DE2631779A1 - Clear aqueous sulphonamide-trimethoprim solutions - contg. a water-soluble sulphonamide salt, trimethoprim and polyvinyl pyrrolidone of K-value 10-18 - Google Patents

Abstract

New clear, aq. sulphonamide/trimethoprim solns. contain (a) a water-soluble sulphonamide salt, (b) trimethoprim and (c) polyvinyl pyrrolidone with a K-value of 10-18 in water, opt. with the addition of further substances and/or solvents. Sulphonamide/trimethoprim solns. are provided for oral, parenteral or external application. The new solns. avoid the need for solvents with poor pharmaceutical acceptability (e.g., propylene glycol, glycerine formal, dimethylacetamide). The solns. also avoid extreme of pH (which can cause local pain on injection). Typical formulation contains 4 g. sulphamoxole sodium, 0.8 g. trimethoprim, 55 g. polyvinyl pyrrolidone (K-value 12), 0.8 g. sodium sulphite and water for injection to 100 ml.

Description

Sulfonamide trimethoprim solutions

The invention relates to clear aqueous solutions containing a sulfonamide salt, Trimethoprim, polyvinylpyrrolidone, optionally with the addition of other substances and / or Contain solvents.

The solutions can be used for oral, parenteral or external application 0 Therapeutically useful solutions containing a sulfonamide, e.g.

Contain sulfamethoxazole, and the sulfonamide potentiator trimethoprim, are known to be able to bring the two poorly soluble active ingredients into solution tread different paths.

For example, you can use the basic trimethoprim with the help a pharmaceutically acceptable acid as an acid addition salt into an aqueous one Transfer the solution and mix with the solution of the sulfonamide in a water-miscible combine polar organic solvents. This way is in the DT-OS 24 00 218 described, the solvent in particular for dissolving the sulfonamide N, N-dimethylacetamide or a polyethylene glycol and as the preferred acid for trimethoprim Citric acid can be used.

Conversely, according to DT-OS 16 17 529, the sulfonamide be converted by a base into a water-soluble salt, and the aqueous Sulphonamide solution with the solution of trimethoprim in a water miscible organic solvents, in particular glycerol formal or a polyethylene glycol, be united0 The solutions presented are not always satisfactory. Disadvantageous is that the specified solvents, in particular propylene glycol, dimethylformamide, Tetraglycol, dimethylacetamide, glycerol formal and polyethylene glycols from pharmacological-toxicological view can be regarded as not entirely harmless. This is especially true for propylene glycol, Glycerin formal and dimethylacetamide, if used in larger amounts over a prolonged period Period of time to be administered parenterally. For propylene glycol, M. Debelic in Prax. Pneumol. 28 (1974), pp. 491 to 499, the reference to restriction due to toxicity of propylene glycol. Mixtures with other substances are in the solvents described only possible to a limited extent. It is also disadvantageous, for example, for solutions according to DT-OS 16 17 521 that they react strongly alkaline. Polyethylene glycols and 1,2-propylene glycol may have the disadvantage of injections that they cause severe pain.

It has now been found that with a clear aqueous solution that a sulfonamide salt, trimethoprim and polyvinylpyrrolidone with a K value of 10 to 18 and any additions of other substances and / or solvents contains, can avoid the disadvantages mentioned.

The solutions according to the invention expediently contain the salt of the sulfonamide in an amount of 1 to 40, preferably 5 to 20%, the trimethoprim in an amount of 0.5 to 10, preferably 1 to 5% and polyvinylpyrrolidone in one Amount from 30 to 80, preferably 40 to 70%, the percentages given here Mean weight / volume percentages. Here, the preferred polyvinylpyrrolidone has one K value from 12 to 14.

In the solutions according to the invention, the trimethoprim is used with the aid brought into solution by polyvinylpyrrolidone. The surprising advantage is that that the content of solvent can even be below 30%. Mixtures with infusion solutions remain clear for more than 6 hours, so that such mixtures are not only immediate must be prepared before use. Furthermore, when using a polyvinylpyrrolidone with a K value of 10 to 18 has a relatively low viscosity the solution reached and this due to the low molecular weight after a Injection again very quickly eliminated from the organism.

A special polyvinylpyrrolidone is used for the solution according to the invention from a K value of 10 to 18, preferably from 12 to 14, or a molecular weight from 2000 to 3500, the production of which is explained in more detail below, in excellent Way suitable, while a low molecular weight polyvinylpyrrolidone, which according to customary Process, for example using hydrogen peroxide as activators is produced in water as a solvent, usually not in the required amount Pharmaceutical quality is obtained N-vinylpyrrolidone-2 is used to produce the polyvinylpyrrolidone in an organic solvent at temperatures 0 over 100 C in the presence of a polymerized organic peroxide by making the polymerization batchwise or continuously with such a peroxide that is attached to the peroxide moiety aliphatic or aliphatic-aromatic substituents with 1 to 8 carbon atoms on both sides per alkyl group. The choice of reaction temperatures above 1000C, one organic solvents and an organic peroxide cause a low molecular weight Polyvinylpyrrolidone with favorable properties is obtained.

The selection of the organic peroxide is of particular importance. Preferred are those which have an alkyl and / or on both peroxide oxygen atoms Aralkyl radical containing 1 to 8 carbon atoms per alkyl radical, and of which e.g.

Dicumyl peroxide, di-tert-butyl peroxide, tert-butyl-cumyl peroxide and 2,2-Di-tert-butylperoxybutane should be mentioned. Di-tert-butyl peroxide is particularly preferred. The amount of organic peroxide used can vary within wide limits and depends on the K value to be set. In general, one uses, based on N-vinylpyrrolidone, 0.1 to 6% by weight, preferably 0.5 to 3% by weight.

Suitable organic solvents are those that are between 50 and 1500C boil, i.e. the reaction can be carried out at normal or elevated pressure will. Suitable solvents are, for example, alcohols such as methanol and ethanol n- and i-propanol, ethers such as dioxane and tetrahydrofuran, halogen compounds such as Chloroform, methylene chloride, tetrachloroethane or hexachloroethane, aromatic hydrocarbons, such as toluene, xylene, cumene or ethylbenzene, as well as mixtures of the solvents mentioned, which are completely miscible with one another, for example mixtures of isopropanol and cumene or a mixture of several aromatic hydrocarbons such as ethylbenzene and toluene, isopropanol is preferably used as the solvent, as this has a strong regulating effect on the molecular weight * The concentration of the monomers in the solution is 5 to 75, preferably 10 to 50 wt.%.

The actual polymerization is carried out in and of itself well-known way, one can combine all components of the approach in a closed system, It is advisable to present a pressure vessel that has been tested up to 200 bar and the air contained in the solutions by evacuating or blowing a Remove inert gas. The temperature is then increased to 100 to 300 ° C., preferably 120 to 2000C, and allowed to polymerize for approx. 3 to 4 hours.

The required K value is set in the following way: 1. By choosing the amount of peroxide, large amounts result in particularly low K values.

2. By choice of solvent; branched chain solvents result in lower K values than straight-chain or unsubstituted aromatic solvents. Secondary alcohols are particularly advantageous.

3. Through targeted adjustment of the monomer concentration; here the increase in the monomer concentration also causes an increase in the K value.

So by specifying the concentration of the monomer, des Peroxide and the type of solvent determine a rough K-value range.

4. By choosing the reaction temperature; so the K-value can be fine set, since the K-value is reduced when the temperature rises.

In a particularly preferred embodiment, the monomer can during be added successively to the polymerization, which also increases the K value more can be lowered.

This can also be done in such a way that vinylpyrrolidone, Mixed solvent and peroxide are added successively. The feed time can vary between 1 and 5 hours.

This process can be used to produce polymers with K values from 10 to 18 obtained, which are particularly suitable for the solution according to the invention.

Through ongoing sampling and determination of the remaining vinylpyrrolidone the course of the polymerization can easily be followed. When the remainder is at If vinylpyrrolidone has fallen well below 1%, the polymerization can be terminated will. The polymerization time is generally 3 to 5 hours.

The solution obtained is worked up in the usual way, e.g. by direct drying according to the usual methods, such as spray drying, roller drying or freeze drying.

In some cases it is useful to use the fully reacted approach To dilute water, the organic solvent optionally in whole or in part to distill off and then to dry. In many cases it is advantageous to have a Switch on steam distillation to remove volatile components, e.g. from vinylpyrrolidone or the activator originate to be removed from the solution.

It should be noted that the preparation of this particularly suitable Polyvinylpyrrolidone is the subject of German patent application P 25 14 127.9.

The sulfonamide salts are in particular the salts with alkali hydroxides, preferably sodium salts, and the salts with organic amines, especially alkanolamines, such as mono-, di-, triethanolamine or dimethylaminoethanol, into consideration.

Of the sulfonamides to be used are sulfamoxol, sulfisomidine, Called sulfamethoxazole. The invention is not intended to apply to specific uses Sulfonamides be restricted. Further examples of pharmaceutically acceptable sulfonamides and thus suitability for use in this invention may include, for example, Remigston's Pharmaceutical Sciences, 14th Edition, 1975, pp. 1105-1113, Mack Publishing Company, Easton, Pennsylvania.

If appropriate, the solutions according to the invention can contain customary additives or auxiliaries are added.

For example, sulfites and other reducing agents come into consideration Substances for color stabilization as well as ethanol, propylene glycol as viscosity-reducing agents Additions in an amount of 10 to 25%.

In the case of injectable solutions, preservatives such as p-hydroxybenzoic acid ester, in the case of oral solutions, taste corrections such as peppermint oil, in the case of ear drops and Eye drop preservatives, such as benzalkonium chloride.

The solutions according to the invention are prepared in a conventional manner, by combining the sulfonamide salt and the trimethoprim with the polyvinylpyrrolidone in Water with stirring and, if appropriate, heating dissolves, if appropriate with addition of other substances and / or solvents.

The order is irrelevant, for example you can Dissolve the sulfonamide salt in water and then the polyvinylpyrrolidone and the Add or give trimethoprim for aqueous polyvinylpyrrolidone solution the sulfonamide salt and the trimethoprim, or you can first dissolve the trimethoprim Help the polyvinylpyrrolidone and then add the sulfonamide salt. Man can too bring the trimethoprim into an aqueous solution with the aid of polyvinylpyrrolidone and this with the aqueous solution of a water-soluble sulfonamide salt to one unite clear solution.

Example 1 (solution for injection) sulfamoxol sodium salt 4.0 g trimethoprim 0.8 g polyvinylpyrrolidone with a K value of 12 55.0 g sodium sulfite 0.8 g water for injections ad 100.0 ml Preparation: Sulphamoxol sodium salt and sodium sulphite are dissolved in water dissolved and added the polyvinylpyrrolidone. The mixture is heated gently stirred until a clear solution has formed. Then the trimethoprim is cut in small Stir in portions until complete dissolution is achieved.

The solution is steri-filtered, in ampoules with nitrogen gassing bottled and sterilized in an autoclave with superheated steam.

Example 2 (solution for injection) sulfamoxol triethanolamine salt 8.00 g Trimethoprim 1.60 g polyvinylpyrrolidone with a K value of 13 40.00 g sodium disulfite 0.50 g ethanol 5.00 g propylene glycol 15.00 g p-hydroxybenzoic acid ester 0.20 g water for injections to 100.00 ml Manufacturing instructions: polyvinylpyrrolidone and sodium disulfite and the p-hydroxybenzoic acid ester are heated in water dissolved, the finely powdered trimethoprim mixed with heating and until dissolved touched. The sulfamoxol triethanolamine salt is then suspended in the mixture and brought into solution with stirring. Ethanol and propylene glycol are added and supplemented with water to the final volume. The solution is sterile-filtered, under Nitrogen gassing under aseptic conditions in brown ampoules of the resistance group A filled.

Example 3 (ear drops) sulfamethoxazole diethylaminoethanol salt 5.0 g trimethoprim 1.0 g polyvinylpyrrolidone with a K value of 14 50.0 g sodium sulfite 0.5 g propylene glycol 25.0 g benzalkonium chloride 50.0 mg demineralized water ad 100.0 ml Production: polyvinylpyrrolidone and trimethoprim and benzalkonium chloride are dissolved in the mixture of water and propylene glycol with heating, sodium sulfite and sulfamethoxazo l-diethylaminoethanol salt dissolved. The clear solution is filtered and filled into dropper bottles.

Example 4 (oral solution) sulfisomidine sodium 8.0 g trimethoprim 1.6 g polyvinylpyrrolidone with a K value of 13.5 40.0 g sodium bisulfite 0.2 g ethanol 15.0 g peppermint oil 200.0 mg demineralized water ad 100.0 ml Manufacturing: Sodium sulfisomidine, sodium bisulfite, and polyvinylpyrrolidone are used in the mixture Dissolved from water and ethanol, added trimethoprim and until a clear solution stirred. Peppermint oil is added and water is added to the solution the final volume is added, filtered and filled into dropper bottles.

Example 5 (eye drops) sulfisomidine monoethanolamine alz 4.0 g Trimethoprim 0.8 g polyvinylpyrrolidone with a K value of 12.5 40.0 g sodium disulfite 0.6 g benzalkonium chloride 50.0 mg demineralized water ad 100.0 ml Preparation: Polyvinyl pyrrolidone and sodium disulfite and benzalkonium chloride are in water dissolved, sulfisomidine monoethanolamine salt and trimethoprim added and up to Formation of a clear solution, stirred with gentle warming. The solution is sterile-filtered and aseptically filled.

Production of PVP: In a pressure reactor with a stirrer, 77 Parts of isopropanol, 6 parts of vinyl pyrrolidone and 0.24 parts of di-tert-butyl peroxide filled. The reactor is closed pressure-tight and pressed on twice and relieving pressure of 4 bar nitrogen, largely freed from atmospheric oxygen. The contents of the reactor are now heated to 1400 ° C., a pressure of 7 bar adjusts and then a mixture of 63 parts of isopropanol and 54 parts Vinylpyrrolidone and 2.16 parts of di-tert-butyl peroxide at 140 to 1450C within closed within 4 hours. Polymerization is then completed for approx. 3 hours until the monomer content has fallen below 0.5% (based on the vinylpyrrolidone used) is. The batch is then cooled to R5 ° C with 60 parts of water diluted and driven off the isopropanol by introducing steam. After reaching an internal temperature of 980 ° C., the distillation is continued until 60 parts of distillate are still present have passed over. The approx. 30% solution is then spray-dried. It a polyvinylpyrrolidone with a K value of 12 is obtained.

The K values are according to H. Fikentscher, Cellulose-Chemie 13, 58 bis 64 and 71 to 74 (1932) determined in 5% aqueous solutions at 200C; thereby means K = k. 103.

Claims (6)

Claims oil Clear, aqueous sulfonamide trimethoprim solutions, characterized in that it is a water-soluble sulfonamide salt, trimethoprim and polyvinylpyrrolidone with a K value of 10 to 18 in water and optionally Additions of other substances and / or solvents. 2. Clear, aqueous sulfonamide trimethoprim solutions according to claim 1, characterized in that they contain the sulfonamide salt in an amount of 1 to 40, the trimethoprim in an amount of 0.5 to 10 and the polyvinylpyrrolidone in one Contains 30 to 80% in water. 3. Clear, aqueous sulfonamide trimethoprim solutions according to claim 1, characterized in that they contain the sulfonamide salt in an amount of 5 to 20, the vrimethoprim in an amount of 1 to 5 and the polyvinylpyrrolidone in one Contains 50 to 70% in water. 4. Clear, aqueous sulfonamide trimethoprim solutions according to claim 1 to 3, characterized in that it is a polyvinylpyrrolidone of a K value from 12 to 14 included. 5. Clear, aqueous sulfonamide trimethoprim solutions according to claim 1 to 4, characterized in that it is a water-soluble salt of sulfamoxol contain. 6. Process for the preparation of clear, aqueous sulfonamide trimethoprim solutions according to claim 1, characterized in that the sulfonamide salt and the trimethoprim with the polyvinylpyrrolidone in water with stirring and optionally with heating if necessary dissolves with the addition of other substances and / or solvents.