NO140578B - PROCEDURE FOR PREPARING A CLEAR INJECTIBLE SOLUTION - Google Patents

Description

The present invention relates to a method for producing a clear chemotherapeutic solution which contains

holds a sulfonamide, as well as a sulfonamide potentiating compound.

Aqueous injectable preparations have previously been produced

rates containing a sulfonamide, as well as a sulfonamide potentiator

end compound where the former is in the form of a pharmaceutically usable salt of the sulfonamide and the sulfonamide potentiating compound, either as a solution in a water-miscible organic solvent or in the form of particles as a dispersion.

In both of these cases, the preparation's pH is strongly alkaline.

It has been found that when the pH in the above solutions

approaches the lower end of the alkaline scale, i.e. approaches neutral pH, insoluble complexes of the sulfonamide and the sulfonamide potentiator may form, e.g. insoluble complexes of "Sulfamethoxazole" and "Trimethoprim". The formation of these complexes makes the preparation unusable for injection.

Although the above-mentioned injectable preparations can be used,

do they have certain limitations, e.g. their high pH can sometimes cause destruction of the tissue at the injection site and haemolysis can sometimes occur which could cause the formation of blood clots elsewhere in the vein. Furthermore, complex formation can take place more quickly when the preparations are added to weakly acidic or neutral intravenous solutions or drops, e.g. saline and dextrose.

It will be understood that the previously known dispersion type

not in any case suitable for intravenous use due to its particulate nature.

More specifically, have regular drops and infusion solutions

for intravenous use usually a neutral to slightly acidic pH, e.g.

as a saline solution, and consequently, if the injectable solution of the previously known type is added to this type of infusion solution or drop mixture, complexes could be formed before the entire infusion mixture has been instilled into the patient (it is usually advantageous that the patients are instilled for periods of from 8 to 24 hours).

It has further been found that sterilizing basic injection preparations in an autoclave at 121°C for 20 minutes (a preferred sterilization technique) usually renders the sulfonamide in the alkaline pH preparations, e.g. "Sulfamethoxazole", to oxidize and cause the preparation to become yellowish discolored. This would make the injection preparation unusable as a pharmaceutical product.

Accordingly, a new and improved injection solution is needed to overcome the disadvantages and limitations associated with the previously known injection solutions. The preparations produced according to the invention can be injected directly into the veins (slowly) without causing clumping or destruction of the tissue.

Furthermore, the relevant solutions are compatible with acidic intravenous infusion solutions such as saline, dextrose or Ringer's solution, as no precipitation is formed over a long period of time in solutions of sufficient quantity.

According to the present invention, a method is provided for the preparation of a clear injectable solution containing 5-40% of a sulfonamide with the general formula:

where Q is a pyrimid-2-yl or -4-yl group which is either unsubstituted or substituted with one or more methyl or methoxy groups; an isoxazolyl group substituted with one or more methyl groups; or an acetyl group; and .1-10% of a sulfonamide potentiator of the general formula:

where R^ is hydrogen or lower alkyl and R£ is a phenyl group substituted with one or more alkoxy, amino, nitro, halogen, alkyl, trifluoromethyl or hydroxy groups, in a solvent comprising a mixture of 30- 90% of a water-miscible solvent and 10-70% water, and this method is characterized by the sulfonamide of formula II in the form of the free acid and/or the potentiator of formula I in the form of a water-soluble, mono-acid addition salt, optionally formed in situ, is successively added to said water-miscible solvent or water or to a mixture thereof, depending on the conditions,

and that the thus obtained solution, if necessary, is added to the other components of the mixture, ensuring that the pH value of the resulting solution is set in the range 4-6.

Norwegian patent no. 127,486 describes aqueous solutions

of a 2,4-diaminopyrimidine and a sulfonamide (in the form of a salt with a base). Despite the fact that it was well known and thus highly desirable to obtain an injectable preparation with an acidic pH value,

as provided according to the present invention, the Norwegian patent only provides preparations with a high (basic) pH value. If it would have been equivalent only to reverse the active ingredients to a sulfonamide and a salt of the potentiator, it is in consideration of the preference for a solution of acidic pH-

value, it is reasonable to assume that such a variant would have been described in the Norwegian patent. However, this is not the case.

According to the patent, they have limited themselves to basic solutions

because it was assumed that this was the only way to keep both active ingredients in solution.

From British Patent No. 1,028,204 relatively dilute solutions (described as concentrates) of a particular sulphonamide and a particular sulphonamide potentiator are known,

which solutions are diluted with water before oral administration.

In the patent, it is stated that a maximum concentration of each of the active ingredients that can be achieved by the described methods is approx. 3.5% and beyond, it is suggested that even these concentrations are surprising in view of what was previously known.

The patent does not suggest that the method can be applied to active ingredients other than the two specifically indicated. The present invention, on the other hand, relates to solutions to be used for parenteral administration, for which it is desirable that higher concentrations of the active ingredients are used, particularly the sulfonamide (the preferred concentration of the sulfonamide is at least 10%). What is taught in the British patent thus leads away from the present invention in that the patent suggests maximum achievable concentrations of the two active ingredients which would generally be insufficient for parenteral administration; furthermore, it is proposed in the patent that such a method is only applicable to the active ingredients specifically indicated therein, and which are not covered by the present invention.

Against this background, it is surprising that clear resolutions of

a sulfonamide and a sulfonamide potentiator at an acidic pH and at a concentration sufficiently high for parenteral administration can be obtained.

British patent no. 1,290,291 describes solutions of a special sulfonamide and a special potentiator which fall outside the scope of the present invention, and the patent does not suggest that the method can be successfully applied to active ingredients other than those indicated there. This British patent, like British patent 1,028,204, relates to relatively dilute solutions which are themselves unsuitable for parenteral administration in view of their low concentration. The described methods are not stated to be applicable for obtaining solutions with sufficient concentration to make them suitable for parenteral administration. Furthermore, unwanted complex formation of the two components can occur and in order to obtain even such relatively diluted solutions, the use of larger amounts of organic solvents is required, which is undesirable when the solutions are to be used for parenteral administration.

US patent no. 3,461,206 describes a preparation comprising a sulfonamide and a benzylpyrimidinesulfonamide potentiator for mixing with fodder for poultry.

This preparation is intended for use in a mixture with poultry feed, and the properties required for pharmaceutical preparations to be used in poultry feed are completely different from those required for pharmaceutical preparations for injection purposes. Furthermore, the preparations contain a low concentration of sulphon-

amide and benzyl pyrimidine enhancer; while the preparations in the present invention have a relatively high concentration of sulfonamide and potentiator. For injectable solutions, it is necessary that you have a reasonably high concentration of the drug present, otherwise you have to inject large volumes of solution, which is undesirable.

Although it is suggested in the US patent that the pyrimidines can be in the form of salts, the patent does not include any examples that use such salts, nor is it suggested that the use of such salts will lead to clear aqueous solutions that have an acidic pH value, and which have a concentration sufficient to make them useful for parenteral administration.

The present method provides for the first

times a solution of a sulfonamide and a potentiator, and which is a clear aqueous solution with a pH value below 7, and a concentration of active ingredients suitable for parenteral administration. The present invention thus provides for the first time a method for obtaining solutions with physical properties which are desirable for use in parenteral administration and which are not taught in the prior art.

The water-soluble pharmaceutical salts of the sulfonamide potentiator used in the present invention can be prepared by reacting such a sulfonamide potentiator and a pharmaceutically usable acid.

A pharmaceutically useful mono-acid addition salt of

a sulfonamide potentiator, or a mono-acid addition salt of a pharmaceutically usable acid and a sulfonamide potentiator is defined as a salt consisting of a mono-protonated sulfonamide potentiator and an anion of a pharmaceutically usable acid. The pH and pKa value of the solution for the pharmaceutically usable acid and sulfonamide potentiator determine the respective ionization steps.

It is well known that the chemotherapeutic and particularly anti-bacterial effects of the sulfonamides and certain 2,4-diamino-pyrimidines are mutually enhanced when these agents work together. Although the action is reciprocal, these 2,4-diamino-pyrimidines are referred to herein as sulfonamide potentiators or sulfonamide potentiating compounds.

As special compounds of particular value are mentioned "Trimethoprim" (2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine), "Diaveridine" (2,4-diamino-5-(3,4-dimethoxybenzyl) pyrimidine), 2,4-diamino-5-(3,4,6-trimethoxybenzyl)pyrimidine, "Ormetoprim"

(2,4-diamino-5-(2-methyl-4,5-dimethoxybenzyl)pyrimidine, 2,4-diamino-5-(3,4-dimethoxy-5-bromobenzyl)pyrimidine and "Pyrimethamine"

(2,4-diamino-5-(5-chlorophenyl)-6-ethylpyrimidine).

All these specific compounds are known to have a useful chemotherapeutic effect and that they act as potentiating compounds on sulfonamides in the manner discussed earlier.

It is assumed that the mono-acid addition salt formed is that

the salt where the acid is bound to the 1-nitrogen atom in the pyrimidine

the rest.

Compounds which can be used as pharmaceutical acids in the formation of water-soluble, pharmaceutically usable monosalts of sulfonamide potentiators are e.g. pharmaceutical mineral acids such as sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, as well as pharmaceutical organic acids such as carboxylic acids with e.g. between 1 and 20 C atoms, preferably 1-10 C atoms, for example

show tartaric acid, citric acid, lactic acid, embonic acid, salicylic acid, glutamic acid, glutaric acid, naphthalene carboxylic acid, acetic acid, or ethylenediamine-tetraacetic acid and other pharmaceutically useful organic acids such as methanesulfonic acid. The acids used for the preparation of salts of the sulfonamide potentiators must be strong acids, i.e. have a lower pKa than the sulfonamide. Currently, the preferred acid is citric acid, as it is readily available and easy to use in practice.

It is important that the sulfonamide is soluble in a medically applicable organic solvent that can be mixed with water and that the sulfonamide is sufficiently soluble in the organic solvent and the prepared solutions at the desired concentration. It is also important that the sulfonamide stays in

solution in the organic solvent and the solutions provided at physiologically applicable pH values and does not form an insoluble complex of sulfonamide/sulfonamide potentiator.

Examples of sulfonamides with antimicrobial and particularly antibacterial action, and thus suitable in connection with the present invention, are described in the book Remington's Pharma-

ceutical Sciences, 14, issue, Mack Publishing Company, Easton, Pennsylvania, (1970) , copyright Philadelphia College of Pharmacy

and Science, on pages 1195-1206, to which reference is hereby made.

Examples of sulfonamides with antimicrobial and particularly antibacterial action for use in the present method and whose action can be potentiated in the manner indicated are "Sulfadimethoxine" (4-(4-aminobenzenesulfonamido)-2,6-dimethoxypyrimidine), "Sulfadiazine" 2-( 4-aminobenzenesulfonamido)pyrimidine), sulfa-doxine-(4-(4-aminobenzenesulfonamido)-5,6-dimethoxypyrimidine), "Sulfadimethoxine" (4-(4-aminobenzenesulfonamido)-2,6-dimethoxy-pyrimidine), "Sulfamethoxazole " (3-(4-aminobenzenesulfonamido)-5- / methylisoxazole), "Sulfadimidine" (2-(4-aminobenzenesulfonamido)-4,6-dimethylpyrimidine), sulfafurazole-(5-(4-aminobenzenesulfonamido)-3,4- dimethylisoxazole and "Sulfacetamide" (N-acetylsulfanilamide).

The sulfonamides are dissolved in a medically usable organic solvent which is miscible with water, preferably by stirring at room temperature. This can be done simply either by adding the sulfonamide to the mixture of organic solvent and water with or without the addition of the salt of the sulfonamide potentiator, or the sulfonamide can be mixed with an organic solvent and then added to the water with or without the addition of the salt of the sulfonamide -potentiator". It is an advantage to ensure that the solution to which the sulfonamide or the salt of the sulfonamide potentiator is added, in the chosen order, is kept at a sufficient volume and pH to prevent the formation of insoluble salts. When preparing therapeutic solutions according to the present invention, for example, the salt of the sulfonamide potentiator can be added to the mixture of organic solvent, water and sulfonamide, or the salt of the sulfonamide potentiator can be formed by adding a pharmaceutically usable acid to the water with or without the addition of the organic solvent and with or without the presence of sulfonamide by adding sulf the onamide potentiator as a base.

The final product formed is free from shedding.

Suitable medically applicable water-miscible organic solvents for dissolving the sulfonamide include polar solvents such as N,N-dimethylacetamide, polyethylene glycols having average molecular weights from 190 to 7500 and containing 2-159 ethylene glycol monomer (CI^C^O) units, 1,2-propylene glycol, glycerol, hexamethylene glycol, 1,3-butylene glycol, ethanol, diethyl acetamide, dimethyl acetamide, dimethyl sulfoxide, dimethyl formamide, di-(1,2-propylene) glycol, glycerol formaldehyde, polyethylene glycol ethers of tetrahydrofurfuryl alcohol and diethylene glycol.

Generally, the ratio of sulfonamide to sulfonamide potentiating compound is in the form of base in the amount required

is used to achieve a therapeutic effect, approximately equal to 5:1 (weight/weight), but you can also use ratios between 10:1 and 0.1:1 (weight/

weight), and in certain cases it may be beneficial to operate with as high a ratio as between 20:1 and 0.1:1 (w/w).

In order to give the injectable solution certain favorable properties, it may be advantageous to add preservative compounds, local anesthetics or other ingredients that increase stability.

It should therefore be understood that other ingredients can be added

as long as these additional ingredients do not destroy the beneficial properties of the injectable solution.

The amount of injectable solution prepared according to

to the present invention which is injected into humans or animals for the treatment of bacterial infections or protozoan infections (if the chosen sulfonamide also has this effect), varies according to the patient's species, weight, age, general state of health and the type and severity of the infection. You can often use from 1 to 1000 ml of solution containing approx. 5% w/v sulfonamide potentiator and approx. 25% w/v sulfonamide when treating bacterial infections caused by e.g. of Proteus mirabilis or Haemophilus influenzae.

The dosing frequency for solutions will depend on the preparation's content of active drugs and the patient's needs.

Under normal conditions, you will be able to use up to approx. 200 mg/kg sulfonamide and up to approx. 150 mg/kg sulfonamide potentiator, calculated as a base, in combination, daily, divided into several doses. However, these numbers are not decisive and the doses can be adjusted according to the patient's needs.

The following examples shall illustrate the invention. When

there is no temperature specified for mixing components

the parts or preparation of the salts, room temperature is used. You can of course use higher or lower temperatures, depending on how quickly you want the mixing or salt formation. All percentages are based on w/v where nothing else is stated.

Example 1

The following ingredients were used:

The citric acid was dissolved in the water. The alcohol and propylene glycol added while stirring to the water. With continuous stirring, TMP was added. Polyethylene glycol 400 and SMX were

added and the mixture stirred until clear. The pH was 4.6. The solution was vacuum filtered through "Whatman No. 2" filter paper. The solution was bubbled with nitrogen for 30 seconds and filled into 5 ml ampoules. The volume above the solution was purged with nitrogen for 10 seconds. The ampoules were heat sealed and autoclaved at 121°C for 20 minutes.

Example 2

Example 1 was repeated, except that 0.1 g of potassium metabisulphite was added to the water after the citric acid. Nitrogen was not used. The solution was sterilized in an autoclave at 121°C for 20 minutes.

Example 3

The following ingredients were used:

The citric acid was dissolved in the water. TMP was added to the solution and stirred until the solution was clear. DMA and SMX were added and the solution stirred until clear. The pH of the solution was 4.6. It was vacuum filtered through "Whatman No. 2" filter paper. The solution was bubbled through with nitrogen for 30 minutes and filled into 5 ml ampoules, the space above the solution was flushed with nitrogen for 10 seconds and the ampoules were heat sealed and autoclaved at 121°C for 20 minutes.

Example 4

Example 3 was repeated, except that 0.6 g of citric acid was used, which gave a solution with a pH of 5.6.

Example 5

The contents of an ampoule (5 ml) of the product from example 3 were drawn up into a syringe and injected into 1 liter of 0.9% sodium chloride with stirring. There was no shedding within 16 hours.

Example 6

The procedure from Example 5 was repeated, except that a solution of 8.60 g sodium chloride and 0.33 calcium chloride with sufficient water to 1 liter, usually called Ringer's solution, was used instead of 0.9% sodium chloride. There was no shedding after 16 hours.

Example 7

The following substances were used:

The citric acid was dissolved in the water. TMP was added with continuous stirring until all dissolved. Polyethylene glycol 400, USP alcohol, propylene glycol and SMX were added to the previous solution and the mixture stirred until the solids were dissolved. The pH was 4.6. The solution was vacuum filtered through "Whatman No. 2" filter paper, the solution nitrogen bubbled, filled into 5 ml ampoules, flushed with nitrogen, heat sealed and autoclaved at 121°C for 20 minutes.

The same amount of ingredients and method were used

as above, except that 0.1 g of potassium metabisulfite was added and the mixture stirred until a clear solution was obtained. This was filled into 5 ml ampoules, heat-sealed, autoclaved at 121°C

for 20 minutes. Discoloration was noted with the nitrogen-flushed mixture, but not with the solution containing bisulphite.

Example 8

The following substances were used:

The citric acid was dissolved in water. TMP was added with constant stirring until a clear solution was formed. Poly-

the ethylene glycol was dissolved in the solution. The propylene glycol,

USP alcohol and SMX were added and stirred to a clear solution. The pH was 5.1. The solution was vacuum filtered through "Whatman No. 2" filter paper, half of the mixture was bubbled with nitrogen, filled into 5 ml vials, flushed with nitrogen, heat sealed, autoclaved at 121°C for 20 minutes.

To the other half was added 0.05 g of potassium metabisulphite and the mixture was stirred until clear. The solution was filled into 5 ml ampoules, heat sealed and autoclaved at 121°C for 20 minutes.

In examples 9 and 10, the method as in example 1 was used, but the listed ingredients were mixed and 8 g of "Sulfamethoxazole" and 1.6 g of "Trimethoprim" were dissolved. In examples 11 and 12, the procedure from example 3 was followed, the listed ingredients were mixed and 8 g of "Sulfamethoxazole" and 1.6 g of "Trimethoprim" were dissolved. In examples 13 and 14, the procedure from example 8 was followed, the listed ingredients were mixed and 8 g of "Sulfamethoxazole" and 1.6 g of "Trimethoprim" were dissolved in the mixture.

Example 15

The following substances were used:

The citric acid was dissolved in the water. TMP was added and the mixture stirred to a clear solution. DMA and "Sulfacetamide" were added and the whole stirred until the mixture was clear. The pH of the solution was 4.7.

Example 16

The following ingredients were used:

The glacial acetic acid and DMA were added to the water and mixed. TMP was added and the mixture stirred until clear. SMX was added and the mixture stirred to a clear solution. The pH of the mixture was 5.8.

Example 17-20

Example 1 was repeated with the exception that instead of "Trimethoprim" the following pyrimidines were used as sulfonamide potentiating compounds: 2,4-diamino-5-(3,4-methylenedioxy-5-methoxybenzyl)pyrimidine, 2,4-diamino- 5-(3,5-diethyl-4-methoxy-benzyl)pyrimidine, 2,4-diamino-5-(3,5-dimethoxy-4-methylbenzyl)-pyrimidine and 2,4-diamino-5-(3, 4,5-triethylbenzyl)pyrimidine.

Example 21

Example 22

In examples 21 and 2 2, the procedure was as follows:

The acid was dissolved in 7/8 of the available water, and "Trimethoprim" was added and dissolved by heating to about 60°c. Then "Sulfamethoxazole" in the organic solvent was dissolved by heating. The two solutions thus obtained were mixed and water was added to the desired volume. The whole was then filtered and filled into suitable containers, and sterilization was immediately carried out by autoclaving.

Claims (1)

Process for the preparation of a clear injectable solution containing 5-40% of a sulfonamide of the general formula: where Q is a pyrimid-2-yl or -4-yl group which is either unsubstituted or substituted with one or more methyl or methoxy groups; an isoxazolyl group substituted with one or more methyl groups; or an acetyl group, and 1-10% of a sulphonamide potentiator of the general formula: where R1 is hydrogen or lower alkyl and R2 is a phenyl group substituted with one or more alkoxy, amino, nitro, halogen, alkyl, trifluoromethyl or hydroxy groups, in a solvent comprising a mixture of 30-90% of a water-miscible solvent and 10-70% water, characterized in that the sulfonamide of formula (II) in the form of the free acid and/or the potentiator of formula (I) in the form of a water-soluble, mono-acid addition salt, possibly formed in situ, is successively added to said water-miscible solvent or water or to a mixture thereof, depending on the conditions, and that the solution thus obtained, if necessary, is added to the other components of the mixture, ensuring that the pH value of the resulting solution is set in the range 4-6.