NO752889L - - Google Patents

Description

Salt

The present invention relates to the salt of 6-[(R)-α-amino-p-hydroxyphenylacetamido]-penicillanic acid with arginine, as well as a method for its preparation.

6-[(R)-oc-amino-p-hydroxyphenylacetamido]-penicillanic acid is an antibiotic with a broad spectrum of action known under the name amoxicillin. Amoxicillin, which is practically insoluble in water and aqueous solutions, as well as its hitherto known salts cannot be used parenterally.

The problem to be solved thus consisted of finding a new non-toxic, parenterally usable form of amoxicillin while maintaining its antibiotic properties.

According to the invention, this problem was now solved by producing the arginine salt of amoxicillin.

The method for producing this salt is characterized by reacting 6-[(R)-α-amino-p-hydroxyphenylacetamido]-penicillanic acid or a hydrated form of this, where the amino group is optionally present in a protected form, with arginine and cleaving off any protective Ice group.

The 6-[(R)-α-amino-p-hydroxy-phenylacetamido]-penicillanic acid used as starting material can instead of a free amino group contain an amino group equipped with a protective group. A thus protected amino group is then transferred in connection with the conversion of 6-[(R)-α-amino-p-hydroxyphenyl-acetamido]-penicillanic acid in a known manner into the free amino group. In this way, an optionally substituted benzyloxycarbonylamiho group can be converted back into the free amino group by catalytic means. hydrogenation.

In the turnover of amoxicillin or a hydrated form

of this with arginine, preferably equivalent amounts of both reactants are used. If desired, however, a surplus of up to approx. 10% arginine. The reaction can be carried out in the presence of water, methanol, dinebyl sulphoxide, dimethylformamide or the like as a solvent. The reaction can also be carried out in a mixture of solvents, for example a mixture of propylene glycol and methanol or in a mixture of water or propylene glycol on one side and ethanol, propanol or isopropanol on the other side, preferably methanol, a mixture of propylene glycol and methanol or a mixture of water or propylene glycol on the one hand and ethanol, propanol or isopropanol on the other is used. Particularly preferred is the use of a mixture of propylene glycol and ethanol. The turnover is conveniently carried out at a temperature between approx. 0°C and 30°C. Preferably, you work at room temperature or, if you work in the presence of water as a solvent, at 5°C.

If the reaction of amoxicillin or a hydrated form thereof is carried out with arginine in the presence of water as a solvent, the isolation of the arginine salt of amoxicillin from the reaction mixture can be carried out by lyophilisation. If a solvent other than water is used, e.g. methanol, dimethyl sulfoxide or dimethylformamide, in order to isolate the arginine salt of amoxicillin from the reaction mixture, this can be stirred together with another solvent, such as e.g. diethyl ether, ethyl acetate or the like, in which the arginine salt of amoxicillin is insoluble. Hereby, at least 2 parts by volume of this second solvent per volume fraction of first solvent.

Is the turnover of the arginine carried out with amoxicillin or

a hydrated form thereof in a mixture of water on the one hand and ethanol, propanol or isopropanol on the other,

it is appropriate to use 15 - 25 parts by volume, preferably 20 parts by volume of water, per 100 parts by volume ethanol and 40 - 60 parts by volume, preferably 50 parts by volume water, per 100 parts by volume propanol or isopropanol. If the reaction of arginine with amoxicillin is carried out in a mixture of propylene glycol on the one hand and methanol, ethanol, propanol or isopropanol on the other, 30 - 50 parts by volume, preferably 40 parts by volume, of propylene glycol, per 100 parts by volume methanol or ethanol and 60 - 100 parts by volume, preferably 75 parts by volume propylene glycol, per 100 parts by volume propanol or isopropanol.

If a mixture of propylene glycol and methanol or a mixture of water or propylene glycol on the one hand and ethanol, propanol or isopropanol on the other is used as a solvent in the preparation of the arginine salt of amoxicillin, in order to isolate this salt from the reaction mixture, the latter can be stirred in a solvent, suitably ethanol, propanol or isopropanol, where the arginine salt of amoxicillin is insoluble. When precipitating the arginine salt of amoxicillin, 3 parts by volume of one aj of these three solvents per volume fraction of the mixture of propylene glycol and methanol used in the production of the arginine salt of amoxicillin or a mixture of water or propylene glycol on the one hand and ethanol, propanol or isopropanol on the other.

The arginine salt of amoxicillin has an antibiotic effect of the same order of magnitude as amoxicillin itself. It has a broad spectrum of action against gram-positive and gram-negative micro-organisms.

The salt according to the invention can be used for the treatment and prophylaxis of infectious diseases. 0.25 to 2 g up

to four times a day in consideration.

Due to its excellent water solubility (more than 10%) and its excellent local tolerability, the salt according to the invention is particularly suitable for parenteral use.

The acute toxicity (LD 50) of the arginine salt of amoxicillin'<J>is 2,500 - 5,000 mg/kg when administered intravenously and more than 5,000 mg/kg when administered subcutaneously in mice. The activity (CD 50) of this substance against Escherichia coli when applied subcutaneously to mice is 4.5 mg/kg.

Pharmaceutical preparations can contain the salt according to the invention in admixture with a pharmaceutical, organic or inorganic inert carrier material suitable for enteral or particularly parenteral use, such as e.g. water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, etc. The pharmaceutical preparations can be in solid form, e.g. as tablets, dragées, suppositories, capsules or especially in liquid form, e.g. as aqueous solutions. If desired, they are sterilized and/or contain auxiliary substances, such as preservatives, stabilisers, wetting or emulsifying agents, salts for changing the osmotic pressure or buffers. They may also contain other therapeutically valuable substances. Preferably, the salt according to the invention is available as an active substance in a dry ampoule.

EXAMPLE 1

To a suspension of 4.20 g of amoxicillin-tri- ! hydrate in 200 ml of water, 1.70 g of L-arginine is added in portions over the course of 10 minutes. After a further 10 minutes of stirring, undissolved material is filtered off and the filtrate is lyophilized.

You get 5.2 g of lyophilisate. Melting point: Decomposes above 200°C.

[a]^<5>= +175.0° (1.0 in water).

EXAMPLE 2

While stirring at room temperature, a suspension of 184 g of L-arginine in 4 1 of absolute methanol is mixed over the course of 3 minutes with 4 29 g of amoxicillin trihydrate and stirred vigorously for 15 minutes. Undissolved material is filtered off and 10 1 diethyl ether is added while stirring. After filtering off the precipitate, wash with 6 1 diethyl ether and dry. You get 491 g of arginine salt. Melting point: Decomposes above 200°C. [cOq<5>= +174.7° (c = 1.0 in water).

EXAMPLE 3

A suspension of 12 g of L-arginine in 21 ml of water is added while stirring at room temperature, 100 ml of absolute ethanol and immediately following 24 g of amoxicillin trihydrate. After stirring for 5 minutes, clear filter and let the syrupy solution flow into absolute ethanol 1.2 1 under vigorous stirring and cooling to -5°C. The precipitated product is filtered off and washed with 400 ml of absolute ethanol. After drying in a vacuum, 20.5 g of arginine salt are obtained. Melting point: Decomposes above 200°C. [a]^<5>= +165.9° (c = 1.0 in water).

EXAMPLE 4

A suspension of 21 g of L-arginine in 70 ml of propylene glycol and 180 ml of absolute ethanol is added to 42 g of amoxicillin trihydrate and stirred vigorously for 45 minutes at room temperature. Then filtered

add while stirring at -5°C 1.4 1 absolute eta-noi. The precipitated salt is filtered off. washed 4 times, each time with 50 ml absolute ethanol and dried in vacuum. 40.4 g of arginine salt is obtained. Melting point: Decomposes above 200°C. [a = +157° (c = 1, in van<n>).

EXAMPLE 5

A suspension of 4.2 g of L-arginine in 60 ml of propylene glycol and 80 ml of isopropanol is added to 8.2 g of amoxicillin trihydrate and

IN

stir vigorously for 60 minutes at room temperature. It is then filtered, and the solution is fed at 5°C with stirring into 500 ml of isopropanol. The precipitated salt is filtered off, washed 4 times, each time with 30 ml isopropanol and dried in vacuum. 8.2 g of arginine salt is obtained. Melting point: Decomposes above 200°C. [a]j)<5>= +168?7° (c = 1, in water).

EXAMPLE 6

A suspension of 20 g of L-arginine in a mixture of 70 ml of propylene glycol and 180 ml of methanol is added with 40 g of amoxicillin trihydrate and stirred vigorously at 20°C for 15 minutes. Filter, wash with a mixture of 28 ml of propylene glycol and 72 ml of methanol and feed the solution with stirring to 1400 ml of isopropanol cooled to 5°C. After 15 minutes, the arginine salt is filtered off, washed 5 times, each time with 50 ml of isopropanol and then dried in a vacuum. 50.2 g of arginine salt is obtained. Melting point: Decomposes above 210°C.

[cc]^<5>= +159° (c = 1.493, in water).

EXAMPLE 7

A suspension of 20 g of L-arginine in a mixture of 70 ml of propylene glycol and 180 ml of absolute ethanol is added with vigorous stirring to 40 g of amoxicillin trihydrate and stirred for 30 minutes at 20°C. A little undissolved material is then filtered off, washed with a mixture of 14 ml of propylene glycol and 36 ml of ethanol and the viscous solution is added with stirring to 1400 ml of isopropanol, cooled to 5°C. Stir for 15 minutes at 5°C and filter off the precipitated arginine salt. The residue is washed 5 times, each time with 50 ml of isopropanol and then 5 times, each time with 50 ml of diethyl ether and then dried in a vacuum. 45.7 g of arginine salt is obtained. Melting point: Decomposes above 210°C. [a]^<5>= +172.2° (c = 1.5, in water).

EXAMPLE 8

A lyophilisate is usually prepared with the following composition referring to 4 ml of solution ready for injection:

EXAMPLE 9 I

In the usual way, 740 mg of the arginine salt of amoxicillin is filled in a dry ampoule. For the preparation of a ready-to-spray solution, this salt is added to 5 ml of sterile water or 5 ml of a sterile physiological saline solution.

Claims (8)

1. Process for the production of the arginine salt of amoxicillin, characterized by reacting 6-[(R)-α-amino-p-hydroxyphenylacetamido]-penicillanic acid or a hydrated form thereof, where the amino group may be present in an optionally protected form, with arginine and clefts of an optionally present protecting group. 2. Method according to claim 1, characterized in that the reaction of 6-[(R)-α-amino-p-hydroxyphenyl-acetamido]-penicillanic acid or a hydrated form thereof with arginine in the presence of methanol or a mixture of water or propylene glycol on one side and ethanol, propanol or isopropanol on the other side as a solvent are carried through. 3. Process according to claim 1 or 2, characterized in that the reaction of 6-[(R)-α-amino-p-hydroxy-phenylacetamido]-penicillanic acid or a hydrated form thereof with arginine is carried out in the presence of a mixture of propylene glycol and ethanol as solvent. 4. Method according to claim 1, characterized in that the reaction of 6-[(R)-α-amino-p-hydroxy-phenylacetamido]-penicillanic acid or a hydrated form thereof with arginine is carried out in the presence of a mixture of propylene glycol and methanol as solvent. 5. Process for the production of pharmaceutical preparations, characterized by mixing the arginine salt of amoxicillin as an active ingredient with non-toxic, inert, common in such preparations, non-toxic, inert, solid and/or liquid carriers and/or excipients suitable for therapeutic use or filling in an ampoule and seals it. 6. Pharmaceutical preparations, characterized by a content of arginine salt of amoxicillin, possibly together with a pharmaceutical carrier material. 7. Pharmaceutical preparation according to claim 6, characterized in that the arginine salt of amoxicillin as active substance is available in a dry ampoule. 8. The arginine salt of amoxicillin.