RU2245135C1 - Method for preparing metronidasol solution for injections - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: the present innovation deals with mixing water for injections, conservation agent, metronidasol till complete dissolving at 50-60 C, adding a buffer (NaOH solution) pH 4.5-6.5 at pre-estimated quantity of water, then one should sterilize the obtained medicinal form due to membranous filtration followed by sterile packaging. As a conservation agent one should apply sodium chloride at the quantity of 1.5-2.0 against metronidasol weight, then metronidasol solution should be supplemented with a half-volume of sodium chloride solution, after complete dissolving the obtained solution should be supplemented with the rest quantity of sodium chloride solution. As for membranous filtration it should be carried out by applying a capsule out of polypropylene with hydrophilic membrane of 1.2 mcm. The method provides no crystallization of an active substance during prolonged period of time.

EFFECT: higher therapeutic efficiency.

1 ex, 1 tbl

Description

The invention relates to medicine, namely to a method for producing a solution of metronidazole for injection.

Metronidazole 1 (β-hydroxyethyl) -2-methyl-5-nitroimidazole has a wide spectrum of action against protozoa, inhibits the development of Trichomonas vaginalis, Entamoeba histolytica, lamblia, etc. 0.5 g in 100 ml of solution is administered intravenously at a rate of 5 ml per minute. They are produced in the form of a 0.5% solution for infusion in ampoules of 10 and 20 ml and in bottles of 100 ml / M.D. Mashkovsky, Medicines, vol. 2, pp. 345-346 /.

Various dosage forms of metronidazole are known: in the form of an ointment (US Pat. RF 2080864), tablets (US Pat. RF 2196571), solutions (US Pat. RF 2173993, 2029548).

A known method for producing an injectable dosage form of metronidazole (V. Buhler, Generic drug formulation, BASF, 1997) containing, as auxiliary components, substances such as propylene glycol, polyvinylpyrrolidone and polyethylene glycol-400. This dosage form has a high viscosity, which complicates the injection, and low stability (the formation of a precipitate of metronidazole during storage).

The use of an injectable dosage form of a complex of metronidazole with polyvinylpyrrolidone has been described in the treatment of pig dysentery (V. L. Tikhonov. V. N. Skvortsov. News of Veterinary Pharmacy and Medicine (Polfa), 1992, No. 2, pp. 43-50), however this work does not indicate the composition of the dosage form.

Injectable aqueous dosage forms of metronidazole are known to be used in medicine (Metrogil, Drug Register, 7th ed. M., 2000) and veterinary medicine (Torgil solution. Vet. Oata Sheet Compenditiun, NOAH, 89/90. London ), but all of them are characterized by a low concentration of the active substance due to the low solubility of metronidazole in water (not more than 0.5%) and, accordingly, a large volume of solution for administration.

A medicine containing metronidazole in the form of a 0.5% aqueous solution is produced in several countries: India, Finland, Poland, Yugoslavia, France. In the USSR, this drug is not manufactured and purchased abroad.

In India, mentronidazole is released under the name metrogil in the form of a 0.5% aqueous solution (pH 5.0-6.0). The composition and method of preparation are unknown.

In Finland, metronidazole is produced under the name tricanix in the form of a 0.5% aqueous solution (Orion company). The composition and method of preparation are unknown.

In Poland, metronidazole is released under the same name in the form of a 0.5% aqueous solution in ampoules of 20 ml of the following composition, wt.%: Metronidazole 0.5, disodium versenate 0.01, water for injection up to 100.0, pH 5JO-7 , 0.

Yugoslavia (Krka company) produces metronidazole under the name efloran (2) in the form of a 0.5% aqueous solution in bottles (100 ml) containing, wt.%: Metronidazole 0.5, sodium chloride 0.7, disodium edithate 0 , 01, water for injection up to 100.

In France (Ron-Pulenc company), metronidazole produces under the name flagil in the form of a 0.5% aqueous solution in bottles (100 ml) containing, wt.%: Metronidazole 0.5, sodium phosphate 0.15, citric acid 0.044 , sodium chloride 0.74, water for injection up to 100. The quantitative and qualitative composition of the flagyl allows to obtain aqueous solutions of metronidazole in a concentration of not more than 0.5%, because of this, to obtain a therapeutic effect, the drug must be administered in large volume (up to 100 ml), which is undesirable.

A known method of producing injectable forms of metronidazole, which consists in dissolving metronidazole in an aqueous solvent in a concentration of from 5.0 to 6.5 wt.% / Volume, containing the following auxiliary components: dimethylacetamide 25-35% (volume / volume); ethanol 40-60% (volume / volume) (US patent No. 4032645).

The disadvantage of this dosage form is the high general toxicity associated with a high concentration of organic solvents, in particular ethanol, and the stability and pharmacokinetics of the drug are also unknown.

The prototype of this invention is a method for producing a solution of metronidazole for injection, including mixing water for injection, a preservative, metronidazole until completely dissolved at a temperature of 50-60 ° C, adding to the resulting solution a pH 4.5-6.5 buffer with a calculated amount of water, sterilization the resulting dosage form by membrane filtration and sterile packaging in a suitable container (US Pat. RF No. 2173993).

The objective of the invention is to provide a method for producing a dosage form of metronidazole, convenient to use, providing high therapeutic efficacy, the absence of crystallization of the active substance for a long time.

This goal is achieved through the use of a method of obtaining a solution of metronidazole for injection, including mixing water for injection, a preservative, metronidazole until completely dissolved at a temperature of 50-60 ° C, adding to the resulting solution a buffer of pH 4.5-6.5 with a calculated amount of water sterilization of the obtained dosage form by membrane filtration and sterile packaging in containers. As a preservative, sodium chloride is taken, taken in an amount of 1.5-2.0 by weight of metronidazole, while solutions of sodium chloride in a concentration of 0.7-1.0% and a solution of metronidazole in a concentration of 0.45-0.55% are preliminarily prepared. then half the volume of sodium chloride solution is added to the metronidazole solution, after the components are completely dissolved, the remaining amount of sodium chloride solution is added to the resulting solution, and membrane filtration is carried out using a 0.2 micron polypropylene capsule with a hydrophilic membrane.

During the study, it was found that the combination of metronidazole with sodium chloride in certain ratios prevents the crystallization of the active compound.

Tests of the obtained dosage form were carried out on farm animals. The therapeutic efficacy of the injectable form obtained by the claimed method was studied for dysentery of piglets caused by Treponema (Serpulina) hyodysenteriae.

A drug Dose and frequency of administration, ml per 10 kg of weight therapeutic efficacy,% According to example 1 1.0 (one time) 98.0 According to example 2 2.0 (once) 100.0 According to example 1 1.0 (twice) 98.4

The invention is illustrated by the following example.

Example 1. In two capacitive heated apparatuses equipped with a stirrer, a sodium chloride solution of 0.7-1.0% concentration and a metronidazole solution of 0.45-0.55% concentration at a temperature of 50-60 ° C are preliminarily prepared for 60 minutes. The amount of metronidazole and sodium chloride is taken in a ratio of 1: 1.5-2.0. Then half the volume of the sodium chloride solution is added to the metronidazole solution, after the components are completely dissolved, the remaining amount of the sodium chloride solution is added gradually over the course of 30 minutes. To the resulting solution add buffer (NaOH solution) pH 4.5-6.5 with the calculated amount of water. Preliminary sterilization of the solution in the apparatus before bottling is not carried out due to the antibiotic properties of the substance itself and the possible increase in the interaction of the drug with the equipment material. Membrane filtration is carried out using a plate holder company "Millipor". A membrane with a pore diameter of 0.2 μm “Vladipor” of the PMAC type is placed in the filter holder. For sterilizing filtration using capsules made of polypropylene with a hydrophilic membrane of 0.2 μm Sartobran P company "Sartrius". Bottling is carried out in accordance with GOST 10782-85 with a dose of 100 ml. Capping is done with stoppers from the rubber mixture 52-369 / 1, crimped with aluminum caps. After bottling, the finished product is sterilized at a temperature of 120 ° C for 15 minutes.

Claims (1)

A method of obtaining a solution of metronidazole for injection, including mixing water for injection, a preservative, metronidazole until completely dissolved at a temperature of 50-60 ° C, adding to the resulting solution a buffer pH 4.5-6.5 with the calculated amount of water, sterilizing the resulting dosage form with a membrane filtration and sterile packaging in containers, characterized in that sodium chloride is taken as a preservative, taken in an amount of 1.5-2.0 by weight of metronidazole, while sodium chloride concentration solutions are preliminarily prepared th 0.7-1.0% and a solution of metronidazole with a concentration of 0.45-0.55%, then half the volume of sodium chloride solution is added to the metronidazole solution, after the components are completely dissolved, the remaining amount of sodium chloride solution is added to the resulting solution and membrane filtration is carried out using a capsule of polypropylene with a hydrophilic membrane of 0.2 μm.