GB1582692A

GB1582692A - Sulphonamide/trimethoprim solutions

Info

Publication number: GB1582692A
Application number: GB29575/77A
Authority: GB
Original assignee: BASF SE
Current assignee: BASF SE
Priority date: 1976-07-15
Filing date: 1977-07-14
Publication date: 1981-01-14
Also published as: DE2631780A1; FR2361103A1; IN145551B; DE2631780C3; BE856847A; JPS5312416A; ZA774215B; FR2361103B1; DE2631780B2

Description

(54) SULFONAMIDE/TRIMETHOPRIM SOLUTIONS (71) We, BASF AKTIENGESELLSCHAFT, a German Joint Stock Company of 6700 Ludwigshafen, Federal Republic of Germany, do hereby declare the invention, for which we pray that a Patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following Statement: The invention relates to clear aqueous solutions which contain a sulfonamide and trimethoprim and which may be administered parenterally, orally or externally.

Therapeutically useful solutions which contain a sulfonamide, e.g. sulfamethoxazole, in the form of a svater-soluble salt, together with the sulfonamide potentiator trimethoprim, have been disclosed. The disadvantage of these solutions is that due to the sulfonamide salt they have a more or less strongly alkaline reaction. This restricts their therapeutic usefulness, e.g.

for parenteral use. Solutions of this nature cannot be injected directly. They must be administered as an infusion, after dilution with, for example, physiological sodium chloride solution. The mixtures with infusion solution must be prepared immediately before use and must be administered within 6 hours of their preparation. As soon as a turbidity or crystals appear, the infusion solution must be replaced by a freshly prepared solution.

According to the present invention there is provided a clear, aqueous, practically neutral as herein defined) solution which contains a sulfonamide in a concentration of from 1 to 20% w/v), trimethoprim in a concentration of from 0.2 to 4% (w/v) and a polyvinylpyrrolidone having a K value (as herein defined) of from 10 to 18 in a concentration of from 20 to 80% (w/v), with or without the addition of further ingredients and/or auxiliaries.

The K value of the polyvinylpyrrolidone in each case is the value as determined by the method of H. Fikentscher, Cellulose-Chemie, 13, (1932)3 pages 58-64 and 71-74, ion a 5%by weight strength aqueous solution at 20"C; K = k.l0 . These solutions are clear, react practically neutral (i.e. have a pH of 7+1) and are eminently suitable for direct parenteral administration.

The solutions according to the invention can, of course, also be diluted with infusion solutions in the conventional manner. Because of their physiological pH, they may be used as eyedrops or eardrops, and when used orally they have the advantage that the polyvinylpyrrolidone masks the bitter taste of the active ingredients.

Furthermore, these solutions can be converted, by addition of conventional pharmaceutical ingredients, into medicaments for use on the skin and the mucous membranes, and for introduction into body cavities. The advantage of these formulations is that the active ingredients are present in solution and hence problems associated with a change in crystal size and shape cannot occur. Such formulations include, for example, wound jellies, wound ointments, film-forming solutions, vaginal jellies, eye ointments, nasal ointments, ointments for use in the mouth, instillations, e.g. nebulizer solutions, and vaginal ovules.

A particular polyvinylpyrrolidone having aK value (as defined hereinbefore) of from 10 to 18, preferably from 12 to 14, oramolecularweight of from 2,000 to 3,500 (a suitable process for the manufacture of the polyvinylpyrrolidone being explained in more detail in the text which follows) is eminently suitable for present purposes, whilst a low molecular weight polyvinylpyrrolidone manufactured in the conventional manner, for example using hydrogen peroxide as the activator, in water as the solvent, is in most cases not obtained in the requisite pharmaceutical quality.

To manufacture the polyvinylpyrrolidone according to a preferred procedure, N vinyl-2-pyrrolidone is polymerized in an organic solvent at above 100"C, the polymerization being carried out batchwise or continuously in the presence of an organic peroxide which carries aliphatic or aliphatic-aromatic substituents of 1 to 8 carbon atoms per alkyl group on either side of the peroxide group. The choice of reaction temperatures above 100"C, of an organic solvent and of an organic peroxide results in the formation of a low molecular weight polyvinylpyrrolidone having advantageous properties.

The choice of the organic peroxide is of particular importance. Those peroxides which have an alkyl and/or aralkyl radical of 1 to 8 carbon atoms per alkyl bonded to each oxygen atom of the peroxide group are preferred; examples are dicumyl peroxide, di-tert.-butyl peroxide, tert.-butyl cumyl peroxide and 2,2-di-tert.-butyl peroxybutane. Di-tert.-butyl peroxide is particularly preferred. The amount of the organic peroxide used can vary within wide limits and depends on the K-value to be obtained. In general, from 0.1 to 6 O/o by weight, preferably from 0.5 to 3% by weight, based on N-vinylpyrrolidone, is used.

Suitable organic solvents are those which boil at from 50 to 1500C, i.e. the reaction may be carried out under atmospheric pressure or superatmospheric pressure. Examples of suitable solvents are alcohols, e.g. methanol, ethanol and n- and i-propanol, ethers, e.g. dioxane and tetrahydrofuran, halogen compounds, e.g. chloroform, methylene chloride, tetrachloroethane or hexachloroethane, aromatic hydrocarbons, e.g. toluene, xylene, cumene or ethylbenzene, and mixtures of the said solvents which are completely miscible with one another, e.g. mixtures of isopropanol and cumene or mixtures of several aromatic hydrocarbons, e.g. ethylbenzene and toluene. Isopropanol is the preferred solvent, since it is a powerful molecular weight regulator. The monomer concentration in the solution is usually from 5 to 75, preferably from 10 to 50, % by weight.

The actual polymerization may be carried out in the conventional manner. A possible method is to introduce all components of the batch into a closed system, advantageously a pressure vessel which has been tested to 200 bars, and to remove the air, contained in the solutions, by application of reduced pressure or by flushing with an inert gas. The temperature is then raised to 100 - 300"C, preferably to 120 - 200"C, and the polymerization is allowed to take place for from about 3 to 4 hours.

The desired K value may be obtained as follows: 1. By the choice of the amount of peroxide; large amounts give particularly low K values.

2. By the choice of the solvent; branched-chain solvents give lower K values than straightchain or unsubstituted aromatic solvents. Secondary alcohols are particularly advantageous.

3. By controlled selection of the manner concentration; an increase in the monomer concentration also increases the K value.

Accordingly, a rough range of K values can be selected by predetermining the concentration of the monomer and of the peroxide, and the nature of the solvent.

4. By choice of the reaction temperature; this permits a fine adjustment of the K value, which is lowered as the temperature is increased.

In a particularly preferred embodiment, the monomer can be added progressively during the polymerization, which results in yet a further lowering of the K value. This embodiment can also be implemented by progressively feeding in a mixture of the vinylpyrrolidone, solvent and peroxide. The period over which the addition is made may vary from 1 to 5 hours.

Using this process, it is possible to obtain polymers with K values of from 10 to 18, which are particularly suitable for the solution according to the invention.

The course of the polymerization can be followed readily by continuously taking samples and determining the residual vinyl-pyrrolidone. When this residual content has fallen substantially below 1%, the polymerization can be discontinued. The polymerization time is in general from 3 to 5 hours.

The solution obtained may be worked up in the conventional manner, e.g. by direct drying in accordance with conventional methods, such as spray drying, drum drying or freeze drying.

In some cases it is advantageous to dilute the reacted batch with water, if appropriate to distil off the organic solvent completely or partially, and then to dry the product. It is frequently advantageous to interpolate a steam distillation in order to remove volatile constituents, originating, for example, from the vinyl-pyrrolidone or the activator, from the solution.

The steam distillation is advantageously carried out by converting the polyvinyl pyrrolidone to an aqueous solution, after completion of the polymerization of the vinylpyrrolidone and before drying, by adding water and distilling off the organic solvent, and then to flush the aqueous polyvinylpyrrolidone solution with from 20 to 200 per cent by weight of steam, based on the weigh tof the pqlyvinylpyrrolidone. After the steam distillation, the polyvinylpyrrolidone is dried in accordance with the conventional methods, i.e. is obtained as a pulverulent product.

Amongst the sulfonamides to be used, sulfamoxole, sulfisomidine and sulfamethóxazole may be mentioned. However, the invention is not limited to the use of specific sulfonamides.

Further examples of sulfonamides which are pharmaceutically useful and therefore useful for the purposes of the present invention may be found, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton Pensylvania, 14th edition, 1975, pages 1105-1113.

Advantageously, the solution contains the sulfonamide in a concentration of from 2 to 15 % (w/v), the trimethoprim in a concentration of from 0.4 to 3% (w/v), and the polyvinylpyrrolidone in a concentration of from 30 to 70% (w/v). The preferred polyvinylpyrrolidone has a K value (as herein defined) of from 12 to 14.

Where appropriate, conventional adjuvants and/or auxiliaries may be added to the solutions of the invention. Examples are sulfites and other reducing compounds for stabilizing the color, ethanol and propylene glycol, in a concentration of 5-25% (w/v) as viscosity-lowering additives, and, for example, preservatives, e.g. p-hydroxybenzoic acid esters, in the case of injectable solutions, flavor correctants, e.g. peppermint oil, in the case of orally used solutions, and preservatives, e.g. benzalkonium chloride, in the case of eyedrops and teardrops.

Examples of conventional additives which may be employed in formulations for external use are polyacrylates, polyethylene glycol, cetyl alcohol, polyoxyethylene monostearate, vinylpyrrolidone/vinyl acetate copolymers, methylhydroxyethylcellulose, glycerol, white petroleum jelly, paraffin oil and gelatin.

The solutions may be prepared in the conventional manner by dissolving the appropriate amounts of sulfonamide and trimethoprim in water, with the aid of the polyvinylpyrrolidone, whilst stirring at room temperature or whilst warming, with or without the addition of one or more further ingredients and/or auxiliaries which may be initially present in the aqueous solution or'lay be added subsequently.

For example, it is possible to dissolve the polyvinylpyrrolidone in water and then to dissolve the sulfonamide and the Trimethoprim in this mixture, whilst stirring and heating, or to dissolve"'the sulfonamide, the trimethoprim and the polyvinylpyrrolidone conjointly in water, whilst stirring and heating.

EXAMPLE 1 (INJECTION SOLUTION) Sulfamoxole 4.0 g Trimethoprim 0.8 g Polyvinylpyrrolidone (K value 12) 30.0 g Sodium sulfite 0.4 g Ethanol 10.0 g Propylene glycol 10.0 g p-Hydroxybenzoic acid ester 0.2 g Water for injections ad 100.0 ml Manufacturing instructions: The polyvinylpyrrolidone, the p-hydroxybenzoic acid ester and the sodium sulfite are dissolved in the mixture of water and propylene glycol, the sulfamoxole and the trimethoprim are dissolved in this solution whilst heating and stirring, ethanol is added and the mixture is made up to its final volume, sterile-filtered and filled aseptically into ampoules.

EXAMPLE 2 (ORAL SOLUTION) Sulfamethoxazole 8.0 g Trimethoprim 1.6 g Polyvinylpyrrolidone (K value 13.5) 55.0 g Sodium bisulfite 0.8 g Ethanol 15.0 g Peppermint oil 0.2 g Demineralized water ad 100.0 ml Manufacturing instructions: The sulfamethoxazole, trimethoprim and polyvinylpyrrolidone are dissolved in the aqueous sodium bisulfite solution with slight heating, the ethanol and peppermint oil are added and the mixture is made up to the final volume and filled into dropper bottles.

EXAMPLE 3 (EYEDROPS) Sulfisomidine 5.0 g Trimethoprim 1.0 g Polyvinylpyrrolidone (K value 12.5) 45.0 g Sodium sulfite 1.0 g Benzalkonium chloride 0.05 g Water for injections ad 100.0 ml Manufacturing instructions: The polyvinylpyrrolidone, benzalkonium chloride and sodium sulfite are dissolved in water, the sulfisomidine and trimethoprim are added and the ingredients are dissolved by heating. The solution is made up to the final volume, sterile-filtered and filled into dropper bottles.

EXAMPLE 4 (EARDROPS) Sulfamoxole 10.0 g Trimethoprim 2.0 g Polyvinylpyrrolidone (K value 14) 50.0 g Sodium bisulfite 1.0 g Propylene glycol 20.0 g Benzalkonium chloride 0.05 g Demineralized water ad 100.0 ml Manufacturing instructions: The sulfamoxole, Trimethoprim, polyvinylpyrrolidone and benzalkonium chloride are dissolved in water, whilst stirring and heating: The sodium bisulfite and the propylene glycol are added; the solution is made up to the final volume, filtered and filled into bottles.

Manufacture of PVP: 77 parts of isopropanol, 6 parts of vinylpyrrolidone and 0.24 part of di-tert.-butyl peroxide are filled into a pressure reactor equipped with a stirrer. The reactor is sealed pressure-tight and substantially freed from atmospheric oxygen by twice forcing in nitrogen to a pressure of 4 bars, and again letting down the pressure. The reactor contents are then heated to 1400C, resulting in a pressure of 7 bars, and a mixture of 63 parts by weight of isopropanol and 54 parts by weight of vinylpyrrolidone and 2.16 parts by weight of di-tert.-butyl peroxide is then run in over 4 hours at from 140 to 1450C. The. polymerization is then continued for about 3 hours, until the monomer content has fallen to below 0.5% (based on vinyl-pyrrolidone employed). The batch is then cooled to 85 "C and diluted with 60 parts by weight of water, and the isopropanol is driven off by passing steam through the batch. After an internal temperature of 98"C has been reached, distillation is continued until a further 60 parts of distillate have passed over. The solution, of about 30% strength, is then spray-dried. A polyvinylpyrrolidone of K value 12 is obtained.

EXAMPLE 5 (WOUND JELLY) Sulfisomidine 8.0 g Trimethoprim 1.6g Polyvinylpyrrolidone (K value 12) 35.0 g Sodium sulfite 0.5 Polyacrylate 1.5 g Polyethylene glycol 400 20.0 g Demineralized water ad 100.0 9 Manufacture: A solution is prepared from the sodium sulfite, sulfisomidine, trimethoprim, polyvinylpyrrolidone and water by heating, and the polyacrylate is dispersed therein. The polyethylene glycol 400 is added to this mixture, which is stirred until a jelly has formed.

EXAMPLE 6 (WOUND OINTMENT) Sulfamoxole 5.0 g Trimethoprim 1.0 g Polyvinylpyrrolidone (K value 13.5) 30.0 g Propylene glycol 15.0 g Cetyl alcohol 10.0 g Liquid paraffin 5.0 g Polyoxyethylene-40 monostearate 6.0 g Methyl p-hydroxybenzoate 0.4 g Demineralized water ad 100.0 g Manufacture: 'The cetyl alcohol, liquid paraffin and polyoxyethylene-40 monostearate are fused together and the solution of methyl p-hydroxybenzoate, sulfamoxole, trimethoprim and polyvinylpyrrolidone in water and propylene glycol is emulsified in the melt at 500C. After cooling, the ointment is homogenized.

EXAMPLE 7 (FILM-FORMING SOLUTION) Sulfamoxole 5.0 g Trimethoprim 1.0g Sodium bisulfite 0.4 g Polyvinylpyrrolidone (K value 14) 25.0 g Vinylpyrrolidone/vinyl acetate copolymer 1.0 g Ethanol 20.0 g Demineralized water ad 100.0 ml Manufacture: The sodium bisulfite and polyvinylpyrrolidone are dissolved in water and the vinylpyrrolidone/vinyl acetate copolymer is dissolved in ethanol. The two solutions are combined and are stirred with the sulfamoxole and the trimethoprim, whilst heating, until a clear solution is formed.

EXAMPLE 8 (VAGINAL JELLY) Sulfamethoxazole 6.0 g Trimethoprim 1.3 g Polyvinylpyrrolidone (K value 12.5) 30.0 g Methyl-hydroxyethyl-cellulose 6.0 g Ethanol 6.0 g Glycerol 10.0 g Lactic acid 1.0 g Methyl p-hydroxybenzoate 0.2 Demineralized water ad 100.0 g Manufacture: The methyl p-hydroxybenzoate and polyvinylpyrrolidone are dissolved in water and the methyl-hydroxethyl-cellulose, glycerol and ethanol are added. The sulfamethoxazole and trimethoprim are stirred into this mixture, whilst heating, until they have dissolved. The pH is brought to 5.5 with lactic acid.

EXAMPLE 9 (EYE OINTMENT) Sulfisomidine 5.0 g Trimethoprim 1.0 g Sodium bisulfite 0.5 g Polyvinylpyrrolidone (K value 12) 40.0 g White petroleum jelly 20.0 g Liquid paraffin 15.0 g Adeps lanae 5.0g Benzyl alcohol 0.5 g Distilled water ad 100.0 g Manufacture: The sulfisomidine, trimethoprim and polyvinylpyrrolidone are heated in water until a clear solution is formed, and the sodium bisulfite is added. This solution is emulsified, at 500C, in the melt of white petroleum jelly, liquid paraffin and adeps lanae. The benzyl alcohol is then added and the mixture is homogenized.

EXAMPLE 10 (OINTMENT FOR USE ON THE MUCOUS MEMBRANES OF THE MOUTH) Sulfamoxole 4.0 g Trimethoprim 0.8 g Polyvinylpyrrolidone (K value 12.5) 35.0 g Ethanol 20.0 g Sodium sulfite 0.5 g Aluminum lactate 1.0 g Methyl p-hydroxybenzoate 0.4 g Guar gum 5.0 g Sodium alginate 2.0 g Demineralized water ad 100.0 g Manufacture: The sodium sulfite, methyl p-hydroxybenzoate and polyvinylpyrrolidone are dissolved in a mixture of ethanol and water. The sulfamoxole and trimethoprim are dissolved in this mixture. The sodium alginate and guar gum are then added, finally followed by the aluminum lactate, and the ointment is homogenized.

EXAMPLE 11 (NASAL OINTMENT) Sulfamethoxazole 6.0 g Trimethoprim 1.2g Propylene glycol 15.0 g Polyacrylate 1.6g Polyvinylpyrrolidone (K value 12.5) 40.0 g Methyl p-hydroxybenzoate 0.3 g Diethanolamine 0.4 g Demineralized water ad 100.0 g Manufacture: A clear solution of the sulfamethoxazole, trimethoprim and polyvinylpyrrolidone in a mixture of propylene glycol, methyl p-hydroxybenzoate and water is prepared. The polyacrylate is dispersed in this solution and the pH is brought to 7.0 with diethanolamine.

EXAMPLE 12 (INSTILLATION) Sulfisomidine 4.0 g Trimethoprim 0.8 g Polyvinylpyrrolidone (K value 12) 40.0 g Propylene glycol 15.0 g Sodium bisulfite 1.0 g Hydroxyethylcellulose 5.0 g Methyl p-hydroxybenzoate 0.3 g Demineralized water ad 100.0 ml Manufacture: The sodium bisulfite, methyl p-hydroxybenzoate and polyvinylpyrrolidone are dissolved in the mixture of propylene glycol, water and hydroxyethylcellulose. The sulfisomidine and trimethoprim are dissolved in this mixture whilst heating and stirring.

EXAMPLE 13 (NEBUUZER SOLUTION) Sulfamoxole 8.0 g Trimethoprim 1.6g Polyvinylpyrrolidone (K value 12) 40.0 g Sodium sulfite 1.0 g Ethanol 20.0 g Pine-needle oil 1.0 g Polyoxyethylene sorbitan oleate 2.0 g Demineralized water ad 100.0 ml Manufacture: The polyvinylpyrrolidone and sodium sulfite ate dissolved in the mixture of ethanol and water. A clear solution of the sulfamoxol and trimethoprim in this mixture is formed by heating and stirring. After cooling, the pine-needle oil, mixed with the polyoxyethylene sorbitan oleate, is added. The solution is nebulized by means of a commercial inhaler appliance. EXAMPLE 14 (VAGINAL OVULES) EXAMPLE 14 (VAGINAL OVULES) Sulfisomidine 10.0 g Trimethoprim 2.0 g Polyvinylpyrrolidone (K value 13.5) 50.0g Propylene glycol 5.0 g Glycerol 5.0 g Gelatin 18.0 g Methyl p-hydroxybenzoate 0.4 g Demineralized water ad 100.0 g Manufacture: The gelatin is swollen in the water which contains a methyl p-hydroxybenzoate. The mixture is heated and glycerol, propylene glycol and polyvinylpyrrolidone are added.

Sulfisomidine and trimethoprim are stirred in this mixture, whilst heating, until a clear solution is formed. The warm solution is cast in ovule molds each holding 2 g. After they are solidified, the ovules are sealed-in moisture-tight.

WHAT WE CLAIM IS: 1. A clear, aqueous, practically neutral (as herein defined) solution which contains a sulfonamide in a concentration of from 1 to 20% (w/v), trimethoprim in a concentration of from 0.2 to 4 % (w/ v) and a polyvinylpyrrolidone having a K value (as herein defined) of from 10 to 18 in a concentration of from 20 to 80% (w/v), with or without the addition of further ingredients and/or auxiliaries.

2. A solution as claimed in claim 1, in which the sulfonamide is used in a concentration of

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **. EXAMPLE 12 (INSTILLATION) Sulfisomidine 4.0 g Trimethoprim 0.8 g Polyvinylpyrrolidone (K value 12) 40.0 g Propylene glycol 15.0 g Sodium bisulfite 1.0 g Hydroxyethylcellulose 5.0 g Methyl p-hydroxybenzoate 0.3 g Demineralized water ad 100.0 ml Manufacture: The sodium bisulfite, methyl p-hydroxybenzoate and polyvinylpyrrolidone are dissolved in the mixture of propylene glycol, water and hydroxyethylcellulose. The sulfisomidine and trimethoprim are dissolved in this mixture whilst heating and stirring. EXAMPLE 13 (NEBUUZER SOLUTION) Sulfamoxole 8.0 g Trimethoprim 1.6g Polyvinylpyrrolidone (K value 12) 40.0 g Sodium sulfite 1.0 g Ethanol 20.0 g Pine-needle oil 1.0 g Polyoxyethylene sorbitan oleate 2.0 g Demineralized water ad 100.0 ml Manufacture: The polyvinylpyrrolidone and sodium sulfite ate dissolved in the mixture of ethanol and water. A clear solution of the sulfamoxol and trimethoprim in this mixture is formed by heating and stirring. After cooling, the pine-needle oil, mixed with the polyoxyethylene sorbitan oleate, is added. The solution is nebulized by means of a commercial inhaler appliance. EXAMPLE 14 (VAGINAL OVULES) EXAMPLE 14 (VAGINAL OVULES) Sulfisomidine 10.0 g Trimethoprim 2.0 g Polyvinylpyrrolidone (K value 13.5) 50.0g Propylene glycol 5.0 g Glycerol 5.0 g Gelatin 18.0 g Methyl p-hydroxybenzoate 0.4 g Demineralized water ad 100.0 g Manufacture: The gelatin is swollen in the water which contains a methyl p-hydroxybenzoate. The mixture is heated and glycerol, propylene glycol and polyvinylpyrrolidone are added. Sulfisomidine and trimethoprim are stirred in this mixture, whilst heating, until a clear solution is formed. The warm solution is cast in ovule molds each holding 2 g. After they are solidified, the ovules are sealed-in moisture-tight. WHAT WE CLAIM IS:

1. A clear, aqueous, practically neutral (as herein defined) solution which contains a sulfonamide in a concentration of from 1 to 20% (w/v), trimethoprim in a concentration of from 0.2 to 4 % (w/ v) and a polyvinylpyrrolidone having a K value (as herein defined) of from 10 to 18 in a concentration of from 20 to 80% (w/v), with or without the addition of further ingredients and/or auxiliaries.

from 2 to 15% (w/v), the trimethoprim in a concentration of from 0.4 to 3 % (w/v), and the polyvinylpyrrolidone in a concentration of from 30 to 70% (w/v).

3. A solution as claimed in claim 1 or claim 2, which contains a polyvinylpyrrolidone having a K value of from 12 to 14.

4. A solution as claimed in any one of the preceding claims in which the sulfonamide is sulfamoxole.

5. A clear, aqueous solution containing a sulfonamide, 'trimethoprim and a polyvinylpyrrolidone substantially as herein described and exemplified.

6. A solution as claimed in any one of the preceding claims wherein the polyvinylpyrrolidone has been made by polymerisation of a vinylpyrrolidone in an organic solvent in the presence of an organic peroxide.

7. A pharamaceutical preparation derived from a solution as claimed in any one of the preceding claims.

8. A pharmaceutical preparation according to claim 7 in the form of a jelly or ointment which includes a gel-forming agent or emulsifier as a further ingredient.

9. A pharmaceutical preparation substantially as hereinbefore described in any one of the specific Examples.

10. A process for the preparation of a solution as defined in claim 1 which comprises dissolving the components in water in the specified proportions while stirring, with 6r without heating and with or without the addition of the further ingredients and/or auxiliaries.

11. A pharmaceutical system comprising sulfonamide, trimethoprim and a polyvinylpyrrolidone having a K value (as herein defined) of from 10 to 18, said materials being present in the system in the proportions defined in claim 1 as individual separate components, as a mixture of all three said materials or as a combination of one of said materials and a mixture of two of said materials separate therefrom and one or more of said materials being in aqueous solution form, together optionally with an aqueous medium, the system being such that on formation of a clear aqueous solution containing all three of said materials from it the resulting solution is practically - neutral (as herein defined).