IE48608B1

IE48608B1 - Medicinal formulation

Info

Publication number: IE48608B1
Application number: IE1455/79A
Authority: IE
Original assignee: Ciba Geigy Ag
Priority date: 1978-08-01
Filing date: 1979-08-08
Publication date: 1985-03-20
Also published as: EP0009559B1; JPS5522693A; DK323579A; IE791455L; DE2963584D1; AU530816B2; CA1134747A; AU4939479A; ZA793928B; EP0009559A1; AR229570A1

Abstract

1. A stable liquid formulation containing 2,6-diamino-5-(3',4',5'-trimethoxybenzyl)-pyrimidine (trimethoprim) and a sulfonamide of the formula I see diagramm : EP0009559,P6,F1 in which R is 6-chloro-2-pyrazinyl or 6-chloro-3-pyridazinyl, or a salt thereof, in the quantity ratio of 1 : 1 to 1 : 20, preferably 1 : 4 to 1 : 5, with a total proportion of 15 to 25 per cent by weight being dissolved in a physiologically compatible, watermiscible solvent, a solubility-promoting agent and a surfactant, and a base in the case where the sulfonamide is not used as a salt, in which composition the solvent used is N-methylpyrrolidone, the surfactant used is bis-(2-ethylhexyl)-Na-sulfosuccinate or poly-oxyethylene-sorbitan monolaurate (polysorbatum 20), the solubility-promoting agent used is hydroxyethyltheophylline or polyvinylpyrrolidone K 25, and the base used is ethenolamine.

Description

The present invention relates to a liquid formulation containing an active-substance combination of 2,6diamino-5-(31,4',5'-trimethoxybenzyl)-pyrimidine (trimethoprim) and a sulfonamide for the control of bacterial and protozoal diseases in animals by means of drinking water application. Besides the stated active substances, the formulation also contains an organic solvent, a solubility-promoting agent and a surfactant.

The effectiveness of sulfonamide-trimethoprim compositions in the control of infectious diseases in humans and in animals is well known. The particular importance of the trimethoprim component derives from the potentiation of the antibacterial and protozoal activity of the sulfonamides .

The administration of this type of active-substance combinations to animals presents however certain difficulties. Thus·,-· in the case of administration in the solid form, by addition to the fodder, a treatment with any promise of success is not possible in the majority of cases since sick animals in general greatly reduce the intake of fodder, or may even refuse it completely. On the other hand, there is usually no reduction in the quantity of water consumed by the animals, so that medication of the animals' drinking water offers a possibility of the enteral introduction of active substances into the animal organism.

A further possibility is the parenteral administration of the active substances by means of injection; however, in view of the need for prophylactic application to numerically extensive groups of animals, which are a major factor in modern livestock production, the injection method is not practicable for reasons of cost. Here too, medication of the drinking water constitutes a useful logical alternative. It is shown therefore that the provision of a stable drinking-water solution of sulfonamide-trimethoprim combinations adapted to meet practical requirements is of great importance for the control of infectious diseases in animals. Furthermore, the medication of drinking water for some species of productive livestock, for example poultry, Is in practice the only possibility of applying treatment to large groups of animals .

The preparation of therapeutically suitable drinkingwater solutions of a sulfonamide in combination with trimethoprim poses however considerable problems, with major factors in this respect being lacking stability of the concentrates and the instability in particular of the active-substance solutions diluted to conform to the dispersion required. This applies all the more at the present time because of the introduction in practice to an ever increasing extent of automatic drinking devices. The smooth functioning of devices of this kind depends however on, among other things, the fully satisfactory condition of the solutions to be dispensed. Thus, the 8 6 0 8 occurrence of precipitations, such as solid deposits, in the solutions provided for preparing the final dilution will inevitably lead to variations in the dosage, in consequence of which a reliably controlled treatment is no longer ensured. The presence of solid constituents in the intermediate dilutions of the drinking-water solutions containing the active substances can moreover result in a disturbance of the functioning of the dispensing apparatus, and this in turn gives rise 10 to losses of valuable material and to additional labour costs .

Since neither trimethoprim nor the sulfonamides have sufficient solubility in water, there are generally used the readily water-soluble salts of these compounds.

The problem arising however is that on combination of the formed salt solutions by bringing the pH value near to the neutral point, a precipitation of the active substances occurs. In order to overcome these difficulties, it has already been frequently suggested that active-substance combinations consisting of trimethoprim and in each case different sulfonamides be converted into a form suitable for therapeutic purposes by the use of organic solvents or solubility-promoting agents. Thus, there is described in the German Offenlegungsschrift No. 2,445,401 the production of anhydrous solutions of active-substance combinations, which solutions are intended for injection purposes and contain a mixture of sulfadimidine and sulfathiazole as the sulfonamide component at a concentration of 24-48%.

The German Offenlegungsschrift No.2,311,214 mentions, in addition to the formation of solid sulfonamidetrimethoprim combinations as feed additives, the production of an injection solution which has a low water content and which has a total active-substance content of about 25%, with N-(4,5-dimethyl-3-isoxazolyl)-sulfanilamide acting as sulfonamide. There ara also mentioned aqueous formulations wherein the content of the stated activesubstance combination for oral administration can be lowered to 5% and below by dilution with water.

The British Patent Specification No. 1,176,395 mentions injectable formulations of trimethoprim with a series of sulfonamides, such as 5,6-dimethoxy-4sulfanilamidopyrimidine, 4,6-dimethyl-2-sulfanilamidopyrimidine, 2,4-dimethoxy-6-sulfanilamidopyrimidine or 3,4-dimethyl-5-sulfonamidoisoxazole, with active-substance concentrations of 12-14%. In order to produce these formulations, the active-substance components have to be taken separately from one another into solution, the sulfonamide being dissolved either together with bases or in one case as Na salt in water, and the trimethoprim in organic solvents or solubility-promoting agents, and the solutions are then mixed together.

On the other hand, for the production of the liquid formulations of trimethoprim with sulfamethazole or sulfacetamide , there is described in the German Offenlegungsschrift No. 2,400,218 a different procedure. The trimethoprim is firstly dissolved, with the addition of acid, in water, and the sulfonamide is then added together with organic solvents or solubility-promoting agents. The active-substance combinations produced in this manner are suggested, according to the above-mentioned patent specification, for injection or for oral administration. Their active-substance concentration is about 8-10%, and in some cases even less than 1%.

A testing of the aqueous formulations proposed in the German Offenlegungsschrift No. 2,311,214 and in the British Patent Specification No. 1,176,395 showed however that these formulations were not satisfactory with respect to their carrier and distributing substances when applied to the active-substance combinations of the present invention, so that it was not possible in practice to produce with these active substances useable stable and clear aqueous solutions.

The prior specifications relate therefore in particular to sulfonamide-trimethoprim formulations of fairly high concentration with and without an addition of water, which are primarily intended for administration by injection, but which are sometimes recommended also for drinking water application. In most cases, the dilution with water is necessary for this purpose in order to adjust the active-substance concentration to give the lower concentration required for this application, and in the concentration range of the intermediate dilutions necessary for automatic drinking devices there occur more or less rapidly precipitations, an effect 2P which results in these solutions becoming unusable. In the case of the formulations already suggested for application in drinking water, there is the disadvantage that the intermediate dilutions remain clear for only a very short time and thus cannot undergo storage, and this factor renders therefore inevitable, depending on the frequency of application, the more or less frequent preparetion of fresh active-substance solutions in water which are intended for as rapid a consumption as possible.

This leads in practice, particularly with the treatment of larger groups of sick animals simultaneously and also in the case of prophylatic medication, which in general is carried out on a broad basis, to a very disadvantageous expenditure in terms of labour and high costs.

Furthermore, reference is made in publications to the fact that some of the solvents and solubilitypromoting agents suggested in the aforementioned patent specifications and Offenlegungsschriften as functional auxiliaries, for example N,N-dimethylacetamide, propylene glycol, dimethylformamide, glycerin formal and polyethylene glycols, cannot be considered altogether safe from a pharmacological-toxic point of view (see in this respect German Offenlegungsschrift No. 2,631,779; H.P. Fiedler, Lexikon der Hilfsstoffe fiir Pharmazie, Kosmetik, 1971; and Prax. Pneumolog. 28 (1971) 491).

Taking as a basis the already mentioned advantages consisting a priori in the administration of medicinal formulations of sulfonamide-trimethoprim combinations for prophylactic and therapeutic treatment by means of drinking water application compared with administration in the form of additives to dry fodder or injections, there is clearly an urgent need to provide aqueous solutions of the stated active-substance combinations which, with regard to clarity and solubility, are stable within a broad concentration range and over a considerable period of time, in order to satisfy requirements in practice to a far greater extent than hitherto.

In order to achieve this objective, there are thus suggested liquid formulations diluted with water, which are of the following composition: 2,6-diamino-5-(3',4',5'-trimethoxybenzyl)-pyrimidine (trimethoprim) and a sulfonamide of the formula I H. ‘2* in which bUS R is 6-chloro-2-pyrazinyl or 6-chloro-3-pyridazinyl, or a salt thereof, in the quantity ratio of 1:1 to 1:20, preferably 1:4 to 1:5, with a total proportion of 15 to 25 per cent by weight being dissolved in a physiologically compatible, watermiscible solvent, a solubility-promoting agent and a surfactant, and a base in the case where the sulfonamide is not used as a salt, in which composition the solvent used is N-methylpyrrolidone, the surfactant used is bis(2-ethylhexyl)-Na-sulfosuccinate or polyoxyethylenesorbitan-monolaurate (polysorbatuas 20), the solubility-promoting agent used is hydroxyethyltheophylline or polyvinylpyrrolidone K 25, and the base used is ethanolamine. With regard to the amounts used, they are preferably 70-90 per cent by weight of solvent, 0.1 - 1.0 per cent by weight of surfactant, and 1-10 per cent by weight of solubilitypromoting agent. In the case of the solubility-promoting agents used, the following amounts are to be considered particularly preferred: for hydroxyethyltheophylline 1.5 per cent by weight, and for polyvinylpyrrolidone K 25 2-4 per cent by weight.

Of the two active-substance combinations mentioned in the foregoing, that which is novel is the combination containing, in addition to trimethoprim, N-[6-chloropyrazinyl-(2)]-sulfanilamide (sulfachloropyrazine) as the sulfonamide, whereas a combination containing, in addition to trimethoprim, N-[6-chloropyridazinyl-(3)]-sulfanilamide (sulfachloropyridazine) as the sulfonamide has previously been described with regard to its active substances (see Magyar Allatorvosok Lapja 12, (1975) 833-836). In the special composition together with the employed functional auxiliaries, suggested according to the present invention, it is however novel.

The present formulations according to the invention render it possible to produce concentrated aqueous solutions which are not only able over a prolonged period of time to remain clear and under normal conditions unaffected in storage, but also able to retain even after dilution with water in a surprising manner their stability properties throughout a wide concentration range. Thus, on the one hand the concentrated forms are stable to the effects of storage and transport, whilst on the other hand the diluted solutions at the place of application can be stored in a stable form as intermediate dilutions over a period of several days as occasion demands, when they can then be converted, without any particular effort, into the desired final dilution form to conform with therapeutic requirements .

The simple dosing and application method which is thus rendered possible and which can be performed without losses of valuable active substances serves in particular to improve the therapeutic efficiency by virtue of more precise dosing of active substance, and also to reduce the expenditure of material and labour.

The advantageous dilution scheme based on the formulations according to the invention is characterised by the following factors: The total amount of active substance in the formulations is in general 15-25 per cent by weight. From these formulations are prepared, in amounts depending on application requirements, clear intermediate dilutions, in which, by the addition of drinking water in the ratio of 5:1 to 50:1, the concentration of active substance can be appropriately reduced without the stability of che intermediate dilutions 8 6 0 8 suffering as a result. These intermediate dilutions of active substance, which remain stable over a period of several days, are stored in the dispensing devices (dispensers) at the place of application, under normal temperature conditions. The amounts of active-substance solution which are required for the treatment of the animals are then automatically taken from these dispensers and by means of suitable dosing devices the final respective concentration required for the treatment is accurately adjusted by the addition of drinking water.

In the case of this final dilution, the proportion of active substance is in general below 1 per cent by weight, in some cases even below 0.1 per cent by weight down to 100 ppm. The stability properties of the formulations according to the invention, which properties are retained even after high dilutions with water, render possible, by application of the dilution principle described, an exact determination of the active-substance dose being administered, so that consequently accurate checking and regulation of the specific treatment are provided.

In the technical world there have so far become known no objections to the functional auxiliaries, such as solvents and solubility-promoting agents, used for the production of the formulations according to the invention, with regard to their toxicological safety in the case of oral administration in the manner described according to the invention.

The active-substance combinations contained in the formulations according to the invention have a broad antibacterial and antiprotozoal spectrum of activity, inter alia against in particular: Escherichia coli, Coccidia, Salmonellae, Staphylococci and Streptococci, and are therefore especially suitable for the prophylatic and therapeutic treatment of infectious diseases in domestic and productive animals, such as poultry, pigs, calves, cattle, sheep and goats. The formulations according to the invention assume therefore, by virtue of the creation of excellent solubility properties, great importance as active-substance carriers for the medication of drinking water precisely for the treatment of large groups of animals, which are at the present time customary in agricultural intensive production.

The active substances used in the formulations 10 according to the invention are known. Thus, 2-diamino-5(3',4',5'-trimethoxybenzyl)-pyrimidine (trimethoprim) is described in Brit. Pharmakopoaia 1973, 484, and N(6-chloropyridazinyl-(3)]-sulfanilamide (sulfachloropyridazine) in the Handbook of Veterinary Drugs, Ed.

Springer New York 1974, 564, as well as in Ullmanns EnzyklopMdie d. Techn. Chemie, Publisher: Chemie Weinheim, 3rd Edition, Vol. 15, and N-[6-chloropyrazinyl-(2)]sulfanilamide (sulfachloropyrazine) is described in the Handbook of Veterinary Drugs, Ed. Springs New York 1974 , 564.

Furthermore, the solvents, solubility-promoting agents and surfactants used as functional auxiliaries are known as such to those skilled in the art.

The active-substance formulations according to the 25 invention are produced by the following process: the active substances, together with a solubility-promoting agent and a surfactant, are dissolved, in a suitable vessel which can be darkened, with the maximum possible exclusion of light and with continuous stirring, in the major part of the intended solvent at a temperature of 10 to 70°C, preferably at 10 to 50°C, the remainder of the solvent is subsequently added, and the solution is filtered, if necessary with the use of filtering auxili48608 aries, for example kieselguhr. In order to accelerate filtration, the temperature can be raised slightly above that maintained during the dissolving process.

The following Examples, which illustrate the active5 substance formulations according to the invention, were carried out at room temperature, with room temperature being understood, according to Ph. Eur. Vol. 1, as being the temperature range of 15 to 25°C.

Example 1 .48 g of sulfachloropyridazine, 3.33 g of trimethoprim, 3.0 g of hydroxyethyltheophylline, 0.5 g of sodium dioctylsulfosuccinate and 4.0 g of ethanolamine are weighed into a suitable vessel which can be darkened, and dissolved, with repeated shaking, in about 80.0 g of N-methylpyrrolidone. The solution is made up to 100 ml with about a further 5.0 g of N-methylpyrrolidone, and subsequently filtered, if necessary with the addition of a filtering auxiliary.

Example 2 14.72 g of sulfachloropyrazine, 3.33 g of trimethoprim, 3.0 g of polyvinylpyrrolidone K 25, 0.5 g of sodium dioctylsulfosuccinate and 4.0 g of ethanolamine are weighed into a suitable vessel which can be darkened, and then dissolved, with repeated shaking, in about 80.0 g of N-methylpyrrolidone The solution is made up to 100 ml with about a further 5.0 g of N-methylpyrrolidone, and subsequently filtered, if necessary with the addition of a filtering auxiliary.

Example 3 .48 g of sulfachloropyridazine, 3.33 g of tri50 methoprim, 3.0 g of polyvinylpyrrolidone K 25 and 0.5 g of sodium dioctylsulfosuccinate are dissolved, with repeated shaking, in 4.0 g of ethanolamine and about 80 g of N-methylpyrrolidone in a suitable vessel which can be darkened, and the solution is made up to 100 ml with about a further 4 g of N-methylpyrrolidone, and subsequently filtered, if necessary using a filtering auxiliary.

Example 4 .48 g of sulfachloropyridazine, 3.33 g of tri10 methoprim, 3.0 g of hydroxyethyltheophylline and 0.5 g of polyoxyethylene sorbitan monolaurate (polysorbatum 20) are dissolved, with repeated shaking, in about 80 g of N-methylpyrrolidone and 4.0 g of ethanolamine in a suitable vessel which can be darkened; the solution is then made up to 100 ml with about a further 4 g of N-methylpyrrolidone, and subsequently filtered, if necessary using a filtering auxiliary.

Example 5 .48 g of sulfachloropyridazine, 3.33 g of tri20 methoprim, 2.0 g of hydroxyethyltheophylline and 0.5 g of sodium dioctylsulfosuccinate are dissolved, with repeated shaking, in about 80 g of N-methylpyrrolidone and 4.0 g of ethanolamine in a suitable vessel which can be darkened, and the solution is made up to 100 ml with about a further 5 g of N-methylpyrrolidone, and subsequently filtered, if necessary using a filtering auxiliary.

Claims

1. CLAIMS:1. A stable liquid formulation containing 2,6-diamino5-(3',4',5'-trimethoxybenzyl)-pyrimidine (trimethoprim) and a sulfonamide of the formula I H 2 N v>-S0 2 -NH-R (i) in which R is 6-chloro-2-pyrazinyl or 6-chloro-3-pyridazinyl, or a salt thereof, in the quantity ratio of 1:1 to 1:20, preferably 1:4 to 1:5, with a total proportion of 15 to 25 per cent by weight being dissolved in a physiologically compatible, watermiscible solvent, a solubility-promoting agent and a surfactant, and a base in the case where the sulfonamide is not used as a salt, in which composition the solvent used is N-methylpyrrolidone, the surfactant used is bis(2-ethylhexyl)-Na-sulfosuccinate or poLyoxyethylenesorbitan-monolaurate (polysorbatum 20), the solubility-promoting agent used is hydroxyethyltheophylline or polyvinylpyrrolidone K 25, and the base used is ethanolamine.

2. A stable liquid formulation according to Claim 1, wherein the amount of solvent used is 70-90 per cent by weight, the amount of surfactant used is 0.1 - 1.0 per cent by weight, and the amount of solubility-promoting agent used is 1-10 per cent by weight.

3. A stable liquid formulation according to Claims 1 and 2, wherein there is used as the solubility-promoting agent 1-5 per cent by weight of hydroxyethyltheophylline. 48 608

4. A stable liquid formulation according to Claims 1 and 2, wherein there is used as the solubility-promoting agent 2-4 per cent by weight of polyvinylpyrrolidone K 25.

5. A process for producing an active-substance combi5 nation according to Claims 1-4, wherein the active substances, together with a solubility-promoting agent, namely hydroxyethyltheophylline or polyvinylpyrrolidone K 25, and a surfactant, namely bis-(2-ethylhexyl)-Nasulfosuccinate or polyoxyethylene sorbitan monolaurate 10 (polysorbatum 20), are dissolved in the major part of the solvent N-methylpyrrolidone at 10° to 70°C, preferably at 10° to 50°C, the formed solution is subsequently made up to the required amount with the remainder of the solvent, and is then filtered, if necessary using filtering auxiliaries 15 and raising the temperature of the solution.

6. Use of the formulation according to Claims 1-4, which comprises continuously mixing this formulation, in the form it is in after it has been intermediately diluted with drinking water, by means of automatic dosing devices, with 20 the customary drinking water being supplied to the animals .