Pasty dialyzing composition for perfusing artificial kidney systems and process for preparing same

The invention provides a pasty composition for perfusing artificial kidney systems for dialysis, the composition comprising about 30 to about 70% by weight of solid electrolyte components consisting of NaCl, KCl, CaCl.sub.2, MgCl.sub.2 and CH.sub.3 COONa and about 70 to about 30% by weight of water, and the composition having a viscosity of about 1,000 to about 7,000 cps at 25.degree. C., and also provides a process for preparing a pasty composition for perfusing artificial kidney systems for dialysis, the process comprising the steps of uniformly mixing NaCl, KCl, CaCl.sub.2, MgCl.sub.2 and CH.sub.3 COONa, adding water and finely dividing the mixture.

FIELD OF THE INVENTION 
The present invention relates to a novel pasty composition for perfusing 
artificial kidney systems for dialysis and a process for preparing the 
composition. 
BACKGROUND OF THE INVENTION 
Dialyzing fluids for perfusing artificial kidney systems (hereinafter 
referred to merely as "dialyzing fluid" unless otherwise indicated) 
currently available are roughly classified into acetate-containing 
dialyzing fluids and bicarbonate-containing dialyzing fluids. 
The acetate-containing dialyzing fluids and bicarbonate-containing 
dialyzing fluids ready for use usually have the following compositions. 
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(A) Acetate-containing dialyzing fluids 
Na.sup.+ 126-145 mEq/l 
K.sup.+ 1.5-3.0 mEq/l 
Ca.sup.++ 2.5-4.0 mEq/l 
Mg.sup.++ 1.0-1.5 mEq/l 
Cl.sup.- 98-108 mEq/l 
CH.sub.3 COO.sup.- 30-42.5 mEq/l 
Glucose 0-300 mg/dl 
(B) Bicarbonate-containing dialyzing fluids 
Na.sup.+ 135-140 mEq/l 
K.sup.+ 0-4.0 mEq/l 
Ca.sup.++ 2.5-3.5 mEq/l 
Mg.sup.++ 1.0-1.5 mEq/l 
Cl.sup.- 106-107.5 
mEq/l 
CH.sub.3 COO.sup.- 4-9 mEq/l 
HCO.sub.3.sup.- 27.5-35 mEq/l 
______________________________________ 
Commercially available acetate-containing dialyzing fluids comprise in 
combination a concentrated dialyzing fluid and glucose either contained 
therein or provided separately as a second fluid and are diluted with 
water before use to give the composition of dialyzing fluid (A). 
Commercially available bicarbonate-containing dialyzing fluids comprise in 
combination a concentrated dialyzing fluid and sodium bicarbonate provided 
separately as a second fluid and are diluted with water before use to give 
the composition of dialyzing fluid (B). 
These commercially available concentrated dialyzing fluids are usually 
contained in a container of polyethylene or the like having a volume of 
about 10-l volume, consequently entailing numerous problems on storing 
space, difficulty in transport and like handling. Further the above 
concentrated dialyzing fluids readily undergo changes in pH or in 
composition during storage and thus are difficult to adjust to the desired 
pH before use and to provide with the intended composition, hence 
problematic also in quality stability. 
To overcome these problems, we conducted extensive research and developed a 
process for producing a dialyzing powder by spray drying method using an 
aqueous solution of electrolyte compounds similar in composition to the 
dialyzing fluid (A) or (B) (without glucose) (Japanese Examined Patent 
Publication No. 34248/1982). We also developed a process for producing a 
bicarbonate-containing dialyzing powder, the process comprising 
pulverizing sodium chloride as the chief component among electrolyte 
compounds to particles of about 20 to about 30 .mu.m, spraying glacial 
acetic acid over the particles for adsorption, and mixing the particles 
with other electrolytic compounds (Japanese Examined Patent Publication 
No. 27246/1983). The dialyzing powders of mixed electrolytic compounds 
obtained by these processes obviate the storing-space and handling 
problems, but raise other problems on producing process, quality, storage, 
etc. as described below. 
The dialyzing powders obtained by the spray-drying method are irregular in 
water content and particle size. Particularly the bicarbonate-containing 
dialyzing powders are difficult to adjust to the desired pH. 
The method spraying the glacial acetic acid over the sodium chloride powder 
for adsorption results in emission of offensive odor and thus in 
deterioration of work environment, and entails difficulty in eliminating 
the irregularity in amounts of minor components in the production lot. 
The dialyzing powders are prone to change in pH. And NaCl, KCl, MgCl.sub.2, 
CaCl.sub.2 and the like for use as the active components have the property 
of solidifying on absorption of moisture, tending to solidify during 
storage. After solidification, the dialyzing product becomes difficult to 
dissolve before use. 
Moreover, loss of powder is likely to occur due to scattering during the 
formation of an aqueous solution of powder. 
SUMMARY OF THE INVENTION 
It is an object of the present invention to provide an acetate-containing 
dialyzing composition and a bicarbonate-containing dialyzing composition 
which are easy to store and to handle. 
It is another object of the invention to provide an acetate-containing 
dialyzing composition and a bicarbonate-containing dialyzing composition 
both excellent in the ability to retain a quality stability for a long 
term. 
It is a further object of the invention to provide an acetate-containing 
dialyzing composition and a bicarbonate-containing dialyzing composition 
both free of the foregoing troubles during production. 
Other objects and features of the invention will become apparent from the 
following description. 
According to the present invention, there is provided a pasty composition 
for perfusing artificial kidney systems for dialysis, the composition 
comprising about 30 to about 70% by weight of a solid electrolyte 
component consisting of NaCl, KCl, CaCl.sub.2, MgCl.sub.2 and CH.sub.3 
COONa and about 70 to about 30% by weight of water, and the composition 
having a viscosity of about 1,000 to about 7,000 cps at 25.degree. C. 
According to the invention, there is also provided a process for preparing 
a pasty composition for perfusing artificial kidney systems for dialysis, 
the process comprising the steps of adding microfine NaCl powder to an 
aqueous solution of KCl, CaCl.sub.2, MgCl.sub.2 and CH.sub.3 COONa and 
kneading the mixture. 
According to the invention, there is further provided a process for 
preparing a pasty composition for perfusing artificial kidney systems for 
dialysis, the process comprising the steps of uniformly mixing NaCl, KCl, 
CaCl.sub.2, MgCl.sub.2 and CH.sub.3 COONa, adding water to the mixture and 
finely dividing the mixture. 
To overcome said problems of the conventional concentrated dialyzing 
solutions and dialyzing powders, we conducted extensive research and found 
that a quality-stable dialyzing composition can be prepared in a pasty 
form by a simple process. The present invention has been accomplished on 
the basis of this novel finding.

DETAILED DESCRIPTION OF THE INVENTION 
The pasty dialyzing composition of the invention comprises about 30 to 
about 70% by weight of solids and about 70 to about 30% by weight of water 
in a homogeneous state without separation between solids and liquid and 
has a viscosity of about 1,000 to about 7,000 cps at 25.degree. C. The 
proportions of KCl, CaCl.sub.2, MgCl.sub.2 and CH.sub.3 COONa in the 
solids are in such range that the ion composition in the aqueous solution 
prepared before use corresponds to the composition of acetate-containing 
dialyzing fluid (A) or bicarbonate-containing dialyzing fluid (B). 
The pasty dialyzing composition of the invention is used in the same manner 
as conventional concentrated liquid dialyzing products or powder dialyzing 
products. For use, the acetate-containing dialyzing composition of the 
invention is supplied for use along with glucose separately provided. 
Before use, the dialyzing composition and glucose are dissolved in water 
in such ratio that the solution has the predetermined electrolyte 
concentration and glucose concentration. The bicarbonate-containing 
dialyzing composition of the invention is similarly supplied for use along 
with sodium hydrogencarbonate, and before use, they are made into an 
aqueous solution of desired concentration. 
We will describe below by way of example two processes for preparing the 
pasty composition of the invention in detail. 
1. First process 
In the first process, sodium chloride is finely divided by an air 
classifying vertical impact mill (commercially avaialble under the 
trademark "micropulverizer") or like pulverizing means. It is preferred to 
use sodium chloride meeting the requirements of Japanese Pharmacopeia and 
having a mean particle size of about 500 .mu.m. The sodium chloride is 
pulverized to a particle size of up to about 105 .mu.m, preferably up to 
about 30 .mu.m. When the microfine sodium chloride powder is over 105 
.mu.m in particle size, the finally obtained product tends to assume not a 
homogeneous pasty form, but a suspension form. Such heterogeneous 
composition is prone to separation between solids and liquid during 
storage, making it difficult to take out of a container or to achieve the 
desired dilution before use and tending to give dilute solutions irregular 
in composition. The finely divided sodium chloride may be further 
classified by a micron-separator or like means to remove coarse particles 
and to obtain particles of uniform particle size. 
Other electrolyte compounds than NaCl are used in the ratio corresponding 
to the composition of dialyzing fluid (A) or (B) and are dissolved in 
water in an amount equal to about 40 to about 100% of the weight of the 
sodium chloride. 
Electrolyte compounds other than NaCl used include KCl, CaCl.sub.2 
(optionally hydrate), MgCl.sub.2 (optionally hydrate) and CH.sub.3 COONa 
(optionally hydrate). 
The proportions of the electrolyte compounds are in such range that the 
aqueous solution prepared before use has the ion composition of dialyzing 
fluid (A) or (B). Typical proportions are about 50.0 to about 90.0% by 
weight of NaCl, 0 to about 5.0% by weight of KCl, about 1.5 to about 4.0% 
by weight of CaCl.sub.2.2H.sub.2 O, about 1.0 to about 3.0% by weight of 
MgCl.sub.2.6H.sub.2 O and about 4.0 to about 45.0% by weight of CH.sub.3 
COONa.3H.sub.2 O. 
Subsequently the microfine sodium chloride powder prepared above is charged 
to a mixer and the aqueous solution of electrolyte compounds are added 
dropwise while fully mixed and ground to give a pasty product. The mixing 
is continued until the mixture becomes homogeneous and pasty. When 
required, a plurality of mixers with different mixing capabilities may be 
sequentially used to effect premixing and fine mixing. In mixing, glacial 
acetic acid may be added to concurrently carry out adjustment of pH. 
2. Second process 
In the second process, NaCl and other electrolyte compounds are used in the 
ratio corresponding to the composition of dialyzing fluid (A) or (B) and 
are diluted with water in an amount equal to about 40 to about 100% of the 
weight of NaCl. The mixture is charged to a mixer and is mixed and ground 
into a paste in the same manner as in the first process by the mixer. At 
the mixing step, the pH may be adjusted with the addition of acetic acid 
as in the first process. The mixing operation may be performed on 
sequential basis employing a plurality of mixers as in the first process. 
In the second process, pulverization of NaCl to be used and selection of 
kinds and proportions of other electrolyte compounds are done in the same 
manner as in the first process. 
Of the two processes, the first process is preferred in view of simplified 
procedure, stabilized production of higher quality product and ease of 
production control. 
Preferred proportions of electrolyte compounds in the pasty 
acetate-containing dialyzing composition of the invention are about 50 to 
about 70% by weight of NaCl, about 1.0 to about 5.0% by weight of KCl, 
about 1.0 to about 4.0% by weight of CaCl.sub.2.2H.sub.2 O, about 1.0 to 
about 3.0% by weight of MgCl.sub.2.6H.sub.2 O and about 25.0 to about 
45.0% by weight of CH.sub.3 COONa.3H.sub.2 O. The predetermined amount of 
glucose solution is conjointly used with the acetate-containing dialyzing 
composition of the invention as conventionally done. 
Preferred proportions of electrolyte compounds in the 
bicarbonate-containing dialyzing composition of the invention are about 
75.0 to about 90.0% by weight of NaCl, 0 to about 4.0% by weight of KCl, 
about 1.5 to about 4.0% by weight of CaCl.sub.2.2H.sub.2 O, about 1.0 to 
about 3.0% by weight of MgCl.sub.2.6H.sub.2 O, about 2.0 to about 12.0 by 
weight of CH.sub.3 COONa.3H.sub.2 O and about 1.0 to about 4.0% by weight 
of glacial acetic acid. The predetermined amount of bicarbonate solution 
is conjointly used with the bicarbonate-containing dialyzing composition 
of the invention. 
In accordance of the present invention, the following results can be 
achieved. 
(1) The pasty dialyzing composition of the invention facilitates storage, 
transportation and handling because it is reduced in volume and weight to 
approximately 1/3 to 1/5 the volume and weight of the conventional 
concentrated dialyzing fluids. 
(2) With a pasty form, the dialyzing composition of the invention causes no 
solidification on absorption of moisture unlike dialyzing powders. 
Consequently the composition can be easy to take out of a container and to 
dilute, and can avoid loss of powder due to scattering. 
(3) With high stability, the pasty dialyzing composition of the invention 
is free of variation in composition of electrolyte ions during storage so 
that the composition of the invention, diluted before use, becomes a 
dialyzing solution constant in composition and pH. 
(4) The pasty dialyzing composition of the invention can be produced with 
ease in a short time and is amenable to multikind and mass production. 
(5) The pasty dialyzing composition of the invention can be produced with 
simple manufacturing equipment through simplified procedure at 
significantly reduced costs. 
EXAMPLES 
The following examples illustrate the invention in further detail. 
EXAMPLE 1 
Sodium chloride (NaCl) meeting the requirements of Japanese Pharmacopeia 
was pulverized and the obtained fine particles were classified to give a 
microfine powder of 10 to 20 .mu.m in mean particle size. 
To 40 kg of distilled water were added with stirring potassium chloride of 
Japanese Pharmacopeia grade (2.537 kg), calcium chloride 
(CaCl.sub.2.2H.sub.2 O) of Japanese Pharmacopeia grade (3.513 kg), 
magnesium chloride (MgCl.sub.2.6H.sub.2 O) of Japanese Pharmacopeia grade 
(2.069 kg) and sodium acetate (CH.sub.3 COONa.3H20) of Japanese 
Pharmacopeia grade (11.165 kg), giving an aqueous solution of electrolyte 
compounds. 
Next, a 79.048 kg quantity of the obtained microfine powder of sodium 
chloride was fed to a mixer and the aqueous solution of electrolyte 
compounds was gradually charged to the mixer to effect kneading, giving a 
pasty product (3,400 cps in viscosity as determined by Brookfield 
viscometer at 25.degree. C.). 
About 1.66 kg of acetic acid was added to the obtained pasty product and 
the mixture was kneaded by a wet mixer to obtain a pasty 
bicarbonate-containing dialyzing material. 
Three 10 g portions of the obtained bicarbonate-containing dialyzing 
material were weighed out for use as test specimens and were analyzed. 
Table 1 below shows the results. 
TABLE 1 
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Specimen 1 
Specimen 2 
Specimen 3 
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NaCl 57.04% 57.08% 57.01% 
KCl 1.92% 1.88% 1.90% 
CaCl.sub.2.2H.sub.2 O 
2.56% 2.58% 2.56% 
MgCl.sub.2.6H.sub.2 O 
1.39% 1.40% 1.38% 
CH.sub.3 COON.sub.a.3H.sub.2 O 
6.98% 7.11% 7.05% 
H.sub.2 O 30.11% 29.95% 30.10% 
pH (5% solution) 
4.51 4.50 4.51 
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Table 1 shows that the obtained pasty bicarbonate-containing dialyzing 
composition of the invention had a homogeneous composition. 
The obtained bicarbonate-containing dialyzing composition was easy to 
handle and underwent no change in composition or pH even after 6-month 
storage in a polyethylene container. A slight separation of liquid phase 
occurred in the paste, but the paste was easily restored to the 
homogeneous state when wholly stirred. 
The obtained bicarbonate-containing dialyzing composition was easily 
dissolved in the predetermined amount of water and the solution was usable 
directly for bicarbonate dialysis. 
EXAMPLE 2 
Sodium chloride (NaCl) meeting the requirements of Japanese Pharmacopeia 
was pulverized and the obtained fine particles were classified to give a 
microfine powder of 10 to 20 .mu.m in mean particle size. 
To 45 kg of distilled water were added with stirring potassium chloride of 
Japanese Pharmacopeia grade (1.16 kg), calcium chloride 
(CaCl.sub.2.2H.sub.2 O) of Japanese Pharmacopeia grade (1.45 kg), 
magnesium chloride (MgCl.sub.2.6H.sub.2 O) of Japanese Pharmacopeia grade 
(1.19 kg) and sodium acetate (CH.sub.3 COONa.3H.sub.2 O) of Japanese 
Pharmacopeia grade (35.28 kg), giving an aqueous solution of electrolyte 
compounds. 
Next 45.27 kg of the obtained microfine sodium chloride powder was placed 
into a mixer and the aqueous solution of electrolyte compounds was 
gradually charged to the mixer to effect kneading, giving a pasty product 
of 5,300 cps in viscosity (as determined by Brookfield viscometer at 
25.degree. C.). 
The obtained pasty product was placed into a wet mixer to perform further 
kneading, giving a pasty acetate-containing dialyzing composition. 
About 15 kg of glucose was added to the obtained acetate-containing 
dialyzing composition. Three 10 g portions of the composition were weighed 
out for use as test specimens and analyzed. Table 2 below shows the 
results. 
TABLE 2 
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Specimen 1 
Specimen 2 
Specimen 3 
______________________________________ 
NaCl 31.09% 31.11% 31.12% 
KCl 0.77% 0.76% 0.79% 
CaCl.sub.2.2H.sub.2 O 
0.95% 1.10% 1.10% 
MgCl.sub.2.6H.sub.2 O 
0.86% 0.88% 0.86% 
CH.sub.3 COONa.3H.sub.2 O 
23.99% 24.20% 24.18% 
Glucose 10.70% 10.72% 10.70% 
H.sub.2 O 31.64% 31.23% 31.25% 
______________________________________ 
Table 2 reveals that the obtained dialyzing material of the invention had a 
homogeneous composition. 
The obtained acetate-containing dialyzing material was easy to handle and 
showed no change in composition or pH even after 6-month storage in a 
polyethylene container. Further, a slight separation of liquid phase 
occurred in the pasty product, but the product was easily restored to the 
homogeneous state when stirred. 
The acetate-containing dialyzing composition was easily dissolved in the 
predetermined amount of water and the solution was usable directly for 
acetate dialysis. 
TEST EXAMPLE 1 
NaCl meeting the requirements of Japanese Pharmacopeia was pulverized by a 
micro-pulverizer and the obtained microfine powder was classified with a 
micron-separator into three kinds of particles, i.e. (a) those of 105 
.mu.m or larger in particle size (500 .mu.m in mean particle size), (b) 
those of 104 to 31 .mu.m in particle size (53 .mu.m in mean particle size) 
and (c) those of up to 30 .mu.m in particle size (11 .mu.m in mean 
particle size). 
The pasty dialyzing product (A) (2,900 cps, 25.degree. C.), the pasty 
dialyzing product (B) (3,100 cps, 25.degree. C.) and the pasty dialyzing 
product (C) (3,400 cps, 25.degree. C.) were prepared in the same manner as 
in Example 1 with the exception of using the three kinds of microfine NaCl 
powders (a), (b) and (c) each for pasty products (A), (B) and (C), 
respectively. 
These pasty products are each placed into a 1000-l beaker (114 mm in 
diameter, 150 mm in height) to observe the changes in the separation 
between the liquid phase and the solid phase over a period of one month. 
The drawings, FIG. 1 A through FIG. 1 C, show the results after a lapse of 
one month. The figures at the bottom of the drawings represent the height 
(%) of the liquid phase after one month. 
In the pasty product (A), the liquid phase and the solid phase began to 
separate immediately after admixing. The height of the liquid phase 
accounted for 28.5% of the height of the product in one month, while the 
solid phase solidified and precipitated, exhibiting no fluidity. 
In the pasty product (B), a slight separation of liquid phase (height 8.7%) 
took place in the upper portion of the paste in one month, yet complete 
homogeneity as well as good fluidity was recovered by stirring. 
In the pasty product (C), only a slight separation (height 2.5%) occurred 
between the solid phase and the liquid phase during one-month storage. The 
pasty product (C) remained pasty with good fluidity as a whole.