Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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Method and Apparatus for the Preparation of Mixtures of
Pharmaceutical Liquids
..
The invention relates to a method and an apparatus for the
preparation of mixtures of pharmaceutical liquids, for example, in-
fusion solutions, with storage containers containing at least two
of the individual mixture components, a vacuum chamber to receive
the container to be filled, and with a connecting hose for each
storage container as well as a hose connected to the container
and connected through a hose connection to the connecting hose of
the storage container.
Preparations comprising several different components have
to be mixed for the most diverse fields of application in medicine,
especially for parenteral feeding in which the individual compo-
nents often cannot be sterilized or prepared or stored together.
For medical as well as practical reasons, a mixed administration
is, however, still preferred. In many instances, it is there-
fore necessary to prepare the mixture in an additional container
which actually means preparing a brand new medicine by the hands
of a physician or pharmacist. When these mix-tures are frequently
used, it is often desirable to have them available in storage.
It is obvious that this preparation of mixed solutions, such 2S,
for example, mixed infusion solutions, generally penetrates the
sealed system of the storage containers, which is most undesir-
able. The object is therefore to accomplish a virtually con-tamin-
ation-free preparation of such mixtures, i.e. a preparation with-
out manual manipulation, with the individual components of the
mixture having a predetermined proportion to one ano~her. ;1~
The state of the art provides for the filling of sterile
bag-like containers by pumping in the individual components. The
filing amount is determined by the reference output volume of the
pump. Additionally, the total mixture is weighed. In addition to
the fact that such mixture preparation and filling methods do not
meet present demands for rapid processing, the known arrangements are
not sealed systems, and thus are not contamination-free. Further-
more, there is the danger of particles rubbing off from the pump
hose. Finally, the dosage system of this apparatus regarding the
individual components is not sufficiently reliable, depending solely
on the total weight of the mixture. Thus, the individual components
might not have the desired proportion to one another.
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There is therefore an urgent need for an arrangement
wllich allows extremely rapid filling of containers with a mixture
of pharmaceutical liquids, précisely adhering to the predetermined
amounts of the individual components, and being contamination-free
in a virtually sealed system. By avoiding any handling of the
arrangement and the containers during filling, it is possible to
prepare such specia~ pharmaceutical liquid mi~tures to be used
according to medical prescription, and to keep them stored by
pharmacists, not by the manufacturers. The air inherent in the
system and present, for example, in the racking hose, can be
ignored.
The object of the invention is acconplished by an arrange-
ment of the initially described type with each of the connection
hoses that are connected to a storage container being ~uided through
a sensor for indicating the air content in the respective hose, and
subsequently through a clamping device connected to the sensor,
with the hose connected to the container being guided through a
sealing device having two sealing points at a distance from one
another, as well as having an intermediate cutting device, the
sealing device being connected with the clamping device.
The container, maintained under external vacuum, is con-
nected to the storage containers holding the individual components
of the mixture to be prepared through a hose, hose connection and
connecting hoses. Because of the vacuum effect, all mixture
components can be transferred to the container at the same time.
If a storage container is empty and if the connecting hose leading
to the hose connectlon is subsequent~y filled with air, then this
condition is imn,edi2tely registered by the corresponding, prefer-
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ably optically acting sensor, and the concomitantly released sig-
nal is transferred to the corresponding clamping device. This
effects the immediate clamping of the respective hose. The vacuum
acting in the vacuum chamber, and transferred to the container to
be filled, ceases to act on the corresponding storage container,
while the emptying of the additional containers containing the
other mixture components continues. The described process (i.e.
that the sensor arranged with each connecting hose clamps the
respective hose when the corresponding storage container is empty
and air appears in the hose) continues until the last sensor has
been activated. This then activates the downstream sealing device,
which mechanically, or depending on the substance, seals the hose
leading to the container to be filled in two places at a distance
from one another. At the same time, the hose is cut between the
two sealing points. It is useful if this arrangement is turned
off at the same time. Having removed the negative pressure in
the chamber, it can be opened and the filled container removed.
The entire process takes less than two minutes, and is thus
essentially faster than any arrangement heretofore kn ~ in the
state of the art.
It is within the scope of the invention acording to the
basic principle, to provide the hose connection at the sides
facing the container to be filled, with two or more hose connec-
tions for the connection of several hoses, each of which is con-
nected to a container. In this specific embodiment, the hose
connection is not only connected to two or more storage contain-
ers (which would mean that the mixture can comprise two or more
individual components), but it can at the same time be connected
to more than one cont2iner to be filled. Clearly, several con-
tainers can be brought to the vacuum chamber at the same time in
this -embodiment an~ thus be filled at the same time. It is~ on the
other hand, in the case of correspondingly smaller vacuum cham-
bers, also possible to bring only one container (i.e. one bag or
the like) of all bags connected to the hose connection to the
vacuum chamber for filling, while the other bags connected with
the hose connection remain outside the vacuum chamber. A positive
differential pressure acts on the container to be filled, while a
negative differential pressure acts on the containers located
outside the chamber. The difference between the two pressures re-
sults in only the container located in the vacuum chamber being
filled. The desired sealed system for contamination-free filling
of pharmaceutical mixtures is maintained in this embodiment as
well. The individual bags connected to the system can succes-
sively be brought into the chamber and filled.
It has been shown to be disadvan,ageous i~ there is an
unnecessarily large distance between the sealing device and the
bags located in the vacuum chamber. The filling hose, remaining
on the container, being sealed at its free end, is often viewed
as disturbing in later use. The invention therefore provides for
the sealing device to be located inside the vacuum chamber. This
results in an extremely short hose length between the sealing
device and the bag to be filled. The sealing device can also be
arranged on the bottom side of the cover of the vacuum chamber
or on the inside of the chamber wall, in any event at a location
where the distance to the bag in the chamber is minimal.
The invention is based on the mixture proportions being
determined by correspondingly measuring volume in the storage
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containers. However, it is also possible to determine the respec-
tive weight of the mixture proportions with the total amcunt
being the amount of the total mixture measured according to the
weight. In order to accomplish this, another feature of the in-`
vention provides for a scale inside the vacuum chamber, with the
container attached to the scale in freely movable fashion, and
with the scale and the sealing device~ whether arranged inside or
outside the vacuum chamber, connected to a control device serving
to preprogram the weight of the individual mixture components. In
this embodiment, the functional process comprises the individual
mixture components being filled in the containers in chronological
succession. I~ the requisite amount of the first mixture portion
has been filled into the container, the scale releases a signal
which activates the clamping device. When the desired filling
level has been reached, the sealing of the connecting hose is also
effected, with an amount of liquid still present in the respective
storage container. At the same time, the signal released from the
scale opens the previously-closed clamping device of the subse-
quent storage- container and its mixture components now flow into
the container. The described process is repeated until the last
storage container, with the last mixture component, has been
reache~. The guidance of the scale is programmed so that the
we ghts of the individual components of the mixtures are added to
one another.
If the last storage container has supplied the desired
and intended amount of liquid for the mixture to be prepared,
the clampinc device is closed and the clamping device, as in the
above embodiment, is directed to sealing the hose leading to the
container as well as to the cutting device. After having opened
~he vacu~lm chamber, the filled container can be removed and
labeled. Thereafter, -the next bag can be brought into the chamber
and filled without renewed connection of a new container and the
concommitantly-related risk of con~amination.
The sealing device of the arrangement according to the
invention is especially dependable, and the arrangement can be
correspondingly simplified when, as the invention further provides,
two operable metal sleeves are pushed onto the hose connected to
the container, at a distance from one another corresponding to the
distance of the sealing position of the,sealing device with the
hose having the metal sleeves then being inserted into the sealing
device. The hose can thus be clamped easily and reliably in a
mechanical fashion by clamping the sleeves. Of course, welding
the hose represents an alternative.
Additional characteristics, details and advantages of the
invention can be observed in the following description of a few
preferred embodiments, as well as from the drawings.
The drawings illustrate:
Fig. 1 is a first embodiment in schematic representation,
Fig. 2 is an enlarged detail of this embodiment.
Fig. 3 is a varied embodiment in broken representation,
Fig. 4 is an additional embodiment, and
Fig. 5 is an additional variation of the invention, in
schematic representation as well.
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In the illustra,ed embodiment, three stora~e containers
3, 4 and 5 in their emptving position, i.en with the sealed open-
ing 6 pointing downwardly, have been hung on a stand 1 or other
frame in corresponding holders 2. A connection hose 7 of
suitable cross-section is connected to each of the container seals
6. In general, these hoses are made of PVC. These connection
hoses 7 are guided past a sensor 9 which addresses the air con-
tained in the hoses 7 in the direction of a hose connection 8.
Sensors 9 can, for example, function optically. A clamping device
r- 10 iS connected to each sensor 99 which operates ma~neticallY.for
eYample, and, if released by a signal from sensor 9, clamps the
respeclive connecting hose 7, preventing a continued conveyance
from the respective storage containers 3, 4, 5.
Hose conection 8 has connection pieces 11, corresponding
to the number of connection hoses 7, tightly connecting the hoses
7. In the embodiment in Figs. 1 and 2, a single downstream con-
nection piece 12 is provided, which is furthermore tightly con-
nected to the hose 13, leading to the container to be filled, i.e.
bag 14. Hose 13 terminates at 15 at the head of the bag 14. Con-
_ tainer 14 as ~ell as the hose system comprising hose 13 and con-
necting hoses 7, hose connection 3 and connection cannulas 16,
form a unit which is produced and packaged in sterile fashion
and not removed from the packaging (not illustrated) until ready
to use, i.e. for the filling of container 14.
The arrangement furthermore comprises a vacuum chamber
18 which is sealed by a hinged cover 19 and is connected to the
vacuum generator 21 via conduit 20 (not illustrated in detail).
In the upper area of wall22, an airtight inlet for the hose 13
~23~
leading to container 14 is provided. The vacuum generator 21 has
a sealing device 23 through which hose 13 is led. Two slightly
movable sleeves 24 are pushed onto hose 13 in a tightly fitting
fashion. As can be sen from Fig. 1, these are located in the seal-
ing device 23 in the area of the two sealing points 25 which have
corresponding utensils for the deformation of sleeves 24 and thus
for the sealing of hose 13. Between the two sealing points 25, a
cutting knife 26 of a cutting device has been arranged in order
to separate hose 13 between the two sealing points 24
~~~ The embodiment according to Figs. 1 and 2 operates as
follows:
The containers 3, 4 and 5 hanging on stand 1 contain the
necessary equal or differing amounts of the various mixture compo-
nents for the pharmaceutical mixture to be prepared. Cannulas 16
of connecting hoses 7 are connected to container seals 6 and to
the hoses placed into unit 27 which comprises sensors 9 and clamp-
ing devices 10 and can also be attached to the stand 1. Then,
hose 13 arranged downstream from hose connection 8 is placed into
the sealing device 23 and the bag 14, arranged at the end of hose
13, is hung onto a hanger 28 on the inside of cover 19 of vacuum
chamber 18. By using the vacuum generator 21, the chamber 13 is
placed under negative pressure, and upon opening clamping devices
10, the contents of storage containers 3, 4 and 5 flow through
the hose system into the containers 14 to be filled (PVC bags).
If the storage containers 3, 4 and 5 contain differing amounts,
the corresponding sensor 9 of the connection hose 7 of the stor-
age containers 3, 4 and 5 having the smallest filling amount
registers air filling first. This immediately releases a signal,
closing the corresponding clamping device 10, which can be operated,
ma~netically, ~or example. Thus, this hose is blocked and no air
can enter into container 14. This process is repeated with the re-
maining stora~e containers. When the las~ sensor 9 registers, all
clamping devices 10 are closed, and sealing device 23 is released,
the sealing points 25 of which seal hose 13, leading to container
14, at two points at a distance from one another. Then, the cut-
ting device 26 cuts the piece of hose situated between the two
sealing points. At the same time, the vacuum generator 21 is
turned off and vacuum chamber 18 ventilated so that cover 19 can
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be opened and container 14 located therein removed, labeled and
trans~erred for further treatment.
The embodiment according to Fig. 3 differs from the one
just described in that the hose connection 8' has more than one con-
necting hose on the downstream side. Three connection pieces 12
in the illustrated embodiment are each connected to a hose 13
leading to a container 14. Two or more than three such connection
pieces 12 can be provided on hose connection 18. The same applies
to connection pieces 11 leading to the storage containers 3, 4 and
,
In this embodiment, a container 14 to be filled is re-
ceived in vacuum chamber 18 and filled in the manner described
above, while the other bags 14 remain outside the vacuum chamber.
Due to the various differential pressures, containers 14 outside
the vacuum chamber 18 remain unfilled, and the liquid only fills
container 14 inside the vacuum chamber 18. In this manner, a
number of containers 14 can be successively filled, presuming
corIespondingly large storage containers 3, 4 and 5 or smaller
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filling volumes of containers 14, suitable for example for pedi-
atric purposes.
Fig. 4 illustrates an embodiment with an electronic scale
30 inside the vacuum chamber 18. It is mounted on the inside of
cover 19 (which seals chamber 18) and has a hanger 28 to receive
container 14 to be filled, which hangs freely in the vacuum cham-
ber 18. Scale 30 is connected to a control device 31 in which the
filling systems, corresponding to the programming of the mixture
comp~nents in the storage containers 3, 4 and 5 are respectively
labeled A, B and C. The control unit 31 is additionally connec-
ted to unit 27 which comprises sensors 9 and clamping de~ices 10.
In this embodiment, which naturally also can be designed as
described in Fig. 3, the determination of the component propor-
tions forming the basis of the mixture to be prepared is made
according to weight. ~or this purpose, all clamping devices 10
are closed at the beginning of the filling process. They are
opened, one by one, in order to fill the preprogrammed amount.
determined by control device 31. As soon as this filling of con-
tainer 14 has been accomplished, as indicated by scale 30, con-
trol device 31 is given a corresponding signal. This in turn
addresses unit 27. Thus, the previously-opened clamping device
10 is closed and the subsequent one is opened so that the nèxt
mixture component can flow into container 14. The weight of the
first mixture component is added to the desired weight propor-
tion of the second component in control device 31. If this
weight is reached by the corresponding filling of container 14,
and indicated by the electronic scale, control device 31 is again
addressed and from here, unit 27 or its clamping devices 10. This
process continues until all mixture parts have been filled up to
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i2~7~
the desired amounts. If a storage container 3, 4 or 5 is emptied
so that air gets into the connecting hose 7, the corresponding
sensor 9 would register and close the connecting hose 7.
The embodiment according to F`ig. 5 is characterized by
the sealing device 23 being arranged inside the vacuum chamber 18.
This results in a very short end 32 of hose 13 remaining on the
bag 14 after cutting hose 13 between the two sealing points 25.
This remaining end is no longer disturbing when using container 14
later on.
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Summary
Method for the preparation of mixtures of pharmaceutical
liquids, for example infusion solutions, from storage containers
containing at least two of the individual mixture components, in
an arrangement with a vacuum chamber to receive the containers to
be filled and with a connecting hose for each storage container
as wellas a hose connected to the container and also connected with
the_connection hoses of the storage containers via a hose connec-
tion, with the attainment of the desired predetermined amount of
each mixture component being indicated by registering air intake
into the individual connection hoses, clamping the respective
connecting hose and sealing and cutting the hose downstream from
the clamping following corresponding registration of air intake
into all present connection hoses.
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