SPECIFICATION
PHARMACEUTICAL AGENT DISSOLVING DEVICE AND METHOD
FOR PREPARING PHARMACEUTICAL SOLUTION
USING THE SAME
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a pharmaceutical
agent-dissolving device and a method for preparing a pharmaceutical
solution using the same, and furthermore relates to a dialysis agent
dissolving device and a method for preparing an artificial perfusion
fluid for hemodialysis using the same.
2. Description of the Related Art
Pharmaceutical agents such as anticancer agents and
thrombolytic agents used in chemotherapy, dialysis agents used in
hemodialysis therapy, and the like are known.
Examples of the chemotherapy include a therapy that
completely cures a disease by delivering a principal agent having a
pharmaceutical effect into the body as an oral preparation, an injection,
or a skin-permeable preparation, thereby allowing the principal agent
to act on the cause of the disease, and a palliative therapy that relieves
pain and itching induced by the cause of a disease. Furthermore,
examples of formulations used in chemotherapy include solid dosage
forms such as tablets or capsules, semisolid dosage forms such as
creams, and liquid dosage forms such as ophthalmic solutions, sprays,
drinkable preparations, or injections.
2
In the case where a pharmaceutical agent (principal agent)
having a pharmaceutical effect is formed into a solution as a liquid
dosage form used in chemotherapy, the pharmaceutical agent is usually
dissolved in a solvent such as water. However, in the case where the
pharmaceutical agent is a substance such as protein, for example, the
pharmaceutical agent may be denatured by an excessive shearing force
or the surface tension of bubbles and thus lose its pharmaceutical effect.
For this reason, with respect to such a pharmaceutical agent that may
be denatured by an excessive shearing force or the surface tension of
bubbles, it is desired to efficiently dissolve the pharmaceutical agent
without denaturing it.
Hemodialysis therapy (hereinafter referred to as
"hemodialysis"), which is also called artificial dialysis therapy, is a
blood purification method most commonly used for patients with
chronic renal failure and the like. In hemodialysis, in order to avoid
uremia, waste products in the blood are removed, and also the
concentrations of serum electrolytes and the water content are
maintained.
Hemodialysis is performed for 3 to 4 hours with respect to a
single patient, and the amount of dialysis perfusion fluid that is needed
is as large as 100 liters to 300 liters, for example, per dose per patient.
Also, it has been pointed out that bacteria are likely to grow in such
perfusion fluids, and so long-term storage of a perfusion fluid has been
considered difficult. Therefore, in actual dialysis facilities, it is a
common practice to prepare a desired artificial perfusion fluid by
dissolving a powdered hemodialysis agent (hereinafter sometimes
referred to as "dialysis agent") in dialysis water immediately before
dialysis.
An artificial perfusion fluid can be obtained by dissolving a
3
dialysis agent in water such as purified water or deionized water to a
final concentration of 8 g/L to 10 g/L. That is to say, to obtain a single
dose of artificial perfusion fluid, it is necessary to dissolve 1 kg to 3 kg of
dialysis agent in 100 liters to 300 liters of water.
In actual preparation of an artificial perfusion fluid, there are
cases where preparation of a large amount of artificial perfusion fluid is
demanded, as, for example, in the cases where preparation of a
plurality of doses is performed at one time, where parallel preparation
for a plurality of patients is performed, and where an artificial
perfusion fluid concentrate having a concentration 30 times to 60 times
greater than that of an ordinary artificial perfusion fluid is prepared in
advance and is diluted as necessary to obtain an artificial perfusion
fluid.
In order to enable the preparation of a large amount of artificial
perfusion fluid, conventionally, a dialysis agent-dissolving device has
been proposed (e.g., see Japanese Laid-Open Patent Publication No.
2001-37870).
FIG. 8 is a schematic diagram of a conventional dialysis
agent-dissolving device that can used in preparation of an artificial
perfusion fluid for hemodialysis. A conventional dialysis
agent-dissolving device 700 includes a preparation tank 710 in which
an artificial perfusion fluid 800 can be prepared and accommodated, a
driving motor 730, a shaft 720 that is inserted to the vicinity of a bottom
portion of the preparation tank 710 and that can be rotated about its
axis by driving of the driving motor 730, and a stirring blade 740 that is
provided on an end portion of the shaft 720 and that can be rotated in
the preparation tank 710 in accordance with the rotation of the shaft
720. The dialysis agent dissolving device 700 is also provided with a
discharge pipe 780 near the bottom portion of the preparation tank 710,
4
and the artificial perfusion fluid 800 prepared in the preparation tank
710 can be discharged as appropriate by opening/closing a valve 790
that is provided in an intermediate portion of the discharge pipe 780.
In the dialysis agent dissolving device 700 shown in FIG. 8, an
artificial perfusion fluid is prepared in the following manner, for
example. First, a predetermined amount of water and a dialysis agent
(usually separated into an agent A and an agent B and containing
electrolyte ingredients such as sodium hydrogen carbonate, sodium
chloride, acetic acid, and the like) are provided into the preparation
tank 710. Then, the stirring blade 740 is rotated via the shaft 720 by
driving of the driving motor 730, and the electrolytes are dissolved in
water. Thus, the artificial perfusion fluid 800 can be prepared.
Here, when an artificial perfusion fluid is to be prepared using
the conventional dialysis agent dissolving device 700, the dissolution of
the dialysis agent in water needs to be performed under gentle stirring.
That is to say, in the case where a dialysis agent containing sodium
hydrogen carbonate is to be dissolved, if a solution containing this
dialysis agent is stirred vigorously, carbon dioxide derived from sodium
hydrogen carbonate may be generated, resulting in an increase in pH of
the solution. To avoid this, it is necessary to be careful so that the
rotation of the stirring blade 740 in the dialysis agent dissolving device
700 is not vigorous.
However, the gentler the rotation of the stirring blade 740, the
longer the time taken to dissolve a dialysis agent constituted by
electrolyte ingredients, and the more difficult to efficiently prepare a
large amount of artificial perfusion fluid. Moreover, in the
conventional dialysis agent dissolving device 700, there are cases where
a portion of the electrolyte ingredients is not dissolved in an area, such
as the area indicated by W in FIG. 8, between the preparation tank 710
5
and the stirring blade 740 and near the shaft 720, and the portion that
remains undissolved settles on the bottom portion of the preparation
tank 710. Thus, there are cases where it is difficult to efficiently and
homogenously prepare an artificial perfusion fluid having a desired
electrolytic concentration at an artificial dialysis site.
Even if vigorous stirring with the stirring blade 740 is possible,
sodium hydrogen carbonate constituting the dialysis agent is an
ingredient that is easily scattered as carbon dioxide. For example,
there is a risk that an artificial perfusion fluid prepared in a state in
which carbon dioxide is scattered may have an increased pH and cannot
retain neutrality of a physiological solution.
The present invention has been made to solve the
above-described problems, and it is an object thereof to provide a
pharmaceutical agent-dissolving device that is capable of preparing a
desired pharmaceutical solution efficiently and in large amounts at one
time while completely dissolving a pharmaceutical agent by a simple
operation without requiring a complicated structure, and a method for
preparing a pharmaceutical solution using the pharmaceutical
agent-dissolving device.
SUMMARY OF THE INVENTION
The present invention provides a pharmaceutical
agent-dissolving device for preparing a pharmaceutical solution,
comprising:
a preparation tank capable of accommodating water and a
pharmaceutical agent;
a driving motor;
a shaft that is inserted to a vicinity of a bottom portion of the
preparation tank perpendicularly to the bottom portion and that can be
6
rotated by driving of the driving motor; and
at least two stages of stirring blades that are provided in
tandem along an axial direction of the shaft and that have blade
surfaces that are inclined, with respect to the axial direction of the
shaft, in the same direction along a rotating direction of the shaft,
wherein a ratio (r2/r0) of a radius of rotation (r2) of a stirring
blade that is positioned nearest to the bottom portion of the preparation
tank, of the at least two stages of stirring blades, to a radius (r0) of the
inside of the preparation tank is 10/100 to 40/100, and a ratio (r1/r0) of a
radius of rotation (r1) of any other stirring blade to the radius (r0) of the
inside of the preparation tank is 40/100 to 90/100.
In one embodiment, the stirring blade that is positioned nearest
to the bottom portion of the preparation tank has a radius of rotation
that is 10% to 80% with respect to a radius of rotation of a stirring blade
that is positioned furthest away from the bottom portion of the
preparation tank.
In one embodiment, an angle (θ2) of inclination that is formed by
the axial direction of the shaft and the individual blade surfaces of the
stirring blade that is positioned nearest to the bottom portion of the
preparation tank is 10° to 50°.
In one embodiment, the angle (θ2) of inclination that is formed
by the axial direction of the shaft and the individual blade surfaces of
the stirring blade that is positioned nearest to the bottom portion of the
preparation tank is equal to or greater than an angle (θ1) of inclination
that is formed by the axial direction of the shaft and the individual
blade surfaces of the stirring blade that is positioned furthest away
from the bottom portion of the preparation tank.
In one embodiment, the stirring blade that is positioned nearest
to the bottom portion of the preparation tank is provided on the shaft
7
while being spaced apart from the bottom portion of the preparation
tank by a distance of 2 cm to 20 cm.
In one embodiment, the stirring blade that is positioned nearest
to the bottom portion of the preparation tank is provided so that an
inside edge of the stirring blade is extended to a pivot of the shaft.
In one embodiment, the pharmaceutical agent-dissolving device
for preparing a pharmaceutical solution of the present invention
includes two stages of stirring blades.
In one embodiment, the pharmaceutical agent is a dialysis
agent for use in preparation of an artificial perfusion fluid for
hemodialysis.
The present invention also provides a method for preparing a
pharmaceutical solution, which comprises:
providing water and a pharmaceutical agent into the
preparation tank of the above pharmaceutical agent-dissolving device;
and
rotating the stirring blades of the pharmaceutical
agent-dissolving device.
In one embodiment, a stirring speed of the stirring blades is 40
rpm to 120 rpm.
In one embodiment, the pharmaceutical agent is a dialysis
agent for use in preparation of an artificial perfusion fluid for
hemodialysis.
According to the present invention, it is possible to prepare a
desired pharmaceutical solution by a simple operation without
requiring a complicated structure. This enables the use by a wider
range of health care workers and the like independently of the levels of
their medical techniques and skills. Furthermore, according to the
present invention, for example, since it is no longer necessary to
8
vigorously stir the pharmaceutical agent, generation of bubbles during
stirring can be reduced, and the pharmaceutical solution can be
prepared in a state in which denaturation of a protein formulation and
the like and/or inclusion of air is reduced. In preparation of an
artificial perfusion fluid for hemodialysis using a dialysis agent, it is
possible to suppress scattering of carbon dioxide and to prevent the
dialysis agent from being incompletely dissolved and partially
remaining undissolved in the preparation tank. Thus, irrespective of
the amount of artificial perfusion fluid that is prepared at one time, a
desired artificial perfusion fluid can be prepared efficiently and in large
amounts. Moreover, the pharmaceutical agent-dissolving device of the
present invention has a relatively simple structure as described above,
and thus is very versatile and allows for easy maintenance and repair.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic diagram showing an example of a
pharmaceutical agent-dissolving device of the present invention.
FIG. 2 is a perspective view of a shaft and stirring blades
provided in the pharmaceutical agent-dissolving device shown in FIG.
1.
FIGS. 3A to 3D show schematic cross-sectional views of stirring
blades attached to the shaft in the present invention, for explaining
examples of the angle of inclination of the stirring blades:
FIG. 3A is a diagram for explaining relationships of the axis of
the shaft with a blade surface and a rotating direction of a stirring
blade in the case where the term "angle θ of inclination that is formed
by an axial direction of the shaft and the blade surface of the stirring
blade" as used herein is represented by a positive value;
FIG. 3B is a diagram for explaining relationships of the axis of
9
the shaft with the blade surface and the rotating direction of the
stirring blade in the case where the term "angle θ of inclination that is
formed by the axial direction of the shaft and the blade surface of the
stirring blade" is represented by a negative value;
FIG. 3C is a diagram for explaining an angle (θ1) of inclination
formed by the axial direction of the shaft and a blade surface of a
stirring blade that is positioned furthest away from a bottom portion of
a preparation tank, of the pharmaceutical agent-dissolving device
shown in FIG. 1; and
FIG. 3D is a diagram for explaining an angle (θ2) of inclination
formed by the axial direction of the shaft and a blade surface of a
stirring blade that is positioned nearest to the bottom portion of the
preparation tank, of the pharmaceutical agent-dissolving device shown
in FIG. 1.
FIG. 4 is a bottom view of the shaft and the stirring blades
provided in the pharmaceutical agent-dissolving device shown in FIG.
1.
FIG. 5 is a bottom view of a shaft and stirring blades provided in
another example of the pharmaceutical agent-dissolving device of the
present invention.
FIG. 6A is a schematic side view of stirring blades attached to a
shaft so that an inside edge of the stirring blades is extended to a pivot
of the shaft according to still another example of a pharmaceutical
agent-dissolving device of the present invention.
FIG. 6B is a bottom view of the stirring blades attached to the
shaft shown in FIG.6A.
FIG. 6C is a perspective view of the stirring blades attached to
the shaft shown in FIG.6A.
FIG. 7 is a schematic diagram showing still another example of
10
the pharmaceutical agent-dissolving device of the present invention.
FIG. 8 is a schematic diagram of a conventional pharmaceutical
agent-dissolving device that can be used in preparation of an artificial
perfusion fluid for hemodialysis.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Hereinafter, the present invention will be described in detail.
Pharmaceutical agent-dissolving device
FIG. 1 is a schematic diagram showing an example of a
pharmaceutical agent-dissolving device of the present invention.
A pharmaceutical agent-dissolving device 100 shown in FIG. 1
includes a preparation tank 110, a driving motor 130, a shaft 120, and
two stages of stirring blades 142, 146.
The preparation tank 110 shown in FIG. 1 is a container (e.g.,
cylindrical container) having a form whose upper side is open and
capable of accommodating water and a pharmaceutical agent. The
preparation tank 110 is composed of, for example, a material having
stiffness and having excellent chemical resistance and corrosion
resistance. Examples of the material composing the preparation tank
110 include thermoplastic resins such as polypropylene, polystyrene,
polyethylene terephthalate, polyethylene, and polycarbonate; and metal
such as stainless steel. It should be noted that the upper side of the
preparation tank 110 shown in FIG. 1 is not necessarily required to be
open at all times as long as water and a pharmaceutical agent can be
provided into the tank, the shaft 120 and the stirring blades 142, 146
can be disposed in the inside of the tank, and the shaft 120 can be
rotated via the driving motor 130. For example, in FIG. 1, the upper
side of the preparation tank 110 may be covered by an openable lid (not
11
shown) with the shaft 120 rotatably passing through the lid.
The preparation tank 110 has a capacity of 50 liters to 500 liters
and preferably 80 liters to 400 liters, for example, so that a
pharmaceutical solution (including an artificial perfusion fluid and the
like) obtained from the above-described water and pharmaceutical
agent can be prepared in large amounts. With respect to an inner wall
of the preparation tank 110, surface treatment for increasing the
chemical resistance may be performed if necessary using a method that
is well known to those skilled in the art. Also, it is preferable that the
inside of the preparation tank 110 has a sufficient height or depth such
that the stirring blades 142, 146 can be rotated inside the tank via the
shaft 120. The height or depth of the inside of the preparation tank
110 may be 50 cm to 250 cm, for example. Furthermore, the radius of
the inside of the preparation tank 110 (i.e., length corresponding to 1/2
of the inner diameter of the preparation tank 110) may be, for example,
5 cm to 60 cm and preferably 20 cm to 40 cm.
In the pharmaceutical agent-dissolving device 100 shown in
FIG. 1, a discharge pipe 180 may be attached to a side surface near a
bottom portion of the preparation tank 110 or to the bottom portion, if
necessary. A pharmaceutical solution 800 prepared in the preparation
tank 110 can be discharged to the outside via the discharge pipe 180 by
opening/closing a valve 190 that is provided in an intermediate portion
of the discharge pipe 180. Also, any filter 194 may be provided in the
discharge pipe 180 in order to remove foreign matter.
The driving motor 130 may be either an alternating-current
motor or a direct-current motor. The driving motor 130 is connected to
one end of the shaft 120, which will be described later, and it is possible
to rotate the shaft 120 about its axis by driving the driving motor 130.
It should be noted that although the driving motor 130 in FIG. 1 is
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disposed directly above the shaft 120, the arrangement of the driving
motor is not limited to this. For example, an arrangement is also
possible in which the driving motor is disposed above the preparation
tank 110 in such a manner that the rotation axis of the driving motor is
parallel to the preparation tank 110, and rotation of the driving motor
is transferred to the shaft 120 via a bevel gear or a worm gear.
Furthermore, in the present invention, in order to rotate the shaft 120
at a lower speed (e.g., 40 rpm to 120 rpm), the driving motor 130 is
preferably provided with a mechanism that can control the number of
rotations.
The shaft 120 has a solid cylindrical shape or a hollow
cylindrical shape, for example, and the other end thereof is inserted to
the vicinity of the bottom portion of the preparation tank 110
perpendicularly to the bottom portion. The shaft 120 can be rotated
about its axis by driving of the driving motor 130. The shaft length is
substantially equal to or longer than the height of the preparation tank
110, for example. The thickness (diameter) of the shaft 120 may be 0.5
cm to 5 cm, for example. The shaft 120 may be composed of, for
example, a material having excellent chemical resistance, such as
stainless steel.
The stirring blades 142, 146 are provided in tandem along the
axial direction of the shaft 120 (i.e., lined up on the axis of the shaft
120). In FIG. 1, the two stages of stirring blades 142, 146 are provided;
however, the present invention is not limited to this configuration. At
least two stages of stirring blades may be provided in tandem along the
axial direction of the shaft 120. The stirring blade 142 is constituted
by a base portion 145 that is fixed around the axis of the shaft 120 and a
plurality of blade portions 143 that extend radially from the base
portion 145 with respect to the axial direction of the shaft 120 and
13
include respective blade surfaces 144. The stirring blade 146 is
constituted by a base portion 149 that is fixed around the axis of the
shaft 120, and a plurality of blade portions 147 that extend radially
from the base portion 149 with respect to the axial direction of the shaft
120 and include respective blade surfaces 148.
In the pharmaceutical agent-dissolving device of the present
invention, the ratio (r2/r0) of the radius of rotation (r2) of the stirring
blade 146 that is positioned nearest to the bottom portion of the
preparation tank 110, of the above-described at least two stages of
stirring blades, to the radius (r0) of the inside of the preparation tank
110 is 10/100 to 40/100, preferably 10/100 to 30/100, and more
preferably 15/100 to 25/100. Furthermore, in the pharmaceutical
agent-dissolving device of the present invention, the ratio (r1/r0) of the
radius of rotation (r1) of any other stirring blade (e.g., the stirring blade
142 in FIG. 1) to the radius (r0) of the inside of the preparation tank 110
is 40/100 to 90/100, preferably 40/100 to 80/100, and more preferably
50/100 to 70/100. Here, the term "radius of rotation of a stirring blade"
as used herein refers to the distance from the center of the shaft in a
plane that is formed by rotation of the stirring blade connected to the
shaft to an end portion of the stirring blade (the distance corresponds to
the radius of the outermost circumference of the stirring blade that is
formed by rotation of the shaft).
Since the stirring blades in the present invention have the radii
of rotation that satisfy the above-described relationships, the
pharmaceutical agent-dissolving device of the present invention is
capable of preparing a pharmaceutical solution efficiently and in large
amounts while completely dissolving the pharmaceutical agent.
Furthermore, in the present invention, there is no particular
limitation on the width and thickness of the above-described stirring
14
blades, and any values thereof may be chosen by those skilled in the art
in accordance with, for example, the capacity of the preparation tank
110 used, the number of blade portions constituting each of the stirring
blades, and the above-described radii of rotation that are set, and the
like. In one embodiment, the above-described stirring blades may
have a width of 1 cm to 5 cm, and a thickness of 0.1 cm to 1 cm.
FIG. 2 is a perspective view of the shaft 120 and the stirring
blades 142, 146 provided in the pharmaceutical agent-dissolving device
shown in FIG. 1.
The base portions 145, 149 respectively constituting the stirring
blades 142, 146 respectively have hollow cylindrical shapes, for
example, and inner surfaces thereof are firmly fixed to the shaft 120.
The plurality of blade portions 143, 147 extending from the
corresponding base portions 145, 149 respectively have rectangular
plate-like shapes, for example, and have the corresponding blade
surfaces 144, 148 that are inclined at predetermined angles, which will
be described later. In the present invention, the number of blade
portions constituting a single stirring blade (i.e., one stage of stirring
blade) may be, for example, 4 to 12 and more preferably 4 to 8. The
numbers of blade portions constituting the corresponding stirring
blades that are provided in tandem with respect to the shaft 120 may be
the same or may be different. That is to say, the number of blade
portions constituting a stirring blade that is positioned on the lower
side with respect to the shaft 120 may be the same as, smaller than, or
greater than the number of blade portions constituting another stirring
blade that is positioned above that stirring blade. Furthermore, in
order to perform uniform stirring, it is preferable that the intervals
(angles around the axis of the shaft 120) of the blade portions provided
for a single stirring blade is substantially uniform.
15
Furthermore, in the present invention, the base portions 145,
149 can be omitted, if necessary. That is to say, the stirring blades
may be configured by directly fixing (e.g., fixation by welding) the blade
portions to the shaft.
In the pharmaceutical agent-dissolving device of the present
invention, the blade surfaces 144, 148 are inclined, with respect to the
axial direction of the shaft 120, in the same direction along the rotating
direction of the shaft 120. That is to say, for example, as shown in
FIG. 2, in the case where the shaft 120 rotates anticlockwise when
viewed from above during stirring, all of the blade surfaces 144, 148 of
the corresponding stirring blades 142, 146 are designed to be inclined in
a direction that causes a gradual upward movement in accordance with
the rotation of the shaft 120.
FIGS. 3A to 3D are schematic cross-sectional views of the
stirring blades attached to the shaft of the pharmaceutical
agent-dissolving device shown in FIG. 1, for explaining examples of the
angle of inclination of the stirring blades.
Preferably, the pharmaceutical agent-dissolving device of the
present invention is designed such that an angle (θ2) of inclination that
is formed by the axial direction of the shaft and a blade surface of a
stirring blade positioned nearest to the bottom portion of the
preparation tank is equal to or greater than an angle (θ1) of inclination
that is formed by the axial direction of the shaft and a blade surface of a
stirring blade positioned furthest away from the bottom portion of the
preparation tank.
Here, the "angle of inclination that is formed by the axial
direction of the shaft and a blade surface of a stirring blade" as used
herein refers to an acute angle out of the angles that are formed by a
line that is parallel to a blade surface in a vertical cross section of a
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blade portion constituting the stirring blade and the axis of the shaft
intersecting each other. As shown in FIG. 3A, in the case where a line
K that is parallel to a blade surface 104 of a blade portion 102
constituting the stirring blade is inclined from the axis L of the shaft in
a direction opposite to the rotating direction (i.e., moving direction of
the blade portion) S of the stirring blade, the angle θ of inclination is
represented by a positive value. As shown in FIG. 3B, in the case
where the line K that is parallel to the blade surface 104 of the blade
portion 102 constituting the stirring blade is inclined from the axis L of
the shaft in a forward direction with respect to the rotating direction
(i.e., moving direction of the blade portion) S of the stirring blade, the
angle θ of inclination is represented by a negative value. Moreover,
the "angle (θ2) of inclination that is formed by the axial direction of the
shaft and a blade surface of a stirring blade positioned nearest to the
bottom portion of the preparation tank" as used herein refers to an
angle of inclination that is associated with the lowermost stirring blade,
of the stirring blades that are provided in tandem along the axial
direction of the shaft, and that is formed by the axial direction of the
shaft and a blade surface of that stirring blade. Furthermore, the
"angle (θ1) of inclination that is formed by the axial direction of the
shaft and a blade surface of a stirring blade positioned furthest away
from the bottom portion of the preparation tank" as used herein refers
to an angle of inclination that is associated with the uppermost stirring
blade, of the stirring blades provided in tandem along the axial
direction of the shaft, and that is formed by the axial direction of the
shaft and a blade surface of that stirring blade.
That is to say, for example, in the case of the pharmaceutical
agent-dissolving device shown in FIG. 1, the blade portions 144, 147 of
the corresponding stirring blades 142, 146 are designed such that with
17
respect to the angle (θ1) that, as shown in FIG. 3C, is formed by a blade
surface 144 of a blade portion 143 constituting the stirring blade 142
shown in FIG. 1 and the axis L of the shaft 120, the angle (θ2) that, as
shown in FIG. 3D, is formed by a blade surface 148 of a blade portion
147 constituting the stirring blade 146 shown in FIG. 1 and the axis L
of the shaft 120 preferably satisfies a relationship θ1 ≤ θ2. In this
regard, it is preferable that the blade surface 148 of each blade portion
147 constituting the stirring blade 146, which is positioned nearest to
the bottom portion of the preparation tank 110, has a smaller slope with
respect to a plane (plane of rotation) that is formed by the rotating
direction (i.e., has a larger positive value of the angle θ of inclination)
than the blade surface 144 of each blade portion 143 constituting the
stirring blade 142, which is positioned further away from the bottom
portion of the preparation tank 110.
With this configuration, the pharmaceutical agent-dissolving
device shown in FIG. 1 makes it possible that during preparation of a
pharmaceutical solution, even if a pharmaceutical agent (e.g., dialysis
agent) that has not yet been dissolved settles on the bottom portion of
the preparation tank 110, especially in the vicinity of a lower end
portion of the shaft 120, the blade surfaces 148 of the blade portions
147, which constitute the stirring blade 146 having the smaller slope,
form an upward moving stream that moves upward from the bottom
portion of the preparation tank 110, thereby causing the undissolved
pharmaceutical agent to move upward in the preparation tank 110.
The pharmaceutical agent that has thus moved upward can have an
opportunity to be more sufficiently stirred in the preparation tank 110
by the blade portions 143 of the stirring blade 142, which is provided
above the stirring blade 146, and dissolution is promoted even more.
While the shaft 120 is rotating, the above-described generation of an
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upward moving stream by the stirring blade 146 and sufficient stirring
by the stirring blade 142 are continuously performed, and thus the
possibility that a portion of the pharmaceutical agent may remain
undissolved on the bottom portion of the preparation tank 110 can be
reduced.
It should be noted that with regard to the angles θ1 and θ2 of
inclination shown in FIGS. 3C and 3D, as long as the above-described
relationship θ1 ≤ θ2 is satisfied, the angle θ1 of inclination is preferably
5° to 45° and more preferably 10° to 40°, and the angle θ2 of inclination
is preferably 10° to 50° and more preferably 15° to 45°.
In the pharmaceutical agent-dissolving device shown in FIG. 1,
there is no particular limitation on both of the lengths of the blade
portions 143, 147 constituting the corresponding stirring blades 142,
146; however, it is preferable that the length of blade portions (blade
portions 147 constituting the stirring blade 146) that constitute a
stirring blade positioned nearest to the bottom portion of the
preparation tank is designed to be shorter than the length of blade
portions constituting any other stirring blade, especially for the reason
that this makes it easy to effectively form the upward moving stream in
the vicinity of the lower end portion of the shaft 120 on the bottom
portion of the preparation tank 110.
Furthermore, in the present invention, the stirring blade
positioned nearest to the bottom portion of the preparation tank has a
radius of rotation that is preferably 10% to 80%, more preferably 25% to
75% and still more preferably 25% to 50% of the radius of rotation of the
stirring blade positioned furthest away from the bottom portion of the
preparation tank.
FIG. 4 is a bottom view of the shaft and the stirring blades
provided in the pharmaceutical agent-dissolving device shown in FIG.
19
1.
In the embodiment shown in FIG. 4, the radius of rotation (i.e.,
length from the center (rotation axis of the shaft) P of the base portion
149 to an end portion of each blade portion 147 in the radial direction)
r2 of the stirring blade 146, which is positioned nearest to the bottom
portion of the preparation tank (e.g., in the case where the radius of the
inside of the preparation tank is 24 cm), is preferably 2 cm to 10 cm and
more preferably 3 cm to 8 cm. Meanwhile, the radius of rotation (i.e.,
length from the center P of the rotation axis to an end portion of each
blade portion 143 in the radial direction) r1 of the stirring blade 142,
which is positioned furthest away from the bottom portion of the
preparation tank, is preferably 4 cm to 20 cm and more preferably 6 cm
to 16 cm.
It should be noted that in the embodiment shown in FIG. 4,
when the shaft and the stirring blades are viewed from the bottom
surface, the blade portions 147 constituting the stirring blade 146 are
arranged between the blade portions 143 constituting the stirring blade
142; however, the arrangement of the blade portions 143, 147 of the
present invention is not limited to this. For example, as shown in FIG.
5, it is also possible that, with respect to the center (rotation axis of the
shaft) P of a base portion 149', blade portions 147' constituting a
stirring blade 146' and blade portions 143' constituting a stirring blade
142' are arranged in an overlapping manner.
Referring again to FIG. 1, in the pharmaceutical
agent-dissolving device 100 of the present invention, the stirring blade
146, which is positioned nearest to the bottom portion of the
preparation tank 110, is provided on the shaft 120 while being spaced
apart from the bottom portion of the preparation tank 110 by a distance
of preferably 2 cm to 20 cm and more preferably 3 cm to 10 cm. For
20
example, if this distance exceeds 20 cm, it may be difficult for the
upward moving stream generated by the rotation of the stirring blade
146 to efficiently move upward an undissolved portion of the
pharmaceutical agent that is located on the bottom portion of the
preparation tank 110.
The distance between adjacent two stirring blades (e.g.,
distance from an upper end of the base portion 149 constituting the
stirring blade 146 shown in FIG. 1 to a lower end of the base portion
145 constituting the stirring blade 142) may be 1 cm to 3 cm, for
example.
The stirring blades constituting the present invention may be
composed of, for example, a material having excellent chemical
resistance, such as stainless steel.
Although an example of the pharmaceutical agent-dissolving
device of the present invention in which the two stages of stirring
blades 142, 146 are provided with respect to the shaft 120 has been
described in the embodiment shown in FIG. 1, the number of stirring
blades of the present invention is not limited to this. In the
pharmaceutical agent-dissolving device of the present invention, at
least two stages of stirring blades may be provided in tandem with
respect to the shaft.
Alternatively, in the pharmaceutical agent-dissolving device of
the present invention, at least two stages of stirring blades 142, 146”
may be provided with respect to the shaft 120 as shown in FIGS.6A to
6C. In this embodiment, the stirring blades 146” that are positioned
nearest to the bottom portion of the preparation tank are provided so
that an inside edge of the stirring blades 146”, corresponding to the
inside edge of the blade portions 147”, are extended to a pivot of the
shaft 120 (i.e., a center axis of a base portion 149”).
21
FIG. 7 is a schematic diagram showing still another example of
the pharmaceutical agent-dissolving device of the present invention.
In a pharmaceutical agent-dissolving device 200 shown in FIG.
7, the preparation tank 110, the driving motor 130, the shaft 120, the
discharge pipe 180, the valve 190, and the filter 194 have the same
configurations as those constituting the above-described device 100
shown in FIG. 1.
In the pharmaceutical agent-dissolving device 200 shown in
FIG. 7, there are provided three stages of stirring blades 246, 252, 242
that have blade surfaces that are inclined, with respect to the axial
direction of the shaft 120, in the same direction along the rotating
direction of the shaft 120. The stirring blade 246 is positioned nearest
to the bottom portion of the preparation tank 110, and is constituted by
a base portion 249 that is fixed around the axis of the shaft 120 and a
plurality of blade portions 247 that extend radially from the base
portion 249 with respect to the axial direction of the shaft 120 and
include respective blade surfaces 248. The stirring blade 242 is
positioned furthest away from the bottom portion of the preparation
tank 110, and is constituted by a base portion 245 that is fixed around
the axis of the shaft 120 and a plurality of blade portions 243 that
extend radially from the base portion 245 with respect to the axial
direction of the shaft 120 and include respective blade surfaces 244.
The stirring blade 252 is provided between the stirring blade 246 and
the stirring blade 242 with respect to the shaft 120 so as to be, for
example, equidistant from these stirring blades, and is constituted by a
base portion 251 that is fixed around the axis of the shaft 120 and a
plurality of blade portions 253 that extend radially from the base
portion 251 with respect to the axial direction of the shaft 120 and
include respective blade surfaces 254.
22
In the pharmaceutical agent-dissolving device 200 shown in
FIG. 7 as well, the angle (θ2) of inclination that is formed by the axial
direction of the shaft 120 and a blade surface 248 of the stirring blade
246, which is positioned nearest to the bottom portion of the
preparation tank 110, is set to be equal to or greater than the angle (θ1)
of inclination that is formed by the axial direction of the shaft 120 and a
blade surface 244 of the stirring blade 242, which is positioned furthest
away from the bottom portion of the preparation tank 110.
Furthermore, in this embodiment, when the angle of inclination that is
formed by the axial direction of the shaft 120 and a blade surface 254 of
the stirring blade 252 is θ3, it is preferable that the angles θ1, θ3, and θ2
of inclination satisfy any of the relationships θ1 ≤ θ3 ≤ θ2, θ1 ≤ θ3 < θ2, θ1
< θ3 ≤ θ2, and θ1 < θ3 < θ2.
With the pharmaceutical agent-dissolving device of the present
invention, a pharmaceutical solution can be prepared by providing
predetermined amounts of water and pharmaceutical agent into the
preparation tank and stirring the mixture. The prepared
pharmaceutical solution may be, for example, transferred to a separate
container (e.g., separate container for hemodialysis if a dialysis agent is
used as the pharmaceutical agent) through the discharge pipe 180 by
opening the valve 190 shown in FIG. 1. The preparation tank, the
driving motor, the shaft, and the stirring blades can be removed
individually, and thus maintenance such as cleaning, parts
replacement, and the like is also easy.
The pharmaceutical agent-dissolving device of the present
invention can be used to prepare pharmaceutical solutions from various
pharmaceutical agents. Examples of the pharmaceutical agents that
can be used include, but not necessarily limited to, anticancer agents
and thrombolytic agents used in chemotherapy; dialysis agents used in
23
hemodialysis therapy; and the like. These pharmaceutical agents may
be any of oral preparations, injections, and skin-permeable
preparations, and may have any of solid dosage forms such as tablets or
capsules; semisolid dosage forms such as creams; liquid dosage forms
such as ophthalmic solutions, sprays, drinkable preparations, or
injections. Furthermore, a pharmaceutical agent that can be used in
the present invention may be a protein formulation that may be
denatured by an excessive shearing force or the surface tension of
bubbles and thus lose its pharmaceutical effect.
Method for Preparing Pharmaceutical Solution
In the present invention, a pharmaceutical solution can be
prepared in the following manner, for example. An example of a
method for preparing a pharmaceutical solution will be described
taking a method for preparing an artificial perfusion fluid for
hemodialysis.
First, the above-described pharmaceutical agent-dissolving
device of the present invention can be used as a dialysis agent
dissolving device, and water and a hemodialysis agent are provided into
the preparation tank of that dissolving device.
There is no particular limitation on the order in which water
and the dialysis agent are provided into the preparation tank. For
example, water may be provided first and then the dialysis agent be
provided, the dialysis agent may be provided first and then water be
provided, or water and the dialysis agent may be provided together.
Alternatively, for example, in the case where a hemodialysis agent used
is separated into an "agent A" and an "agent B" such as those described
later, preparation may be performed by a procedure other than the
above-described providing procedures in which a solution of the agent A
24
and water as well as a solution of the agent B and water are separately
produced, and these solutions are finally mixed together.
Furthermore, in the case where concentrated liquid of the
dialysis agent is to be prepared, the above-described pharmaceutical
agent-dissolving device of the present invention can be used as a
dialysis agent dissolving device as well.
In the case where preparation of such concentrated liquid is
performed, first, water and a dialysis agent are provided into the
preparation tank of the dissolving device. More specifically, with the
pharmaceutical agent-dissolving device of the present invention, it is
possible to prepare "concentrated liquid of the agent A" by, for example,
adding the agent A of the dialysis agent to a volume of water
corresponding to 1/30 to 1/60 of a desired final volume. On the other
hand, with the pharmaceutical agent-dissolving device of the present
invention, it is possible to prepare "concentrated liquid of the agent B"
by, for example, adding the agent B of the dialysis agent to a volume of
water corresponding to 1/15 to 1/30 of the desired final volume.
Conventionally, in preparation of the "concentrated liquid of the
agent A " and the "concentrated liquid of the agent B " as described
above, the amount of dialysis agent that should be dissolved with
respect to an amount of water that is used is larger than usual, and
thus both the agent A and the agent B of the dialysis agent are not
easily dissolved. However, with the pharmaceutical agent-dissolving
device of the present invention, both of the agent A and the agent B can
be dissolved in water more efficiently. In addition, since preparation
in such concentrate form is possible, the resulting volume is 1/15 to 1/60
with respect to the volume of an ordinary artificial perfusion fluid for
hemodialysis that is not prepared in the concentrate form, and thus
subsequent handling, such as conveyance, at a health care site is easy.
25
Water that is provided into the preparation tank may be
purified water and dialysis water (RO water), for example. The
volume of water that is provided varies depending on the capacity of the
preparation tank and the amount of the dialysis agent, the amount of
artificial perfusion fluid that is required to be prepared, and the like,
and thus is not necessarily limited, but may be, for example, 10 liters to
480 liters, preferably 20 liters to 400 liters, and more preferably 30
liters to 300 liters.
It should be noted that in the case where concentrated liquid for
an artificial perfusion fluid is to be prepared, the volume of water can
be set, with consideration given to the amount of dialysis agent that is
used and the like, in such a manner that the concentration of the
concentrated liquid is 15 times to 60 times and more preferably 20
times to 40 time greater than the concentration of the artificial
perfusion fluid to be finally prepared.
The dialysis agent includes, for example, a dialysis agent that
can be used to prepare a conventional artificial perfusion fluid for
hemodialysis, and in the case where, for example, an artificial perfusion
fluid for hemodialysis containing bicarbonate is to be prepared, a
dialysis agent separated into an agent A mainly containing a citric acid
ingredient and a plurality of electrolyte ingredients and an agent B
mainly containing bicarbonate can be used.
In the case where an artificial perfusion fluid for hemodialysis
containing bicarbonate is to be prepared, an example of the citric acid
ingredient constituting the agent A is citric acid, and the citric acid may
be any of a hydrate, an anhydride, and a combination thereof.
Furthermore, citrate (e.g., sodium citrate or the like) other than
chloride may also be contained in the citric acid as the citric acid
ingredient.
26
The content of the citric acid ingredient in the above-described
agent A varies depending on the contents of the electrolyte ingredients
that are used, a desired concentration in the artificial perfusion fluid to
be prepared, and the like, and thus is not necessarily limited; however,
based on the content of citrate ions in the artificial perfusion fluid to be
prepared, a content that gives, for example, 1.5 mEq/L to 5 mEq/L and
preferably 2 mEq/L to 3 mEq/L can be set by those skilled in the art.
When the content of the citric acid ingredient is as such, the artificial
perfusion fluid can be prepared so as to have a pH of, for example, 7 to
8.5 and preferably 7.5 to 8.
Another example of the dialysis agent is a dialysis agent that is
separated into an agent A mainly containing an acetic acid ingredient
and a plurality of electrolyte ingredients, and an agent B mainly
containing bicarbonate.
Examples of the acetic acid ingredient of the agent A
constituting this other dialysis agent include acetic acid and/or sodium
acetate.
The content of the acetic acid ingredient in the above-described
agent A varies depending on the contents of the electrolyte ingredients
that are used, a desired concentration in the artificial perfusion fluid to
be prepared, and the like, and thus is not necessarily limited; however,
based on the content of acetate ions in the artificial perfusion fluid to be
prepared, a content that gives , for example, 2 mEq/L to 12 mEq/L and
preferably 2.5 mEq/L to 10 mEq/L can be set by those skilled in the art.
When the content of the acetic acid ingredient is as such, the artificial
perfusion fluid can be prepared so as to have a pH of, for example, 7 to
8.5 and preferably 7.2 to 7.6.
In the case where an artificial perfusion fluid for hemodialysis
containing bicarbonate is to be prepared, examples of the plurality of
27
electrolyte ingredients constituting the agent A include chlorides (e.g.,
sodium chloride, magnesium chloride, potassium chloride, calcium
chloride, a combination thereof, and the like) other than those of citric
acid and acetic acid. Furthermore, a citric acid salt such as sodium
citrate or an acetic acid salt such as sodium acetate may be separately
contained as the plurality of electrolyte ingredients.
The contents of the plurality of electrolyte ingredients described
above vary depending on the content of the above-described citric acid
ingredient used, a desired concentration in the artificial perfusion fluid
to be prepared, the amount of the artificial perfusion fluid to be
prepared, and the like, and thus is not necessarily limited; however,
any contents can be set by those skilled in the art. It should be noted
that in the present invention, it is preferable that among the plurality
of electrolyte ingredients described above, sodium chloride has the
greatest content when compared with each of the other electrolytes (i.e.,
calcium chloride, potassium chloride, and magnesium chloride). The
reason for this is that the contents of the electrolytes are set to match
the concentrations of the electrolytes in the blood.
In the present invention, the content of sodium chloride that can
be contained in the above-described agent A varies depending on the
content of the citric acid ingredient used, the contents of the other
electrolyte ingredients, a desired concentration in the artificial
perfusion fluid to be prepared, and the like, and thus is not necessarily
limited; however, based on the content of sodium ions in the artificial
perfusion fluid to be prepared, a content that gives, for example, 75
mEq/L to 150 mEq/L and preferably 80 mEq/L to 145 mEq/L can be set
by those skilled in the art.
Also, the above-described agent A may contain other ingredients
in addition to the citric acid ingredient and the electrolyte ingredients
28
that are described above. Alternatively, the citric acid ingredient may
be replaced by the other ingredient. An example of the other
ingredient is a pH adjuster. An example of the pH adjuster is an
organic acid, and examples of the organic acid include oxalic acid,
tartaric acid, maleic acid, ascorbic acid, oxalacetic acid, gluconic acid,
isocitric acid, malic acid, and pyruvic acid as well as a combination
thereof. With respect to the other ingredients of the above-described
agent A, appropriate amounts can be appropriately chosen by those
skilled in the art insofar as the function of the agent A for dialysis is not
inhibited.
In the case where an artificial perfusion fluid for hemodialysis
containing bicarbonate is to be prepared, an example of the bicarbonate
constituting the agent B is sodium hydrogen carbonate.
The content of the bicarbonate in the above-described agent B
varies depending on the contents of the citric acid ingredient and
electrolyte ingredients for use in the agent A, a desired concentration in
the artificial perfusion fluid to be prepared, the amount of artificial
perfusion fluid to be prepared, and the like, and thus is not necessarily
limited; however, a content that gives, for example, 15 mEq/L to 45
mEq/L and preferably 25 mEq/L to 40 mEq/L in the artificial perfusion
fluid to be prepared can be set by those skilled in the art.
Moreover, in the case where both of the agent A and the agent B
contain sodium chloride, the total amount of sodium chloride can be
appropriately chosen by those skilled in the art so as to satisfy the
amount of sodium chloride that is required for preparation of the
artificial perfusion fluid.
The providing of the dialysis agent into the preparation tank
may be performed by any of separately providing these agents A and B
into the tank, simultaneously providing these agents A and B, or
29
providing these agents A and B together with a mixture that is
prepared in advance immediately before the providing.
After water and the dialysis agent are provided into the
preparation tank, the stirring blades of the pharmaceutical
agent-dissolving device are then rotated.
It is preferable that the rotation of the stirring blades is
performed at an appropriate stirring speed so that the solution in the
preparation tank is not stirred vigorously, by controlling the number of
revolutions of the driving motor or the shaft. The purpose of this is to
avoid generation of unwanted air bubbles in the solution in the
preparation tank. The stirring speed of the stirring blades varies
depending on the capacity of the preparation tank, the amount of
artificial perfusion fluid to be prepared, the sizes of the stirring blades,
and the like and thus is not necessarily limited, but may be set at, for
example, 40 rpm to 120 rpm and preferably 50 rpm to 100 rpm.
It should be noted that during stirring in the preparation tank,
there is no particular limitation on the stirring temperature and the
like; however, stirring may be performed at room temperature. The
stirring time varies depending on the capacity of the preparation tank,
the amount of artificial perfusion fluid to be prepared, the sizes of the
stirring blades, and the like and thus is not necessarily limited, but
may be, for example, 5 minutes to 20 minutes.
According to the preparation method of the present invention, a
desired artificial perfusion fluid can be prepared in an extremely easy
and safe manner by preventing the dialysis agent from being
incompletely dissolved and partially remaining undissolved on the
bottom portion of the preparation tank while suppressing generation of
air bubbles in the solution using the above-described stirring speed and
stirring time. The prepared artificial perfusion fluid is taken out of the
30
preparation tank and transferred into a separate container for
hemodialysis that is used for many purposes in the art.
The prepared artificial perfusion fluid is carefully applied to a
dialysis patient at a dose, which varies depending on the dialysis time
but may be, for example, 100 liters to 300 liters, using a method known
to those skilled in the art. In the case of a concentrated dialysis fluid
that is prepared and conveyed in the form of a concentrate, the
concentrated dialysis solution is diluted with water and prepared into a
desired dialysis solution using a dialyzer, and the resulting dialysis
solution is carefully applied to the dialysis patient.
Examples
Hereinafter, the present invention will be more specifically
described by means of examples. It is to be understood that the
present invention is not limited to the examples below.
It should be noted that in Examples and Comparative Examples
below, an agent A and an agent B having respective compositions
shown in Table 1 were used as a dialysis agent. Moreover, in
preparation of artificial perfusion fluids, the pharmaceutical
agent-dissolving device shown in FIG. 1 was used. A specific
configuration of the device used was as shown in Table 2 below.
31
Table 1
Composition of dialysis agent used
Agent A Agent B
Sodium chloride 183.0g/L
(89.0wt%)
Sodium bicarbonate 59.2g/L
Potassium chloride (71.6wt%) 5.5g/L
(2.7wt%)
Calcium chloride 8.1g/L
(3.9wt%)
Magnesium chloride 3.8g/L
(1.8wt%)
Sodium chloride 23.5g/L
Anhydrous citric acid (28.4wt%) 3.9g/L
(1.9wt%)
Sodium citrate 1.4g/L
(0.7wt%)
The “wt%” shows a value based on the total weight of the agent A or the agent B.
Table 2
Dialysis agent dissolving device used
Preparation tank
Polyethylene container having a capacity of 100 liters
Inner diameter: 50 cm (inside radius: 25 cm)
Used with upper side kept open
Driving motor Variable DC motor
Shaft Made of stainless steel, diameter: 2 cm
Stirring blade
Two stages of stirring blades
(Upper side)
Made of stainless steel, angle θ1 of inclination: 15°
Radius of rotation: 16.25 cm
Width: 3 cm
(Bottom portion side)
Made of stainless steel, angle θ2 of inclination: 30°
Radius of rotation: 6.5 cm
Width: 3 cm
Distance from bottom portion of preparation tank to lower end
of stirring blade on bottom portion side: 3 cm
Example 1:
32
First, 25 liters of purified water and 6.2 kg of the agent A were
provided into a preparation tank of a pharmaceutical agent-dissolving
device (see Tables 2 and 3) that was produced based on FIG. 1. After
that, stirring was performed by rotating the stirring blades at a rotation
speed of 65 rpm, and the time taken to completely dissolve the agent A
in the preparation tank was measured. After it was confirmed that
the agent A was completely dissolved, purified water was further added
until the total amount of 30 liters, and thus concentrated liquid of the
agent A was obtained. It was confirmed that the agent A was
completely dissolved in the preparation tank until 15 minutes had
elapsed after the addition of the agent A. The obtained results are
shown in Table 3.
Separately, 25 liters of purified water and 2.5 kg of the agent B
were similarly provided into the preparation tank of the
above-described dialysis agent dissolving device. After that, stirring
was performed by rotating the stirring blades at a rotation speed of 65
rpm, and the time taken to completely dissolve the agent B in the
preparation tank was measured. After it was confirmed that the agent
B was completely dissolved, purified water was further added until the
total amount of 30 liters, and thus concentrated liquid of the agent B
was obtained. It was confirmed that the agent B was completely
dissolved in the preparation tank until 10 minutes had elapsed after
the addition of the agent B. The obtained results are shown in Table 3.
It was confirmed by the foregoing procedure that both of the
concentrated liquid of the agent A and the concentrated liquid of agent
B were excellent for an artificial perfusion fluid. After that, the
concentrated liquid of the agent A and the concentrated liquid of the
agent B as well as purified water were continuously mixed within a
commercially available artificial dialyzer in a ratio (volume ratio) of 1 :
33
1.83 : 34, and the resulting mixed solution was used for artificial
dialysis of a patient.
Example 2:
Purified water and the agent A were provided into the
preparation tank of the pharmaceutical agent-dissolving device that
was produced in Example 1, and concentrated liquid of the agent A was
obtained in the same manner as in Example 1 except that stirring was
performed by rotating the stirring blades at 100 rpm. Furthermore,
purified water and the agent B were provided into the preparation tank
of the pharmaceutical agent-dissolving device, and concentrated liquid
of the agent B was obtained in the same manner as in Example 1 except
that stirring was performed by rotating the stirring blades at 100 rpm.
The obtained results are shown in Table 3.
It was confirmed by the foregoing procedure that both of the
concentrated liquid of the agent A and the concentrate liquid of the
agent B were excellent for an artificial perfusion fluid. After that, the
concentrated liquid of the agent A and the concentrated liquid of the
agent B as well as purified water were continuously mixed within a
commercially available artificial dialyzer in a ratio (volume ratio) of 1 :
1.83 : 34, and the resulting mixed solution was used for artificial
dialysis of a patient.
Example 3:
A pharmaceutical agent-dissolving device based on FIG. 1 was
produced in the same manner as in Example 1 except that the number
of blade portions constituting the stirring blade on the upper side was
changed to 6.
Then, concentrated liquid of the agent A was obtained in the
34
same manner as in Example 1 except that the preparation tank of this
pharmaceutical agent-dissolving device was used. Furthermore,
concentrated liquid of the agent B was obtained in the same manner as
in Example 1 except that the preparation tank of the pharmaceutical
agent-dissolving device was used. The obtained results are shown in
Table 3.
It was confirmed by the foregoing procedure that both of the
concentrated liquid of the agent A and the concentrated liquid of the
agent B were excellent for an artificial perfusion fluid. After that, the
concentrated liquid of the agent A and the concentrated liquid of the
agent B as well as purified water were continuously mixed within a
commercially available artificial dialyzer in a ratio (volume ratio) of 1 :
1.83 : 34, and the resulting mixed solution was used for artificial
dialysis of a patient.
Example 4:
A pharmaceutical agent-dissolving device based on FIG. 1 was
produced in the same manner as in Example 1 except that the number
of blade portions constituting the stirring blade on the upper side was
unchanged at 4 and the number of blade portions constituting the
stirring blade on the bottom portion side was changed to 6.
Then, concentrated liquid of the agent A was obtained in the
same manner as in Example 1 except that this pharmaceutical
agent-dissolving device was used. Furthermore, concentrated liquid of
the agent B was obtained in the same manner as in Example 1 except
that the preparation tank of this pharmaceutical agent-dissolving
device was used. The obtained results are shown in Table 3.
It was confirmed by the foregoing procedure that both of the
concentrated liquid of the agent A and the concentrated liquid of the
35
agent B were excellent for an artificial perfusion fluid. After that, the
concentrated liquid of the agent A and the concentrated liquid of the
agent B as well as purified water were continuously mixed within a
commercially available artificial dialyzer in a ratio (volume ratio) of 1 :
1.83 : 34, and the resulting mixed solution was used for artificial
dialysis of a patient.
Example 5:
A pharmaceutical agent-dissolving device based on FIG. 1 was
produced in the same manner as in Example 1 except that the angle (θ2)
of inclination of the blade surfaces of the stirring blade on the bottom
portion side was changed to 15°, which was the same as the angle (θ1) of
inclination of the blade surfaces of the stirring blade on the upper side.
Then, concentrated liquid of the agent A was obtained in the
same manner as in Example 1 except that this pharmaceutical
agent-dissolving device was used. Furthermore, concentrated liquid of
the agent B was obtained in the same manner as in Example 1 except
that a preparation tank of this pharmaceutical agent-dissolving device
was used. The obtained results are shown in Table 3.
It was confirmed by the foregoing procedure that both of the
concentrated liquid of the agent A and the concentrated liquid of the
agent B were excellent for an artificial perfusion fluid. After that, the
concentrated liquid of the agent A and the concentrated liquid of the
agent B as well as purified water were continuously mixed within a
commercially available artificial dialyzer in a ratio (volume ratio) of 1 :
1.83 : 34, and the obtained mixed solution was used for artificial
dialysis of a patient.
Example 6:
36
A pharmaceutical agent-dissolving device based on FIG. 1 was
produced in the same manner as in Example 1 except that the angle (θ2)
of inclination of the blade surfaces of the stirring blade on the bottom
portion side was changed to -40°.
Then, concentrated liquid of the agent A was obtained in the
same manner as in Example 1 except that this pharmaceutical
agent-dissolving device was used. Furthermore, concentrated liquid of
the agent B was obtained in the same manner as in Example 1 except
that a preparation tank of this pharmaceutical agent-dissolving device
was used. With respect to each of the agent A and the agent B, it was
visually confirmed that in 20 minutes after stirring, the agent partially
remained undissolved in the preparation tank and required additional
stirring. The obtained results are shown in Table 3.
Example 7:
Purified water and the agent A were provided into the
preparation tank of the pharmaceutical agent-dissolving device
produced in Example 1, and concentrated liquid of the agent A was
obtained in the same manner as in Example 1 except that stirring was
performed by rotating the stirring blades at 30 rpm. Furthermore,
purified water and the agent B were provided into the preparation tank
of the pharmaceutical agent-dissolving device, and concentrated liquid
of the agent B was obtained in the same manner as in Example 1 except
that stirring was performed by rotating the stirring blades at 30 rpm.
With respect to each of the agent A and the agent B, it was visually
confirmed that in 20 minutes after stirring, the agent partially
remained undissolved in the preparation tank and required additional
stirring. The obtained results are shown in Table 3.
37
Example 8:
Purified water and the agent A were provided into the
preparation tank of the pharmaceutical agent-dissolving device
produced in Example 1, and concentrated liquid of the agent A was
obtained in the same manner as in Example 1 except that stirring was
performed by rotating the stirring blades at 150 rpm. Furthermore,
purified water and the agent B were provided into the preparation tank
of the pharmaceutical agent-dissolving device, and concentrated liquid
of the agent B was obtained in the same manner as in Example 1 except
that stirring was performed by rotating the stirring blades at 150 rpm.
With respect to each of the solutions that were respectively prepared
from the agent A and the agent B, it was visually confirmed that air
bubbles were generated in the preparation tank after stirring. The
obtained results are shown in Table 3.
Example 9:
A pharmaceutical agent-dissolving device based on FIG. 1 was
produced in the same manner as in Example 1 except that the two
stages of stirring blades 142, 146 were replaced with the two stages of
stirring blades 142, 146” shown in FIGS.6A to 6C, that is, the inside
edges of the stirring blades 146” were extended to a pivot of the shaft
120.
Then, concentrated liquid of the agent A was obtained in the
same manner as in Example 1 except that this pharmaceutical
agent-dissolving device was used. Furthermore, concentrated liquid of
the agent B was obtained in the same manner as in Example 1 except
that the preparation tank of this pharmaceutical agent-dissolving
device was used. The obtained results are shown in Table 3.
It was confirmed by the foregoing procedure that both of the
38
concentrated liquid of the agent A and the concentrated liquid of the
agent B were excellent for an artificial perfusion fluid. After that, the
concentrated liquid of the agent A and the concentrated liquid of the
agent B as well as purified water were continuously mixed within a
commercially available artificial dialyzer in a ratio (volume ratio) of 1 :
1.83 : 34, and the resulting mixed solution was used for artificial
dialysis of a patient.
Comparative Example 1:
A pharmaceutical agent-dissolving device based on FIG. 1 was
produced in the same manner as in Example 1 except that the stirring
blade on the bottom portion side was removed from the pharmaceutical
agent-dissolving device described in Example 1 (i.e., only the stirring
blade on the upper side was left unremoved).
Then, concentrated liquid of the agent A was obtained in the
same manner as in Example 1 except that this pharmaceutical
agent-dissolving device was used. Furthermore, concentrated liquid of
the agent B was obtained in the same manner as in Example 1 except
that the preparation tank of this pharmaceutical agent-dissolving
device was used. With respect to each of the agent A and the agent B,
it was visually confirmed that the agent was not completely dissolved in
the preparation tank after 20 minutes had elapsed from the start of
stirring, and an undissolved portion of the agent remained near the
center of the bottom portion of the preparation tank. The obtained
results are shown in Table 3.
It was confirmed by the foregoing procedure that both of the
concentrated liquid of the agent A and the concentrated liquid of the
agent B were unsatisfactory for an artificial perfusion fluid.
39
Comparative Example 2:
A pharmaceutical agent-dissolving device based on FIG. 1 was
produced in the same manner as in Example 1 except that the stirring
blade on the upper side was removed from the pharmaceutical
agent-dissolving device described in Example 1 (i.e., only the stirring
blade on the bottom portion side was left unremoved).
Then, concentrated liquid of the agent A was obtained in the
same manner as in Example 1 except that this pharmaceutical
agent-dissolving device was used. Furthermore, concentrated liquid of
the agent B was obtained in the same manner as in Example 1 except
that the preparation tank of this pharmaceutical agent-dissolving
device was used. With respect to each of the agent A and the agent B,
it was visually confirmed that the agent was not completely dissolved in
the preparation tank after 20 minutes had elapsed from the start of
stirring, and an undissolved portion of the agent remained in the
periphery of the bottom portion of the preparation tank. The obtained
results are shown in Table 3.
It was confirmed by the foregoing procedure that both of the
concentrated liquid of the agent A and the concentrated liquid of the
agent B were unsatisfactory for an artificial perfusion fluid.
Comparative Example 3:
A pharmaceutical agent-dissolving device based on FIG. 1 was
produced in the same manner as in Example 1 except that the length of
the stirring blade on the bottom portion side was changed such that the
radius of rotation of this stirring blade was 10 cm (i.e., the radius of the
inside of the preparation tank/the radius of rotation of the stirring
blade on the upper side/the radius of rotation of the stirring blade on
the bottom portion side = 100/65/40).
40
Then, concentrated liquid of the agent A was obtained in the
same manner as in Example 1 except that this pharmaceutical
agent-dissolving device was used. Furthermore, concentrated liquid of
the agent B was obtained in the same manner as in Example 1 except
that a preparation tank of this pharmaceutical agent-dissolving device
was used. With respect to each of the agent A and the agent B, it was
visually confirmed that the agent was not completely dissolved in the
preparation tank after 20 minutes had elapsed from the start of
stirring, and an undissolved portion of the agents remained near the
center of the bottom portion of the preparation tank. The obtained
results are shown in Table 3.
It was confirmed by the foregoing procedure that both of the
concentrated liquid of the agent A and the concentrated liquid of the
agent B were unsatisfactory for an artificial perfusion fluid.
Comparative Example 4:
A pharmaceutical agent-dissolving device based on FIG. 1 was
produced in the same manner as in Example 1 except that the length of
the stirring blade on the bottom portion side was changed such that the
radius of rotation of this stirring blade was 1.25 cm (i.e., the radius of
the inside of the preparation tank/the radius of rotation of the stirring
blade on the upper side/the radius of rotation of the stirring blade on
the bottom portion side = 100/65/5).
Then, concentrated liquid of the agent A was obtained in the
same manner as in Example 1 except that this pharmaceutical
agent-dissolving device was used. Furthermore, concentrate liquid of
the agent B was obtained in the same manner as in Example 1 except
that the preparation tank of this pharmaceutical agent-dissolving
device was used. With respect to each of the agent A and the agent B,
41
it was visually confirmed that the agent was not completely dissolved in
the preparation tank after 20 minutes had elapsed from the start of
stirring, and an undissolved portion of the agents remained near the
center of the bottom portion of the preparation tank. The obtained
results are shown in Table 3.
It was confirmed by the foregoing procedure that both of the
concentrated liquid of the agent A and the concentrated liquid of the
agent B were unsatisfactory for an artificial perfusion fluid.
42
Table 3
Number of
blade
portions
constituting
stirring blade
on upper
side
Number of
blade portions
constituting
stirring blade
on bottom
portion side
Ratio *1) of
inside radius
of tank and
radii of
rotation of
stirring
blades
Angle (θ1) of
inclination of
blade
surface of
stirring blade
on upper
side
Angle (θ2) of
inclination of
blade
surface of
stirring blade
on bottom
portion side
Rotation
speed of
stirring blades
(rpm)
State of dialysis agent during stirring
Suitability for
artificial
perfusion fluid
Example 1 4 4 100/65/25 15° 30° 65 Agent A: completely dissolved before 15 min. had elapsed
Agent B: completely dissolved before 10 min. had elapsed Excellent
Example 2 4 4 100/65/25 15° 30° 100 Agent A: completely dissolved before 15 min. had elapsed
Agent B: completely dissolved before 10 min. had elapsed Excellent
Example 3 6 4 100/65/25 15° 30° 65 Agent A: completely dissolved before 15 min. had elapsed
Agent B: completely dissolved before 10 min. had elapsed Excellent
Example 4 4 6 100/65/25 15° 30° 65 Agent A: completely dissolved before 15 min. had elapsed
Agent B: completely dissolved before 10 min. had elapsed Excellent
Example 5 4 4 100/65/25 15° 15° 65 Agent A: completely dissolved before 15 min. had elapsed
Agent B: completely dissolved before 10 min. had elapsed Excellent
Example 6 4 4 100/65/25 15° -40° 65 Both of agents A and B were not completely dissolved within 20
min. Acceptable
Example 7 4 4 100/65/25 15° 30° 30 Both of agents A and B were not completely dissolved within 20
min. Acceptable
Example 8 4 4 100/65/25 15° 30° 150 Inclusion of air bubbles was observed in both of solutions
prepared from agents A and B, respectively Acceptable
Example 9 4 4*2) 100/65/25 15° 30° 65 Agent A: completely dissolved before 13 min. had elapsed
Agent B: completely dissolved before 8 min. had elapsed Excellent
Comparative
Example 1 4 0 100/65/0 15° - 65
Both of agents A and B were not completely dissolved and
undissolved portion thereof remained near center of bottom
portion of tank even after 20 min. had elapsed
Unsatisfactory
Comparative
Example. 2 0 4 100/0/25 - 30° 65
Both of agents A and B were not completely dissolved and
undissolved portion thereof remained in periphery of bottom
portion of tank even after 20 min. had elapsed
Unsatisfactory
Comparative
Example 3 4 4 100/65/40 15° 30° 65
Both of agents A and B were not completely dissolved and
undissolved portion thereof remained near center of bottom
portion of tank even after 20 min. had elapsed
Unsatisfactory
Comparative
Example 4 4 4 100/65/5 15° 30° 65
Both of agents A and B were not completely dissolved and
undissolved portion thereof remained near center of bottom
portion of tank even after 20 min. had elapsed
Unsatisfactory
*1) Expressed as "radius of inside of preparation tank/radius of rotation of stirring blade on upper side/radius of rotation of stirring blade on bottom portion side".
*2) The stirring blades 146” shown in FIGS. 6A to 6C were used.
43
It can be seen from Table 3 that with the pharmaceutical
agent-dissolving devices that were used especially in Examples 1 to 5
and 9, the dialysis agents were completely dissolved with no
undissolved portion thereof remaining on the bottom portion of the
preparation tank, and the concentrated liquid of the agent A and the
concentrated liquid of the agent B that were excellent for artificial
perfusion fluids were prepared.

CLAIMS
1. A pharmaceutical agent-dissolving device for preparing a
pharmaceutical solution, comprising:
a preparation tank capable of accommodating water and a
pharmaceutical agent;
a driving motor;
a shaft that is inserted to a vicinity of a bottom portion of the
preparation tank perpendicularly to the bottom portion and that can be
rotated by driving of the driving motor; and
at least two stages of stirring blades that are provided in
tandem along an axial direction of the shaft and that have blade
surfaces that are inclined, with respect to the axial direction of the
shaft, in the same direction along a rotating direction of the shaft,
wherein a ratio (r2/r0) of a radius of rotation (r2) of a stirring
blade that is positioned nearest to the bottom portion of the preparation
tank, of the at least two stages of stirring blades, to a radius (r0) of the
inside of the preparation tank is 10/100 to 40/100, and a ratio (r1/r0) of a
radius of rotation (r1) of any other stirring blade to the radius (r0) of the
inside of the preparation tank is 40/100 to 90/100.
2. The pharmaceutical agent-dissolving device of claim 1, wherein
the stirring blade that is positioned nearest to the bottom portion of the
preparation tank has a radius of rotation that is 10% to 80% with
respect to a radius of rotation of a stirring blade that is positioned
furthest away from the bottom portion of the preparation tank.
3. The pharmaceutical agent-dissolving device of claim 1 or 2,
wherein an angle (θ2) of inclination that is formed by the axial direction
45
of the shaft and the individual blade surfaces of the stirring blade that
is positioned nearest to the bottom portion of the preparation tank is
10° to 50°.
4. The pharmaceutical agent-dissolving device of any of claims 1 to
3, wherein the angle (θ2) of inclination that is formed by the axial
direction of the shaft and the individual blade surfaces of the stirring
blade that is positioned nearest to the bottom portion of the preparation
tank is equal to or greater than an angle (θ1) of inclination that is
formed by the axial direction of the shaft and the individual blade
surfaces of the stirring blade that is positioned furthest away from the
bottom portion of the preparation tank.
5. The pharmaceutical agent-dissolving device of any of claims 1 to
4, wherein the stirring blade that is positioned nearest to the bottom
portion of the preparation tank is provided on the shaft while being
spaced apart from the bottom portion of the preparation tank by a
distance of 2 cm to 20 cm.
6. The pharmaceutical agent-dissolving device of any of claims 1
to 5, wherein the stirring blade that is positioned nearest to the bottom
portion of the preparation tank is provided so that an inside edge of the
stirring blade is extended to a pivot of the shaft.
7. The pharmaceutical agent-dissolving device of any of claims 1 to
6, comprising two stages of the stirring blades.
8. The pharmaceutical agent-dissolving device of any of claims 1 to
46
7, wherein the pharmaceutical agent is a dialysis agent for use in
preparation of an artificial perfusion fluid for hemodialysis.
9. A method for preparing a pharmaceutical solution, which
comprises:
providing water and a pharmaceutical agent into the
preparation tank of the pharmaceutical agent-dissolving device of any
of claims 1 to 8; and
rotating the stirring blades of the pharmaceutical
agent-dissolving device.
10. The method of claim 9, wherein a stirring speed of the stirring
blades is 40 rpm to 120 rpm.
11. The method of claim 9 or 10, wherein the pharmaceutical agent
is a dialysis agent for use in preparation of an artificial perfusion fluid
for hemodialysis.