampules are broken, natural separation of
liquid and gas occurs since the liquid flows to the output of the
container and any system gas/air rises upward into the free space
of the container. The question of incorrect mixing of substances in
system gas/air therefore does not come up in the container for the
mixing syringe, since the gas, air escapes into the container via
the pressure compensation branch. The pressure compensation device
in this practical example is therefore not designed as a welded-on
bag, but is achieved by dimensioning of the container and the
arrangement of the substance outlet or via a branch of the pressure
compensation opening into the container without adversely affecting
the substance.
[0061] According to a fifth practical example the substance could
be contained in a carpule or its carpule barrel, which is
preferably calibrated. Carpule includes the carpule plunger movable
in the carpule barrel. As in a variant according to the fourth
practical example, the thing to do here is to construct the
container from two chambers, one pressure compensation device being
provided per chamber. A cannula can be provided in the first
chamber, which faces the carpule barrel or its puncture stopper
with its tip and extends with its opposite end into the connector.
The connector could also be present here as a plastic tube that can
be connected in sterile fashion, which is to be connected in a
sterile fashion to the connector of another system, a target
system.
[0062] The second chamber could consist of a cylindrical section
and a bellows, in which case the carpule barrel is contained within
a cylindrical section as well as part of the carpule plunger and
the rest of the carpule plunger is contained within the bellows.
This chamber and a coupling tube of the first chamber could be
movable relative to each other and preferably fastenable in a
predetermined position to each other with respect to performance of
the puncture process. Transfer of substance occurs after a flow
connection is made to the connector in that the carpule plunger
displaces a sliding stopper within the carpule barrel. The carpule
according to the fifth practical example permits batchwise and
volume-precise delivery of substance from the carpule barrel of the
first closed system into another closed system. The device
according to the fifth practical example could be particularly
useful as a disposable article.
[0063] A receptacle within a closed system, the source system,
already containing a substance for transfer, is expediently closed
after filling in order to prevent emergence of substance within the
container. A closure is naturally provided that is easy to open and
also can be closed. The closure in ampules, bottles or the carpule
barrel could be in the form of a puncture stopper. The puncture
stopper could consist of elastomer and preferably be teflon-coated.
As an alternative to a receptacle in the form of evacuated supply
vessel with puncture stopper, commercial sample vessels closable
airtight with a screw closure or snap closure could also be used.
Substance receptacles made of borosilicate glass are preferably
used, which are suitable for aggressive substances that attack
plastic. An aggressive substance could be, for example, dimethyl
sulfoxide (DMSO), which is to be transferred into another system
that contains the stem cells of a patient for their storage. This
practical example is especially significant with respect to storage
stability of the substance DMSO of two years in the borosilicate
glass receptacle. A connection consisting of PVC is only briefly
contacted during transfer of DMSO so that the dissolution processes
are not set in motion. By sterile connection of the connections of
both systems the DMSO enters the other closed system, which is
present for example in the form of a freezing bag with a stem cell
preparation. Apart from DMSO, another substance can also be
contained in the receptacle which is incompatible with another
component. Closed systems that are pure target systems could be
tube and bag systems.
[0064] With respect to the fourth and fifth practical example the
connector of a system with source function could be connectable in
sterile fashion to another closed system, which contains an
internal line. The internal line could be manipulated via the
bellows of the container and permits precise positioning in another
target system. The cross section of the internal line is smaller
than that of the connector of the source and target system.
[0065] With respect to the sterility of the device desired form the
outset, its components before connection could be arranged with the
other closed system within a sterile package. A blister package is
preferably prepared. The package could also have a smooth surface
without undercuts or recesses so that disinfection and introduction
to the clean room is facilitated. Disinfection could occur with 70%
ethanol so that the requirements for introduction of the package
into cleanroom areas are met. Additional evacuation of the package
is also possible. Pyrogen freedom of the package could also be
produced and it could be gamma-sterilized.
[0066] A particular advantage of the device according to the
invention lies in the fact that inexpensive receptacles, like
ampules, bottles, syringes, carpules and connections which are
otherwise used in open systems can be applied to fully closed
systems. This is possible because the arrangement of the
inexpensive source systems can occur in a closed system in a
corresponding container or plastic enclosure, which can interact
with the other closed systems. Inexpensive source systems could
therefore be used in a device according to the invention and made
accessible to medical and scientific work. In principle, storage of
any substance for complex preparation steps within a receptacle in
a closed system is desirable.
[0067] There are different possibilities of configuring and
modifying the instructions of the present invention advantageously.
For this purpose the patent claims, on the one hand, and the
following application of several practical examples in addition to
variance of the device, on the other hand, are referred to by means
of the drawing. In conjunction with the explanation of the
mentioned practical examples of the invention preferred embodiments
and modifications of the instructions are also generally explained.
In the drawing
[0068] FIG. 1 schematically depicts a first practical example of
the device according to the invention based on the gravity
principle with a collapsible bag,
[0069] FIG. 2 schematically depicts the object from FIG. 1 combined
with another device according to the invention in the form of a
calibrated drip chamber to form an overall system,
[0070] FIG. 3 schematically depicts a variant of a second practical
example of the device according to the invention in the form of a
gravity-operated metering device,
[0071] i. in FIG. 3A a first variant of the device in a blister
package,
[0072] ii. in FIG. 3B the object of FIG. 3A ready for
operation,
[0073] iii. in FIG. 3C a schematic view of a second variant of the
device with an inlet and several outlets,
[0074] iv. in FIG. 3D a schematic view of a third variant of the
device with several inlets and an outlet,
[0075] v. in FIG. 3E a schematic view of a fourth variant of the
device with several inlets and several outlets,
[0076] FIG. 4 schematically depicts a variant of a third practical
example of the device according to the invention based on the
gravity principle with an ampule as receptacle,
[0077] FIG. 5 schematically depicts a variant of the third
practical example of the device according to the invention based on
the gravity principle with a bottle as receptacle and with
integrated drip chamber,
[0078] FIG. 6 depicts the object from FIG. 5 in a blister
package,
[0079] FIG. 7 schematically depicts a variant of the third
practical example of the device according to the invention with an
overall system consisting of a source system and combined
source/target system based on the gravity principle with an ampule
as receptacle and with special holding device
[0080] i. in FIG. 7A in the rest position and
[0081] ii. in FIG. 7B in the operating position,
[0082] FIG. 8 schematically depicts a variant of a fourth practical
example of the device according to the invention with a syringe
within the container
[0083] i. in FIG. 8A in the rest position and
[0084] ii. in FIG. 8B in the operating position,
[0085] FIG. 9 schematically depicts a modification of the object in
FIG. 8 with an internal line as connection piece,
[0086] FIG. 10 schematically depicts another variant of the fourth
practical example of the device according to the invention with a
syringe and holding device in the container,
[0087] FIG. 11 schematically depicts another variant of the fourth
practical example of the device according to the invention with a
syringe in a two-chamber container,
[0088] i. in FIG. 11A the device in a blister package,
[0089] ii. in FIG. 11B the device during connection of the closed
system to a source system,
[0090] iii. in FIG. 11C the device in the operating position--here
puncturing of an ampule of the source system,
[0091] iv. in FIG. 11D the device in the operating position--here
emptying of air in the ampule of the source system,
[0092] v. in FIG. 11E the device in the operating position--here
suction of substance from the ampule of the source system,
[0093] vi. in FIG. 11F the device in the operating position--here
sterile separation of the connector from the connector of the
source system,
[0094] vii. in FIG. 11G the device in the rest position--readiness
for transfer of the substance removed from the source system into a
target system,
[0095] FIG. 12 schematically depicts another variant of the fourth
practical example of the device according to the invention with
flow connection between the ampule plunger and the ampule barrel of
the syringe,
[0096] i. in FIG. 12A the device in the rest position, empty state
of the ampule barrel,
[0097] ii. in FIG. 12B the device during the suction process,
[0098] iii. in FIG. 12C the device at the end of the suction
process, complete filling of the ampule barrel of the syringe,
[0099] iv. in FIG. 12D the device coupled to additional closed
systems by means of a system with internal line,
[0100] FIG. 13 schematically depicts the object from FIG. 12 as
part of an overall system combined with the source system from FIG.
7,
[0101] i. in FIG. 13A the device in the rest position, empty state
of the ampule barrel, cannulas outside of the ampule of the source
system,
[0102] ii. in FIG. 13B device with prepared source system,
[0103] iii. in FIG. 13C the device during the suction process
and
[0104] iv. in FIG. 13D the device during transfer of the substance
into a target system and
[0105] FIG. 14 schematically depicts a fifth practical example of
the device according to the invention in the form of a carpule with
a two-chamber container--here in the rest position.
[0106] FIGS. 1 to 14 show a device for transfer of the substance
between closed systems G, G/Z, Z, G+G/Z, in which the systems G,
G/Z, Z, G+G/Z can be connected to each other in sterile fashion and
separated from each other in external fashion and have means for
transfer of the substance.
[0107] According to the invention a pressure compensation device 1
is provided, which is in sterile flow connection with at least one
system G, G/Z, Z, G+G/Z. In the present five practical examples
with all their variants the pressure compensation device 1 is
bonded, namely welded to system G, G/Z, Z, G+G/Z.
[0108] The means to transfer substance includes at least one
connector 2 for sterile connections with at least one additional
system G, G/Z, Z, G+G/Z. Generally the connectors 2 are formed as
thermoplastic tubes.
[0109] In all practical examples a container 3 is provided to form
system G, G/Z, Z and the connector 2 is welded in sterile fashion
to container 3 of system G, G/Z, Z.
[0110] Depending on the variant, the container 3 has a base plate 4
and/or cover plate 5 and/or at least one holding device 6.
[0111] It is shown in FIGS. 1, 2, 4 to 14 that at least one part of
the wall of the container 3 is designed flexible so that the means
for transfer of substance could be operated at least partially from
the outside through the flexible wall. FIGS. 4 to 14 show that the
flexible wall is present in the form of a bellows 7.
[0112] The first practical example of a very simple design of the
device according to the invention according to FIGS. 1 and 2 is
based on the gravity principle in order to transfer a substance
from closed source system G in the other closed system Z or G/Z.
The container 3 is present as a collapsible, flexible bag with a
volume of 30 mL, which is already filled with substance and whose
connector 2 faces the floor in the operating position.
[0113] In both variants of the first practical example the
connector 2 extends slightly with one end in sealed fashion through
the base plate 4 in container 3 into the substance and is provided
there with a reclosable snap closure 8. The snap closure 8 consists
of a sealing material, is equipped with a fastening bridge 9 and
can be operated through the flexible wall of the container 3. The
connector 2 has a metering valve 13. The connector 2 in FIG. 1 is
available for sterile connection to the closed target system Z.
[0114] The device according to the invention according to the
variant depicted in FIG. 2 of the first practical example forms an
overall system G+G/Z, which combines the closed systems G and G/Z
connected to each other in sterile fashion at the plant via
connection piece 15. System G/Z of the overall system G+G/Z
essentially corresponds to the device described in FIG. 3B
according to second practical example. A cross connector is denoted
14, which symbolizes the sterile system connection between
connector 2 of overall system G+G/Z with the connector 2 of the
target system Z.
[0115] In the second practical example according to FIGS. 3A to 3E
the container 3 is provided as a calibrated drip chamber 12 to
accommodate the substance, which is constructed essentially of a
base plate 4 and a cover plate 5 and a plastic jacket extending in
between. FIGS. 3A and 3B show a variant with two connectors 2,
which include an inlet 10 and an outlet 11 pointing toward the
floor in the operating position. The inlet 10 and the outlet 11
extent through the base plate 4 and the cover plate 5 of the drip
chamber 12 and are welded tightly in them. The pressure
compensation device 1 is also connected in sealed fashion to the
cover plate 5 of drip chamber 12 and extends into it. Both
connectors 2 are assigned a metering valve 13.
[0116] A device according to FIGS. 3A to 3E represents a closed
source and target system G/Z in the sense of a gravity-operating
metering device, which can be combined with different source
systems G and target systems Z and thus permit sterile and
volume-precise transfer of the substance. The device is to be
removed before use from a sterilized blister package 16.
[0117] The components of a device according to the invention
according to all practical examples are arranged with a sterilized
blister package 16 before sterile connection to another closed
system G, G/Z, Z, which is shown as an example in FIGS. 3A, 11A and
6. The blister packet 16 is pyrogen-free and gamma-sterilized. The
blister packet 16 is also disinfected with 70% ethanol.
[0118] The variant depicted in FIG. 3C shows an inlet 10 connected
in sterile fashion to source system G and four outlets 11, which
are connected in sterile fashion to the target systems Z via two
connectors 2. Two of the outlets 11 are still without function
here. A metering 13 is assigned to a connector 2 on the outlet
side.
[0119] Another variant of the device with four inlets 10 is shown
in FIG. 3D, which are connected in sterile fashion via connectors 2
to four source systems G and in which a metering valve 13 is
provided for each. A mixture of four substances can be produced
here in drip chamber 12. In the variant depicted in FIG. 3D only
one outlet 11 is provided, whose connector 2 is connected in a
sterile fashion to the target system Z and has a metering valve
13.
[0120] Finally a fourth variant of the second practical example of
the device according to the invention is shown in FIG. 1E with four
inlets 10 and four outlets 11 as well as a metering valve 13 on
each connector 2. The mixture produced from the substances of
source systems G can be transferred from drip chamber 12 into
target systems Z.
[0121] The third practical example of the device according to the
invention is depicted in FIGS. 4 to 7 in different variants, which
are also based on the gravity principle. A receptacle 17 in the
form of a bottle or ampule is contained in the container 3 of
source system G, within which the substance is situated and whose
closure faces the floor in the operating position. The single
connector 2 in the operating position also faces downward. The
receptacle 17 is present in FIGS. 4 and 7 as an ampule, in FIGS. 5
and 6 as a bottle. A puncture stopper 20 is provided as closure.
The pressure compensation device 1 extends through base plate 4
into vessel 3 and is connected tightly and in sterile fashion. The
receptacle 17 is fastened to the cover plate 5 of container 1. On
the outside of cover plate 5 an eye 21 is arranged, which serves
for a suspension of the device. A short cannula 18 serves for
transfer of the substance present here as liquid. In addition a
long cannula 19 is provided for air supply. In the operating
position both cannulas 18, 19 puncture the puncture stopper 20 of
receptacle 17 and extend into it and the substance situated there,
the long cannula ultimately extending beyond the level of the
substance. The short cannula 18 is in flow connection with
connector 2. Special holding devices 6 are provided for the
cannulas 18, 19 in the variants of the third practical example
depicted in FIGS. 4 and 7 on base plate 4.
[0122] The variant of the third practical example depicted in FIG.
4 implements a semiquantitative substance transfer and is
particularly simple and cost-effective to produce. The volume of
the receptacle 17, namely the ampule, is predetermined and it can
also be estimated how much was removed via the predetermined
immersion depth of the short cannula 18 into the ampule. On removal
of the total amount the precise volume is present over the entire
volume of the receptacle 17 and the immersion depth of the short
cannula 18. Removal of a partial amount can occur by means of the
metering valve 13. The long cannula 19 opens into the container 3
so that pressure compensation can occur via the pressure
compensation device 1 that discharges into container 3. In the
device depicted in FIG. 4 the bellows 7 in the rest position is
present in the deployed state, is supported by a stabilizer not
shown here and contains the two cannulas 18, 19 spaced by the
puncture stopper 20, which are fastened to base plate 4 or holding
device 6. The short cannula 18 extends with its connection piece 15
facing away from receptacle 17 into the connector 2 in the form of
a PVC tube. The operating position depicted in FIG. 4 shows that a
stabilizer is no longer present and that the bellows 7 is
compressed, in which case the displaced air escapes into the
pressure compensation device 1.
[0123] The device depicted in FIG. 4 is operated as follows from
the outside via bellows 7 of the container 3: [0124] sterile
connection of connector 2 of the closed source system G to the
connector 2 of target system Z, [0125] removal of a stabilizer (not
shown here), [0126] compression of the bellows 7 and puncturing of
the puncture stopper 20 with both cannulas 18, 19, filling of the
pressure compensation device 1 with the air displaced from
container 3, [0127] introduction of the substance through the short
cannula 18 into connector 2, [0128] regulation of transfer of
substance of source system G via metering valve 13.
[0129] A somewhat more demanding variant of the third practical
example is depicted in FIGS. 5 and 6. There the cover plate 5 of a
calibrated drip chamber 12 is integrated, namely welded into the
base plate 4 of the container 3 and is part of source system G.
Outlet 11 and connector 2 emerge from the drip chamber 12. The two
cannulas 18, 19 extend into the drip chamber 12 via connection
pieces 15 and inlets 10. In addition to the two inlets 10
cooperating with the connection pieces 15, a third free inlet 10 is
provided, which connects the drip chamber 12 to the container 3 so
that the pressure equalization device 1 of container 3 is also
responsible for pressure equalization in the drip chamber 12. The
connection piece 15 of the short cannula 18 has a metering valve 13
which can be adjusted via bellows 7. A metering valve 13 is also
provided on connector 2.
[0130] FIG. 6 shows a device according to FIG. 5 within blister
package 16, which includes a stabilizer 22 with protective devices
23 for the two cannulas 18, 19. The stabilizer 22 is fastened to
the holding device 6 within blister package 16, which is shown in
FIG. 5. The connection pieces 15 of the two cannulas 18, 19 are
fastened in a retaining plate 24 on their end on the cannula side.
When the device is brought into operation, the retaining plate 24
with the cannulas 18, 19 is released via the bellows 7 from the
stabilizer 22 and the protective devices 23 and the puncture
stopper 20 of the receptacle 17 is punctured until the retaining
plate 24 lies against it.
[0131] Another variant of the third practical example of the device
according to the invention shows in FIGS. 7A and 7B a receptacle 17
in the form of an ampule similar to that of FIG. 4 but with
differences relative to it.
[0132] One difference is that an overall system G+G/Z is prescribed
there, which consists of a source system G and a combined
source/target system G/Z as shown in FIG. 3B. Here the sterile
connection is produced between source system G and combined
source/target system G/Z at the plant through a connection piece
15, which is equipped with a metering valve 13. The connection
piece 15 of the short cannula 18 discharges in a calibrated drip
chamber 12. The long cannula 19 opens into the pressure
compensation device 1 via its connection piece 15. The pressure
compensation device 1 is connected via two additional connection
pieces 15 to container 3 in the drip chamber 12 and therefore
ensures pressure compensation everywhere in the overall system
G+G/Z. A connector 2 protrudes from the overall system G+G/Z,
especially from the drip chamber 12, which is connected in a
sterile fashion to the connector 2 on the target system Z.
[0133] Another difference is that the holding device 6 is designed
in the form of a slotted sleeve, which is supported in the rest
position in FIG. 7A against the shoulder of the ampule and ensures
spacing of the cannulas 18, 19 relative to the puncture stopper 20.
In the operating position according to FIG. 7B the holding device 6
is pushed over the ampule, in which the cannulas 18, 19 puncture
the puncture stopper 20.
[0134] The container 3 as in FIG. 4 is a combination of enclosure
and bellows 7. The latter extends in the rest position in the area
of the holding device 6, whereas the receptacle 17 is almost
enclosed.
[0135] FIGS. 8 to 13 show a fourth practical example of the device
according to the invention in which the means for transfer of
substance include a calibrated syringe with an ampule plunger 25
and an ampule barrel 26.
[0136] According to the variants of the four practical examples
depicted in FIGS. 8 to 11, the syringe is arranged within the
container 3 and can be operated from the outside via its bellows 7
extending between the cover plate 5 and base plate 4. In the
syringes according to FIGS. 12 and 13 the container 3 is formed by
a bellows 7 in the area of the ampule plunger 25, which is
connected in sealed fashion to the ampule barrel 26. The end of the
ampule plunger 25 facing away from the ampule barrel 26 is glued to
the base plate 4 of the container 3. The ampule barrel 26 in all
variants of the fourth practical example temporarily accommodates
the substance.
[0137] FIGS. 8A, 8B show the arrangement of the syringe and the
receptacle 17 in the form of an ampule filled with substance with
puncture stopper 20 within container 3 by mean of matching holding
devices 6, which are molded onto the base plate 4. The receptacle
17 has a puncture stopper 20 and consists here of borosilicate
glass. Dimethyl sulfoxide (DMSO) is contained in a substance in the
receptacle 17. The puncture stopper 20 consists of elastomer and is
teflon-coated for chemical stability. The holding devices 6
according to the two variants depicted in FIGS. 8A, 8B and 9 hold
the receptacle 17, a protective device 23 for the cannula 28 of the
syringe, the connection piece 15 and the ampule barrel 26 with
ampule plunger 25.
[0138] A stabilizer 22 is provide in the container 3 according to
FIG. 8A, which has the task of holding the receptacle 17 contained
in container 3 and the cannula 28 for the syringe (i.e., components
that might loosen) in position during transport. The connector 2
and the pressure compensation device 1 are each connected via a
passage opening (not further shown) to the container 3, in which a
sealing connection (here a welded connection) is made on the
passage opening.
[0139] The device depicted in FIGS. 8A and 8B according to the
variant there of the fourth practical example is operated as
follows from the outside via bellows 7, after the sterile
connection to target system Z is completed: [0140] connection of
the ampule barrel 26 of the syringe to cannula 28--here via a Luer
lock connection, [0141] puncturing of the puncture stopper 20 of
receptacle 17 and introduction of the cannula 28 into the
substance, [0142] suction of the substance into the ampule barrel
26 by extension of the ampule plunger 25, [0143] loosening of the
cannula 28 and positioning in the protective device 23 in the
holding device 6, [0144] as shown in FIG. 8B, connection of the
ampule barrel 26 to the connection piece 15--here via a Luer lock
connection, [0145] tightening of the syringe in an syringe pump 29,
[0146] transfer of the substance from the ampule barrel 26 into the
connection piece 15, connector 2 and finally into system Z by
introducing ampule plunger 25 into ampule barrel 26, [0147] sterile
disconnection of the systems G and Z after transfer.
[0148] In FIGS. 8A and 8B the connection piece 15 is present as a
tubular connection piece, in FIG. 9 as an internal line 27. In the
variant depicted in FIG. 9 the receptacle 17 is empty and the
system there is initially target system Z. Substance removal is
carried out at a predetermined location via the internal line 27
connected on ampule barrel 26, which after sterile connection to
source system G through connectors 2 enters and is positioned in
it. The following steps are carried out when the internal line 27
is positioned in source system G: [0149] connection of the ampule
barrel 26 to the internal line 27--here via a Luer lock connection,
[0150] suction of the substance from system G into the ampule
barrel 26 by retracting the ampule plunger 25 and filling the
syringe, [0151] loosening of the internal line 27 from the ampule
barrel 26, [0152] connection of the ampule barrel 26 to cannula 28,
[0153] puncturing of the puncture stopper 20 of receptacle 17 and
introduction of the substance from the ampule barrel 26 into the
receptacle 17 by introducing the ampule plunger 25 into ampule
barrel 26, [0154] removal of the cannula 28 from the receptacle 17,
loosening of the cannula 28 from the ampule barrel 26 and
positioning in the protective device 23, [0155] withdrawal of the
internal line 27 from system G, spiral winding and arrangement,
[0156] sterile disconnection of systems G and Z after transfer,
[0157] reuse of the filled receptacle 17 in the clean room.
[0158] The syringe depicted in FIG. 10 is already provided at the
plant with a substance in ampule barrel 26 and has a valve 30 on
its ampule barrel 26 for opening and closure. This device is
furnished in the filled state and represents a source system G.
Here only a single holding device 6 is provided on the base plate 4
of container 3. The free end of the ampule barrel 26 forms the
connector 2 that passes through the base plate 4 in sealed fashion.
This is a disposable article that is disposed of after
emptying.
[0159] The variant of the fourth practical example of the device
according to the invention depicted in FIGS. 11A and 11G also shows
a syringe, which is already packaged with a cannula 28 on the
ampule barrel 26 and has a cannula closure 31. Here a specially
designed container 3 is provide with two chambers 32, 33, which are
connected via two connection pieces 15 to the pressure compensation
device 1. The first chamber 32 contains the ampule plunger 25 of
the syringe and the second chamber 33 contains the ampule barrel 26
with the cannula 28 and the cannula closure 31. The end of the
ampule plunger 25 is firmly connected to the base plate 4 of the
first chamber 32. The second chamber 33 of the container 3 forms
the connector 2 for sterile connection to the connector of another
closed system G, Z on the end facing away from the first chamber
32.
[0160] The other closed system G apparent from FIGS. 11B to 11F is
in the form of an ampule containing the substance, which has a
plastic enclosure with a connector 2 extending from it for sterile
connection of connector 2 of the container 3 and the first closed
system G/Z. The ampule of the closed system G consists of
borosilicate glass and is equipped with a puncture stopper 20 made
of elastomer. The device in question is operated as follows from
the outside via bellows 7 from the corresponding chamber 32, 33 of
container 1: [0161] removal of the device from the blister package
16 shown in FIG. 11A, [0162] sterile connection of connector 2 of
the closed system G/Z with connector 2 of the enclosed ampule of
the closed system G and removal of the cannula closure 31 in FIG.
11B, [0163] in FIG. 11C: puncture of the puncture stopper 20 of the
ampule of system G, introduction of cannula 28 into the ampule of
system G, [0164] in FIG. 11D: introduction of the ampule plunger 25
into ampule barrel 26 and introduction of air from the ampule
barrel 26 into the ampule of system G containing the substance, in
which case an overpressure is formed there so that fine metering of
the substance is made possible during removal without a vacuum
effect; on size reduction of chambers 32, 33 the pressure
compensation device 1 is filled with air from chambers 32, 33,
[0165] in FIG. 11E: beginning of suction of the substance from
system G into the ampule barrel 26 by filling of the ampule plunger
25 from the ampule barrel 26, in which the system G/Z has a target
function; on increasing size of chambers 32, 33 air enters them
from the pressure compensation device 1, [0166] in FIG. 11F:
suction of substance from system G into the ampule barrel 26 is
completed, sterile disconnection of connector 2 of the closed
system G/Z from the connector 2 of system G occurs, [0167] in FIG.
11G: readiness for sterile connection with another closed system Z
in order to transfer the substance transferred from system G/Z,
which now has a source function, into system Z.
[0168] In the other variant of the fourth practical example of the
device according to the invention depicted in FIGS. 12A to 12D the
ampule plunger 25 is in flow connection with the ampule barrel 26.
The ampule plunger 25 is connected via a connector 2 in sterile
fashion to a source system G. This connector 2 extends as an inner
tube into ampule plunger 25 and opens centrally in the free end of
ampule plunger 25 into ampule barrel 26. The connector 2 on the
side of the ampule plunger is equipped with a metering valve 13. A
connector 2 is formed from the ampule barrel 26, which is connected
in sterile fashion to a closed system Z and includes a metering
valve 13.
[0169] For suction of substance from source system G the connector
2 on the ampule barrel 26 is closed, the one on ampule plunger 25
is opened and the latter moved out form the ampule barrel 26. The
substance then flows from source system G into ampule barrel 26.
The specially designed syringe here is a combination of source and
target system G/Z. During filling the target function comes into
play, during transfer to target system Z the source function does.
To convey the substance drawn from system G into system G/Z into
the target system Z the metering valve 13 is closed on the side of
the ampule plunger and opened on the side of the ampule barrel. The
ampule plunger 25 is introduced to the ampule barrel 26 and thus
transfers the substance to system Z.
[0170] The connector 2 emerging from the ampule barrel 26 in FIG.
12D is connected in sterile fashion to a closed system Z with an
internal line 27. Internal line 27 is manipulated via the bellows 7
of container 3 and introduced to a next closed system G/Z in order
to position the substance there precisely.
[0171] An overall system G+G/Z consisting of a closed source system
G with the features of the source system according to FIGS. 7A, 7B
and a closed system G/Z with the features shown in FIGS. 12A to
12D, including the source and target function, is shown in FIGS.
13A to 13D. In this variant, in which the third and fourth
practical examples overlap, each system G and G/Z within the
overall system G+G/Z has its own pressure compensation device 1
with connection pieces 15. With reference to system G the pressure
compensation device 1 is in flow connection with container 3 and
the long cannula 19. With reference to system G/Z the pressure
compensation device 1 is also in flow connection with the container
3 there. Sterile connection of the two systems G and G/Z to the
overall system G+G/Z is produced at the plant via the connection
piece 15 that extends into the ampule plunger 25 up to its tip. The
substance is drawn into the ampule barrel 26 via the small cannula
18 connected to the connection piece 15 from receptacle 17 and
finally from there transferred to the target system Z. FIG. 13A
shows the rest position in which the cannulas 18, 19 are still
fastened in the holding device 6. The puncture stopper is already
punctured in FIG. 13B, the bellows 7 of container 3 of the source
system G is collapsed and the pressure compensation device 1 is
filled with displaced air. The metering valve 13 on the connection
piece 15 is opened in FIG. 13C and the ampule plunger 25 of the
syringe filled, in which case the pressure compensation device 1
now contains less air and the volume of the bellows 7 is increased.
The substance of the source system G flows into the ampule barrel
26 according to the drawn arrows. In FIG. 13D the suction process
is completed. The ampule plunger 25 transfers the substance
according to the drawn arrows from the ampule barrel 26 into
connector 2 and finally to the target system Z. During this
transfer the metering valve 13 is closed on the side of the ampule
plunger and opened on the side of the ampule barrel.
[0172] A fifth practical example of the device according to the
invention according to FIG. 14 deals with a calibrated carpule as
means for transfer of substance with a carpule plunger 34 and a
carpule barrel 35 in which the substance is contained. The carpule
barrel 35 is closed with puncture stopper 20. The transparent
container 3 contained in the carpule includes two chambers 32, 33.
Each chamber 32, 33 is in flow connection with a pressure
compensation device 1. The first chamber 32 includes a cannula 36,
which faces with its tip the puncture stopper 20 of the carpule
barrel 35 and with its opposite end formed as a connection piece 15
extends into the connector 2.
[0173] A sliding stopper 37 is movable over the carpule plunger 34.
The carpule plunger 34 is arranged in the second chamber 33, which
includes a bellows 7 and a cylindrical section in the form of a
stable sleeve 38. The end of the carpule plunger 34 is glued to the
cover plate 5 on which the bellows 7 is arranged. The bellows 7
then grades into the stable sleeve 38, which also accommodates the
carpule barrel 35. An annular shoulder 40 facing radially inward is
provided on the end of the sleeve 38 on the carpule barrel side,
against which the carpule barrel 35 is supported. The sleeve 38 on
the end of the carpule barrel 35 on the plunger side also has an
annular shoulder 41 facing radially inward, which counteracts an
axial movement of the carpule plunger 35. While the annular
shoulder 40 is already molded onto sleeve 38, the annular shoulder
41 is formed by introducing a ring into sleeve 38 after
introduction of the carpule barrel 35 into sleeve 38, which is
welded to sleeve 38 and thus forms the annular shoulder 41.
[0174] The first chamber 32 is welded onto the annular shoulder 40
of sleeve 38. The chambers 32, 33 are in flow connection to the
slightest degree but not sufficient to use only one pressure
compensation device 1. In addition, the first chamber 32 has a
coupling tube 39 and in it a bellows 7 welded onto the base plate
4. The coupling tube 39 overlaps the free end of the stable sleeve
38, both components are movable relative to each other and contain
snap-in devices in the form of a recess 42 and protrusion 43 which
engage in the operating position and fix the position of cannula 36
in carpule barrel 35.
[0175] The device present as a source system G already filled at
the plant with substance according to the fifth practical example
is operated as follows: [0176] sterile connection of connector 2 of
the closed system G to the connector 2 also present as a plastic
tube of the closed system Z, [0177] movement of the coupling tube
39 with bellows 7 and the cannula 36 of the first chamber 32 welded
onto the base plate 4 onto the stable sleeve 38 of the second
chamber 33 up to recess 40, in which case the cannula 36 punctures
the puncture stopper 20 of the carpule barrel 35 filled with
substance and is immersed in the substance and the protrusion 41
snaps into recess 40; the pressure compensation device 1 there is
filled with air through the volume reduction of the first chamber
32, [0178] the bellows 7 of the second chamber 33 and the carpule
plunger 34 are moved to the sliding stopper 37 and in this case the
pressure compensation device 1 there is filled with air through the
volume reduction of the second chamber 33, [0179] the sliding
stopper 37 is pushed in the carpule barrel 35 in the direction of
cannula 36 and substance displaced into cannula 36 and the desired
amount of substance transferred to receptacle system Z; [0180]
after substance transfer in the desired amount sterile
disconnection of connector 2 of the closed system G occurs form the
connector 2 of system Z.
[0181] FIGS. 3A, 6 and 11A show that the components of the device
according to the invention with a closed system G or G/Z are
arranged within a sterile package, namely a blister package 16
before sterile connection to the other closed system Z and/or G.
The package has a smooth surface without recesses, to which a
disinfectant, especially 70% ethanol, is applied, since this is
introduced to a clean room.
[0182] With respect to further features not shown in the figures,
the general part of the description is referred to. Finally, it is
pointed out that the instructions according to the invention are
not restricted to the practical examples just explained.
LIST OF REFERENCE NUMBERS
[0183] 1 Pressure compensation device [0184] 2 Connector [0185] 3
Container [0186] 4 Base plate [0187] 5 Cover plate [0188] 6 Holding
device [0189] 7 Bellows [0190] 8 Snap closure [0191] 9 Fastening
bridge [0192] 10 Inlet [0193] 11 Outlet [0194] 12 Calibrated drip
chamber [0195] 13 Metering valve [0196] 14 Cross connector/system
connection [0197] 15 Connection piece [0198] 16 Blister package
[0199] 17 Receptacle [0200] 18 Short cannula [0201] 19 Long cannula
[0202] 20 Puncture stopper [0203] 21 Eye [0204] 22 Stabilizer
[0205] 23 Protective device [0206] 24 Holding plate [0207] 25
Ampule plunger [0208] 26 Ampule barrel [0209] 27 Internal line
[0210] 28 cannula [0211] 29 Syringe pump [0212] 30 Valve [0213] 31
Cannula closure [0214] 32 First chamber [0215] 33 Second chamber
[0216] 34 Carpule plunger [0217] 35 Carpule barrel [0218] 36
Cannula [0219] 37 Sliding stopper [0220] 38 Cylindrical section,
sleeve [0221] 39 Coupling tube [0222] 40 Annular shoulder [0223] 41
Annular shoulder [0224] 42 Recess [0225] 43 Protrusion [0226] G
closed system/source system [0227] Z closed system/target system
[0228] G/Z closed system with source and target function [0229]
G+G/Z overall system consisting of G and G/Z
* * * * *