LU83802A1 - PHARMACEUTICAL COMPOSITIONS CONTAINING 1- (2-3'-CARBOXYPROPIONYL OXYETHYL) 2-METHYL-5-NITROIMIDAZOLE OR ITS SALTS, AS ACTIVE THERAPEUTIC AGENTS AGAINST DISEASES CAUSED BY ANAEROBIC GERM - Google Patents

Description

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The present invention relates to imidazole derivatives consisting of 1- (2-3'-carboxypropionyl oxyethyl) -2-methyl-5-nitroimidazole having the formula: 5 r \ I; —ch3 * ·

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CHo-CH9-0-C-CH9-CH7-C-Q-H

ZZI, Z ^ 11 10 0 0 and its salts with organic or inorganic, pharmaceutically acceptable bases, for example, the salts of alkali metals, alkaline earth metals, ammonia, amines = 25 aliphatics, for example mono- or di-ethanolamine, aliphatic amino acids and cyclic amines.

More particularly, the present invention relates to pharmaceutical compositions containing these derivatives and to methods for treating, with these compositions, infections caused by anaerobic bacteria "for example Peptostreptococcus, Bacteroides fragilis, Bacteroides melaninogenicus, Furobacterium, J Clostridium perfringens and other Clostridium species.

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The salts of compound I have the additional advantage of being water soluble, which allows them to be used for parenteral administration.

The use of 1- (2-3'-carboxypropionyl oxyethyl) -5 2-methyl-5-nitroimidazole or its salts can be used in combination with excipients or coatings normally used in pharmaceutical products.

In clinical practice, the compounds of the present invention are administered parenterally, rectally or topically.

The compositions for oral administration include tablets or tablets, sugar-coated pills, dispersible powders or granules. In these solid mixtures, the active compound is administered with at least one inert diluent such as calcium carbonate, potato starch, alginic acid, microcrystalline cellulose, methylcellulose, lactose or sucrose. The mixtures may also include additional substances other than inert diluents, such as, for example, lubricants, for example magnesium stearate, stearic acid and talc. Liquid mixtures for oral administration include emulsions, solutions, suspensions, and syrups as well as elixirs, pharmaceutically acceptable, also containing inert diluents. These mixtures can also contain additives such as humectants and sweeteners, flavoring agents and aromatic suspending products, as well as preservatives. The compositions can also be compounded for oral administration in capsule form with an absorbable material such as gelatin, containing the active substance, with or without the addition of diluents or excipients.

For parenteral administration, the compounds can be administered in sterile aqueous or non-aqueous solutions, suspensions or emulsions. Some examples- ”? pies of non-aqueous solvents or suspending media ï /

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These are: propylene glycol, polyethylene glycol, dioxolanes, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. These mixtures can also contain additives such as preservatives, humectants, emulsifiers and dispersing agents. They can also be sterilized, for example, by filtration through filters retaining bacteria, by incorporation into the mixture of sterilizing agents, by irradiation 1 10 or by heating. They can also be made as solid sterile mixtures which can be dissolved in sterile water or some other sterile injectable medium immediately before use.

For topical application, the active substance can be incorporated into a suitable vehicle such as a cream or ointment, or a pessary, an ovum or a tablet or a tablet for insertion into the vagina. The percentage of active ingredients in the mixtures of the present invention can be varied such that the proportion is suitable to provide an adequate dose with which the desired therapeutic effect will be obtained.

It will appear that the composition can be administered at the same time in various different forms. In human therapy, mixtures must generally be ad-25 ministers and pharmaceutical compositions formulated in such a way that, in the case of oral or topical administration, is administered per day 0.230 to 3.0 g of active substance ; in the case of parenteral administration, 0.150 to 1.5 g per day, and, in the case of rectal administration, 50 0.125 to 2.0 g per day.

Thus, the solutions described below in Examples 1 to 3, 8 and 9 can be administered intravenously to adult humans (500 mg every 8 hours), at the rate of 5 ml / min and to children under 12 to 55 years (7.5 mg / kg-100 ml of solution) every 8 hours at the rate of 5 ml / min.

The oral doses described below in Examples 4 to 6 and 10 can be administered (500 mg) three times! S times a day for 7 days or more.

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• The composition which can be administered rectally in Example 7 can be administered to adults 1-3 times a day for three days and, after the fourth day, a suppository every 10 hours for four days.

For children under 12, a dose of 500 mg 5 can be administered three times a day for three days and, after the fourth day, a suppository every 12 hours for four days.

The compounds and compositions can also be used as prophylactic agents in surgery, as well as in renal and hepatic abscesses and for gangrene.

It will be understood that the foregoing dose ranges v are optimum and that variations are permitted within the scope of protection of the present invention, in some cases.

The present invention is illustrated by the following nonlimiting examples.

EXAMPLE 1

To prepare an aqueous solution of 1- (2,3'-carbon-xypropionyl oxyethyl) -2-methyl-5-nitroimidazole (I) at 35.0 S, 35.0 g of the compound are dissolved in a mixture of diethnolami - ne (13.56 g) and water (50 cm "*) and it is brought to a volume of 3100 cm with water.

The pH of the solution obtained is approximately 25 °.

EXAMPLE 2

To prepare a 35.0% aqueous solution of the magnesium salt of (I), 35.0 g of (1) are reacted with basic magnesium carbonate (5.9 g) mixed with 50 water (70 cm ^), stirring and heating to approximately 50 ° C. When this solution has ceased to give off gas, it is brought to a volume of 100 cm 3 with water and filtered. The solution obtained has a pH of approximately 5.7.

55 EXAMPLE 3 = To prepare a 25.0% aqueous solution of the sodium salt -. Jl of (I), 35.0 g of (I) is caused to react with? Λ ï v ....

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sodium bicarbonate (10.76 g), mixing with water (40 cm ^), stirring and heating to approximately 50 ° C. When the solution has ceased to give off gas, it is brought to a volume of 100 cm 3 with water and it is filtered.

The solution obtained has a pH of approximately 6.5.

EXAMPLE 4 4 Tablets or tablets for oral administration, prepared by the ordinary technique, have the following composition. : 1- (2-3'-carboxypropionyl oxyethyl) -2-methyl- 5-nitroimidazole 0.250 g

Starch 0.190 g 15 Product called Aerosil 200 0.050 g

Magnesium stearate 0.025 g EXAMPLE 5

Tablets or tablets for oral administration, prepared by the ordinary technique, have the following composition: 1- (2-31-carboxypropionyl oxyethyl) -2-methyl-5-nitroimidazole 0.500 g

Product says Plasdone 0.025 g

Product called Avicel pH 102 0.130 g 25 Talc 0.014 g

Magnesium stearate 0.005 g

Dye 0.014 g k 'EXAMPLE 6

Vaginal tablets or vaginal tablets, 50 prepared by the ordinary technique, have the following composition: 1- (2-31-carboxypropionyl oxyethyl) -2-methyl- 5-nitroimidazole 0.500 g

Corn starch 0.683 g 55 Alginic acid 0.050 g 6 Aerosil 200 product 0.060 g

If Magnesium stearate 0.0010 g y s “6.

EXAMPLE 7

Vaginal ova or vaginal suppositories, prepared by the ordinary technique, have the following composition: 5 1- (2-5'-carboxypropionyl oxyethyl) -2-methyl- 5-nitroimidazole 20.83 g

0.1 N soda solution 72.00 cm "*

Mannitol 30.00 g 4 Timerosal 0.00025 g 3 10 Distilled water, excipient (q.s,) 100.00 cm

The solution is sterilized by means of a sterile membrane filter known as 0.22 and is placed in bottles “in the form of an ampoule to be lyophilized from 5 cm 3 in parts of 3.0 cm '*. The product can be reconstituted for use with 3 cm 3 of sterile water for injection.

EXAMPLE 9

Solution for injection: 8 g of micronized powder of 1- (2-3'-carboxypropio-nyl oxyethyl) -2-methyl-5-nitroimidazole are introduced aseptically into a bulb-shaped bottle. Then the product is sterilized at 100 ° C for one hour. During this time, a solution is prepared having the following composition:

Sodium aminoacetate or 25 2-aminoethanol 20 g

Distilled water, excipient (q.s.) 100 cm

The solution thus obtained is sterilized by filtration through a membrane called 0.22; 20 cm ^ of this solution are taken and the contents of the ammo-shaped bottle are dissolved. The solution obtained should not be used later than 2 hours after its preparation, EXAMPLE 10 suspension for oral administration 1- (2-3'-carboxypropionyl oxyethyl) -2-methyl- 55 5-nitroimidazole 1.5 g

Sucre dit Glass 18 g | Nipagine sodium salt 0.108 g ^ Nipasol sodium salt 0.012 g "i

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Saccharin sodium salt 0.03 g

Sodium diacid phosphate 0.1983 g

Sodium monoacid phosphate 0.1017 g

Carboxymethylcellulose 0.18 g 5 Mannitol 3.87 g

Total 24 g

The mixture obtained is reconstituted with water to a volume of 60 ml at the time of use. This | suspension must be used within seven days * 10 at the latest and the remainder must be discarded, EXAMPLE 11

Ointment for topical preparation: 1- (2-3'-carboxypropionyl oxyethyl) -2-methyl-5-nitroimidazole 0.750 g 15 Cetyl alcohol 10.5 g

Stearyl alcohol 9.3 g

Liquid petrolatum 25.5 g

Glycerin '15 g

Solid petrolatum 33.9 g 20 Product called Nipagine 0.36 g

Nipasol product 0.09 g

Product says Span 60 2.3 g

Tween 60 product 2.3 g

The present invention is not limited to the exemplary embodiments which have just been described, it is on the contrary susceptible to modifications and variants which will appear to those skilled in the art.

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Claims (10)

1. Pharmaceutical composition in unit dosage form, suitable for the treatment of diseases caused by anaerobic microorganisms, characterized in that it comprises a quantity, therapeutically effective, of a compound chosen from, group consisting of 1- (2-3'-carboxypropionyl oxyethyl) -2-methyl-5-nitroimida-zole and its salts with pharmaceutically acceptable bases or acids and a pharmaceutically acceptable carrier. 2. Composition according to claim 1, characterized in that the bases come from ammonia, alkali or alkaline earth metals. 3. Composition according to claim 1, character-ized in that the acids are aliphatic amino acids. 4. Composition according to claim. 1, characterized in that the anaerobic microorganism is chosen from the group consisting of Peptostreptococcus, Bacte-roides fragilis, Bacteroides melaninogenicus, Furobacterium, Clostridium perfringens and Clostridium Sp. 5. Composition according to claim 1, characterized in that it is in a form suitable for parenteral administration. 6. Composition according to claim 1, character-ized in that it is suitable for oral administration. 7. Composition according to claim 1, characterized in that it is suitable for topical administration. i “„ 8 - A composition according to claim 1, characterized in that it is suitable for rectal administration. 9. Composition according to claim 1, characterized in that it is suitable for vaginal administration. 35 10 - Composition suitable for use as a prophylactic agent in surgery, characterized in that it comprises, as active ingredient, l- (2-3'-carboxypropionyl oxyethyl) -2-methyl ~ 5-nitroimidazole .