Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
RAN 4410/96-01
1055926
The pre~ent invention relates to a salt. More
particularly, the invention is concerned with a salt of a
penicillanic acid derivative, a proces-s for the manufacture
thereof and pharmaceutical preparations containing same.
The salt provided by the present invention is the salt
of 6-l(R)-a-amino-p-hydroxyphenylacetamido]-penicillanic acid
with arginine.
6-[(R)-a-Amino-p-hydroxyphenylacetamido]-penicillanic
acid is an antibiotic which is known under the name amoxycillin
and which ha~ a wide spectrum of activity. Amoxycillin, which
is practically in~oluble in water and aqueous solutions, as
well a it3 hitherto known salts, can not be administered
parenterally.
There has accordingly been a need for a new, non-toxic,
parenterally admini~trable form of amoxycillin while retaining
the antibiotic propertiea thereof.
It has now been found in accordance with the present
invention that the arginine ~alt of amoxycillin satisfies the
foregoing requirements.
According to the process provided by the pre~ent
invention, the arginine salt of amoxycillin is manufactured
by reacting 6-[(R)-a-amino-p-hydroxyphenylacetamido]-
-penicillanic acid or a hydrated form thereof, the amino group
Me/26.6.1975 - 2 -
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being optionally present in protected form, with arginine and
cleaving off a protecting group which may be present.
The 6-[(R)--amino-p-hydroxyphenylacetamido]-penicillanic
acid used as the starting material can contain an amino group
provided with a protecting group instead of a free amino group,
Such a protected amino group is then converted, following the
reaction of the 6-[tR)-~-amino-p-hydroxyphenylacetamido]-
penicillanic acid with arginlne, into a free amino group in a
manner known per se. Thus, for example, an optionally sub-
stituted benzyloxycarbonylamino group can be re-converted into
a free amino group by catalytical hydrogenation.
In the reaction of amoxycillin or a hydrated form thereof
with arginine there are preferably used equivalent amounts of
both reactants. ~owever, an excess of up to about 10% of
arginine can be used if desired. The reaction can be carried
out in the presence of water, methanol, dimethyl sulphoxide,
dlmethylformamide or the like, or in the presence of a mixture
of propyleneglycol and methanol or of a mixture of water or
propyleneglycol on the one side and ethanol, propanol or iso-
propanol on the other side, as a solvent, there being prefer-
ably used methanol, a mixture of propyleneglycol and methanol
or a mixture of water or propyleneglycol on the one side and
ethanol, propanol or isopropanol on the other side. Most
preferred ls the use of a mixture of propyleneglycol and
ethanol. The reaction i5 conveniently carried out at a temper~
ture between about 0C and 30C. The reaction is preferably
carried out at room temperature or, when water is used as the
solvent, at 5C.
1055926
When the reaction of amoxycillin or a hydrated form thereof
with arginine ls carried out in the presence of water as a
solvent, the isolation of the arginlne salt of amoxycillin
from the reaction mixture can be carried out by lyophilisation.
When the reaction of amoxycillin of a hydrated form thereof
with arginine is carried out in the presence of a solvent
other than water, e.g. methanol, dimethyl sulphoxide or
dimethylformamide, the lsolation of the arginine salt of amoxy-
clllin from the reaction mixture can be carried out by stirring
the reaction mixture in a second solvent, e.g. diethyl ether,
ethyl acetate or the llke, in which the arginine salt of amoxy-
cillin is insoluble. In thls case, at least 2 volumes of the
second solvent are conveniently used per volume of the first
solvent.
When the reactlon of axginine with amoxycillin or a
hydrated form thereof is carried out in the presence of a
mixture of water and ethanol, propanol or isopropanol, as a
solvent, there are conveniently used 15-25 volumes, preferably
20 volumes, of water per 100 volumes of ethanol and 40-60
volumes, preferably 50 volumes, of water per 100 volumes of
propanol or isopropanol. When the reaction of arginine with
amoxycillin or a hydrated form thereof is carried out in the
presence of a mixture of propyleneglycol and methanol, ethanol,
propanol or isopropanol, as a solvent, there are conveniently
used 30-50 volumes, preferably 40 volumes, of propyleneglycol
per 100 volumes of methanol or ethanol and 60-100 volumes,
preferably 75 volumes, of propyleneglycol per 100 volumes of
propanol or isopropanol. When a mixture of propyleneglycol and
methanol or a mixture of water or propyleneglycol on the one
side and ethanol, propanol or isopropanol on the other side is
used as a solvent, the arginine salt of amoxycillin can be
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isolated from the reaction mixture by stirring the reaction
mixture in a solvent, conveniently ethanol, propanol or iso-
propanol, in which the arglnine salt of amoxycillin is insoluble.
In order to precipitate the arginine salt of amoxycillin, there
are conveniently used 3 volumes of one of these three solvents
per volume of the mixture of propyleneglycol and methanol or
per volume of the mixture of water or propyleneglycol on the
one side and ethanol, propanol or isopropanol on the other
side, used as solvent in the reaction of arginine with amoxy-
clllin.
The arginine salt of amoxycillin has an antibioticactivity in the order of that of amoxycillin. It possess a
wide spectrum of activity against gram-positive and gram-
-negative microorganisms.
The salt provided by the present invention can be used
for the treatment and prophylaxis of infectious diseases and
as disinfection agents. Individual dosages of ca 0.25 g to
2 g up to four times per day can be administered to adults.
On the basis of its excellent water-solubility (more than
10%) and of its excellent local tolerability, the salt provided
by the present invention is particularly suitable for parenteral
administration.
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The acute toxicity (LD 50) of the arginine salt of
amoxycillin amounts to 2500-5000 mg/kg upon intraveneous
administration and to more than 5000 mg/kg upon subcutaneous
administration to mice. The activity (CD 50) of the arginine
salt of amoxycillin against Escherichia coli upon subcutaneous
administration to mice amounts to 4.5 mg/kg.
Pharmaceutical preparations provided by the present
invention can contain the arginine salt of amoxycillin in
association with a compatible pharmaceutical carrier material.
Such a carrier material can be an organic or inorganic inert
carrier material suitable for enteral or, especially, parenteral
administration such as, for example, water, gelatin, gum arabic,
lactose, starch, magnesium stearate and the like. The
pharmaceutical preparations can be made up in a solid form
(e.g. as tablets, dragées, suppositories or capsules) or,
especially, in a liquid form (e.g. as aqueous solutions). The
pharmaceutical preparations may be sterilised and/or may contain
adjuvants such as preserving, stabilising, wetting or
emul~ifying agents, salts for varying the osmotic pressure or
buffers. The pharmaceutical preparations may also contain
therapeutically valuable materials other than the salt provided
by the present invention. Preferably, the arginine salt of
amoxycillin ls contained as active substance in a dry ampoule.
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The following Examples illustrate the process provided
by the present invention:
Example 1
1.70 g of L-arginine are added portionwise within 10
S minutes to a suspension of 4.20 g of amoxycillin trihydrate
in 200 ml of water stirred at 5C. After stirring for a
further 10 minutes, undissolved material is filtered off under
suction and the filtrate is lyophilised. There are obtained
5.2 g of lyophilisate. Melting point: decomposition above
200C. [a]25 = +175.0 (c = 1.0 in water).
Example 2
A suspension of 184 g of L-arginine in 4 litres of
absolute methanol, stirred at room temperature, is treated
within 3 minutes with 429 g of amoxycillin trihydrate and the
lS mixture is vigorously stirred for a further 15 minutes.
Insoluble material is filtered off under suction and the
filtrate is introduced into 10 litres of diethyl ether. The
precipitate is filtered off under suction, washed with 6 litres
of diethyl ether and dried. There are obtained 491 g of the
arginine salt of amoxycillin. Melting point: decomposition
above 200C. []25 = +174.7 (c = 1.0 in water).
Example 3
To a suspension of 12 g of L-arginine in 21 ml of water,
stirred at room temperature, are added 100 ml of absolute
ethanol and immediately thereafter 24 g of amoxycillin
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trihydrate. After stirring for 5 minutes, the mixture is
filtered clear under suction and the syrupy solution allowed
to flow into 1.2 litres of vigorously stirred absolute ethanol
cooled to -5C. The precipitated product is filtered off
under suction and washed with 400 ml of absolute ethanol.
After drying in vacuo, there are obtained 20.5 g of the arginine
salt of amoxycillin. Melting point: decompo~ition above
200C. [~]25 = +165.9 (c = 1.0 in water).
Example 4
42 g of amoxycillin trihydrate are added to a suspension
of 21 g of L-arginine in 70 ml of propyleneglycol and 180 ml
of absolute ethanol and the mixture is intensively stirred for
45 minutes at room temperature. The mixture is then filtered
and the fi~trate introduced into 1.4 litres of absolute ethanol
at -5C while stirring. The precipitated salt is filtered off
under suction, washed four times with 50 ml of absolute ethanol
each time and dried in vacuo. There are obtained 40.4 g of
the arginine salt of amoxycillin. Melting point: decompo-
sition above 200C. [a]25 = +157 (c = 1 in water).
Example 5
8.2 g of amoxycillin trihydrate are added to a sl~spension
of 4.2 g of L-arginine in 60 ml of propyleneglycol and 80 ml
of isopropanol and the mixture is intensively stirred for 60
minutes at room temperature. The mixture is then filtered
and the filtrate introduced into 500 ml of isopropanol at 5C
while stirring. The precipitated salt is filtered off under
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suction, washed four times with 30 ml of isopropanol each time
and dried in vacuo. There are obtained 8.2 g of the arginine
salt of amoxycillin. Melting point: decomposition above
200~C. [~]D5 ' +168.7 (c = 1 in water).
Example 6
To a suspension of 20 g of L-arginine in a mixture of
70 ml of propyleneglycol and 180 ml of methanol are added
40 g of amoxycillln trihydrate and the mixture is stirred at
20C for 15 minutes. The mixture is then filtered, washed wlth
a mixture of 28 ml of propyleneglycol and 72 ml of methanol
and added to 1,4 1 of isopropanol stirred at 5C. After
stirring at 5C for a further 15 minutes, the precipitated
arginine salt of amoxycillin is filtered off under suction and
washed five times wlth 50 ml of i~opropanol. After drying in
vacuo, there are obtained 50,2 g of the arginine salt of
amoxycillin. Melting point: decomposition above 210C.
[]D5= ~159 (c = 1,493 in water).
Example 7
To a suspension of 20 g of L arginine in a mixture of
70 ml of propyleneglycol and 180 ml of absolute ethanol,
vigorously stirred at 20C, are added 40 g of amoxycillin
trihydrate and the mixture is stirred for a further 30 minutes
at 20C. Insoluble material in then filtered off, washed with
a mixture of 14 ml of propyleneglycol and 36 ml of absolute
ethanol and the viscous solution is added to 1,4 1 of isopro-
panol stirred a 5C. After stirring at 5C for a further
15 minutes, the precipitated arginine salt of amoxycillin is
filtered off under suction and washed five times with 50 ml of
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isopropanol and then flve times wlth 50 ml of diethyl ether.
After drying in vacuo, there are obtalned 45,7 g of the
arginine salt of amoxyclllin. Melting point: decomposition
above 210 C. [~]D = +172,2 (c = 1,5 in water).
The following Examples illustrate typical pharmaceutical
preparations containing the arginine salt of amoxycillin
provided by this invention:
Example A
A lyophilisate of the following composition, based on 4 ml
of ready-for-use injection solution, is manufactured in the
usual manner:
Arginine salt of amoxycillin370 mg
Methyl p-hydroxybenzoate 1.1 mg
Propyl p-hydroxybenzoate 0.135 mg
Example B
740 mg of the arginine salt of amoxycill~n are filled
into a dry ampoule in the usual manner. In order to prepare
a ready-for-use injection solution, 5 ml of sterile water or
5 ml of a sterile physiological sodium chloride solution are
added to thi salt.
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