IL43954A - Chemotherapeutic solutions containing a sulfonamide and a 5-benzyl-2,4-diaminopyrimidine mono acid addition salt sulfonamide potentiator - Google Patents

Abstract

Compounds of the formula 10 in which R<7>, R<8> and R<9>, which can be identical or different, are each an alkyl or alkoxy group with 1 to 4 carbon atoms, or R<7> and R<8> together are an alkylenedioxy group with 1 to 4 carbon atoms, are prepared by reacting correspondingly substituted benzylacrylo- or benzylpropionitrile with guanidine. The compounds are intended in the form of their pharmaceutically acceptable monoacid addition salts as potentiator for sulphonamides in the preparation of clear aqueous solutions of sulphonamides in a medicinally acceptable, water-miscible organic solvent and water. The clear aqueous solutions are suitable for injection and infusion purposes and are distinguished by being well tolerated and having high stability. They can, for example, be injected directly into the veins without causing clot formation or tissue damage. <IMAGE> [GB1469521A]

Description

43934/2 Ckemotherapeutic solutions containing* a sulfonamide and a 5-¾ensyl«*2»A*diamjbaopyrimidlne mono acid additio 1 s¾l sulfanamide potentiator ΪΗΒ WELLCOME KWHDATION LIMITED 0. 41959 solutions containing a sulphonamide and a sulphonamide potentiator.

Aqueous injectable preparations containing both a sulphonamide and a sulphonamide potentiator have previously been prepared using a pharmaceutically acceptable salt of the sulphonamide, either with the sulphonamide potentiator in solution in a water miscible organic solvent or with the sulphonamide potentiator in the form of particles as. a dispersion. In both of these cases the pH of the formulation is highly basic.

It has been found that when the pH of the above solutions approaches the lower end of the basic scale, i.e. approaches neutral pH, insoluble complexes of the sulphonamide and the sulphonamide potentiator, e.g. insoluble complexes of sulfamethoxazole and trimethoprim may form. Formation of these complexes render the preparation unusable for injection purposes.

Although the above mentioned injectable preparations are useful they have certain limitations, i.e. their high pH may at times cause tissue damage at the injection site and at times haemolysis may occur which could cause formation of blood clots in the veins elsewhere. In addition, complexing may occur at a more rapid rate when the formulations are added to slightly acid or neutral intravenous solutions or drips, e.g. saline and dextrose.

It should be understood that the prior art dispersioi is not suitable in any event for intravenous (hereinafter abbreviated to "I.V.") use because of its particulate nature.

More particularly, common I.V. drips and infusions conventionally have a neutral to slightly acidic pH, e.g. saline, and accordingly if the ' injectable solution of the prior art is added to this type of infusion solution or drip, insoluble complexes tend to form prior to the" complete infusion of the patient (conventionally it is desirable that the patients be infused for periods of 8 to 24 hours).

It has also been found that the sterilization of basic pH injectable preparations utilizing an autoclave at 121°C. for 20 minutes (a preferred sterilization technique because of its acceptability) usually causes the sulphonamide in the basic pH preparations, e.g. sulfamethoxazole, to oxidize and the preparation to take on a yellowish discoloration. This would make the injectable preparation unacceptable as a pharmaceutical product.

Accordingly, a new and improved injectable solution was required to overcome the limitations of the prior art injectable preparations. The invention described hereinafter overcomes the limitations of the above mentioned injectable preparations in that it is injectable directly into the veins (slowly) without causing clotting or tissue damage. In addition, the solution of this invention is compatible with acidic I.V. infusions such as saline, dextrose or Ringer's solution in that no precipitation occurs over long periods of time when used with solutions of sufficient volume. The product of this invention is also useful orally (undiluted or if mixed with fluids) unlike highly basic solutions of preparations. Apart from pharmaceutical compatibility considerations, such highly basic solutions and preparations tend to cause tissue damage in the digestive system.

According to the present invention there is provided a clear solution for oral or parenteral administration, comprising a chemothereipeutic amount of sulphonamide having antimicrobial activity in a medicinally acceptable water - miscible organic solvent and an effective sulphonamide potentiatin amount of a water -, soluble , pharmaceutically acceptable mono acid addition salt of a sulphonamide potentiator in water, said clear solution having a pH in the range 2 to 7· In a further aspect *of the invention there is provided a method of making the above solution which comprises combining the sulphonamide, organic, solvent , sulphonamide potentiator, in association with the appropriate amount of salt fonning acid, and water and then adjustin , if necessary, the pH of the mixture so as to lie in the range 2 to 7 either by altering the proportions of the various components or by adding pharmaceutically acceptable acid0 In particular, this invention is directed to a new and improved clear aqueous injectable solution of a chemotherapeutic effective amount of a sulphonamide having antibacterial activity or other antimicrobial activity in a medicinally acceptable water miscible organic solvent and an effective sulphonamide potentiating amount of a water soluble pharmaceutically acceptable acid addition mono salt of a sulphonamide potentiator in water. 43954/2 Additionally, it is preferable that the injectable „ solution contain an amount of a pharmaceutically acceptable acid sufficient to maintain the overall solution at a pH (acidic) to prevent the formation of ah insoluble sulphonamide - sulphonamide potentiator complex after or during formation of the solution. The water soluble pharmaceutically acceptable salts of the sulphonamide potentiator may be formed by the reaction of a sulphonamide potentiator and a pharmaceutically acceptable acid.

A pharmaceutically acceptable mono acid addition salt of a sulphonamide potentiator or a mono acid addition salt of a pharmaceutically acceptable acid and a sulphonamide potentiator is defined herein as a salt consisting of a mono protonated sulphonamide potentiator and an anion of a pharmaceutically acceptable acid. The pH of the solution and the pKa's of the pharmaceutically acceptable acid and the sulphonamide potentiator will determine the respective ionisation states.

It is well known that the chemotherapeutic , especially the antibacterial, activities of the sulphonamides and of certain 2 , 4-diaminopyrimidines are mutually enhanced when these agents are acting together. Although the enhancement is mutual, these 2 , -diaminopyrimidines are herein referred to as sulphonamide potentiators.

Specific pyrimidines and methods of synthesis thereof are described, for example, in Israel Patent Specifications Nos. 27424, 24534, 26755 and 29384; British Patent Specifications Nos. 715,813; 734,801; 875,562; 920,412; 957,797; 1,223,881; 1,261,455; 684,759; 774,094; 774,095; 913,710; 970,583; 1,084,103; 1,088,102; 1,129,084; United States Patent Speci ications Nos. 2 , 92 , 1 and 3 , 02 1 , 332 , and South African Patent Specification No. 6^/5 l8 , ■ Sulphonamide potentiators of the foregoing classes are als disclosed in Belgian Patent Specifications Nos. 782 , 153 ; 782 , 154 77^ , 8 1 and 789 , 90k.

This invention is not limited to the use of a specific sulphonamide-potentiator. It is, however, important that the sulphonamide-potentiator form pharmaceutically acceptable mono acid addition salts which are soluble in water in satisfactory concentrations at phys ologically acceptable pH levels.

An important class of such sulphonamide-potentiators particularly useful in this invention as pharmaceutically acceptable acid addition mono salts are 2 , ¾-diaminopyrimi-dines carrying a substituted benzyl group in the 5-position together with or without lower alkyl group in the 6-position, More particularly preferred 2 , -diaminopyrimidines carrying a substituted benzyl group in the 5-position may be represented by the formula (I) wherein R1 is hydrogen or lower alkyl, methyl or substituted by one or more alkoxy; such as, lower alkoxy; such as, methoxy, ethoxy, or isobutoxy, amino, nitro, halogen, preferably chlorine, \ alkyl; such as lower alkyl ; such as methyl, ethyl or trifluoromethyl , and hydroxy groups, particularly preferred is aryl of this formula II wherein one or both and R¾ are hydrogen, halogen, preferably chlorine, lower alkyl and lower alkoxy and wherein one or both R^ and Rg are halogen, preferably chlorine or bromine, lower alkyl and lower alkoxy.

In the above , alkyl and alkoxy are defined as containing 1 to 20 carbon atoms and lower alkyl and alkoxy are defined as containing from 1 to 6 carbon atoms and most preferably 1 to 3 carbon atoms and may contain straight or branched alkyl or alkoxy groups.

A class of 2 , 4-diamino-5-benzylpyrimidines which are particularly preferred are those of formula: where R , R AND R are the same or different and can each represent alkyl or alkoxy groups having from 1 to 4 carbon atoms, or R7 anci R8 taken together can represent an alkylene dioxy group having from 1 to carbon atoms ^ such as a methylene dioxy group.

As specific compounds of high value there may be mentioned trimethoprim |2 , 4-diamino-5~ ( 3 i 15-trimethoxybenzyl ) pyrimidineJ, diaveridine 2 , ½-diamino-5- ( 3 , l-dimethoxybenzyl ) pyrimidine J, 2 , 'i-diamino-5- ( 3 ,¾ i G-trimethoxybenzyl ) pyrimidine ormetoprini Qi , 2 , ):-diamino-5-(3 , 4-dimethoxy-5-bromobenzyl ) pyrimidine , and pyrimethamine |j2 , 4-diamin©-5- ( 4—chlorophenyl )-6-ethylijyrimidine|]o All these specific compounds are known to have highly valuable chemotherapeutic activity and to be potentiators of sulphonamides in the sense referred, to above.

It is believed that the mono acid addition salt which is formed is the salt in which the acid is combined with the 1-nitrogen atom of the pyrimidine moeity.

Substances which can be used as pharmaceutically acceptable acids to form water soluble pharmaceutically acceptable mono salts of the sulphonamide potentiator, are —for example, pharmaceutically acceptable mineral acids such as sulfuric, phosphoric, hydrochloric, hydrobromic , hydroiodic, as well as pharmaceutically acceptable organic acids such as pharmaceutically acceptable carboxylic acids preferably having between 1 to 20 carbon atoms and most preferably 1 to 10 carbon atoms; e.g., tartaric, citric, lactic, embonic, salicylic, glutamic,, glutaric, naphthoic, acetic, and ethylenediamine-tetra acetic acid and other pharmaceutically acceptable organic acids such as methane sulphonic acid. The acids used herein to form the salts or the .salts of the sulphonamide potentiator must be stronger acids, i.e., have a lower pKa than the sulphonamide. At present, the preferred acid is citric acid, being conveniently accessible and acceptable for the practice of the invention.

This inventio is not limited to the use of a specifi sulphonamide. It is, however, important that the sulphonamide used be soluble in a medicinally acceptable organic solvent which is miscible in water and that the sulphonamide be sufficiently soluble in the organic solvent and the solutions of the invention at the desired concentrations. It is also invportant that the sulphonamide stay in solution in the organic solvent and the solutions of the invention at a physiologically acceptable pll value and not form a sulphonamide-sulphonamide potentiator insoluble complexβ Examples of stilphonamide s having antimicrobial especially antibacterial activity and thus suitable for use in this invention are described in the text Remington 1 s Pharmaceutical Sciences, Fourteenth Edition, Mack Publishin Company, Easton, Pennsylvania, copyrighted in 1970 by the Philadelphia College of Pharmacy and Science on pages 1195-1206 and are incorporated herein by reference hereto.

A convenient general formula wmrid-for a preferred class of sulphonamides for use in the present invention is represented by formula III wherein Q is a substituted or unsubstituted pyrimidin-2-yl or -4-yl group or a substituted isoxazolyl group.

As examples of sulphonamides having antimicx-obial e.g. antibacterial activity for use in this invention, the action of which is capable of being thus potentiated, there may be mentioned sulfadimethoxine Γδ- ( 4-aminobenzener-sulphonamido ) -2 , 4-dimethoxy-pyrimidine]] , sulphadiazine £2- ( 4-aininobenzenesulphonainido ) pyriniidinej sulfadoxine (4-aminobenzenesulpbonamido )-5 i 6-dimethoxy-pyrimidinel], sulphadimethoxine [[ - ( 4-aminobenzenesulphonamido 2 , 6-dimethoxypyriniidineI] , sulphamethoxazolg ( 4~aminobenzene sulphonamido ) -5-methylisoxazole3, sulphaquinoxaline £2- sulphadiinidineC2- (4-aminobenzenesulphonamido ) -4 , 6-dimethylpyrimidine_|, sulfafurazole .5- ( -aminobenzenesulphonainido ) -3 , 4-dimethylisox zoleD , and sulfacetamide]N-sulfanilyacetamidejj.

The sulphonamides may be dissolved conveniently in a medicinally acceptable organic water miscible solvent preferably by stirring at room temperature. This may be accomplished readily either" by adding the sulphonamide to the combination of the organic solvent and the water with or without the salt of the sulphonamide-potentiator present, or the sulphonamide may be mixed with the organic solvent and then both added to the water with or without the presence of the salt of the sulphonamide potentiator present. It is preferable to insure that the pH of the solution to which the sulphonamide or the salt of the sulphonamide potentiator is added in any order is maintained at a volume and pH sufficient to prevent formation of insoluble salts. In making the therapeutic solution of this invention the salt of the sulphonamide potentiator may be added for example, to the combination of the organic solvent , the water and the sulphonamide , or the salt of the sulphonamide potentiator may be formed by adding a pharmaceutically acceptable acid to the water with or without the presence of the organic solvent and with or without the presence of the sulphonamide by adding the sulphonaniide-poteritiator as base.

The end product formed, that is the solution of this invention, is precipitate free.

Suitable medicinally acceptable water miscible organic solvents for dissolving the sulphonamide include polar solvents such as N ,N-dimethylacetamide , polyethylene glycols having average molecular Aeights from about 1 O to 75ΟΟ and containing 2 to 159 ethylene glycol monomer (CH CH O) units; 1, 2-propylene glycol, glycerin, hexamethy-lene glycol, 1,3-butylene glycol, ethanol, diethylacetamide , dimethylaetamide , dime thylsulfoxide , dimethylfc^mamide, di ( 1 , 2-propylene glycol, glycerin formal, polyethylene-glycoethers of tetrahydrofurfuryl alcohol and diethylene glycol.

Usually the ratio of sulphonamide to sulphonamide potentiator as base useful to obtain a therapeutic effect is of the order of 5 * 1 (w/w) , though ratios lying between 10 : 1 to 0.1 : 1 (w/w) are useful, and in certain cases it may be found desirable to have a ratio of as high as between 20 : 1 to 0. 1 : 1 (w/w) .

In accordance with this invention the injectable or oral solution contains from about 15 to 60 percent (all percentages in this application mean W./V. percentages unless otherwise specified) preferably 10 to 50 percent (v/v) and most preferably 20 to ¾0 percent watei^and 30 to 90 percent, preferably O to 80 percent and most preferably (v/v) 50 to 70 percent of the organic solvent.

The injectable or oral solution also contains 1 to about 0 percent and preferably about 10 to 30 percent of the sulphonafnd.de and from 1 to 10 percent and preferably 1 to 5 percent of the sulphonamide potentiator calculated as base . ' The pH of the solution of this invention is from for example 2" to 6 2 to ^P*"eferably from to 6 and most preferably from 4. 5 to 5 · 5 especially for solutions of trimethoprim and sulfamethoxazole. The pH is preferably maintained within these pH limits by the addition of a suf icient amount of a pharmaceutically acceptiible acid, the preferred amount being between 0. 5 to 3 · ϊο . Examples of suitable pharmaceutically acceptable acids as set forth earlier in the description are incorporated herein.

In order to add certain desirable properties to the . injectable or oral solution product, it may be advantageous to add preservatives, local anaesthesia component's or other ingredients to enhance stability. Accordingly, it should be understood that other ingredients may be added so long as these additional ingredients do not detract from the desirable properties of the injectable or oral solution.

The quantity of the injectable or. oral solution of this invention which can be injected into or orally administered to a host mammal or animal for the treatment of bacterial infections or even protozoan infections (if the sulphonamide selected also possesses this activity) varies according to the species of the host, its size, its age, general condition of health and severity and type of infection. Conveniently from about 1 ml. to about 1000 ml. of a solution containing about 5 percent W. V. of the sulphonamide potentiator and about 25 percent W./V. of the sulphonamide can be employed in the treatment of bacterial infections such as those caused k Proteus mirabilis or Haemophilus influenzae.

The frequency . at which the injectable or oral solution of this invention will be administered to a host will vary depending upon the quantity of the active medicaments present therein and the needs and requirements of the host.

Under ordinary circumstances , however, up to about 200 mg/kg of the sulphonamide and up to about 150 mg/kg of the sulphonamide potentiator (calculated as base) in combinations can be administered daily in several dosages. It is to be understood, however, that the mentioned ranges are in no sense critical and the dosages can be adjusted in accordance with the needs of the host.

The product of this invention is primarily intended for parenteral use. However, it can be used orally undiluted or for example , with the addition thereof to drinking water, milk, fruit juices, etc.

Flavourings such as cherry, orange, etc. may be added.

Oral solutions of this inventions are particularly convenient for the treatment of humans, most particularly children, and in poultry for the treatment of coccidiosis.

The following examples further illustrate this invention. It is to be noted that all temperatures are in degrees centigrade, unless otherwise specified and where no temperature is given for the mixing of the ingredients or to prepare the salt, room temperature is the temperature at which the ingredients were mixed or at which temperature the salt was formed. Obviously higher or lower temperatures may be used depending on how quickly it is desired for the mixing or the formation of the salt to take place as is well known by those skilled in the art. All percentages in this application mean W/V percentages, unless otherwise specified.

Example 1 The following ingredients were used: Citric Acid (anhydrous) 1.2 g.

Sulfamethoxazole (SMX) 8.0 g.

Trimethoprim (TMP) 1.6 g.

Polyethylene Glycol 400 30.0 ml.

Propylene Glycol 40.0 ml.

USP Alcohol (95% ethanol) 13.0 ml Water 17.0 ml.

The citric acid was · dissolved in the water. The USP alcohol and propylene glycol were added with stirring to the water. With continuous stirring, the TMP was added to the above. The 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 sparged with nitrogen for 30 seconds and filled into 5 ml. ampuls. The area above the solution was purged with nitrogen for 10 seconds. The ampuls were heat sealed and autoclaved at 121°C. for 20 minutes.

- - Example 2 Example 1 was repeated except that 0.1 g. of potassium metabisulfite was added to the water after the citric acid.

AlsO/ nitrogen was not used. The solutipn was autoclaved at J.2l°C. for 20 minutes.

Example 3 The following ingredients were used: Citric Acid (anhydrous) 1.2 g.

Sulfamethoxazole 8.0 g.

Trimethoprim 1.6 g.

N, N-Dimethylacetamide (DMA) 50.0 ml.

Water 50.0 ml.

The citric acid was dissolved in the water. The TMP was added to the solution and stirred until clear. The DMA and SMX were added and the mixture stirred until clear. The pH of the solution was 4.6. The solution was vacuum filtered through Whatman No. 2 filter paper. The solution was sparged with nitrogen for 30 minutes and filled in 5 ml. ampuls. The area above the solution was purged with nitrogen for 10 seconds. The ampuls were heat sealed and autoclaved at 12l°C. for 20 minutes . .

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

Example 5 The contents of one ampul (5 ml.) of the product of Example 3 were drawn into a syringe and injected into 1 litre of 0.9% sodium chloride with agitation. No precipitate appeared within •16 hours. · Example 6 The procedure used in Example 5 was followed except a solution of 8.60 g. sodium chloride and 0.33 g. calcium chloride with sufficient water to make 1 litre/ commonly referred to as Ringers Solution, was used instead. of 0.9% sodium chloride. No precipitate was observed within 16 hours.

Example 7 The following ingredients were used: Citric Acid (anhydrous) 1.0 g.

Polyethylene Glycol 400 50.0 ml.

USP Alcohol (95% ethanol) 10.0 ml.

Propylene Glycol . 10.0 ml.

Sulfamethoxazole 8.0 g.

Trimethoprim 1.6 g.

Water 30.0 ml.

The citric acid was dissolved, in the water. The TMP was then added with continuous stirring until solution was affected. The Polyethylene Glycol 400, USP alcohol (95% ethanol), propylene glycol , and SMX were added to the above and the mixture stirred til the solids dissolved. The pH was 4.6. The solution was vacuum filtered through Whatman. No. 2 filter paper. The solution was nitrogen sparged, filled into 5 ml. ampuls, nitrogen purged, heat sealed, and autoclaved at 121°C. for 20 minutes.

The same amount of ingredients and procedure were followed except 0.1 g. of potassium metabisulfite was added and the mixture stirred until a clear solution was obtained. It was filled into 5 ml. ampuls, heat sealed, autoclaved at 121°C. for 20 minutes. Discoloration was noted with the nitrogen purged batch but not with the batch with bisulfite.

Example 8 The following ingredients were, used: Water 40.0 ml.

Citric Acid (anhydrous) 0.9 g.

Trimethoprim 1.6 g.

Polyethylene Glycol 4000 48.0 g.

Propylene Glycol 10.0 ml.

USP Alcohol (95% ethanol) 10.0 ml.

Sulfamethoxazole 8.0 g.

The citric acid was dissolved in the water. The TMP v/as added with continuous stirring until a clear solution was obtained. The polyethylene glycol was dissolved in the solution. The propylene glycol, USP alcohol (95% ethanol), and SMX were then added and stirred to give a clear solution. The pH was 5.JL. The solution was vaccum filtered through Whatman No. 2 filter paper. Half the batch was nitrogen sparged, filled into 5 ml. ampuls, nitrogen purged,, heat sealed, and autoclaved at 121°C. for 20 minutes.

To the other half, 0.05 g. of potassium metabisulfite was added and the mixture stirred until .clear .- The solution was filled into 5 ml. ampuls, heat sealed, and autoclaved at for 20 minutes.

In Examples 9 and 10 following the method of Example 1, the lis were mixed and 8 g. of sulfamethoxazole and 1.6 g. of trimethoprim we In Example 11 and 12 following the method of Example 3, the listed in mixed and 8 g. of sulfamethoxazole and 1.6 g. of trimethoprim were dis In Examples 13 and 14 following the method of Example 8 the listed i were mixed and 8 g. of sulfamethoxazole and 1.6 g. of trimethoprim we USP Example Water* Citric Acid ' Polyethylene N ,N-dimethylacetamide Alcohol P (anhydrous) Glycol** 9 15 1.2 400/30 — 10 10 40 1.2 400/50 - 10 11 50 . 1.2 400/10 40 - 12 50 0.9 6000***/12 40 - 13 50 0.9 400/10 38 - 14 50 0.9 4000***/24 30 *Liquids are by volume in ml., solids by weight in grams **The first number indicates the polyethylene glycol used, the second the vo ***Solids Example 15 The following ingredients were used: DMA 7.5 ml.

Sulfacetamide , 2.0 g.

Citric Acid (anhydrous) 0.15 g.

Trimethoprim 0.40 g.

Water 17.5 m.

The citric acid was dissolved in the water.. The TMP was added and the mixture was stirfced until a clear solution was obtained. The DMA and sulfacetamide were added and the mixture stirred til clear. The pH of the solution was 4.7.

Example 16 The following ingredients were used: Sulfamethoxazole 2.0 g.

Trimethoprim 0.4 g.

Water 12.5 ml .

DMA 12.5 ml.

Glacial Acetic Acid 0.1 ml.

The glacial acetic acid and DMA were added to the water and mixed. The TMP was added and the mixture stirred until clear. The SMX was added and the mixture stirred to give a clear solution. The pH of the solution was 5.8. - - 43954/2 4 Examples 17 - 20 Example 1 was repeated with the exception that instead of trimethoprim there was used as the sulfonamide potentiator the following pyrimidines : 2,4-diamino-5-(3i4-methylenedioxy-5-methoxybenzyl ) pyrimidine ; 2 , -diamino-5- ( 3 » 5-diethyl-4-methoxy benzyl )pyrimidine ; 2 , 4-diamino-5- ( , 5-dimethoxy-A-methylbenzyl ) pyrimidine. and 2, -diamino-5-(3,+, 5-triethylbenzyl ) pyrimidine .

Example 22 USP Alcohol, (95% ethanol) 9.0 ml.

Citric Acid, anhydrous 0.9 g.

Liquid Sucrose 10.0 ml .

Polyethylene Glycol 400 46.0 ml.

Potassium Metabisulfite 0.1 9· Sodium Saccharin 0.1 9· Sulfamethoxazole 8.0 9· Trimethoprim 1.6 g.

Flavor, soluble q. s.

Water, Purified, q.s. to 100.0 ml.

The citric acid, sodium saccharin and potassium metabisulphite were dissolved in water. The polyethylene glycol 400 was then dissolved in the solution, and the liquid sucrose alcohol , and soluble flavour were added with stirring. The trimethoprim was added and stirring was continued until the trimethoprim was dissolved. The sulphamethoxazole was added and the mixture was stirred until a clear solution suitable for oral administration was obtained. Suitable soluble flavouring agents may be either natural flavours e.g. lime, orange, or artificial flavours e.g. cherry, raspberry.

Claims (16)

43954/2 CLAIMS;

1. A clear solution for parental administration comprising 1 to 40% (g/lOOml) of a. sulphonamide of the formul wherein Q is a pyrimid-2-yl or -4-yl group or a pyrimid-2-yl or -4-yl group substituted by one or more methyl or methoxy groups or an isoxazolyl group substituted by one or more methyl groups, or Q is an acetyl group, 30-90% (ml/ml) of a medicinally acceptable water-miscible organic solvent 10 to 70% (v/y) of water and 1 to 10% (g/lOOml) of the mono acid addition salt of a compound of the formula (I) : wherein is hydrogen or lower alkyl and is a phenyl group substituted by one or more alkoxy, amino, nitro, halogen, alkyl, triflu'oromethyl or hydroxy groups, said clear solution having a pH in the range 4 to 6.

2. A clear solution according to claim 1 wherein ]¾2 is a phenyl group substituted by one or more lower alkoxy, amino, nitro, halogen, lower alkyl, trifluoromethyl or hydroxy 43954/2 groups.

3. A clear solution according to either claim 1 to 2 wherein R„ is a group of the formula (II)':' wherein one or both of and R^ are hydrogen, halogen, lower alkyl and lower alkoxy and wherein one or both of R and R, are halogen, lower alkyl and lower alkoxy. 6

4. A clear solution according to claim 1 wherein R, is hydrogen and R„ is a group: wherein R^ , Rg and R^ are the same or different and can each represent C^_^ alkoxy groups.

5. A clear solution according to claim 1 wherein the compound of the formula (I) is trimethoprim jj. , 4-diamino-5-(3,4, 5-trimethoxybenzy1) pyrimidine^ .

6. A clear solution according to claim 1 wherein the compound of the formula (I) is diaveridine [j2 , 4-diamino- 5- ( 3 , 4 ,-dimethoxybenzyl) pyrimidine__L ., 43954/2

7. A clear solution according to any one of claims 1-6 wherein the mono acid addition salt of a compound of the formula (I) is formed from a pharmaceutically acceptable carboxylic acid having between 1 to 10 carbon atoms.

8. A clear solution according to an one of claims 1 to 6 wherein the sulphonamide is sulphamethoxazole , sulfadimethoxine or sulphadiazine.

9. A clear solution according to any one of claims 1 to 8 wherein there is 1 to 10% (g/lOOml) of sulphonamide present.

10. A clear solution according to any one of claims 1 to 9 having a pH in the range 4.5 to 5.5.

11. A clear solution according to any one of claims 1 to 10 wherein the clear solution also contains a pharmaceutically acceptable *acid.

12. A clear solution according to claim 11 wherein the pharmaceutically acceptable acid is present in an amount of from 0.5 to 3.5 per cent, by weight of the solution.

13. A clear solution according to any one of claims 1 to 12 wherein the water-miscible organic solvent is selected from a polyethylene glycol having an average molecular weight from about 190 to 7500 and containing 2 to 159 ethylene glycol monomer (CH2CH20) units, 1 , 2-propylene glycol, glycerin, hexamethylene glucol, 1,3-butylene glycol, ethanol, diethylacetamide , dimethylacetamide , dimethylsulphoxide . , dimethylformamide , di ( 1 , 2-propylene) glycol , glycerin formal, polyethyleneglycoethers of tetrahydrofurfury1 alcohol and. diethylene glycol . * ; 43954/2

14. A clear solution according to claim 13'wherein + the water-miscible organic solvent is dimethylacetamide , a polyethylene glycol, propylene glycol, ethanol or glycerin formal. ·

15. A clear solution according to any one of claims! to 14 wherein the ratio of sulphonamide of the formula (III) 4-present to a compound of the formula (I) present in approximately 5:1.

16. . A clear solution according to claim 1 as hereinbefore described with reference to any one of the foregoing Examples.