NO781688L - PROCEDURE FOR THE PREPARATION OF PHARMACOLOGICAL ACTIVE AGENTS - Google Patents

Description

Procedure for the production of pharmacologically active agents.

The present invention relates to pharmaceutical formulations and in particular formulations of nitroimidazole antimicrobial agents with improved solubility characteristics.

Nitroimidazole antimicrobial drugs are a valuable class of agents characterized by having a 5-nitroimidazole nucleus and are particularly useful in the treatment of protozoan infections such as trichomoniasis and amoebiasis and also in the treatment of anaerobic bacterial infections. The class includes such compounds as tinidazole, metronidazole and nimorazole. A problem with this class of compounds is their poor solubility in aqueous media, which makes formulation of aqueous injectable compositions difficult. An advantageous method of slubilizing nitroimidazole antimicrobial drugs has now been found. makes it possible to easily prepare aqueous solutions suitable for parenteral injection. Such formulations are of particular value in the systemic treatment of anaerobic bacterial infections.

Thus, according to the invention, a pharmaceutical composition is provided which comprises a nitroimidazole antimicrobial drug in mixture with a pharmaceutically acceptable salt of

a mono- or di-hydroxybenzoic acid or with a mono- or di-hydroxybenzyl alcohol.

The pharmaceutical composition according to the invention can be in the form of a sterile aqueous solution or in the form of a solid mixture prepared by mixing the components or by lyophilizing a sterile aqueous solution of the components.

Other components may also be present, e.g. an acid or base may be added to neutralize the solution

(if necessary) and to provide a pH in the physiologically tolerable range suitable for an injectable formulation. Salts (eg sodium acetate, sodium lactate, sodium succinate or sodium chloride) and other solution ingredients (eg dextrose or mannitol) can also be added to make the solution isotonic.

If a salt or a hydroxybenzoic acid is used, a dihydroxybenzoic acid, especially gentisic acid (2,5-dihydroxybenzoic acid), is preferred. Also suitable are 2,3-, 3,4- and 3,5-dihydroxybenzene acids and salicylic acid. The preferred salt is the ammonium salt, but the sodium salt is also suitable as well as salts with organic bases such as L-arginine, meglumine (N-methyl glucamine), ethanolamine and choline. Alternatively, hydroxybenzoic acid can be used as the free acid and can be neutralized by adding an equivalent amount of the desired base to give an aqueous solution of salts for addition of the nitroimidazole drug.

A preferred hydroxybenzyl alcohol is gentisyl alcohol, or mono- or dihydroxybenzyl alcohols, e.g. salicylic alcohol can also be used. The use of a hydroxybenzyl alcohol has the advantage that a base is not necessary to

neutralize the formulation.

The amount of hydroxybenzoic acid or hydroxybenzyl alcohol required depends on the individual and final concentration required for the nitroimidazole used as well as the type of particular hydroxybenzoic acid or hydroxybenzyl alcohol used.

It has now been found that preparing an aqueous solution of tinidazole in a concentration suitable for intravenous administration, i.e. in a concentration of up to 50 mg per ml, requires an amount of gentisic acid from 2 to 4 parts by weight based on tinidazole, preferably approx. 2.8 parts by weight. To produce a higher concentration of tinidazole, more suitable for intramuscular injection, i.e. a concentration up to 200 mq per ml, requires a lower ratio of gentisic acid to tinidazole, i.e. an amount of gentisic acid from 1 to 2 parts by weight based on the tinidazole, preferably approx. 1.4 parts by weight.

Without a solubilizer, tinidazole is only soluble in water up to 5 mg per ml.

In practice, a solution of the nitroimidazole drug can be prepared by adding it to an aqueous solution of the salt of hydroxybenzoic acid or to a solution of the hydroxybenzyl alcohol. The mixture is stirred until the nitroimidazole is dissolved, the pH is adjusted if necessary and the solution is then sterile filtered using a bacteria-tight membrane and filled into sterile containers of an appropriate volume for the intended use of the drug. Thus, for human use as an intravenous injectable formulation, containers containing 10 ml of a solution of tinidazole at a concentration of 50 mg per ml would be suitable, while for intramuscular use containers containing 4 ml of a solution of tiniazole at 200 mg per ml are used.

Alternatively, the solution after sterilization can be lyophilized by freeze-drying in a conventional manner, e.g. by cooling to -40°C and subjecting the frozen solution to high vacuum for 24 hours to give a solid product. It may be desirable to store the product in this form, as the solution is easily returned immediately before use by simply adding the required volume of water.

Similar formulations can be prepared using other nitroimidazole drugs, e.g. aqueous injectable formulations can be prepared using metronidazole, nimorazole, ornidazole and bamnidazole with gentisic acid.

The following are examples of pharmaceutical compositions according to the invention.

EXAMPLE 1

An intravenous injectable formulation of tinidazole was prepared with the following composition:

The gentisic acid was stirred with half of the water and the dilute ammonia solution was added slowly until all the solid had dissolved and the final pH of the solution was 0.25 + 0.2. Slow addition is necessary to avoid discoloration of the gentisic acid. The tinidazole was then added and stirred until a chlorine solution formed which was diluted with water to give the final volume of 1 liter. The solution was sterilized according to the method from the British Pharmacopoeia (1973) by filtering through a bacteria-tight filter under aseptic conditions and filled into sterile glass containers.

EXAMPLE 2

An intravenous injectable formulation of tinidazole was prepared as described in Example 1 but with the following composition:

EXAMPLE 3 - 5

Intravenous injectable formulations of tinidazole were prepared as described in Example 2 except that the following acids were used instead of para-hydroxybenzoic acid:

EXAMPLE 6

An intravenous, injectable formulation of tinidazole was prepared with the following composition:

The sodium salicylate was dissolved in half the water and the tinidazole was added and stirred which gave a clear solution. Water was added to a final volume of 100 ml and the solution was sterile filtered into containers as described in example 1.

EXAMPLE 7 - 11

Intravenous injectable formulation of tinidazole was prepared as described in Example 1 except that instead of ammonia solution 1, equivalent amounts of the following bases were added in each case to neutralize the gentisic acid:

EXAMPLE 12

An intravenous injectable formulation of tinidazole was prepared with the following composition:

The Gentisyl alcohol was dissolved in half of the water and the tinidazole was added and stirred to give a clear solution. The volume of the solution was made up to 100

ml and the solution was sterile filtered into glass containers as described in example 1.

EXAMPLE 13

An intravenous injectable formulation of tinidazole was prepared as described in Example 12 except a metahydroxybenzyl alcohol was used instead of gentisyl alcohol.

EXAMPLE 14

A sterile aqueous solution of tinidazole and gentisic acid

(4 mL) prepared as described in Example 1 was freeze-dried under vacuum at -40°C for 24 hours to give a yellowish solid.

EXAMPLE 15

The product from example 14 was recovered by adding water for injection E.P. to the container. The solid dissolved immediately giving a clear solution. The volume of added water was varied, giving solutions of tinidazole with the following concentrations:

EXAMPLE 16

An intramuscular injectable formulation of tinidazole was prepared as described in Example 1 but with the following composition:

EXAMPLE 17

One intravenous injectable formulation of metronidazole of the following composition was prepared using the procedure of Example 1:

EXAMPLE.18

An intravenous injectable formulation of himorazole of the following composition was prepared using the procedure of Example 1:

EXAMPLE 19

An intravenous injectable formulation of bamnidazole with

the following composition was prepared using the procedure of Example 1:

EXAMPLE 20

An intravenous injectable formulation of ornidazole of the following composition was prepared using the procedure of Example 1:

Claims (9)

1. Process for producing a pharmaceutical formulation of a nitroimidazole drug characterized in that the nitroimidazole drug is treated with an aqueous solution of a pharmaceutically acceptable salt of a mono- or dihydroxy-benzoic acid or a mono- or dihydroxybenzyl alcohol, sterilization and, if desired, lyophilization of the resulting solution. 2. Method According to claim 1, characterized in that tinidazole is used as a nitroimidazole drug. 3. Method according to claim 1, characterized in that metronidazole, nimorazole, ornidazole or bamnidazole is used as the nitromidazole drug. 4. Method according to claims 1-3, characterized in that the nitroimidazole drug is treated with an aqueous solution of a pharmaceutically acceptable salt of gentisic acid. 5. Method according to claim 4, characterized in that the pharmaceutically acceptable salt is the ammonium salt. 6. Method according to claims 1-3, characterized in that the nitroimidazole drug is treated with an aqueous solution of gentisyl alcohol. 7. Process for producing an aqueous injectable solution of tinidazole according to claim 2, characterized in that the tinidazole is treated with an aqueous solution of the ammonium salt of gentisic acid and sterilized. 8. Method according to claim 7, characterized in that the tinidazole is used in a concentration of up to 50 mg per ml and the gentisic acid is present in an amount of approx. 2.8 parts by weight based on tinidazole present. 9. Method according to claim 7, characterized in that the tinidazole is used in a concentration of up to 200 mg per ml and the gentisic acid is present in an amount I of approx. 1.4 parts by weight based on the tinidazole present.