Note: Descriptions are shown in the official language in which they were submitted.
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The invention relates to solutions for parenteral
perfusion ~or nutrition and/or supply,of calories, containing
phosphorus, and for the treatment of hypophosphataemia and
hypercalcaemia.
In parenteral nutrition, which iis usually carried
out with perfusion solutions, which coIltain amino acids,
carbohydrates, vitamins and essential minerals, it is also
necessary to include an ade~uate supply of phosphorus (see,
for example RVBERG R.L. Allen, et al.: Hypophosphatemia
with H~pophosphaturia in Hyperalimentation. Surg. Forum~
2~:87, 1971). The simul~aneous administration of essent1al
nutrients, Pspecially amino acias, carbohydrates and
minerals, together with calcium and phosphorus, is particular-
ly important, and the availability o~ inorganic phosphate
is absolutely essential for "total parenteral nu~rition" ~ -
("hyperalimentation"). Because of the use of highly purified
amino acids in present-day parenteral nutrition, this phosphorus~
~iciency is particulæly liable to manifest itself since,
in contrast to the situation when casein hydrolysis products
were employed, there is now no phosphate available from the
raw materials.
Moreover, the administration of phosphorus is not
only necessar~ to cover the daily requirements of parenteral
nutrition, but also to treat existing hypophosphataemias
and hypercalcaemias. (D. Schwander, Intravenose Applikation
;von Phosphat (Intravenous Administration of Phosphate), Med.
: ~ .
Neuheiten No. 3/4, 1973~.
Furthermore, it is ~nown that in carbohydrate
therapy an undesired lowering of the inor~anic serum phosphate
level may occur. CDer initiale Phosphatabfall im Serum von
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Gesunden und Leberkranken nach intravenoser Verabreichung
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von Hexosen und 2ucheralkoholen (The Initial Decrease in
Phosphate in the Serum of Healthy Persons and Patients
Sllffering from Liver Diseases, after Intravenous Adminis-
tration of Hexoses and Sugar Alcohols), H.P. Wolf, W.
Queisser and K. Beck, Klin, Wochenschrift 47th year of
publication, issue 20, pages 1084-1086, 1969)~
These reasons make clear the importance of the
intravenous administration of sources of phosphorus.
Hitherto it was unfortunately only possible to
inject phosphorus, during the perfusion, in the form of
inorganic phosphate, or to mix it with other substrates,
shortly before administration, under aseptic conditions in
the dispensary. The high level of technical effort and
expenditure on personnel required for this, and the great
danger of bacterioloyical contamination ~S.J. Dudrick,
American Journal of Hospital Pharmacy 28:82-91 (Feb.) 1971
necessarily imposes se~ere limits on its routine use in
clinics.
The preparation of a complete, sterilisable,
phosphorus-containing parenteral nutrient solution which
can be handled easily and safely has hitherto not proved
possible. This was due, inter alia, to the calcium content
and the relatively high pH value of these solutions lpH > 6).
In addition, heat sterilisation causes precipltation of
calcium phosphate. Furthermore~ these solutions mostly
also contain magnesium~ This also leads to precipitates of
magnesium jammonium phosphate in the presence o inorganic
.
phosphate and of the small amounts of ammonia (from the
amino acids~ produced during stPrilisation, and as a result ~ -
significantly
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limits the stability of the preparation even at low concen-
~, trations. In addition, incompatibilities result if trace
elements and inorganic phosphate are present, since
precipitates (for example iron phosphate) can again be formed.
Even in perfusion solutions which are ~ree from electrolytes,
precipitates with inorganic phosphate are frequently formed,
since they may be caused by traces of, for example, calcium
ions and iron ions, which may come rom the filters and/or
the raw materials.
According to the present inventionl all these
problems can surprisingly be eliminated if the perfusion sol
~ ution contains a glycerophosphate as source of phosphorus in
; addition to the other requisite ingredients. Surprisingly,
it has also proved possible to prepare the solution with a
ph ~ 6 and make it stable and heat-sterilizable.
The present invention accordingly provides, in one
aspect, a stable, heat sterilizable solution for parenteral
perfusion having a pH value greater than 6 for the treatment
or prophylaxis of hypophosphataemia consisting essentially
of amino acids,lcarbohydrates, essential minerals, and, as
the source of phosphorus, a therapeutically active amount
providing up to 95 mmols of phosphorus per liter of the
solution of a water-soluble non-toxic glycerophosphate.
The present invention also provides, in another
aspect, a sta~le, heat sterilizable solution for parenteral
perfusion having a pH value greater than 6 for the treatment
or prophylaxis of hypercalcaemia consisting essentially of
; amino acids, carbohydrates, essential minerals, and, as a
source of phosphorus, a therapeutically active amolmt provi-
ding up to 95 mmols of phosphorus per liter of the solution
of a water-soluble non-toxic glycerophosphate selected from
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the group consisting of magnesium, sod.ium and potassium
glycerophosphates.
In the solutions of the present invention useful
for the treatment or prophylaxis of hypophosphataemia, the
phosphorus may be present as sodium, potassium, magnesium
or calcium glycerophosphate, or as a combination of these.
In the case of solutions useful for the treatment or
prophylaxis of hypercalcaemia, the glycerophosphate salt is
selected from the magnesium, sodium and potassium salts,
10or combinations thereof. By combining the various salts it
is possible, for a given intended phosphorus content, so to
provide part of the cation requirements of the solution and
to provide the remainder of the latter by addition of other
salts containing the desired
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cations. It has been demonstrated that glycexophosphates
are on the one hand effective phosphate donors and on the
other hand toxicologically harmless when used in the
requisite amount.
The effectiveness has been demonstrated by the
experimental results shown graphically in the Figure.
Curve 1 shows the liberation of inorganic phosphate after
injection o glycerophosphate. Curve II shows the complete
normalisation o~ the serum inorganic phosphate level
following simultaneous injection of fructose and glycero-
phosphate, while Curve III shows that the administration
of fructose alone, in the same amount, causes a drop in the
phosphate level.
In vitro experiments have shown that at pH 7.4 both
acid phosphata~e and alkaline phosphatase splits glycero-
phosphate to form glycerine and inorganic phosphate.
Further it has ~een found ln vitro that the phospha- -
tases present in blood plasma produce a time-dependent,
satisfactory splitting of the glycerophosphate. Thus, for
example, addi~ion of 1~ mol of glycerophosphate to 250~1~
.
of plasma at an incubation temperature of 37C causes the
liberation of about 50% of the glycerine and in~rganic
phosphate after one hour and 75% after two hours.
Toxicity te6ts have demonst~ated that glycerophosphates
are toxicologically harmless. The actute toxicity is about
the same for ~- and ~ -sodium glycerophosphate (LD50= 3.8
~and 3.4 g/kg, respectively, in ratsl. In dogs, the subacute
toxicity is of a similar order of magn1tude. Doses of up to
2 g~kg administered intravenously were tolerated without
any symptoms over the course of 14 days.
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The Examples given below of perfusion solutions
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containing glycerophosphate illustrate the inventionO
The solutions can be prepared in the usual manner
in accordance with the present state of the technique of
preparation (of such solutions) and are heat-sterilisable,
sterile, free from pyrogen and stable.
EXAMPLE 1
Laevulose 60.00 g/l
G1UCQSe monohydrate 33.00 g/l
Xylitol 30.00 g/l
10 Sodium glycerophosphate.5H2O 9.184 g/l
Potassiwm chloride 1.864 g/l
Magnesium chloride.6H2O . - 0.610 g/l
Zinc sulphate.7H2O 0.022 g/l
Vitamin Bl chloride.HCl 0.004 g/l
L,Malic acid 2.270 g/l
EXAMPLE 2
Laevulose 100.00 g/l
Glucose monohydrate 55.00 g/l ~ .
Xylitol 50.00 g/l
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20 Calcium glycerophosphate 0.630 g/1
Sodium glycerophosphate.5H2O 5o204 g/l
EXAMP~E 3
Sodium glycerophosphate.5H2O . 3.061 g/l
.: Sodium chloride . 0.409 g/l `:
.
: : Sodium acetate.3H2O 1.905 g/l
Potassium chloriae~ 1.118 g~l
: P~tasaium acetate . 0.491 g/l
Sodium hydroxide ~ 0.420 g/l
Potassium h~droxide 0.561 g~l
Calcium chloride.2H2~ 0.36~ g/1
Magnesium acetate.4H2O 0~643 g/1
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L-Isoleucine 0.755 g/l
L-Leucine 1.100 g/l
L-Lysine.HCl. 1.250 g/l
L-Methionine 1.050 g/l
L-Phenylalanine lolO0 g/l
L-Threonine 0.500 g/l
L-Tryptophane 0.225 g/l
L-~Iistidine 0.500 g/l
L-Arginine 2.000 gJl
L-Alanine 3.000 g/l
L-Proline 3.500 g/l
L-Glutamic acid 4.500 g/l
L-Valine 0.750 g/l
Glycine 5.000 g/l
Sorbitol 125.000 g/l
Nicotinic acid amide 0.020 g/l
Pyridoxine hydrochloride 0.015 g/l
Na riboflavin-5'-phosphate 0.002 g/1
EXAMPLE 4
20Potassium glycerophosphate : 1.692 g/1
Sodium glycerophosphate 5.204 g/1
Calcium glycerophosphate 0.630 g/1
Sodium chloride 0.409 g/l
: Potassîum chloride 0.372 g/l
Potassium acetate 0.491 g/l
Sodium hydroxide , 0.410 g/l
Potassium hydroxide 0.561 g/1
Sodium acetate.3H2O 1.224 gJl
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Magnesium acetate~4H20 0.643 gh
L~Isoleucine 0.775 g/l
L,Leucine . ~.1.100 g/l
h-Lysine.HCl 1O250 g~1
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L,~Iethionine 1,050 ~/1
L,Phenylalanine 1.100 g/l
L-Threonine 0.500 g/l
L-Tr~ptophane 0.225 g/l
~-~istidine 0~500 g/l
L-Arginine 2O000 g/l
L,~lanine .3~000 g/l
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L-Proline 3O500 g/l ~
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~-Glutamic acid 4~500 g/1
L Valine 0.750 g/l
Glycine S.000 g/l
Sorbitol 70.000 g/l
~yli~ol . ~.0~0 ~
Glycerine 35O000 g/l
~icotinic acid amide 0.020 g~l
Pyridoxine hydrochloride 0~015 g~l
~a riboflavin-5'-phosphate 0.002 g/l : ~
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