NL8105449A - PHARMACEUTICAL PREPARATIONS CONTAINING 1- (2,3'-CARBOXYPROPIONYLOXYETHYL) -2-METHYL-5-NITROIMIDAZOL AS AN ACTIVE SUBSTANCE AS A MEDICINE AGAINST ANAEROBIC MICROORGANISMS CAUSED BY DISEASES. - Google Patents

Description

/ <ïw B. v. a, ïg | "Vo 2531" 2 DEC 1981 |

Pharmaceutical preparations containing 1- (2,31-carboxypropionyloxyethyl) -2-methyl-5-nitroimidazole as an active ingredient as a drug against anaerobic microorganism diseases.

The invention relates to derivatives of imidazole 1- (2,3 * -carboxypropioriyloxyethyl) -2-methyl 5-nitroimidazole of the formula 1 and salts thereof with pharmaceutically acceptable inorganic or organic bases, for example alkali metal, alkaline earth metal , ammonium, aliphatic amino acid, mono- or diethanolamine and cyclic amine salts.

In particular, the invention relates to pharmaceutical preparations containing these derivatives and methods for treating infections caused by anaerobic bacteria, eg Peptostreptococcus, Bacteroldes fragilis,

Bacteraides, - melaninogenicus, Furobacterium, Clostridium perfringens and other species of Clostridium.

The salts of the compound of the formula I have the additional advantage that they are water soluble, making them suitable for parenteral administration.

The use of 1- (2,31-carboxypropionyloxyethyl) -2-methyl 5-nitro midazole or its salts can be in combination with excipients or coatings normally used in pharmaceuticals.

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

The preparations for oral administration include tablets, sugar-coated pills, dispersible powders or granules. In these solid mixtures, the active compound is administered together with at least 25; one inert diluent such as calcium carbonate, potato starch, alginic acid, microcrystalline cellulose, methyl cellulose, lactose or sucrose. The mixtures can also contain substances other than the inert diluents, such as, for example, lubricants, for example 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 diluents. These blends may also contain additives "TTÖTTT9" -2-4 such as wetting and sweetening agents, aromatizing agents and aromatic suspending agents and preservatives.

The formulations may also be mixed in capsule form for oral administration with an absorbable material such as gelatin, which contains the active material with or without addition of diluents or excipients.

For parenteral administration, the compounds can be administered in aqueous or non-aqueous sterile solutions, suspensions or emulsions. Some examples of non-aqueous solvents or suspension media are: propylene glycol, polyethylene glycol, dioxilanes, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. These blends may also contain additives such as preservatives, wetting agents, emulsifying agents and dispersing agents. They can also be sterilized, for example, by filtering through bacteria-retaining filters, by adding to the mixture of sterilizing agents, by irradiation or by heating. They can also be made in the form of solid sterile mixtures that can be dissolved in sterile water or any other sterile injectable medium ready for immediate use.

For topical application, the active ingredient can be introduced into a suitable vehicle such as cream or ointment, or a cap. ovulum or tablet for insertion into the sheath. The content of active ingredients in the mixtures according to the invention can vary in such a way that the amount is suitable for providing an adequate dosage with which the desired therapeutic effect can be obtained.

It will be understood that the preparation can be administered in different forms at the same time. In human therapy, the mixtures are generally administered and the pharmaceutical preparations formulated in such a way that, in the case of oral or topical administration, 0.250-3.0 g of active ingredient is administered per day; for parenteral administration 0.150-1.5 g per day and rectally 0.125-2.0 per day.

For example, the solutions described in Examples I - III, VIII and IX can be administered intravenously (500 mg every 3 3 35 8 hours) and 5 cm / min and to children under 12 years old (7.5 mg / kg 100 cm 3 solution) every 8 hours at 5 cm / min.

8 ï 0 5 4 4 9 '-3-

The orally administered doses described in Examples IV-VI and X can be administered (500 mg) three times a day for seven days or more.

The rectally formulated composition of Example VII can be administered to adults 1-3 times a day for 3 days and after the fourth day a suppository every ten days for four days. In children under 12, a dose of 500 mg can 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 preparations can also be used as prophylactics in surgery as well as in renal and hepatic abscesses and gangrene.

It will be clear that the above-mentioned dosage ranges are optimal and that variations are possible within the scope of the invention in certain cases.

The invention is further illustrated by the following examples.

Example I

To prepare an aqueous solution of 1- (2,3-20 carboxypropionyloxyethyl) -2-methyl · S-nitroimidazole (I) of 35.0%, 35.0 g of the compound are dissolved in a mixture of diethanolamine ( 13.56 g] and water (50 cm 3) and the mixture made up to a volume of 100 cm with water.

The pH of the resulting solution is about 6.

Example II

To prepare a 35.0% aqueous solution of the magnesium salt of (I), 35.0 g of (I) are reacted with basic magnesium carbonate (5.9 g) mixed with water (70 cm), stirring and heating to about 50 ° C. When gas evolution has ceased, the mixture is brought to a volume of 100 cm with water and then filtered. The resulting solution has a pH of about 5.7.

Example lil. .

1 net

To prepare a 25% aqueous solution of sodium 35 salt of (I), 35.0 g of (I) are reacted with sodium bicarbonate (10.76 g), mixed with water (40 cm 3), stirring and heating to about 50 ° C. When gas evolution has ceased, the mixture is introduced -------- 8 | o 5T4 9 ------------------ ~ - 3

. ï X

-4- at a volume of 100 cm with water and then filtered.

The resulting solution has a pH of about 6.5.

Example IV

Tablets for oral administration, manufactured according to the conventional technique, have the following composition: 1 - (2,3'-carboxypropionyloxyethyl) - 2-methyl-5-nitroimidazole 0.250 g

Starch 0.190 g

Aerosil 200 0.050 g 10 Magnesium stearate 0.025 g

Example V

Tablets for oral administration manufactured according to the conventional technique have the following composition: 1- (2,3'-carboxypropionyloxyethyl) 15 2-methyl-5-nitroimidazole - 0.500 g -.

Piasdon 0.025 g

Avicel pH 102 0.130 g

Talc "0.014 g

Magnesium stearate 0.005 g 20 Dye 0.014 g

Example VI

Vaginal tablets prepared by the conventional technique have the following composition: 1- (2,3'-carboxypropionyloxyethyl) -25 2-methyl-5-nitroimidazole 0.500 g

Corn starch 0.683 g

Algic acid 0.050 g

Aerosil 200 0.060 g

Magnesium stearate 0.0010 g 30 Example VII '.

Vaginal ovules or suppositories manufactured according to the usual technique have the following composition: * 8 1 0 5 4 49 ......; : -5- - - / t 1- (2,31-carboxypropionyloxyethyl) - 2-methyl-5-nitroimidazole 20.83 g

Sodium hydroxide solution 0.1 N 72.00 cm 3

Mannitol 30.00 g 5 Timerosal 0.00025 g 3

Distilled water s.q. 100.00 cm

The solution is sterilized by a 0.22 sterile membrane fliter and placed in ampoule vials to be lyophilized from 5 cm in 3.0 cm portions. The product can be

O

10 reconstituted for use with 3 cm sterile water for injections.

Example IX

A solution for injection: 8 g of micronized powder of 1- (2,3'-carboxypropionyloxyethyl) -2-methyl-5-nitroimidazole is placed aseptically in an ampoule vial.

The product is then sterilized at 100 ° C 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 cm3. The solution thus obtained is sterilized by filtration.

through a 0.22 membrane; 20 cm 2 of this solution is taken and the contents of the ampoule vial are dissolved. The resulting solution should be used no later than two hours after preparation.

Example x 25 Suspension for oral administration: 1 - (2,3'-carboxypropionyloxyethyl) - 2-methyl-5-nitroimidazole 1.5 g

Glass sugar 18. g

Sodium nipagin 0.108 g 30 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 35 Mannitol 3.87 g

Total 24 g 8 1 0 5 4 4 9 _..... ": '- * -¾ -6-

The resulting mixture was reconstituted with water to a volume of 60 cnf * at the time of use. This suspension should be used within a maximum of seven days and the rest discarded.

5 Example XI

Ointment for topical administration: 1- (2,3'-carboxypropionyloxyethyl) -2-methyl-5-nitroimidazole 0.750 g 10 Cetyl alcohol 10.5 'g

Stearyl alcohol 9.3 g

Liquid Vaseline 25.5 g

Glycerol 15 g

Solid Vaseline 33.9 g «15 Nipagine 0.36 g

Nipasol 0.09 g

Span-60 2.3 g

Twee-60 ·, 2.3 g "'*' *. J t t 8Γ0Τ4Τ9" "~": -

Claims (19)

A unit dose pharmaceutical composition suitable for treating anaerobic microorganism diseases comprising a therapeutically effective amount of a compound selected from the group consisting of 1- (2,3'-carboxypropionyl-oxyethyl) -2-methyl-5 nitroimidazole and its salts with pharmaceutically acceptable bases or acids and a pharmaceutically acceptable carrier. Preparation according to claim 1, characterized in that said bases are derived from ammonia, alkali or alkaline earth metals. 3. A composition according to claim 1, characterized in that said acidic egg are aliphatic amino acids. Preparation according to claim 1, characterized in that said anaerobic microorganisms are selected from the group consisting of Peptostreptococcus, Bacteroides fragilis, Bacteroides melaninogenicus, Furobacterium, Clostridium perfringens and Clostridium. Sjp_. The formulation of claim 1 in a form suitable for. parenteral administration. . - 6. Preparation according to condusion 1 suitable for oral administration. A composition according to claim 1 suitable for topical administration. A compound according to claim 1 suitable for rectal administration. A composition according to claim 1 suitable for vaginal administration. 10. A method of treating diseases caused by anaerobic microorganisms, characterized in that a therapeutically acceptable amount of a compound selected from the group consisting of 1- (2,31-carboxypropionyloxyethyl) is administered to a human affected by the disease. -2-methyl-5-nitroimidazole and its salts with pharmaceutically acceptable bases or acids. Process according to claim 10, characterized in that non-basic bases are derived from ammonia, alkali metals or alkaline earth metals. Method according to claim 10, characterized in that said acids are aliphatic amino acids. 810 ü 4 4 9 "a- V. j -8- A method according to claim 10, characterized in that said anaerobic microorganisms are selected from the group consisting of Peptostreptococcus, Bacteriodes fragilis, Bacteriodes melaninoqenicus, Furobacterium, Clostridium perfringens and Clostridium Sp. A method according to claim 10, characterized in that said compound is administered parenterally. A method according to claim 10, characterized in that said compound is administered orally. 16. A method according to claim 10, characterized in that said compound is administered topically. A method according to claim 10, characterized in that said compound is administered rectally. A method according to claim 10, characterized in that said compound is administered vaginally. 19. A composition suitable for use as a prophylactic in the art comprising as an active ingredient 1- (2,3'-carboxypropionyl-oxyethyl) 2-methyl 5-nitroimidazole. · "; v ------:: '