DK143997B - PROCEDURE FOR STABILIZING SULPHONAMIDE / POTENTIATOR SOLUTIONS - Google Patents

Description

in 143997

The present invention relates to a process for stabilizing aqueous and / or with water to form clear solutions of diluent sulfonamide / potentiator solutions which dissolve in glycerol formulation containing ca. 5 to 10% by weight of the combination of active substances with an active substance-weight ratio of sulfonamide to potentiator from 4: 1 to 6: 1.

Combinations of sulfonamides with certain pyrlmidine derivatives have gained considerable practical importance as antibacterial agents as they have a broad spectrum of action and are frequently better tolerated than antibiotics.

They have proven particularly beneficial in the treatment of bacterial diseases of the urinary tract and of the respiratory organs.

As sulfonamide, the combination preparations may contain the known compounds of this class of substances, cf. the comparison in Ehrhart / Ruschig, Arzneimittel, Vol. 4, pages 88 and 89 (1972). Particularly preferred are the newer sulfonamides, especially 3-sulfanilamino-5-methylisoxazole (sulfamethoxazole), 2rsulfanilamino-4,5-dimethyloxazole (sulfamoxole), 4-sulfanilis amino 5,6-dimethoxypyrimidine (sulformethoxine), but also 2-sulfanilaminopyrimidine (sulfadiazine) and 4,6-dimethylsulfapyrimidine (sulfadimidine).

As potentiators, 2,4-diaminopyrimidines are primarily considered which are substituted with a substituted benzyl or phenyl group at the 5-position and may contain an alkyl * substituent at the 6-position. Particularly preferred compounds are 2,4-diamino-5 (3,4,5-trimethoxybenzyl) pyrimidine (trimethoprim), 2,4-diamino-5 (3,4-dimethoxybenzyl) pyrimidine (diaveridine), 2.4- diamino ** 5 (3,4,6-trimethoxybenzyl) pyrimidine, 2,4-diamino-5 (2-methyl-4,5-dimethoxybenzyl) pyrimidine (ormethoprim) and 2,4-diamino ^ 5 (4 (chlorophenyl) 6-ethylpyrimidine (pyrimethamine).

Particularly preferred combinations, which have also been used in practice for a long time, contain sulfamethoxazole or sulfamoxole and tri-methoprim. In all cases, the sulfonamide is present in a substantial excess relative to the potentiator. Generally, the ratio of sulfonamide to potentiator is at 4: 1 to 6: 1, especially at 5; 1. Both for toxicological and pharmacological reasons it has been found important that the optimum ratio of the active substances is strictly adhered to.

This requirement can be met without major difficulties in the preparation of tablets for oral administration. By contrast, significant problems arise in the composition of juices or syrups, which are particularly desirable in the medical treatment of children, and in the composition of injectable preparations needed both in human medicine (for parenteral injection or as an infusion solution) as well as in for the veterinary medicine. The difficulty is due to the fact that both classes of active substances have only very little solubility in the usual solvents such as e.g. water, and additionally are prone to formation of heavily soluble complexes. All prior art juice preparations are available as suspensions. Apart from the technological difficulties in making such suspensions (cf. HJ Dechow et al., Arzneim.-Forsch. 26, 596 to 612, especially 605 (1976)), there is a major disadvantage that a completely homogeneous distribution of the active substances cannot be guaranteed with certainty. Before use, such suspensions must be shaken, but the danger of inaccurate dosing is great. In particular, there is a risk that, at the start of treatment, the dosage will be too low due to insufficient shaking, and therefore in the subsequent course, the dosage will be too high and the ratio of the active substances to be shifted.

The attempts to prepare solutions of the active substances which have become known in the literature have so far not produced any satisfactory results, as is already proved by the fact that to this day is an orally administrable preparation in the form of a clear juice or syrup in which the active substances are dissolved did not enter the market. Irish Patent No. 198/66 describes the preparation of solutions containing sulfaquinoxaline in the form of the sodium salt and diaveridine. As solvents, propylene glycol, polyethylene = glycol and similar organic solvents are used together with up to 10% by weight of water. The solutions exhibit only a relatively low concentration of active substance and, when prolonged, are found to have insufficient stability. Particularly important is that, when diluted with large amounts of water, they immediately precipitate the active substance. As a result of the use of the sulfonamide in the form of an alkali salt, the solutions react strongly alkaline, limiting their similarity and adversely affecting their stability. In the air, the solutions change during yellowing so that they must be stored under oxygen exclusion.

The same applies to the solutions known from Austrian Patent No. 270,869 which contain the sodium salt of the sulfonamide and the potentiator in a solvent mixture of water and an organic water miscible solvent. Organic solvents include, inter alia, polyethylene glycol ethers of tetrahydrofurfuryl alcohol, certain glycols and glycerol formal (mixtures of 4-hydroxymethyl-1,3-dioxolane and 5-hydroxy-1,3-dioxane), usually in a ratio of approx. 1: 3. Because of their high pH values from 8 to 11, and which are usually above 10, these solutions must be filled air-tightly in ampoules and consumed as soon as possible after addition to an infusion carrier solution. They are not suitable for the preparation of orally administrable compositions.

The solutions of sulfa = dimidine and pyrimethamine described in GB Patent No. 1,290,291 in various glycols, including glycosol formaldehyde, may initially be diluted with water, but with long standing the active substances are separated.

The clear solutions of sulfonamides and monoacid addition salts of sulfonamide potentiators according to DE publication no.

2,400,218 is set to an acidic pH with a pharmaceutically acceptable acid to avoid formation of an insoluble sulfonamide-sulfonamide potentiator complex. The pH of these solutions is preferably 2 to 6, especially 4 to 6 and most preferably 4.5 to 5.5. According to the disclosure disclosure, insoluble complexes of sulfonamide and sulfonamide potentiator are formed when the pH of the solutions approaches the lower end of the basic scale, i.e. neutral pH values.

The invention, on the other hand, is primarily aimed at providing sulfonamide / potentiator solutions which react neutrally and are completely stable. The solutions should be aqueous or dilute with water so that they can be added to aqueous infusion carrier solutions if desired.

4 U 3997

Surprisingly, it has been found that, despite the previous unsuccessful attempts in the art, this can be achieved when using the glycerol formaldehyde solution in combination with certain solvents or bring the acidic reacting glycerol formal (pH 5.6). ) at a neutral pH (about 6.5 to 7.5) by the addition of alkanolamine, preferably triethanolamine.

Thus, the invention relates to a process for stabilizing aqueous and / or with water to form clear solutions of dilute sulfonamide / potentiator solutions, which dissolve in glycosol formulation containing approx. 5 to 10% by weight of the combination of active substances with an active substance-weight ratio of sulfonamide to potentiator from 4: 1 to 6: 1, which is characterized by adding 20 to the glycerol formal solution - calculated in terms of the amount of glycerol formaldehyde 50% by weight ethanol and / or 4 to 10% by weight polyvinylpyrrolidone and / or 4 to 10% by weight of a neutral mixture of an alkali or amine salt of a mono- or multi-base organic oxy acid with the free acid and / or an alkanolamine, in such amounts that the solution has a pH value of 6.5 to 7.5. In a preferred embodiment of the invention, the stability of the solutions under certain conditions, especially by using glycerol formal / ethanol or glycerol formal / alkanolamine as solvent system, can be further enhanced by the addition of an ethylene oxide / propylene oxide block copolymer.

Contrary to the disclosures in DE Publication No. 2,400,218, the solutions prepared by the process of the invention, despite their nearly neutral to slightly basic and therefore physiologically preferred pH values, do not lead to undesirable precipitates. They may be diluted with water in any ratio, while this does not apply to the same extent to the compositions according to DE Publication No. 2,400,218. In these, precipitates are avoided only when sufficiently diluted solutions are prepared.

The solutions prepared by the process of the invention can be prepared both as anhydrous concentrates which can be diluted with water without precipitation phenomena and as aqueous preparations. Especially for the dilution with larger quantities of water, the additional solvents used in the process according to the invention are of crucial importance, since otherwise precipitation of the active substances is observed. Thus, for example, a clear miscibility with water or aqueous carrier solutions is obtained when polyvinylpyrrolidone is added to the solution of the combination of active substances in glycerol formal alone or in a mixture of glycerol formal and ethanol. The same effect is obtained by the addition of alkali or amine salts of organic oxy acids such as lactic acid, citric acid, salicylic acid, glucuronic acid or glucuronic acid lactone. Especially as amines come alkylamines, e.g. diethylenamine and alkanolamines such as triethanol = amine. Particularly preferred compounds are sodium lactate, citrate and salicylate as well as diethylenamine or triethanolamine lactate. The ratio of base to oxy acid is chosen so that the mixture reacts neutral. For the most part, an excess of acid is required.

With the present invention, it has for the first time been possible to prepare orally administered syrups or juices in which the active substances are not suspended but are clearly dissolved. This is achieved so that not only the active substances, but also the flavors necessary for such preparations (eg, anise oil, caramel oil, vanillin) and sweeteners (sugar, sodium cyclamate, saccharin) can be dissolved in the solvent combination used in the process according to the invention. in the required concentration. This is very surprising as the sweeteners cannot be dissolved in glycerol form. However, by adding ethanol and water, these additives succeed in dissolving without the active substances themselves precipitating. Even a small amount of boiling salt useful for flavor rounding can easily be added.

An orally administered juice can be prepared by dissolving approx. 5% by weight of the active ingredient combination and further usual flavors and sweeteners for approx. 45 to 55% by weight glycerol formal, approx. 15 to 20% ethanol, approx. 1 to 4% by weight ethylene oxide / propylene oxide block copolymer and water in addition to obtain 100% by weight.

The Galenic literature on sulfonamide / potentiator combinations discusses the issue of the grain size of the active substances as well as the need for the addition of surfactants very broadly, not only on the durability of the suspensions, but also on the bio-usefulness of the active substances. or disposability. It will be appreciated that the utility of the solutions prepared by the process of the invention is substantially improved over the known suspensions.

In using the solutions prepared by the method of the invention for parenteral administration, e.g. as an addition to infusion carrier solutions (physiological saline or grape sugar solutions) it is only necessary to make the solutions germ free and pyrogen free. As the solutions are heat stable, their sterilization presents no difficulty. Particularly suitable for this application are those solutions which further contain polyvinylpyrrolidone and / or a neutral mixture of a salt of an organic oxy acid with the free acid and / or alkanolamine until neutral reaction.

The following examples serve to illustrate the invention. Example 1.

The following ingredients were dissolved with each other to make a juice: 4,000 g of sulfamethoxazole 0.800 g of trimethoprim 48,600 g of glycerol formal 48% 17,400 g of ethyl alcohol r the term "Pluronic F 68" ®) 0.500 g of saccharin sodium 1,500 g of sodium cyclamate 0.030 g of anise oil 0.030 g of sodium chloride distilled water up to 100,000 ml. ca. 25%

A juice was obtained in which all the active substances were clearly dissolved and which, even after prolonged storage, proved to be completely stable. The bitter taste of the active substances is sufficiently corrected by the flavors and sweeteners. The pH of the solution was 7.2.

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Example 2.

f 143997

To prepare a concentrate, 2 g of sulfamethoxazole and 0.4 g of trimethoprim were dissolved in 15 ml of glycerol formal. To this solution was added a solution of 2 g of polyvinylpyrrolidone in 10 ml of ethyl alcohol, and then up to 30 ml of solution was filled with glycerol. The pH of the solution was 7.2.

Example 3

To prepare a concentrate, 2 g of sulfamethoxazole and 0.4 g of trimethoprim were dissolved in 15 ml of glycerol formal and a solution of 2 g of polyvinylpyrrolidone in 10 ml of water was added. Then up to 30 ml of solution was filled with glycerol formal. The pH of the solution was 6.7.

Example 4

To prepare a concentrate, 2 g of sulfamethoxazole and 0.4 g of trimethoprim were dissolved in 15 ml of glycerol formal. Separately, 2 ml of triethanolamine was adjusted to pH 7 with lactic acid, then water was filled up to 10 ml. Then the two solutions were mixed together and up to 30 ml of solution were filled with glycerol formal.

Example 5

2 g of sulfamethoxazole and 0.4 g of trimethoprim were dissolved in 15 ml of glycerol = formal. Separately, 1 ml of diethylenamine was brought to pH 7 with lactic acid and then up to 10 ml was filled with water. The two solutions were mixed together and up to 30 ml of solution were filled with glycerol formaldehyde.

Example 6

2 g of sulfamethoxazole and 0.4 g of trimethoprim were dissolved in 15 ml of glycerol = formal. Separately, 2 g of sodium lactate was dissolved in 10 ml of water and adjusted to pH 7 with lactic acid. The solutions were mixed with each other and filled up to 30 ml solution with glycerol formal.

Example 7

2 g of sulfamethoxazole and 0.4 g of trimethoprim were dissolved in 15 ml of glycerol formal. Separately, 2 g of sodium citrate was dissolved in 10 ml of water and adjusted to pH 7 by the addition of citric acid. After mixing the two solutions, up to 30 ml of solution were filled with glycerol formal.

Example 8.

2 g of sulfamethoxazole and 0.4 g of trimethoprim were dissolved in 20 ml of glycerol formal and up to 15 ml were filled with methanol. The pH was adjusted to 7 with triethanolamine.

Example g.

2 g of sulfamethoxazole and 0.4 g of trimethoprim were dissolved together with 0.5 g of polyvinylpyrrolidone in 10 ml of glycerol formal, and up to 20 ml of 1,2-propylene glycol was charged, then adjusted to pH 7 with 0.35 g of triethanolamine.

Examples of 4 g of sulfisoxazole and 0.8 g of pyrimethamine were added to 80 ml of glycerol formulation. Separately, 6 ml of triethanolamine was adjusted to pH 7 with lactic acid. The two solutions were mixed together and up to 100 ml of glycerol formal was added. Finally, the solution was adjusted to pH 6.5 with lactic acid.

Example 11 8 g of sulfadiamine and 1.6 g of pyrimethamine were added to 70 ml of glycerol formulation. Separately, 8 g of triethanolamine was dissolved in 10 ml of water and adjusted to pH 7 with lactic acid. The two solutions were mixed together and up to 100 ml of glycerol formal was added. The pH was adjusted to 6.5 to 7.

Example 12 4 g of sulfapyridine and 0.6 g of pyrimethamine were dissolved in 80 ml of glycerol form and added 7 g of triethanolamine lactate. The solution was then brought up to 100 ml with glycerol formal and adjusted to pH 6.5.

Example 13 8 g of sulfisoxazole and 1.6 g of trimethoprim were dissolved in 80 ml of glycerol formulation. Separately, 5 g of triethanolamine was adjusted to pH, 7 by addition of lactic acid. The two solutions were mixed together and brought up to 100 ml with glycerol formal. Finally, the solution was adjusted to pH 6.5 to 7.

Example 14 8 g of sulfadiamidine and 1.6 g of trimethoprim were dissolved in 80 ml of glycerol = formal and 8 g of triethanolamine lactate added. The solution was brought up to 100 ml with glycerol formal and adjusted to pH 6.5 to 7.

First, the concentrates of Examples 2 to 14 are suitable for preparing juices or syrups for oral administration. In these cases, as described in Example 1, additional flavors and sweeteners must be added to overstate the bitter taste of the active substances.

On the other hand, the concentrates of Examples 2 to 14 are also suitable for parenteral administration, whereby their neutral reaction is particularly valuable. The miscibility of the concentrates with aqueous solutions is so good that commercially ready infusion solutions containing sulfonamide / potentiator can be prepared. When used, it is then no longer necessary to introduce the concentrate-filled concentrate into a carrier solution prior to the infusion, but the finished infusion solution is immediately available.

Claims (2)

143997 ίο Comparative Experiment 1 Similar to Example 15 of Austrian Patent No. 270,869, 8 g of sulfamethoxazole and 4.8 g of triethanolamine were dissolved in ca. 20 ml distilled water. To this solution, 2.5 g of trimethoprim dissolved in 80 ml of glycerol formal was added. The solution thus obtained exhibited a pH of 8.5 and, due to its alkaline reaction, did not appear to be stable but stained on standing. Comparative Experiment 2 According to Example 5 of British Patent Specification No. 1,290,291, 4 g of sul = fadiamine and 0.5 g of pyrimethamine were dissolved in 80 ml of glycerol formaldehyde. By diluting this solution (pH 6.6) with water, the active substances were insoluble after a few hours. On the other hand, if you add so much triehanolamine and lactic acid to the same solution that the pH is between 6.5 and 7.5, the solution after dilution with water is virtually unlimited. Comparative Experiment 3 According to the instructions of German Publication No. 2,400,218, a solution of the citric acid monoaddition salt of trimethoprim in a little water was prepared, to which was added a solution of sulfamethoxazole in a glycol / ethanol mixture. The solution thus obtained (pH 4.6) proved to be resistant, but upon dilution with water a precipitate formed which was again dissolved in a very large excess of water. Accordingly, the solutions prepared according to the invention are miscible with water in any ratio. 1. Method for stabilizing aqueous and / or with water to form clear solutions diluent sulfonamide / potency =