FR2624736A1 - Novel water-dispersible pharmaceutical compositions based on ornidazole - Google Patents

Abstract

The invention relates to the field of therapeutic chemistry. It relates more specifically to antiparasitic and anti-infectious pharmaceutical compositions containing, as active principle, ornidazole dissolved in an aqueous vehicle containing a polycarboxylic acid alcohol. These compositions find use for the treatment of deep mycoses or parasitic infections, in venous perfusion or in permucosal applications.

Description

The present invention relates to new pharmaceutical anti-parasitic and anti-infectious compositions dispersible in water or in physiological media.

It relates more particularly to new pharmaceutical compositions in which the active principle is in the form soluble in aqueous media or dispersible in such media.

It specifically relates to anti-parasitic pharmaceutical compositions, the active principle of which is ornicole in a form where it is soluble in water even at high concentrations or else where it is dispersible by contacting with aqueous media, especially biological media.

Ornidazole or 2-methyl N (3-chloro 2-hydroxy propyl) 5-nitro (1H) imidazole has the formula

It was first described by M. HOFFER and E. GRUBERG in J. Med. Chem. 17C (1974) lbl9.

It is a very effective anti-trichomonas, anti-amoebic and anti-fungal agent against anaerobic germs which is often administered by venous infusion. However, the treatment of these parasitoses and in particular that of hepatic amoebiasis requires the use of large doses often of several grams per day.

The administration of an effective dosage of 1 g per 24 h by intravenous route is difficult because of the very low solubility of this active ingredient in aqueous media so that the commercial form, currently on the market , is a solution in a mixture of ethanol and propylene glycol. This solution is intended to be diluted by an infusion liquid. Ornidazole does not always remain dissolved under these conditions and the infusion liquid becomes cloudy by precipitation of the active ingredient.

Ornidazole is sparingly soluble in water (4 to 250) and significantly more soluble in organic solvents. It is also known that substituted nitro imidazoles such as metronidazole are more soluble in dilute acid solutions (hydrochloric acid 1/10) but these solutions are very acidic and incompatible with a venous infusion.

However, it has now been found that it is possible to dissolve ornidazole in an aqueous medium using organic acids devoid of toxicity. These are hydroxylated polycarboxylic acids or alcohol acids. They are relatively weak acids of pK close to 4 very soluble in water.

They react with ornidazole, a weak base, to give a stable, perhaps ionic, water-soluble combination with a pH close to neutral. To ensure better stability of this combination, it is preferable to maintain a slight excess of hydroxylated polycarboxylic acid while adjusting the pH using a buffer system.

The term “hydroxylated polycarboxylic acids” denotes organic acids comprising several acid functions and at least one alcohol function such as, for example, citric acid, tartaric acid, gluconic acid, citramalic acid, acid tartronic, senesic acid and the like. Among these acids, citric acid is 1IG preferred cide.

It is therefore thus possible to produce stable solutions of orndazole, the pH of which is within physiological limits and the administration of which by venous route poses no physical compatibility problem or tolerance problem at the injection site.

This combination being fairly soluble in water, it is possible to produce more concentrated solutions than those currently encountered on the market and which can serve as a basis for topical preparations such as creams or preparations for mucous membranes such as ova.

It is also possible to isolate this combination in solid form and to use it as it is to produce dry forms intended for application per mucosa in the form of vaginal tablets due to their rapid and complete dissolution in contact with liquids. biological.

The combination according to the invention is rapidly absorbed and exhibits significant tissue diffusion and then majority urinary elimination. It has a strong activity in the treatment of trichomoniasis, lambliase and infections with anaerobic germs Results of the order of 9C ç of success were observed with doses corresponding to 1 g of ornidazole for 24 to 46 hours then that with metronidazole for the same efficacy, repeated and prolonged administrations (treatments of 5 days for lambliase and 1L days for trichomoniasis) are necessary.

The compositions according to the invention are produced by placing the ornidazole in suspension in water, adding, with stirring, the hydroxylated polycarboxylic acid in slight excess until complete dissolution, adjusting the pH if necessary and then distributing the solution obtained in unit doses or by incorporating it as it is or after evaporation of the water in preparations for topical or percutaneous use.

Preferably, an amount of hydroxylated polycarboxylic acid such as citric acid is added to the aqueous suspension of ornidazole in excess of 1G to 4C> relative to the stoichiometry and more particularly from 15 to 3C. The operation is carried out at a temperature between G and 6C and preferably between 4C and 600 where the reaction is accé managed. The pH of the solution being in the vicinity of 4.5, it should be brought back to a more physiological pH by the addition of a phospho-phosphate buffer which makes it possible to obtain a pH of approximately 6.5
The solution thus obtained has a concentration of active principle which ranges from G, 5 to 25 by weight and preferably from 1 to 15. The solution can be concentrated in vacuo or even evaporated to dryness to obtain the combination of the two constituents in solid form.

The solution can be used as it is or diluted in perfusion liquids without risk of precipitation or else, incorporated into a lipophilic excipient to make a cream or an emulsion of the water in oil type or even ova.

The combination in solid form can be mixed with inert excipients such as Kaolin, bentonite, calcium carbonate, dimagnesium phosphate or lactose, in order to produce dry forms such as tablets or vaginal capsules.

The following examples illustrate the invention without, however, limiting it.

EXAMPLE 1.

 Ornidazole solution for injection, 5 S.

5L g of ornicazole are suspended in 90L ml of water and kept under vigorous stirring. 17.48 g of citric acid is gradually added, ie an excess of 2L <. The solution becomes completely clear. A solution of phosphate buffer pH 7 (phosphate mono potassium phosphate disouique) is added until a pH of 6.5 is obtained. It is then made up to 1 ml with distilled water. It is then filtered on sintered glass and then sterilized by fiitration on a filter membrane or by heat. The solution is aseptically distributed in 200 ml flasks each containing 1 g of ornidazole.

EXAMPLE 2.

 1% ornidazole solution.

7.5 g of ornidazole are suspended in 500 ml of water. The suspension is heated to 50 while stirring. 3.2 g of tartaric acid are then added in portions and the heating is kept at 50 until all the active principle is dissolved.

The solution is filtered through a sintered glass and sealed tightly.

EXAMPLE 3.

 Eggs at 1.5 g ornidazole.

1.5% ornidazole solution prepared according to
Example 2 .......... 1000 ml
Gelatin ..........

25L g
methyl p.oxybenzoate .... 0.15 g
Water ... qsq lúCG ova with an average weight of
4.5L g

Claims (8)

 R E Y E N D I C A T I D N S The subject of the invention is: 1. New antiparasitic pharmaceutical compositions  and ornidazole-based anti-infectives characterized in  what ornidazole is dissolved in a medium  aqueous using a hydroxylated polycarboxylic acid. 2. The pharmaceutical compositions according to claim 1  in which the hydroxylated polycarboxylic acid is in  excess compared to stoichiometry. 3. The pharmaceutical compositions according to claim 1  and claim 2 which further contain an agent  buffer which maintains the pH in the vicinity of neutrality. 4. The pharmaceutical compositions according to one of the claims  cations 1 to 3 in dry form after evaporation of the medium  aqueous. 5. The pharmaceutical compositions according to one of the claims  cations 1 to 4, in which polycarboxylic acid  hydroxylated is preferably citric acid, tar acid  stick, glucaric acid or citramalic acid. 6. The pharmaceutical compositions according to one of the claims  cations 1 to 5 in which the excess polycarboxy acid  the hydroxylated liquefy is from 10 to 4G% compared to the stroke chemistry. 7. A process for obtaining pharmaceutical compositions  according to one of claims 1 to 6 in which one puts in  ornidazole solution in an aqueous medium containing a  hydroxylated polycarboxylic acid in excess relative to the  stoichiometry, adjust if necessary the solution pu  physiological values and, where appropriate, concentrates  or dry evaporate the solution to obtain the combination  in solid form. 8. Use of the pharmaceutical compositions obtained  according to claim 7 for the purpose of obtaining a medicament  antiparasitic and anti-infectious administered by route  parenteral or by the mucosal route.