Note: Descriptions are shown in the official language in which they were submitted.
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Pharmaceutical composition for peritoneal dialysis
D e s c r i p t i o n
The invention concerns pharmaceutical compositions which
contain a hydrocolloid and their use for peritoneal
dialysis.
Peritoneal dialysis (PD) is a method of systemic lavage
in temporary or chronic renal insufficiency. The
function of the kidneys is to remove end-products of
metabolism (urea or uric acid) or substances supplied
with the diet (e.g. potassium) from the body. When there
is a loss of kidney function this results in poisoning
of the organism by accumulation of such substances if no
substitute measures are taken. Apart from peritoneal
dialysis, haemofiltration and haemodialysis (systemic
lavage) also come into consideration as substitute
measures for the partial or complete loss of kidnev
function. These alternatives to peritoneal dialysis are
associated with a great deal of apparatus and with the
availability of an access to a blood vessel which
disadvantages for the patient.
In contrast peritoneal dialysis, in particular in the
form of continuous ambulatory peritoneal dialysis
(CAPD), has the advantage of less encroachment on the
patients and lack of dependence on stationary apparatus.
The disadvantage of conventional hyperosmolar peritoneal
dialysis is damage to the peritoneal epithelium by the
use of hyperosmolar solutions that are used to achieve
an excretion of the desired substances from the blood
into the peritoneal cavity. In conventional peritoneal
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dialysis it is necessary to achieve this effect by the
addition of 1 t~ 5 % by weight glucose or other
osmotically active substances (e~g. sorbitol) to the
lavage solution. The passage of glucose from the
abdominal cavity into the organism has a nutritive
effect which in some circumstances can be of
considerable significance and is undesirable.
The object of the present invention is therefore to
provide pharmaceutical compositions for peritoneal
dialysis which avoid the aforementioned disadvantages of
the previously common PD and in particular of continuous
ambulatory peritoneal dialysis. This object is achieved
by the present invention.
According to claim 1 the subject matter of the invention
is a pharmaceutical composition for peritoneal dialysis
containing a starch ester as the colloid-osmotically
active substance in which the starch is substituted with
acyl groups of monocarboxylic acids or dicarboxylic
acids or mixtures of mono- and dicarboxylic acids each
with 2 to 6 C atoms in an amount of 1 to 12 ~ by weight
in combination with a physiologically acceptable
electrolyte and/or one or several other osmotically
active substances.
Practical embodiments thereof are the subject matter of
claims 2 to 7.
It is known that starch derivatives, dextrans and
gelatins, preferably with a molecular weight > 40000,
can be used as a blood plasma substitute (plasma
expanders) (cf. e.g. US-A 3,937,821; DE-A 33 13 600;
"Romp Chemielexikon, 9th Volume, page 919, 1509).
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It has now been found that starch esters as defined in
claim 1 and which are distinguished by a high water
binding capability are very well suited for use in
peritoneal dialysis.
According to the invention it is possible by dispensing
with hyperosmolar solutions or in the case of a
combination with conventionally used osmotically active
substances by substantially reducing the hyperosmolarity
of the lavage solutions in particular by doing without
glucose or by reducing the concentration of glucose as
the previously most important component to achieve a
milder dialysing effect without damaging the peritoneal
epithelium and with a lower nutritive action. According
to the invention the difference in the osmotic pressure
or the difference in colloid osmotic pressure is not of
importance as the effective force for the excretion of
end-products of metabolism into the peritoneal cavity
but rather the water binding capability of acyl starch
in the peritoneal cavity. The hydrocolloid effect causes
a binding of water in the peritoneal cavity, a so-called
"solvent drag" which is comparable with the effect of an
osmotic pressure difference. This "solvent drag" leads -~
to an excretion of substances into the peritoneal cavity
and thus exerts the dialysing effect.
The invention therefore also concerns the use of the
aforementioned pharmaceutical composition according to
the invention for peritoneal dialysis.
The molecular weight (weight average Mw) is preferably
> 1000 Daltons. The upper limit of the molecular weight
range of the starch esters is in this case uncritical
and is in particular dependent on the fact that they
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should not lead to deposits in the organism. The upper
limit of molecular weight which also depends on the type
of starch ester is usually ca. lO00000 Daltons. A
molecular weight of (~r) of ca. 100000 to 200000 Daltons
is preferably used.
The starch esters which are particularly preferred
according to the invention are starch esters with a
molar substitution of 0.1 to 1.5. Starch esters are
esters with organic carboxylic acids and in particular
with aliphatic mono- and dicarboxylic acids with 2 to 6
carbon atoms such as e.g. acetic acid, propionic acid,
butyric acid, isobutyric acid and in particular acetic
acid. The molar substitution MS is preferably 0.3 to
0.5. A particularly preferred starch ester according to
the invention is acetyl starch, in particular with a
molecular weight (Mw) of 100000 to 200000 Daltons and a
substitution MS of 0.3 to 0.5.
The pharmaceutical composition according to the
invention for peritoneal dialysis also contains a
physiologically acceptable electrolyte and/or another
osmotically active substance. The concentration of
starch ester is preferably 1 to 12 % w/v, in particular
2 to 6 % w/v relative to the total pharmaceutical
composition.
Electrolytes which come into consideration as
physiologically acceptable electrolytes are those which
are usually used in compositions for peritoneal dialysis -
i.e. in particular for example sodium chloride, calcium
chloride, salts of the lower carboxylic acids with 2 to
4 carbon atoms, in particular acetic acid.
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The other osmotically active substance can be a lower
molecular organic compound, in particular one which is
used for example in conventional hyperosmolar peritoneal
dialysis and preferably consists of polyvalent alcohols,
monosaccharides, disaccharides such as e.g. glycerol,
sorbitol, maltose and primarily glucose and/or amino
acids.
The pharmaceutical compositions according to the
invention can contain one or several starch esters
according to the invention in combination with one or
several of the osmotically active substances in water.
The starch esters used according to the invention can be
produced according to the application with the title
"Process for the production of starch esters for
clinical, in particular parenteral use" of the same
applicant, file number P 4123000Ø The production of
the pharmaceutical composition is carried out in a known
manner e.g. by mixing the components and the ~
pharmaceutical vehicle, the starch ester being - ;
preferably used in the form of a powder obtained by
drying, e.g. by spray drying, drum drying or vacuum
drying, and grinding.
The invention therefore also concerns the use of a
starch ester in which the starch is substituted with
acyl groups of monocarboxylic acids or dicarboxylic "
acids or a mixture of mono- and dicarboxylic acids each
with 2 to 6 C atoms for the production of a
pharmaceutical composition for peritoneal dialysis
according to claim 9. Practical embodiments of this use
are set forth in the subclaims 10 to 15.
2~31fi~
During dialysis the hydrocolloids used in the lavage
solution pass from the peritoneal cavity into the blood.
As a consequence those starch esters are especially
suitable which are degraded in the organism and are thus
not stored even in long-term treatment.
A particularly preferred starch ester according to the
invention is acetyl starch. These starch esters can be
degraded and metabolised by the action of endogenous
enzymes. As a resu~t of this physiological degradation
glucose is also formed in addition to oligosaccharides,
isomaltose and maltose. As a consequence it is also
possible to carry out a peritoneal dialysis without the
addition of glucose (glucose-free peritoneal dialysis).
Part of the glucose formed during the degradation of the
starch ester, such as acetyl starch, is excreted into
the peritoneal cavity even during the dialysis and as a
consequence it is possible to reduce the nutritive
effect of peritoneal dialysis with starch esters. An
influence of peritoneal dialysis carried out with starch
ester on the fat metabolism of experimental animals was
not detected. "Glucose-free peritoneal dialysis"
therefore has major advantages compared to conventional
peritoneal dialysis in which glucose solutions of higher
percentage are used. In addition degradation by
endogenous enzymes prevents storage of starch esters. In
contrast to hydroxyethyl starch even after a 5 day
peritoneal dialysis with acetyl starch no polysaccharide
was detected in high concentrations in the organs of the
examined experimental animals.
The aforementioned results are based on animal ;
experiments on bilaterally nephrectomized rats. The
blood of the animals was purified of urea as a reference
substance or of corresponding electrolytes (e.g.
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potassium) by use of a 3 % acetyl starch solution with
addition of appropriate electrolytes. The animals could
be maintained in an adequate state of health ~y daily
peritoneal dialysis over a period of 5 days. Comparative
experiments were carried out with solutions which
contained glucose (2 ~ w/v). In addition investigations
were carried out with solutions which contained a
combination of acetyl starch according to th~ invention
with 1 ~ by weight glucose as the other osmotically
active substance. Dialysis effects were observed in all
cases which were not only due to differences in the
osmotic or in the colloid osmotic pressure. An
approximation of the plasma concentration and lavage
solution concentration was also achieved by using
isomolar hydrocolloid solutions according to the
invention (i.e. without osmotically active gradients).
This therefore proves that the hydrocolloid effect
causes a binding of water in the peritoneal cavity and
exerts a dialysing effect by means of the so-called
"solvent drag" which corresponds to that of an osmotic
pressure difference.
Even after a 5 day successful peritoneal dialysis with
acetyl starch solutions only traces of acetyl starch
were detected in the serum of the dialysed animals
(cf. Fig. 1). When the organs were examined acetyl
starch was detected neither in the spleen nor in the
liver or lungs. It can therefore be concluded from these
investigations that acetyl starch which enters the blood
circulation during the peritoneal dialysis is rapidly
and completely degraded by endogenous enzymes.
It is intended to elucidate the invention in more detail
by the following examples.
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Example
Production of acetyl starch (AST) solutions for
continuous ambulatory peritoneal dialysis (CAPD)
250 ml of each of the CAPD solutions listed in the
following Table 2 were prepared. The electrolyte mixture
stated in Table 1 was used for this. Acetyl amylopectin
with a molar substitution MS of 0.355 and a Mw of ca.
200000 Daltons was used as the acetyl starch (AST). The
solutions were dispensed into 20 ml piercing vials~
Table 2 shows that the solutions prepared in this way
have a good stability. Even after sterilisation there -
was only a negligible saponification of the ester
groups.
Table
(Electrolyte mixture for CAPD solutions with AST)
M mmol/l g/l
58.443 sodium chloride 120 7.013
136.080 Na acetate.3H2O 25 3.402
147.020 Ca chloride.2H2O 2 0.294
60.053 acetic acid 5 0.303
osmolarity mOsmol/l 301
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Table 2 ; ~
(CAPD solutions with AST) ~ ;-
No.AST Gluc mOsmol/l pH acetic acid re~idual Mw.10 3*Mn.10 3
g/l g/l free esterif. acetyl groups.
mmoltl mmol/l mol/mol ~
:,:
1/1 30 - 301 5.49 3.28 53.66 - 313 153 before
~teril.
5.25 5.34 51.51 0.96 230 140 30'100 ;
4.85 11.49 45.17 0.84 219 134 8'121
~ .,
1/2 30 0.901 306 5.44 3.28 53.88 - 306 155 before
steril.
5.21 5.44 51.51 0.96 233 142 30'100
4.86 11.49 46.24 0.86 216 134 8'121
~ .
2/1 45 - 301 5.46 3.39 78.61 - 325 153 before
steril.
5.19 5.95 76.68 0.98 203 130 30'100
4.79 14.06 70.01 0.89 223 136 8'121
-
2/2 45 0.901 306 5.48 3.39 78.29 - 275 147 before
teril.
5.18 6.36 76.14 0.97 218 136 30'100
4.81 14.06 68.12 0.88 226 138 8'121
* The higher ~w's and Mn's before sterilization are
probably mainly due to formation of aggregates.
All solutions were almost colourless even after the
sterilization. As expected the sterilization caused a
slight acetyl cleavage . The residual acetyl content was
ca. 96 % in a mild sterilization (30 min at 100C) and
ca. 86 % after sterilization for 8 minutes at 121C. It
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is therefore expedient to carry out a mild
sterilization.
The following further solutions according to the
invention for peritoneal dialysis using the electrolytes
stated in Table 1 were prepared in a similar manner:
1. 3 % acetyl starch solution (molar substitution 0.3
or 0.5)
2. Combination solution with 1.5 % acetyl starch and
1 % glucose (as an example of an osmotically active
substance)
3. 3 % hydroxyethyl starch solutions HES with 200/0.5
(weight average of the molecular weight ca. 200000
Daltons, molar substitution 0.5 mol), HES 100/0.7,
HES 40/0.5, HES 70/0.7 and HES 450/0.7.
4. 3 % hydroxyethyl starch solutions (HES 40/0.5 and
HES 200/0.5) with 1 ~ glucose.
Example 2
Procedure for peritoneal dialysis
.
Wistar rats with a body weight of 250 to 350 g are
bilaterally nephrectomized under anaesthesia. In
addition two indwelling catheters with external leads
are surgically introduced into the abdominal cavity. As -~
a substitute for kidney function 6 to 8 lavages of the ~-
abdominal cavity are carried out by introducing 60 to
100 ml lavage solution in each case . After a period of
30 to 60 minutes in each case, the lavage solution is
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drained off.
With this treatment it is possible to keep the animals
alive and in good health over longer periods despite the
lack of kidneys. 5 dialysis days were chosen as the
experimental period. On the 5th day blood samples were
taken from the orbita immediately before the start of
dialysis. After the last dialysis of the day the animals
were killed under anaesthesia by exsanguination from the
abdominal aorta. Subsequently the following organs were
excised for further examinations: spleen, liver, lungs.
Figure 1 shows the serum content (in mg/ml) after the
5th dialysis ~5th day).
Figure 2 shows the content of hydrocolloid in the spleen
~in mg/g) after the 5th dialysis (5th day).
In Fig. 1 and 2
A, B, C denote: 3 % acetyl starch (acetylamylopectin)
solutions without addition of glucose,
D to H denote: 3 % hydroxyethyl starch solutions without
addition of glucose and namely with HES 100/0.7 (D), HES
40/0.5 (E), HES 70/0.7 (F), HES 200/0.5 (G) and HES
450/0.7 (H)-
Fig. 3 shows the urea content in the serum before andafter the 5th dialysis (5th day) and in the dialysate.
I, J, K denote: 3 % acetyl starch solution without
glucose (extraction 36 %) and namely the serum content
before dialysis (I), after dialysis (J) and in the
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dialysate (K);
L, M, N denote: 3 % HES 40to.s solution with 1 % glucose
~extraction 39.4 ~) and namely the serum content before
dialysis (L), after dialysis (M) and in the dialysate
(N); :~
0, P, R denote: 3 % HES 200/0.5 solution with 1 %
glucose (extraction 42 ~) and namely the serum content
before dialysis (O), after dialysis (P) and in the
dialysate (R).
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