Note: Descriptions are shown in the official language in which they were submitted.
1
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Description ~<u... s :l ~..~
The invention relates to a process for the production of a
contrast medium in usable dosage forms. It further relates to a
device for the production of an administrable contrast medium
consisting of at least one concentrate and at least one diluent.
Contrast media have become important auxiliary agents for
diagnostic processes, such as ultrasonic, x-ray or nuclear
resonance diagnoses. Thus, for example, the administration of a
contrast medium to a patient improves the evaluation of an x-ray
image, since as a result, higher--contrast images are obtained.
Because of this fact, the medical personnel can better evaluate
the data made available by such an image.
Regarding the dosage, numerous factors are to be considered
in the determination of the dosage amount and dosage
concentration of the contrast medium to be administered, for
example, the type of the diagnostic examination used, how this
diagnostic examination is performed, the k~ody area of the patient
to be tested as well as the age, the body weight and the state of
health of the patient. In view of these numerous factors,
contrast media, such as x-ray contrast media, can be obtained in
a number of concentrations, for example, 120-400 mg of I/ml, and
in a plurality of dosage amounts, for example, 1 ml-250 ml.
Despite the numerous concentrations and dosage amounts, however,
not every individual situation of the individual patient can be
taken into account.
Despite this multiplicity ofidosages, which are commercially
available (concentrations and sizes), it is often unavoidable
2
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~. ~ :J ?
in clinical use that only a partial amount is necessary for the
test and the remaining amount is discarded. A reuse is excluded
in this connection, since this would represent a
contraindication.
Because of the numerous diagnostic tests and the high prices
of modern contrast media, however, such a waste represents a
considerable cost factor for clinical practice or medical
practice. In addition, numerous forms of contrast media have to
be kept in stock, by which the stand-by costs increase
considerably. In the cases in which a new testing technique
requires new forms of preparation, the often long time intervals
for the development and approval of new bottle sizes and/or
concentrations also represent a drawback.
In thelsame manner, the plurality of forms of administration
of contrast media on the production side also represents a
drawback, since only relatively small production batches can be
produced, the storage requirement is increased, the logistics are
difficult, and more expensive and extended development and
approval times are the result. In addition, only little:
flexibility in the contrast media production exists for changes
of the preparation forms, as they are required by the market.
These drawbacks have not been eliminated to this day.
In the pharmaceutical field, a plurality of filling devices
are known, with which solutions can be mixed in portions, for'
example, from WO 84/00139 or De-OS 33 15 031.
WO 84/00139 thus describes a mixing device, which exhibits
suitable agents for monitoring the filling of pharmaceutical
CA 02077712 2002-08-20
3
solutions. In this way, solutions ar<~ filled, which are
taken from various cc>ntairm,:rs. F3ut: a spec:i fic mixture to
guarantee uniform concentr:~ti~:>na in the finished, solution
appropriate to use does not occur_
Also, only infusion ~;o:Lut icns E<:~r ipar~ent:eral feeding are
mixed with the mixing device known cram DF-OS 33 15 031,
without reference being made to the pr<obl.ems of the
production of cc>ntrast medic.zm solutic>n:>.
Moreover, both known devi_c~~s are not suitable for
mixing liquids with greatly di.f_ferE.mt cler~sities, single a
simple bringing together ~:of such liquids does not r_ause a
uniformly diluted soluti~~n, as is necessary for the
mcsntioned uses .
The object. of the i:n~~~ention therefore i.s to make
available a process of t:~f, above-mentr~oned type, with which
patient-specific, indica L c orl-:~peci t is ~~ont cast medium
compositions with appropriate dosage can be produced,
without a plurality of f~.~a:ms ~;f admina. ~tration having to be
kept ready for use and/o:r considerable amo~.~nts of waste
occurring.
Moreover, contrast mE~ciia and opt:i.~~rlally desired
"additives" can be administ.erod in one dosage by which the
comfort for the patient :Ls increased.
The present invention provider a process for the
production of a diagnostic contrast. medium comprising at
lE:ast one contrast agent anc-1 an aqueous solution, the
process comprising delive~-i.ng, under st~eri 1_e conditions, a
predetermined amount of at= least: a first contrast medium
concentrate containing 3'~0-45() mg of IJm:l <>f X-ray contrast
accent, 0.5-4 mol of NMR c:cynt_rast agent!1_:iter, or an
ultrasound contrast agent., from at least a first container
by a first pipe to a mix:i_rog cr:amber, deli.vc>rinc~ a
predetermined amount of c~ii_luent from a se:~c:md cJontainer by
a second pipe to the mixing cruan~ber, wherein the
CA 02077712 2002-08-20
.i 8
predetermined amounts ar~~ rni~.ed tc> form <~ phy:~iologic.ally
compatible preparation, an<v d~~li..vfer::inca tloc;~ re:>ui_tant.
mixture to a di scharge :~t~~t i.c.~n .
The present invention also provides <i devic:e for
production of a contrast medium, the alevic°e comprising at
least one concentrate container contairoinc~ concentrated
contrast media, at least c>ne dil.uerot cvonta:ainer containing a
diluent suitable for use with contrast mecvl:i.a, a first feed
pipe and a second feed pipc> in connect: i.orr with,
respectively, the concentrate container and the diluent
container, the feed pipes also being in f=lui_d communication
with a mixing chamber, a delivery pipe in fluid
communication with the fecad pipes, a rn:ixi.ng ch.arruber
provided between the feed pipes and tr~f:a dE:livery pipe,
metering elements in the feed pipes wl~:ich meter,
respectively, predetermined a°.nounts of the concentrated
contrast media and the diluent, means for determination of
mitered amounts of the concentrated cc-_>rntrast media and the
diluent, metering device iro t'~oe del.i..vrm:y pipe, which
discharges contrast medium from an end of t:he delivery
pipe, and control unit which _ontrols i::he metering
elements.
The present invention also provides a kit for
p=roduction of a contrast rnedi~.~rn, comprising a concentrate
containing 350-450 mg of I/ml of X-ray contrast agent,
0.5-4 mol/liter of NMR corrt:rast agent c:~r a concentrated
ultrasound contrast agent, in a first container with a
volume of 0.1-100 1, and an a~~lueous di.l.uent in a second
container with a content of 1-100 liters.
In the process accerciinct to the invention, one
or more contrast; medium conce~nt rates <rre used in
suitable containers, which are flowab.l.e and highly
concentrated. These concentrates are used in the
form of solutions, dispersions or as fl.owable
° ~~~aMw~~y~,~ °.'~
ac:~ ~.. ~' a a .~. .
(free-flowing) powders and are introduced in suitable concentrate
containers.
In addition, one or more diluents are used fox mixing with
the concentrates, for example, sterile or unsterile water. But
on the other hand, pharmaceutical solutions can also be used as
diluents and/or solvents or dispersing agents for the dilution of
the concentrate. Finally, even diluted contrast medium solutions
can be used for mixing with the contrast medium concentrates.
The contrast medium concentrates can exhibit concentrations
which lie above the values which were produced previously for
administration reasons (e.g., viscosity). Thus, for example, x-
ray contrast medium concentrates with a content of 350-450 mg of
I/ml are used or NMR contrast media in solution or dispersion
with 0.5 mol/liter in the form of Gadopentetat-dimeglumines or
other NMR contrast media based on paramagnetic ions. But
different contrast medium concentrates can also be used for
different medical techniques, for example, for x-ray, nuclear
resonance or ultrasonic diagnosis.
If the contrast medium concentrates are present in,powder
form, these powders can consist to 100% of the respective
contrast medium or optionally contain other solid galenical
auxiliary agents (which, e.g., improve the flowability of the
contrast medium).
The weight ratio of contrast medium to auxiliary agent can
be selected at will.
X-ray contrast media can contain, for example, iotrolan,
iopromide, iohexol, iosimide, metrizamide, salts of amidoacetic
dal <.. .7 .l v) .x.
acid, iotroxic acid, iopamidol, 5-hydroxyacetamido-2,4,6-triiodo-
isophthalic acid-(2,3-dihydroxy-N-methylpropyl)-(2-hydroxyethyl)-
diamide, 3-carbamoyl-5-[N-{2-hydroxyethyl)-acetamido]-2,4,6-
triiodo-benzoic acid-[(1RS,2SR)-2,3-dihydroxy-1-
hydroxymethylpropyl]amide and dispersions of slightly soluble x-
ray contrast media, such as iodipamide ethyl ester.
For example, gadolinium DTPA, gadolinium DOTA, the
gadolinium complex of 10(1-hydroxymethyl-2,3-dihydroxypropyl]-
1,4,7-tris-[(carboxymethyl)-1,4,7,10-tetraazacyclodecane], iron
or manganese porphyrin chelates and stable magnetite dispersions
belong to NMR contrast media.
For example, dispersions of galactose microparticles with or
without additives in water or a galactose solution and
dispersions of microbeads of enclosed air (for example,
cyanacrylates or albumin microbeads) as well as other injectable
microparticles belong to ultrasonic contrast media.
According to the process of the invention, a predetermined
amount of contrast medium concentrate is mixed with a
predetermined amount of diluent and optionally other additives to
formulate the desired dosage form of the contrast medium.
Contrast media can also be mixed with ol~e another for
different fields of use. In this way, two or more different
tests can be performed on patients with only one dosage, which
represents a marked improvement of the comfort of the patient..
Such a mixture of two or more~contrast media is usually consumed
immediately after the mixings so that no stability problems
occur.
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As diluent, for example, a physiologically compatible liquid
vehicle is suitable which contains optionally usable additives.
Thus, for example, as diluent, sterile or unsterile water can be
used, which optionally exhibits buffer substances and/or
additives having an isotonic effect, as well as optionally
complexing agents, such as CaNa2EDTA.
As diluent, a comparatively less concentrated contrast
medium can also be used, for example, in a concentration of 0--0.5
mol/1 or 0-350 mg of I/1 or 0-100 mg of particles/ml.
Usable additives are, for example, inorganic or organic
salts or buffer substances, such as sodium chloride, Iris-buffer,
phosphate buffer, citrate buffer, glycine buffer, citrate
phosphate buffer, maleate buffer and the like. Further, they
include monosaccharides or disaccharides, such as glucose,
lactose, saccharose or trehalose, sugar alcohols, such as
mannitol, sorbitol, xylite or glycerol, or water-soluble
polymers, such as dextrans or polyethylene glycols.
The process according to the invention can further be used
for the production of dosage forms which are usable for:,a
plurality of administration techniques, for example, for
intravascular, subarachnoid, intraneural and. oral administration.
Further, the process according to the invention makes
possible, depending on the diagnostic formulation of the problem,
a concentration or volume change of the contrast medium in the
course of the administration.
Thus, different concentrations or volumes automated in
succession can be produced and administered in situ.
Also, it is possible to change the originally provided
dosage form during the test relative to concentration or volume
if the originally administered dose still was not able to produce
the desired diagnostic result.
The contrast medium concentrate is present in a flowable
form, for example, as solution, dispersion or powder. In the
last-mentioned case, the solvent can act as solvating agent
and/or dispersion medium.
The device according to the invention for performing the
process according to the invention first exhibits at least one
contrast medium concentrate container and at least one diluent
container. A predetermined amount of fluid is removed in each
case from these containers, and the removal can be performed
either simultaneously or successively. The respectively removed
predetermined amounts of fluid are fed to a mixing zone or a
mixing chamber, in which both fluids are mixed, and a uniform
contrast medium in the usable dosage farm is achieved. The
concentrate container and the diluent container are each
connected by pipes with the mixing zone. The conveying:of the
fluids can take place either automatically because of the effect
of gravity or by active pumping action by a pump, for example, a
vacuum pump or a peristaltic pump.
If the conveying takes place under the effect of gravity, in
each case shutoff devices, far example, valves, are provided in
the inflow pipes to the mixing zone, which are activated by a
control unit in a predetermin,sd way. In this way, the amount of
the fluid present in the respective container and the pipe cross
8
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P~ __~ a' J ~.a~.. .s
section as well as the pipe length determine the amount of
inflowing fluid as well as the inflow rate of the fluid.
:If, however, pumps axe used, a peristaltic pump in the non-
activated state acts as a shutoff unit, but in the activated
state pumps the fluid from the respective container to the mixing
zone. If the fluid is pumped into the mixing zone with the help
of a vacuum, shutoff elements are again placed in the inflow
pipes, which are activated together with the vacuum unit.
The inflow pipes can be connected either directly with the
mixing chamber or else also can be combined in front of the
mixing chamber, and a single pipe goes from the junction point to
the mixing chamber, so that a Y-connection is made.
The above-described pump and shutoff devices usually do not
operate precisely enough, so that for the precise determination
of the amount and the concentration of the dosage form,
advantageously a unit for the determination of the amounts of
fluid is provided, with which the amount of fluid removed from
the respective container can be determined. Such units include,
for example, flow sensors in the inflow pipes, with which the
amount of fluid that has flowed through per unit of time can be
determined. On the other hand, weighing machines can also be
used, which determine either the increase of the amounts of fluid
in the mixing chamber or else the respective reduction of the
amounts of fluid in the respective container. Finally,
volumetrically operating units can also be placed in the mixing
chamber or the output container, with which the inflowing volume
or the outflowing volumes can be determined.
9
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In each case, the outflawing or inflowing amounts of fluid
or fluid volumes can be determined exactly with these sensors as
a function of the activation time of the shutoff elements or
pumps. These sensors are electrically linked with the control
unit and send suitable signals as respective actual value to the
control unit.
From the signals sent, the control unit itself calculates
the respective amounts, volumes and/or concentrations of the
conveyed materials or the mixture actually contained in the
mixing chamber. 2t is known that desired concentrations of the
form of administration can be securely controlled by the specific
density or densities of the contrast medium compound or compounds
used.
In iodized x-ray contrast media, a high density typically
occurs. Here, the density can be used as a usable indicator for
the determination of the concentration. In such a case, a
density sensor is provided inside the mixing chamber. On the
other hand, the optical rotation can also be a usable
determination parameter. Of course, volumetric or grava~metric
determination parameters, i.a., can also be used.
As stated above, the actual signal for the control unit is
used to control the pumps or the shutoff elements as a function
of a previously adjusted setpoint value; which can,be manually
input in the control unit by an input unit.
The control unit sends suitable control signals to operate
the shutoff elements and pi.~mps and receives the sensor signals,
which pertain to the amounts of fluid which have been removed
' ~ io
~-j~-~t- ~ a
from the containers and/or have been supplied to the mixing
chamber.
Further, the mixing chamber can be connected by a discharge
pipe with a means for administering the contrast medium, for
example, hypodermic syringes, which are filled in succession with
the contrast medium in the desired dosage form. Finally, the
mixing chamber can be connected as an alternative with one or
more containers for storage of one or more cartridges for
pressure injectors or can be connected directly to a patient for
a direct infusion.
Tha discharge pipe going from the mixing chamber is in this
case also provided with a shutoff element, which is closed during
the mixing process and is opened only for filling purposes.
According to another advantageous embodiment, the feed pipe
arrangement is connected with an additional container, which
exhibits a cleaning and flushing liquid. As a result, the pipes,
shutoff elements, pumps, the mixing chamber, the collecting
chamber, the receiving container and the like can be flushed. As
liquid, every suitable cleaning medium can be suitable for this
purpose, for example, sterile or nonsterile water with or~without
additives. In addition, the diluent itself pan be used as
flushing fluid.
The arrangement according to the invention can further be
connected with a collecting chamber, in which the fluid used
during the cleaning stage can be collected.
The mixing chamber can be connected with empty containers,
which are closed, for example, by a septum. In such sterile
11
~~1 J~ .J~~~t., A
containers, the contrast medium is kept in its dosage form. Iri
this case, sterile infusion or injection bottles made of plastic
or glass are suitable, as also infusion bags.
According to another embodiment, the arrangement according
to the invention can be connected directly to an extruder, with
which suitable plastic containers are produced. Finally, the
arrangement can be used for the purpose that such empty
containers or a hypodermic syringe axe filled directly or else a
direct infusion can be performed on the patient.
According to another advantageous embodiment, the
arrangement according to the invention is connected with a
sterilization unit. Such a sterilization unit can exhibit, for
example, a steam generator, which is connected by a connecting
pipe with the entire pipe arrangement and the shutoff element,
pumps and the containers, etc. On the other hand, as a
sterilization unit, a liquid disinfectant, for example, peracetic
acid, can also be used, and after the sterilization process,
attention must be paid that any possible disinfectant residues
are removed with sterile water. Finally, the sterilization of
the arrangement according to the invention is performed less
often that the flushing.
The contrast medium concentrate container can exhibit any
desired size, for example, 0.1-100 1, especially about 1 l, 5 1,
l, 50 1 and the like. The containers can be produced from any
suitable material which is suitable for storing the concentrated
pharmaceutically acceptable,contrast medium and, for example,
thermally stable plastic, glass or metal advantageously can be
12
~~y'~.~ ~
sterilized. These containers can either be reusable or else
suitable only for one-time use.
Advantageously, the sterilized device is kept in sterilized
state with the help of a sterile filter placed in the pipe
sections. In addition, the mixing effect in the mixing zone or
mixing chamber can be improved in that a stirring device is
provided in the mixing zone or mixing chamber.
The contrast medium is present inside the container in high
concentration. A solution with a concentration which is either
equal to or higher than that of commercially available dosage
forms of the contrast medium is considered as a concentrated
solution and/or dispersion. As the example of an iodized x-ray
contrast medium, the concentration of the contrast medium in the
receiving container is in an amount of about 350-450 mg of I/ml.
In NMR contrast media, for example, in Gadopentetat dimeglumines
(dimeglumines Gd-DTPA), the commercially available concentration
is usually at about 0.5 moll. Consequently, concentrated
solutions or dispersions of the NMR contrast medium exhibit an
equal or higher concentration content, for dissolved
concentrates, for example, greater than or equal to 0.5 mol/1,
especially a content of 0.5-4 mol/1. ,
Although with the process according to the invention, a
usable dosage form is preferably produced from a concentrated
contrast medium, it is also possible to use the process according
to the invention for reducing the concentration of commercially
available dosage forms of contrast media.
13
According to another embodiment of the invention, a set is
made available which can be used in connection with the above-
described system for formulating usable dosage forms of contrast
media. Such a set exhibits a first container with a specific
contrast medium and a second container with a specific suitable
diluent. These containers of the set preferably have means for
connection with the device according to the invention to transfer
predetermined amounts of fluid from each of the containers to the
mixing chamber. A set can exhibit, for example, the first
container with 0.1-100 liters of a concentrated x-ray contrast
medium with a concentration of 350-450 mg of I/ml and a second
container with 1-100 liters of diluent, which is suitable for the
formulation of an x-ray contrast medium in pharmaceutically
acceptable forms. On the other hand, the set can also contain a
first container with 100 ml to 100 liters of an NMR contrast
medium with a concentration of 0.5-4 mol per liter.
The invention is explained based on an embodiment.
Figure 1 shows a basic sketch of the mixing arrangement
according to the invention.
Device 10 shown in figure 1 exhibits a container 12 for a
contrast medium concentrate and a container ~.4 .for a solvent or
diluent. Both containers 12 and 14 are connected by inflow pipes
16 and 18 with a mixing chamber 20. In the example, both pipes
16 and 18 are brought together in a single pipe 19 upstream from
mixing chamber 20, a pipe which then ands in mixing chamber 20.
But such a connection is not necessary. Consequc;ntly, both pipes
16 and 18 can also be connected directly with mixing chamber 20.
14
~..~ ~ J~ ~ ~~.. ~
A discharge pipe 22, whose ends 24 can be connected with
receiving containers (bottles, bags or syringe arrangements), not
shown originates from mixing chamber 20.
A first metering element 26 is inserted in first inflow pipe
16, and a second metering element 28 is inserted in second inflow
pipe 18. In addition, a third metering element 30 is inserted in
discharge pipe 22.
Mixing chamber 20 is connected with a weighing device 32,
which can determine the respective present weight condition of
mixing chamber 20.
Metering elements 26, 28 and 30 as well as weighing device
32 are connected by signal lines 36-40 with a control unit 42.
Control unit 42 further exhibits an input unit 44, with which
certain data can be input into control unit 42.
According to an advantageous embodiment, a sterile filter 46
is provided downstream from third metering element 30 in
discharge pipe 22.
In addition, device 10 is advantageously provided with a
sterilization unit 48, which exhibits, for example, a steam
generator 50, which is connected by an inflow pipe 52 with a
fresh water source, not shown. This steam generator 50 is
connected by a discharge pipe 54 with inflow pipes 16, 18, and a
shutoff arrangement 56 in the form of a three-way valve is placed
on the junction point. This shutoff arrangement 56 is connected
by a signal line 58 also with control unit 42.
i Downstream from mixing chamber 20, a collecting chamber 60,
which is provided for receiving rinsing agent solutions and the
7. 5
like, goes from discharge pipe 22. This collecting chamber 60 is
also connected with discharge pipe 22 by a shutoff arrangement 62
in the form of a three-way valve.
The activation of shutoff device 62 takes place in this case
over a signal line 64 by control unit 42.
Further, a discharge valve 66 can be provided on the end of
discharge pipe 22, which also is connected by a signal line 68
with control unit 42. Finally, steam generator 50 is connected
by a signal line 51 with control unit 42.
Device 10 shown in figure 1 can exhibit in both containers
12 and 14 the above-mentioned concentrates and diluents. In this
way, device 10 is nct limited to both containers 12 and 14, but
it can exhibit a plurality of these containers, which each are
connected with the mixing chamber by separate feed pipes, in
which the respectively suitable shutoff or metering elements are
inserted.
Metering elements 26, 28 and 30 used in inflow pipes 16 and
18 and in discharge pipe 22 operate because of the gravitational
force principle, i.e., -in the active state, metering elements 26,
28 and 30 are open and in the opening period let the fluids
respectively present upstream pass through. ,As a consequence,
they act as shutoff devices. They can therefore be replaced
equally by other metering devices, for example, peristaltic
pumps, which work in the nonactivated state as shutoff elements
and in the activated state can convey the fluid respectivel,y~
present upstream: i
Device 10 shown in figure 1 is operated as follows:
16 ~ J-. ,m,,.,m,.~i ,a ~o~
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The contrast medium present in container 10 exhibits --- as
initially described -- a specific composition and concentration.
Both the contrast medium used and its concentrate concentration
can be input by input unit 44 into control unit 42. To produce a
finished usable contrast medium in mixing chamber 20, the
operator has to feed the amount of the contrast medium to be
mixed by feeding unit 44, whereupon the control unit calculates
from the desired contrast medium concentrate and the diluent in
each case the amounts to be conveyed from containers 12 and 14
into the mixing chamber. Metering elements 26 and 28 are then
opened in succession, and the respective fluids flow from
container 12 or 14 into mixing chamber 20. In this case the
content of mixing chamber 20 is monitored by weighing machine 32,
which after reaching the first amount determined by control unit
40, for example, the concentrate amount, closes metering element
26 and activates metering element 28. After reaching the second
setpoint amount in mixing chamber 20, second metering element 28
is deactivated.
Then, third metering element 30 and optionally outlet valve
66 are activated, to convey either a part or the entire content
of contrast medium, which is contained in mining chamber 20, to
outlet 24 of discharge pipe 22. Consequently, third metering
element 30 can be used not only for the production of a
preparation but rather also of several preparations from mixing
chamber 20.
17
Since a sterile filter 46 is provided downstream from
metering element 30, all units which are present upstream from
this sterile filter 46 remain in the sterilized state.
After emptying mixing chamber 20 or containers 12 and 14,
entire device 10 is sterilized by sterilization unit 48, and
steam having a sterilizing effect is conveyed by entire pipe
arrangement 16, 18, 22, mixing chamber 20 and sterile filter 46
up to collecting chamber 60.
It is to be added that weighing unit 32 for determining the
fluid amounts flowing into mixing chamber 20 can be replaced by a
volume measuring unit.
Finally, in inflow pipe 52 for fresh water, a pyrogenic
filter 70 can also be provided, which optionally effectively
retains pyrogens present in inflowing water. This sterile water
can also be used as the diluent in container 14 for flushing
purposes in a separate flushing process.
Translator s note: The translation of °'Gadopentetat," first
appearing in the first line on page 6 of the German text, was not
found in available sources. The term appears in the German
spelling in the translation on page 4, line 5 of second paragraph
from bottom, arid on page 12, line 12 from bottom.
