CH652597A5 - PHARMACEUTICAL COMPOSITION, CONTAINING 1- (2-3'-CARBOXYPROPIONYLOXYAETHYL) -2-METHYL-5-NITROIMIDAZOLE. - Google Patents

Description

The invention relates to a pharmaceutical composition according to claim 1 and a composition effective as a prophylactic in surgery according to claim 10.

The derivatives of imidazole 1- (2,3'-carboxypropionyloxyethyl) -2-methyl-5-nitroimidazole have the formula

H / -CH3 1

N02 '^ N'

1

CH, - CH, -0-C- CH - CH, - C-0 -H

2 2 <s 2 2a

The salts with pharmaceutically acceptable (inorganic or organic) bases or acids can be formed from alkali metal, alkaline earth, ammonia, aliphatic amino acid, i.e. Mono- or diethanolamine and the cyclic amine salts.

The compositions according to the invention are suitable for treating infections caused by anaerobic bacteria, e.g. by Peptostreptococcus, Bacteroides fragilis, Bacteroides melaninogenicus, Furobacterium, Clostridium perfringens and other types of Clostridium.

The salts of compound I have the additional advantage that they are water-soluble, which enables their parenteral administration.

The composition is preferably in the form of metered units.

1- (2,3'-Carboxypropionyloxyethyl) -2-methyl-5-nitro-imidazole or its salts can be used in combination with drug carriers or coatings which are common in pharmaceutical products.

The compositions of the present invention can be in parenteral, rectal or topical form.

The compositions for oral administration include tablets, sugar-coated pills, dispersible powders or granules. In these solid mixtures, the active compound can be processed together with at least one inert additive, extender or diluent, e.g. B. with calcium carbonate, potato starch, alginic acid, microcrystalline cellulose, methyl cellulose, lactose or sucrose. The mixtures can also contain other additional substances as inert additives, extenders or diluents, for example lubricants such as magnesium stearate, stearic acid, talc. The liquid mixtures for oral administration include emulsions, solutions, suspensions and pharmaceutically acceptable syrups and elixirs, which also contain inert additives, extenders or diluents. These mixtures can also contain additives such as humidifiers and sweetening, flavoring and aromatic suspensions and preservatives. The compositions may also be bound for oral administration in the form of capsules with an absorbable material, such as gelatin, which contains the active substance with or without additives, extenders or diluents or excipients.

For parenteral administration, the substances can be processed in aqueous or non-aqueous sterile solutions, suspensions or emulsions. Some examples of non-aqueous solvents or suspending agents are: propylene glycol, polyethylene glycol, dioxilanes, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. These mixtures can also contain additives such as preserving, moisturizing, emulsifying and dispersing agents. They can also be sterilized, for example by filtration through bacteria-retaining filters, by incorporating sterilizing agents into the mixture, by irradiation or by heating. They can also be made in the form of solid sterile mixtures which can be dissolved in sterile water or other sterile injectable agent immediately before use.

For topical administration, the active substance can be incorporated in a suitable vehicle, for example in a cream or ointment, a pessary, an Ovu-50 lum or a tablet for insertion into the vagina. The percentage of active ingredients in the mixtures can vary such that the proportion is suitable for an appropriate dosage with which the desired therapeutic effect can be achieved.

55 The composition can be processed in several different forms for simultaneous administration. In human therapy, the mixtures must generally be administered and the pharmaceutical compositions must be formulated in such a way that 0.250 to 3.0 grams of active substance are administered daily in the case of oral and topical administration, 0.150 to 1.5 grams daily in the case of parenteral administration and rectally 0.125 to 2.0 grams daily.

The solutions described in the following Examples I to III and VIII can be administered intravenously to adults 65 (500 mg every 8 hours) and 5 ml / min. and in children under 12 years (7.5 mg per kg - 100 ml solution) every 8 hours at 5 ml / min. be administered.

The orally administrable doses in the following

3rd

652 597

Examples IV through VI and IX can be administered three times a day for 7 days or more (500 mg).

The composition to be administered rectally of Example VII can be administered to adults one to three times a day for 3 days and, after the fourth day, a suppository every 10 hours for 4 days. Children under 12 years of age can be given a dose of 500 mg three times a day for 3 days and after the fourth day a suppository every 12 hours for 4 days.

The compositions can also be used as prophylactic agents in surgery as well as in liver and kidney abscesses and gangrene.

The dosage ranges mentioned are optimal and changes thereof are permitted in certain cases within the scope of the invention.

The invention is illustrated by the following, non-limiting examples:

Example I

To prepare a 35.0% aqueous solution of 1- (2,3'-carboxypropionyloxyethyl) -2-methyl-5-nitroimide-azole (I), 35.0 grams of the compound are mixed in a mixture of diethanolamine (13.56 Grams) and water (50 cm3) and brought to a volume of 100 cm3 with water.

The pH of the solution obtained is approximately 6.

Example II

To prepare a 35.0% aqueous solution of the magnesium salt of (I), 35.0 grams of (I) are reacted with basic magnesium carbonate (5.9 grams), mixed with water (70 cm3), stirred and brought to approx 50 ° C heated. When the gas release has ceased, the mixture is brought to a volume of 100 cm 3 with water and filtered. The solution obtained has a pH of about 5.7.

Example III

To prepare a 25.0% aqueous solution of the sodium salt of (I), 35.0 grams of (I) are reacted with sodium bicarbonate (10.76 grams), mixed with water (40 cm3), stirred and brought to approx. 50 ° C heated. When the gas release has ceased, the mixture is brought to a volume of 100 cm 3 with water and filtered.

The solution obtained has a pH of about 6.5.

Example IV

Tablets for oral administration, made by the usual technique, have the following composition:

- ~ r Sr —J - ~ (

2-methyl-5-nitroimidazole 0.250 g

Starch 0.190 g

Aerosil 200 0.050 g

Magnesium stearate 0.025 g

Example V

Oral tablets made by the usual technique have the following composition: 1- (2,3'-carboxypropionyloxyethyl) -

2-methyl-5-nitroimidazole 0.500 g

Plasdone 0.025 g

Avicel pH 102 0.130 g

Talc ~ 0.014 g

Magnesium stearate 0.005 g

Colorant 0.014 g

Example VI

Vaginal tablets, manufactured according to the usual technique, have the following composition:

1- (2,3'-carboxypropionyloxyethyl) -

2-methyl-5-nitroimidazole 0.500 g

Corn starch 0.683 g

Alginic acid 0.050 g

Aerosil 200 0.060 g

Magnesium stearate 0.0010 g

Example VII

Vaginal ovula or suppositories, manufactured according to the usual technique, have the following composition: 1- (2,3'-carboxypropionyloxyethyl) -

2-methyl-5-nitroimidazole 20.83 g

Sodium hydroxide solution 0.1 N 72.00 cc

Manitol 30.00 g

Timerosal 0.00025 g distilled water s.q. 100.00 cc

The solution is sterilized using a 0.22 sterile membrane filter and placed in ampoule bottles to be lyophilized from 5 cm3 in 3.0 cm3 portions. The product can be reused for use with 3 cc sterile water for injection.

Example VIII A solution for injection:

8 g of finely ground l- (2,3'-carboxypropionyloxyethyl) -2-methyl-5-nitroimidazole powder is aseptically placed in an ampoule bottle. Then the product is sterilized at 100 ° C for one hour. A solution of the following composition is now being prepared: sodium acetate amino acid or 2-amino ethanol 20 g distilled water s.q. 100 cc

The solution thus obtained is sterilized by filtration through a 0.22 membrane. 20 cm3 of this solution are taken and the contents of the ampoule bottle are dissolved. The solution obtained should be used no later than two hours after its preparation.

Example IX

Suspension for oral administration: l- (2,3'-carboxypropionyloxyethyl) -

2-methyl-5-nitroimidazole 1.5 g

Sugar 18.0g

Sodium nipagin 0.108 g

Sodium nipasol 0.012 g

Sodium saccharin 0.03 g

Dibasic sodium phosphate 0.1983 g

Monobasic sodium phosphate 0.1017 g

Carboxymethyl cellulose 0.18 g

Manitol 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 should be used within a maximum of seven days and the rest should be discarded.

Example X Ointment for Topical Administration: 1 - (2,3'-Carboxypropionyloxyethyl) -

2-methyl-5-nitroimidazole 0.750 g

Cetyl alcohol 10.5g

Stearic alcohol 9.3 g liquid petroleum jelly 25.5 g

Glycerin 15 g solid Vaseline 33.9 g

Nipagin 0.36 g

Nipasol 0.09 g

Span 60 2.3 g

Tween 60 2.3 g

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Claims (10)

652597 1. Pharmaceutical composition effective against diseases caused by anaerobic microorganisms, in particular against infections caused by Pepto streptococcus, Bacteroides fragilis, Bacteroides melaninoge-nicus, Furobacterium, Clostridium perfringens and Clostridium Sp., Containing a therapeutically effective amount of a substance from group 1- (2,3'-Carboxypropionyloxy-ethyl) -2-methyl-5-nitroimidazole 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 of the salts are derived from ammonia, alkali metals or alkaline earths. 2nd PATENT CLAIMS 3. Composition according to claim 1, characterized in that the acids of the salts are aliphatic amino acids. 4. Composition according to one of claims 1 to 3, in the form of dose units. 5. Composition according to one of claims 1 to 4, in parenterally administrable form. 6. Composition according to one of claims I to 4, in orally administrable form. 7. Composition according to one of claims 1 to 4, in topically administrable form. 8. Composition according to one of claims 1 to 4, in rectally administrable form. 9. Composition according to one of claims 1 to 4, in vaginally administrable form. 10. Composition effective as a prophylactic in surgery against anaerobic-bacterial infections, containing an active ingredient from the group 1- (2,3'-carboxypropionyloxyethyl) -2-methyl-5-nitroimidazole and its salts with pharmaceutically acceptable bases or acids .