IE41514B1 - A salt of amoxycillin - Google Patents

Abstract

1464065 Salt of amoxycillin F HOFFMANNLA ROCHE & CO AG 20 Aug 1975 [21 Aug 1974 22 May 1975 24 June 1975] 34607/75 Heading C2C Novel salt of argenine with 6-R-α-amino-phydroxyphenylacetamido - pencillinic acid is prepared by reacting arginine with the acid or a hydrated form thereof, in which the amino group is optionally protected and removing the protecting group if necessary. The salt has anti-bacterial activity and forms with a carrier a pharmaceutical composition which may be administered orally parenterally or rectally.

Description

The present invention relates to a salt. More particularly, the invention is concerned with a salt of a penicillanic acid derivative, a process for the manufacture thereof and pharmaceutical preparations containing same.

The salt provided by the present invention is the salt of 6-[(R)-α-amino-p-hydroxyphenylacetamido]-penicillanic acid with arginine. 6-[(R)-α-Amino-p-hydroxyphenylacetamido]-penicillanic acid is an antibiotic which is known under the name amoxycillin and which has a wide spectrum of activity. Amoxycillin, which is practically insoluble in water and aqueous solutions, as well as its hitherto known salts, can not be administered parenterally.

There has accordingly been a need for a new, non-toxic, parenterally administrable form of amoxycillin while retaining the antibiotic properties thereof.

It has now been found in accordance with the present invention that the arginine salt of amoxycillin Satisfies the foregoing requirements.

According to the process provided by the present invention, the arginine salt of amoxycillin is manufactured by reacting 6-[(R)-α-amino-p-hydroxyphenylacetamido]-penicillanic acid or a hydrated form thereof, the amino group 41614 being optionally present in protected form, with arginine and cleaving off a protecting group which may be present.

The 6-[(R)-α-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-[(R)-a-protected amino-p-hydroxyphenylacetamidql -penicillanic acid with arginine, into a free amino group in a manner known per se. Thus, for example, an optionally substituted 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. However, 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, dimethylformamide or in the presence of a mixture of propyleneglycol and methanol or of a mixture of water or propyleneglycol on the one hand and ethanol, propanol or isopropanol on the other hand. As the solvent there is I preferably used methanol, a mixture of propyleneglycol and methanol or a mixture of water or propyleneglycol on the one hand and ethanol, propanol or isopropanol on the other hand.

Most preferred is a mixture of propyleneglycol and ethanol.

The reaction is conveniently carried out at a temperature between 0°C and 30°C. The reaction is preferably carried out at room temperature or, when water is used as the solvent, at 5LC.

When the reaction of amoxycillin or a hydrated form thereof with arginine is carried out in the presence of water as a solvent, the isolation of the arginine salt of amoxycillin from the reaction mixture can be carried out by lyophilisation. When a solvent other than water (e.g. methanol, dimethyl sulphoxide or dimethylformamide) is used, the isolation of the arginine salt of amoxycillin from the reaction mixture can be carried out by stirring the reaction mixture in a second solvent (e.g. diethyl ether, or ethyl acetate) in which the arginine salt of amoxycillin is insoluble. In this case, at least 2 volumes of the second solvent are conveniently used per volume of the first solvent.

When the reaction of arginine 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 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 a mixture of propyleneglycol and methanol, ethanol, propanol or I 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 hand and ethanol, propanol or isopropanol on the other hand is used as a solvent, the arginine salt of amoxycillin can be isolated from the reaction mixture by stirring the reaction mixture in 41Q14 a solvent, conveniently ethanol, propanol or isopropanol, in which the arginine salt of amoxycillin is insoluble. Xn 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 hand and ethanol, propanol or isopropanol on the other hand used as solvent in the reaction of arginine with amoxycillin.

The arginine salt of amoxycillin has an antibiotic activity in the order of that of amoxycillin. It possesses 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 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 lOt) and of its .excellent local tolerability, the salt provided by the present invention is particularly suitable for parenteral administration.

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 ea^t of amoxycillin against Escherichia coli upon subcutaneous administration to mice amounts to 4.5 mg/kg. ' |b: - 5 41514 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 or magnesium stearate. The pharmaceutical preparations can be made up in a solid form (e.g. as tablets, dragees, 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 emulsifying 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. The salt provided by the present invention is preferably contained as the active ingredient in a dry ampoule.

The following Examples illustrate the process provided by the present invention: Example 1 1.70 g of L-arginine are added portionwise within 10 5 minutes to a suspension of 4.20 g of amoxycillin trihydrate in 200 ml of water stirred at 5°C. 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 200’C. E«3q5 - +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 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 200°C. [«Ip5 = +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 41S14 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 -5°C. 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: decomposition above 200°C. [a]25 = +165.9° (c = 1.0 in water).

Example 4 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 filtrate introduced into 1.4 litres of absolute ethanol at -5°C 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: decomposition above 200°C·. [a]2^ = +157° (c = 1 in water).

Example 5 8.2 g of amoxycillin trihydrate are added to a suspension 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 5°C while stirring. The precipitated salt is filtered off under 41S14 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. [a]25 = +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 amoxycillin trihydrate and the mixture is stirred at 20°C for 15 minutes. The mixture is then filtered, washed with a mixture of 28 ml of propyleneglycol and 72 ml of methanol and added to 1.4 litres of isopropanol stirred at 5°C. After stirring at 5°C for a further 15 minutes, the precipitated arginine salt of amoxycillin is filtered off under suction and washed five times with 50 ml of isopropanol. After drying in vacuo, there are obtained 50.2 g of the arginine salt of amoxycillin. Melting point: decomposition above 2lO°C. [a]25 = +159° (c = 1.493 in water).

Example 7 I 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 20°C, are added 40 g of amoxycillin trihydrate and the mixture is stirred for a further 30 minutes at 20°C. Insoluble material is 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 litres of isopropanol stirred at 5°C. After stirring at 5°C for a further 15 minutes, the precipitated arginine salt of amoxycillin is filtered off under suction and washed five times with 50 ml of isopropanol and then five times with 50 ml of diethyl ether. After drying in vacuo, there are obtained 45.7 g of the arginine salt of amoxycillin. Melting point: decomposition above 210°C. [a]^ = +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 amoxycillin 370 mg Methyl p-hydroxybenzoate 1.1 mg Propyl p-hydroxybenzoate 0.135 mg Example B 740 mg of the arginine salt of amoxycillin are filled 20 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 this salt.

Claims (9)

1. ) The arginine salt of amoxycillin.

2. ) A process for the manufacture of the arginine salt of amoxycillin, which process comprises reacting 6-j\R)-a-amino5 -p-hydroxyphenylacetamido]-penicillanic acid or a hydrated form thereof, the amino group being optionally present in protected form, with arginine and cleaving off a protecting group which may be present.

3. ) A process according to claim 2, wherein the reaction of io 6-[(R)-α-amino-p-hydroxyphenylacetamido]-penicillanic acid or a hydrated form thereof with arginine is carried out in the preeence of methanol or of a mixture of water or propyleneglycol on the one hand and ethanol, propanol or iospropanol on the other hand as a solvent. 15

4. ) A process according to claim 2 or claim 3, wherein the reaction of 6-E-(R)-α-amino-p-hydroxyphenylacetamido]-penicillanic acid or a hydrated form thereof with arginine is carried out in the presence of a mixture of propyleneglycol and ethanol as a solvent. 20

5. ) A process according to claim 2, wherein the reaction of

6. ) A process for the manufacture of the arginine salt of amoxycillin, substantially as hereinbefore described with I, reference to any one of Examples 1 to 7. 6-t(R)-α-amino-p-hydroxyphenylacetamido]-penicillanic acid or a hydrated form thereof with arginine is carried out in the presence of a mixture of propyleneglycol and methanol as a solvent. 41814

7. ) The arginine salt of amoxycillin, when manufactured by 5 the process claimed in any one of claims 2 to 6 inclusive.

8. ) A pharmaceutical preparation which contains the arginine salt of amoxycillin optionally in association with a compatible pharmaceutical carrier material.

9. ) A pharmaceutical preparation according to claim 8 which 10 contains the arginine salt of amoxycillin as the active ingredient in a dry ampoule.