Note: Descriptions are shown in the official language in which they were submitted.
PHARMACEUTICAL COMPOSITION CONTAINING
1-(2-3'-CARBOXYPROPIONYL OXYETHYL)-2-METHYL
-5-NITROIMIDAZOLE AS ACTIVE THERAP~UTIC AGENT
AGAINST DIS ASES CAUSED BY ANAEROBIC GERMS
BACKGROUND AND SIJMMARY OF THE INVENTION
This invention relates ~o the deTivatives of
imidazole 1-(2-3'-carboxypropionyl oxyethyl)-Z-methyl-5-
nitroimidazole having the formula:
/ N
~ II C~
N02'~N /
CH2 CH2 0~ CH2--CH2-~--O~
and salts thereof with pharmaceutically acceptable
inorganic or organic bases3 e.g., alkali metal, alkaline-
earth metal/ ammonia, aliphatic amino acid, i.e., mono-
or di-ethanolamine and the cyclic amine salts.
More particularly, the invention relates to
pharmaceutical compositions containing these derivatives
and methods of treatment therewith of infections caused by
anaerobic bacteria,-e.g., Pep~ostreptococcus, Bacteroides
fragilis, Bacteroides melaninoge~icus, Furobacterium,
Clostridium perfringens and other species of Clostridium.
The salts of Compound I have the added
2S advantage of being soluble in water, which allows them to
be used for parenteral administration.
~2~
The use of l-t2-3l-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 cellulose7 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 9 also containing inert diluents. These mixtures
may also contain additives such as humectant agents and
sweetening, flavoring and aromatic suspensories and
preservatives. The compositions 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 addi~ion of diluents or excipien*s.
For parenteral administration, the compounds
may be administered in a~ueous or non-aqueous sterile
solutions, suspensions or emulsions. Some examples of
non-aqueous solvents or suspensory media are: propylene
glycol, polyethylene glycol, dioxilanes 3 vegetable oils
such as olive oil, and injectable organic esters such as
ethyl oleate. These mixtures may also contain additives
-3-
such as preservative, humectant, emulsi~ying 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. Ihey may also be manufac-
tured in the ~orm of solid sterile mixtures which can be
dissolved in sterile water or some other sterile
injectable medium immediately be~ore 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 ~roportion 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 adminis-
tered and the pharmaceutical compositions formulated in
such a way that, in the case of oral or topical adminis-
tration9 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, ~he solutions described below in Examples
I to III, V~II and IX may be administered intravenously
to adult humans ~500 mg every 8 hours) and 5 ml/min and
to children under 12 (7O5 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 o~
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
-4-
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:
_AMPLE I.
In order to prepare an âqueous solution of
1-~2-3'-carboxypropionyl oxyethyl)-2-methyl-5-
nitroimida~ole ~ 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 approxi-
mately 6.
EXAMPLE II.
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 approxima*ely
50C. 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.
-5-
EXAMPLE III.
In order to prepare a 25.0~ aqueous solution
of the sodium salt of ~I), 35.0 g of (I) is made to
react with sodium bicarbonate (10.76 g), mixing with
water ~40 cc),.stirring and heaking to appToximately
50C. 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 approxi-
mately 6..5.
EXAMPLE IV.
Tablets for oral administration? prepared by
the usual *echnique, have the following composition:
1-(2-3~-carboxypropionyl oxyethyl)-
2-methyl.-5-nitroimidazole 0.250 g
15 Starch 0.190 g
Aerosil 200 0 050 g
Magnesium stearate 0.025 g
EXAMPLE V.
Table.ts for oral administration, prepared by
the usual technique, have the following composition:
1-~2-3'-carboxypropionyl oxyethyl)- -
2-methy.1-5-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
* Trade Mark
--6--
EXAMPLE VI.
Vaginal tablets, prepared by the usual
technique, have the following composition:
l-(2-3'-carboxypropionyl oxyethyl)-
2-methyl-5-nitroimidazole 0.500 g
Cornstarch 0.683 g
Alginic acid 0.050 g
Aerosil 200 0.060 g
Magnesium steaTate 0.0010 g
EXAMPLE VII.
Vaginal ovules or suppositories, prepared by
the usual technique, have the following composition:
l-~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 0.00025 g
Distilled water sOq. 100.00 cc
The solution is sterilized by means of 0.22 sterile
2~ 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
~or injection.
~EXAMPLE VIII
A solution for injection:
8 g of micronized powder of 1-(2-3'-carboxy-
propionyl oxyethyl~-2-methyl-5-nitroimidazole is intro-
duced aseptically into an ampul bottle. Then the product
is steriliz-ed 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 IX
Suspension for oral administration:
1-(2-3t-carboxypropionyl oxyethyl)-
2-methyl-5-nitroimidazole 1.5 g
Glass sugar 18 g
Sodium nipagin 0.108 g
15 Sodium nipasol 0.012 g
Sodium saccharin 0.03 g
50dium dibasic phosphate 0.1983 g
Sodium monobasic phosphate 0.1017 g
Carboxymethyl cellulose 0.18 g
20 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.
"
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-8~
EXAMPLE X
Unguent foT topical preparation:
1-(2-3'-carbosypropionyl oxyethyl)-
Z-methyl-5-nitroimidazole 0.750 g
5 Cetyl alcohol 10.5 g
Stearilic alcohol 9.3 g
Liquid vaseline 25.5 g
Glycerine 15 g
Solid vaseline 33.9 g
10 Nipagin* 0.36 g
Nipasol* 0.09 g
Span*60 2.3 g
Tween*60 2.3 g
* Trade Mark
