GB2089208A - Antibacterial compositions containing 1-(2,3'-carboxypropionyl oxyethyl)-2-methyl-5-nitroimidazole - Google Patents

Abstract

Pharmaceutical compositions for the treatment of diseases caused by anaerobic microorganisms comprise as the active ingredient 1-(2-3'- carboxypropionyl oxyethyl)-2-methyl-5- nitroimidazole or a pharmaceutically acceptable salt thereof. The compositions may be administered parenterally, orally, topically, rectally or vaginally.

Description

SPECIFICATION Pharmaceutical composition containing 1-(2,3'-carboxypropionyl oxyethyl)-2-methyl-5-nitroimidazole as active therapeutic agent against diseases caused by anaerobic germs Background and Summary of the Invention This invention relates to the derivatives of imidazole 1-(2-3'-carboxypropionyl oxyethyl)-2-methyl-5nitroimidazole having the formula:

and salts thereof with pharmaceutically acceptable inorganic or organic acids and bases, e.g., alkali metal, alkaline-earth metal, ammonia, aliphatic amino acid, i.e., mono- or di-ethanolamine and the cyclic amine salts and aliphatic amino acids.

More particularly, the invention relates to pharmaceutical compositions containing these derivatives and methods of treatment therewith of infections caused by anaerobic bacteria, e.g., Peptostreptococcus, Ba ctero ides fragilis, Bacteroides meianinogenicus, Furobacterium, Clostridium perfringens and other species of Clostridium.

The salts of Compound I have the added advantage of being soluble in water, which allows them to be caused for parenteral administration.

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

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

The compositions for oral administration include tablets, sugar-coated pills, dispersable powders or granules. In these solid mixtures, the active compound is administered together with at least one inert diluent such as calcium carbonate, potato starch, alginic acid, microcrystalline cellulose, methyl cellulose, lactose or sucrose. The mixtures may also include additional substances other than the inert diluents, such as, for example, lubricating agents, e.g., magnesium stearate, stearic acid, talc. The liquid mixtures for oral administration include emulsions, solutions, suspensions, and pharmaceutically acceptable syrups and elixirs, also containing inert diluents. These mixtures may also contain additives such as humectant agents and sweetening, flavoring and aromatic suspensories and preservatives.The composions may also be compounded for oral administration in capsule form with an absorbable material such as gelatine, containing the active substance with or without the addition of diluents or excipients.

For parenteral administration, the compounds may be administered in aqueous or non-aqueous sterile solutions, suspensions or emulsions. Some examples of non-aqueous solvents or suspensory media are: propylene glycol, polyethylene glycol, dioxilanes, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. These mixtures may also contain additives such as preservative, humectant, emulsifying and dispersant agents. They may also be sterilized, for example, by filtration through bacteria-retaining filters, by incorporation into the mixture of sterilizing agents, by irradiation or by heating.

They may also be manufactured in the form of 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 may be incorporated into an appropriate vehicle such as a creme or unguent, or a pessary, ovule, or tablet for insertion into the vagina. The percentage of active ingredients in the mixtures of the present invention may vary in such a way that the proportion is appropriate for providing an adequate dosage with which to obtain the desired therapeutic effect.

It will be apparent that the composition may be administered at the same time in several different forms. In human therapy, the mixtures must generally be administered and the pharmaceutical compositions formulated in such a way that, in the case of oral or topical administration, 0.250 to 3.0 g of active substance is administered per day; in the case of parenteral administration, 0.150 to 1.5 g per day; and rectally, 0.125 to 2.0 per day.

Thus, the solutions described below in Examples I to Ill, VIII and IX may be administered intravenously to adult humans (500 mg every 8 hours) and 5 ml/min and to children under 12 (7.5 mg/kg-100 ml of solution) every eight hours at 5 ml/min.

The orally administrable dosages described below in Example IV to VI and X may be administered (500 mg) three times a day for seven days or more.

The rectally administrable composition of Example VII may be administered to adults 1-3 times a day for three days and after the fourth day a suppository every ten hours for four days. In children under 12 a dosage of 500 mg may be administered three times a day for three days and after the fourth day a suppository every twelve hours for four days.

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

It will be understood that the foregoing dosage ranges are optimal and that variations therein are permissible within the spirit of the invention in certain instances.

The invention is illustrated by the following non-limiting examples; Example I In order to prepare an aqueous solution of 1-(2-3'-carboxypropionyl oxyethyl)-2-methyl-5-nitroimidazole (I) at 35.0%, 35.0 g of the compound is dissolved in a mixture of diethanolamine (13.56 g) and water (50 cc) and is brought to a volume of 100 cc with water.

The pH of the solution obtained is approximately 6.

Example Il In order to prepare a 35.0% aqueous solution of the magnesium salt of (I), 35.0 g of (I) are made to react with basic magnesium carbonate (5.9 g) mixed with water (70 cc), stirring and heating to approximately 50"C.

When it has ceased giving off gas, it is brought to a volume of 100 cc with water and filtered. The solution obtained has a pH of approximately 5.7.

Example 111 In order to prepare a 25.0% aqueous solution of the sodium salt of (1), 35.0 g of (I) is made to react with sodium bicarbonate (10.76 g), mixing with water (40 cc), stirring and heating to approximately 50"C. When it has ceased giving off gas, it is brought to a volume of 100 ce with water and filtered.

The solution obtained has a pH of approximately 6.5.

Example IV Tablets for oral administration, prepared by the usual technique, having the following composition: 1 -(2-3'-carboxypropionyl oxyethyl)- 2-methyl-5-nitroimidazole 0.250 g Starch 0.190g Aerosil 200 0.050 g Magnesium stearate 0.025g Example V Tablets for oral administration, prepared by the usual technique, have the following composition: 1-(2-3'-carboxypropionyl oxyethyl) 2-methyl-5-nitroimidazole 0.500 g Plasdone 0.0259 Avicel pH 102 0.130 g Talc 0.014g Magnesium stearate 0.005g Colorant 0.014 9 Example VI Vaginal tablets, prepared by the usual technique, have the following composition:: 1 -(2-3'-ca rboxypropionyl oxyethyl) 2-methyl-5-nitroimidazole 0.500g Cornstarch 0.683g Alginic acid 0.050 g Aerosil 200 0.060g Magnesium stearate 0.0010 g Example VII Vaginal ovules or suppositories, prepared by the usual technique, have the following composition: 1 -(2-3'-carboxypropionyl oxyethyl ) 2-methyl-5-nitroimidazole 20.83 g Sodium hydroxide solution 0.1 N 72.00 cc Manitol 30.00 g Timerosal 0.00025g Distilled water s.q. 100.00 cc The solution is sterilized by means of 0.22 sterile membrane filter and is placed in ampul bottles to be lyophilized from 5 cc into 3.0 cc portions. The product may be reconstituted for use with 3 cc of sterile water for injection.

Example IX A solution for injection: 8 g of micronized powder of 1 -(2-3'-carboxypropiony oxyethyl)-2-methyl-5-nitroimidazole is introduced aseptically into an ampul bottle. Then the product is sterilized at 100C for one hour. Meanwhile a solution is prepared with the following composition: 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 cc of this solution is taken and the content of the ampul bottle dissolved. The solution obtained should be used no later than two hours following its preparation.

Example X Suspension for oral administration: 1-(2-3'-carboxypropionyl oxyethyl) 2-methyl-5-nitroimidazole 1.5 9 Glass sugar 18 g Sodium nipagin 0.108g Sodium nipasol 0.0129 Sodium saccharin 0.03g Sodium dibasic phosphate 0.1983 g Sodium monobasic phosphate 0.1017 g Carboxymethyl cellulose 0.18 9 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 seven days at most and the remainder discarded.

Example XI Unguent for topical preparation: 1-(2-3'-carboxypropionyl oxyethyi)- 2-methyl-5-nitroimidazole 0.750 g Cetyl alcohol 10.5 g Stearilic alcohol 9.3 g Liquid vaseline 25.5g Glycerine 15 g Solid vaseline 33.9 g Nipagin 0.369 Nipasol 0.09 g Span 60 2.3 g Tween 60 2.3 9

Claims (14)

1. A pharmaceutical composition containing as active ingredient 1 -(2,3'-carboxypropionyl oxyethyl)-2methyl-5-nitroimidazole or a salt thereof with a pharmaceutically acceptable base or acid.

2. A composition as claimed in claim 1 wherein said base is derived from ammonia, alkali or alkaline earth metals.

3. A composition as claimed in claim 1 wherein said acid is an aliphatic amino acid.

4. A composition as claimed in any preceding claim, containing a pharmaceutically acceptable carrier.

5. A composition as claimed in claim 4, in which the carrier is a solid, liquid or unguent pharmaceutical carrier.

6. A composition as claimed in any preceding claim in a form suitable for parenteral administration.

7. A composition as claimed in any of the preceding claims 1 - 5 in a form suitable for oral administration.

8. A composition as claimed in any of the preceding claims 1 - 5 in a form suitable for topical administration.

9. A composition as claimed in any of the preceding claims 1 - 5 in a form suitable for rectal administration.

10. A composition as claimed in any of the preceding claims 1 - 5 in a form suitable for vaginal administration.

11. A composition as claimed in claim 1 in a form suitable for use as a prophylactic agent in surgery.

12. A composition as claimed in any preceding claim in units each containing a unitary dose of the said active ingredient.

13. A method of preparing a pharmaceutical composition comprising admixing with a pharmaceutically acceptable carrier or inert diluent a therapeutically effective amount of 1 -(2-3'-carboxyprnpionyl oxyethyl)-2methyl-5-nitro-imidazole or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition according to any one of Examples I to Xl hereinbefore.