CA1134747A - Medicinal formulation - Google Patents
Medicinal formulationInfo
- Publication number
- CA1134747A CA1134747A CA000332815A CA332815A CA1134747A CA 1134747 A CA1134747 A CA 1134747A CA 000332815 A CA000332815 A CA 000332815A CA 332815 A CA332815 A CA 332815A CA 1134747 A CA1134747 A CA 1134747A
- Authority
- CA
- Canada
- Prior art keywords
- solubility
- per cent
- weight
- promoting agent
- solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
- A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Case 5-11955/E
MEDICINAL FORMULATION
Abstract Stable aqueous liquid formulation containing an active-substance combination of 2,6-diamino-5-(3',4',5'-trimethoxybenzyl)-pyrimidine (trimethoprim) and a sulfonamide of the formula
MEDICINAL FORMULATION
Abstract Stable aqueous liquid formulation containing an active-substance combination of 2,6-diamino-5-(3',4',5'-trimethoxybenzyl)-pyrimidine (trimethoprim) and a sulfonamide of the formula
Description
l t ;~4 ~47 Case 5-11955/E
MEDICINAL FORMULATION
The present invention relates to a liquid formulation containing an active-substance combination of 2,6-diamino-~-(3',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 .he stated active substances, the formulation also contains an organic solvent, a solubility-promoting agent and a surfactant.
The effectiveness of sulfonamide-trimethoprim compo-sitions 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 diffi-culties. 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 sic~ animals in general greatly reduce the inta~e of fodder, or may even refuse ~t completely. On the other ~ '7'~7 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 ma~or factor in modern livestock production, the injection method i5 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 drinking-water 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 o~ this ~ind depends however on, among other things, the fully satisfactory condition of the solutions to be dispensed Thus, the 113~'7~7 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 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 c~mpounds.
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 diffi-culties, it has already been frequently suggested that active-substance combinations consisting of trimethoprim and in each case different sulfonamides be converted in~o a form suitable for therapeutic purposes by the use of organic solvents or solubility-promoting agents. Thus, there is described in the German Offenlegungsschrift ~o.
MEDICINAL FORMULATION
The present invention relates to a liquid formulation containing an active-substance combination of 2,6-diamino-~-(3',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 .he stated active substances, the formulation also contains an organic solvent, a solubility-promoting agent and a surfactant.
The effectiveness of sulfonamide-trimethoprim compo-sitions 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 diffi-culties. 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 sic~ animals in general greatly reduce the inta~e of fodder, or may even refuse ~t completely. On the other ~ '7'~7 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 ma~or factor in modern livestock production, the injection method i5 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 drinking-water 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 o~ this ~ind depends however on, among other things, the fully satisfactory condition of the solutions to be dispensed Thus, the 113~'7~7 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 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 c~mpounds.
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 diffi-culties, it has already been frequently suggested that active-substance combinations consisting of trimethoprim and in each case different sulfonamides be converted in~o a form suitable for therapeutic purposes by the use of organic solvents or solubility-promoting agents. Thus, there is described in the German Offenlegungsschrift ~o.
2,445,401 the production of anhydrous solutions of active-substance combinations, which solutions are intended for injection puxposes and contain a mixture of sulfadimidine and sulfathiazole as the sulfonamide com-ponent at a concentration of 24-48%.
The German Offenlegungsschrift ~o.2,311,214 mentions, in addition to the formation of solid sulfonamide-trimethoprim combinations as feed additives, the production of an in3ection solution which has a low water content and 11~ 4~4 which has a total active-substance content of about 25%, with N-(4,5-dimethyl-3-isoxazolyl)-sulfanilamide acting as sulfonamide. There are also mentioned aqueous formulations wherein the content of the stated active-substance 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-4-sulfanilamidopyrimidine, 4,6-dimethyl-2-sulfanilamido-pyrimidine, 2,4-dimethoxy-6-sulfanilamidopyrimidine or
The German Offenlegungsschrift ~o.2,311,214 mentions, in addition to the formation of solid sulfonamide-trimethoprim combinations as feed additives, the production of an in3ection solution which has a low water content and 11~ 4~4 which has a total active-substance content of about 25%, with N-(4,5-dimethyl-3-isoxazolyl)-sulfanilamide acting as sulfonamide. There are also mentioned aqueous formulations wherein the content of the stated active-substance 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-4-sulfanilamidopyrimidine, 4,6-dimethyl-2-sulfanilamido-pyrimidine, 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 Offen-legungsschrift 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 c binations 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 &erman Offenlegungsschrift No. 2,311,214 and in the 113'~7~7 British Paeent 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 l~wer 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 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 preparation 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 medica~ion, which in general is carried out on a broad basis, to a very disadvantageous expenditure in terms of labour and high costs.
11347~7 Furthermore, reference is made in publications to the fact that some of the solvents and solubility-promoting 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 GenmEnOffenlegungsschrift No. 2,631,779;
~.P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik, 1971; and Prax. Pneumolog. 2$ (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
H2 ~ SU2-N~
in which ~13~747 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, water-miscible 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 polyoxyethylene-sorbitan-monolaurate (Tween 20), the solubility-promoting agent used is hydroxyethyltheophylline or polyvinyl-pyrrolidone 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 solubility-promoting 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-chloro-pyrazinyl-(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 Allatorvoso~ Lapja 12, (197~) 833-836). In the special composition together with the employed functional 11;3~747 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 sltbstance, and also to reduce the expenditure of material and labour.
The advantageous dilution scheme based on the formu-lations 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 drin~ing water in the ratio of 5:1 to 50:1, the conc~n-tration of active substance can be appropriately reducPd without the stability o~ the intermediate dilutions 11347'~7 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 fr~m these dispensers, and by means of suitable dosing devices the final respective concentration required for the treatment is accurately adjusted by the addition of drin~ing 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 chec~ing 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, Sa~monellae, Staphylococci and Streptococci, and are therefore especially suitable for the prophylatic and therapeutic treatment of infectious diseases in 1~3474~
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 according to the invention are known. Thus, 2-diamino-5-(3',4',5'-trimethoxybenzyl)- wrimidine (trimethoprim~
is described in Brit. Pharmakopoeia 1973, 484, and N-l6-chloropyridazinyl-(3)]-sulfanilamide (sulfachloro-pyridazine) in the Handbook of Veterinary Drugs, Ed.
Springer New Yor~ 1974, 564, as well as in Ullmanns Enzyklop~die d. Techn. Chemie, Publisher: Chemie Weinheim, 3rd Edition, Vol. 15, and N-L6-chloropyrazinyl-(2)3-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 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 possi~le exclusion of light and with continuous stirring, in the major part of the intended solvent at a temperature of 10 to 70C, 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 auxili-.. . . . . . . . .. .
~ 7 aries, for example kieselguhr. In order to acceleratefiltration, the temperature can be raised slightly above that maintained during the dissolving process.
The following Examples, which illustrate the active-substance formulations according to the invention, were carried out at room temperature, with room tempera-ture being understood, according to Ph. Eur. Vol. 1, as being the temperature range of 15 to 25C.
Example 1 15.48 g of sulfachloropyridazine, 3.33 g of tri-methoprim, 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 dar~ened, 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 dioctyl-sulfosuccinate 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 subsPquently filtered, if necessary with the addition of a fi~tering auxiliary.
xample 3 15.48 g of sulfachloropyridazine, 3.33 g o~ tri-methoprim, 3.0 g of polyvinylpyrrolidone K 25 and 0.5 g 113~7'~7 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 .
15.48 g of sulfachloropyridazine, 3.33 g of tri-methoprim, 3.0 g of hydroxyethyltheophylline and 0.5 g of polyoxyethylene sorbitan monolaurate (Tween ~ 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 15.48 g of sulfachloropyridazine, 3.33 g of tri-methoprim, 2.0 g of hydroxyethyltheophylline and 0.5 g of sodium dioctylsulfosuccinate are dissolved, with repeated sha~ing, 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 lO0 ml with about a further 5 g of N-methylpyrrolidone, and subsequently filtered, if necessary using a filtering auxiliary.
On the other hand, for the production of the liquid formulations of trimethoprim with sulfamethazole or sulfacetamide, there is described in the German Offen-legungsschrift 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 c binations 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 &erman Offenlegungsschrift No. 2,311,214 and in the 113'~7~7 British Paeent 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 l~wer 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 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 preparation 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 medica~ion, which in general is carried out on a broad basis, to a very disadvantageous expenditure in terms of labour and high costs.
11347~7 Furthermore, reference is made in publications to the fact that some of the solvents and solubility-promoting 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 GenmEnOffenlegungsschrift No. 2,631,779;
~.P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik, 1971; and Prax. Pneumolog. 2$ (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
H2 ~ SU2-N~
in which ~13~747 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, water-miscible 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 polyoxyethylene-sorbitan-monolaurate (Tween 20), the solubility-promoting agent used is hydroxyethyltheophylline or polyvinyl-pyrrolidone 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 solubility-promoting 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-chloro-pyrazinyl-(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 Allatorvoso~ Lapja 12, (197~) 833-836). In the special composition together with the employed functional 11;3~747 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 sltbstance, and also to reduce the expenditure of material and labour.
The advantageous dilution scheme based on the formu-lations 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 drin~ing water in the ratio of 5:1 to 50:1, the conc~n-tration of active substance can be appropriately reducPd without the stability o~ the intermediate dilutions 11347'~7 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 fr~m these dispensers, and by means of suitable dosing devices the final respective concentration required for the treatment is accurately adjusted by the addition of drin~ing 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 chec~ing 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, Sa~monellae, Staphylococci and Streptococci, and are therefore especially suitable for the prophylatic and therapeutic treatment of infectious diseases in 1~3474~
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 according to the invention are known. Thus, 2-diamino-5-(3',4',5'-trimethoxybenzyl)- wrimidine (trimethoprim~
is described in Brit. Pharmakopoeia 1973, 484, and N-l6-chloropyridazinyl-(3)]-sulfanilamide (sulfachloro-pyridazine) in the Handbook of Veterinary Drugs, Ed.
Springer New Yor~ 1974, 564, as well as in Ullmanns Enzyklop~die d. Techn. Chemie, Publisher: Chemie Weinheim, 3rd Edition, Vol. 15, and N-L6-chloropyrazinyl-(2)3-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 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 possi~le exclusion of light and with continuous stirring, in the major part of the intended solvent at a temperature of 10 to 70C, 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 auxili-.. . . . . . . . .. .
~ 7 aries, for example kieselguhr. In order to acceleratefiltration, the temperature can be raised slightly above that maintained during the dissolving process.
The following Examples, which illustrate the active-substance formulations according to the invention, were carried out at room temperature, with room tempera-ture being understood, according to Ph. Eur. Vol. 1, as being the temperature range of 15 to 25C.
Example 1 15.48 g of sulfachloropyridazine, 3.33 g of tri-methoprim, 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 dar~ened, 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 dioctyl-sulfosuccinate 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 subsPquently filtered, if necessary with the addition of a fi~tering auxiliary.
xample 3 15.48 g of sulfachloropyridazine, 3.33 g o~ tri-methoprim, 3.0 g of polyvinylpyrrolidone K 25 and 0.5 g 113~7'~7 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 .
15.48 g of sulfachloropyridazine, 3.33 g of tri-methoprim, 3.0 g of hydroxyethyltheophylline and 0.5 g of polyoxyethylene sorbitan monolaurate (Tween ~ 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 15.48 g of sulfachloropyridazine, 3.33 g of tri-methoprim, 2.0 g of hydroxyethyltheophylline and 0.5 g of sodium dioctylsulfosuccinate are dissolved, with repeated sha~ing, 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 lO0 ml with about a further 5 g of N-methylpyrrolidone, and subsequently filtered, if necessary using a filtering auxiliary.
Claims (7)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A stable substantially water-free liquid formulation containing 2,6-diamino-5-(3',4',5'-trimethoxybenzyl)-pyrimidine (trimethoprim) and a sulfonamide of the formula I
(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, with a total proportion of 15 to 25 per cent by weight being dissolved in a physiologically compatible, water-miscible 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 polyoxyethylene-sorbitan-monolaurate (Tween 20), the solubility-promoting agent used is hydroxyethyltheophylline or polyvinyl-pyrrolidone K 25, and the base used is ethanolamine.
(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, with a total proportion of 15 to 25 per cent by weight being dissolved in a physiologically compatible, water-miscible 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 polyoxyethylene-sorbitan-monolaurate (Tween 20), the solubility-promoting agent used is hydroxyethyltheophylline or polyvinyl-pyrrolidone K 25, and the base used is ethanolamine.
2. A stable liquid formulation according to claim 1, where-in the quantity ratio of the active substances is 1:4 to 1:5.
3. 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.
4. A stable liquid formulation according to Claim 1, 2 or 3, wherein there is used as the solubility-promoting agent 1-5 per cent by weight of hydroxyethyltheophylline.
5. A stable liquid formulation according to Claim 1, 2 or 3, wherein there is used as the solubility-promoting agent 2-4 per cent by weight of polyvinylpyrrolidone K 25.
6. A process for producing an active-substance combination according to Claim 1, wherein the active substances, together with a solubility-promoting agent, namely hydroxyethyltheophylline or polyvinylpyrrolidone K 25, and a surfactant, namely bis-(2-ethylhexyl)-Na-sulfosuccinate or polyoxyethylene sorbitan mono-laurate (Tween 20), are dissolved in the major part of the solvent N-methylpyrrolidone at 10° to 70°C, the formed solution is sub-sequently made up to the required amount with the remainder of the solvent, and is then filtered, if necessary using filtering auxiliaries and rising the temperature of the solution.
7. A process according to Claim 5, wherein the dissolution in the major part of the solvent is carried out at a temperature of from 10° to 50°C.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH821778 | 1978-08-01 | ||
| CH8217/78-3 | 1978-08-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1134747A true CA1134747A (en) | 1982-11-02 |
Family
ID=4336949
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000332815A Expired CA1134747A (en) | 1978-08-01 | 1979-07-30 | Medicinal formulation |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP0009559B1 (en) |
| JP (1) | JPS5522693A (en) |
| AR (1) | AR229570A1 (en) |
| AU (1) | AU530816B2 (en) |
| CA (1) | CA1134747A (en) |
| DE (1) | DE2963584D1 (en) |
| DK (1) | DK323579A (en) |
| IE (1) | IE48608B1 (en) |
| ZA (1) | ZA793928B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1099795B (en) * | 1978-10-09 | 1985-09-28 | Narxer S P A | THERAPEUTIC COMPOSITION FOR THE TREATMENT OF INFECTIONS AND DISEASES OF FARM ANIMALS |
| JPS61181232U (en) * | 1985-04-27 | 1986-11-12 | ||
| HU212498B (en) * | 1992-11-06 | 1996-07-29 | Egyt Gyogyszervegyeszeti Gyar | Process for producing water-soluble pharmaceutical compositions, containing sulfachlorpyridazin-sodium and trimethoprim |
| JP6186533B1 (en) * | 2017-03-31 | 2017-08-23 | ナガセ医薬品株式会社 | Process for producing maxacalcitol-containing aqueous preparation |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1028292B (en) * | 1954-03-13 | 1958-04-17 | Wuelfing J A Fa | Process for the production of stable solutions of rutin |
| US3728452A (en) * | 1971-01-20 | 1973-04-17 | Abic Ltd | Water-soluble composition comprising sulfadimidine and pyrimethamine |
| GB1538903A (en) * | 1975-04-11 | 1979-01-24 | Nelson Res & Dev | Carrier for a topically applied physiologically active agent or cosmetic agent |
| US4018889A (en) * | 1976-01-02 | 1977-04-19 | Pfizer Inc. | Oxytetracycline compositions |
| IL49412A (en) * | 1976-04-14 | 1979-03-12 | Abic Ltd | Water-soluble composition comprising sulfadimidine and pyrimethamine |
| DE2627706C2 (en) * | 1976-06-21 | 1982-11-18 | Saarstickstoff-Fatol Gmbh, 6685 Schiffweiler | Process for the production of neutral, stable sulfonamide potentiator solutions that can be diluted with water to form clear solutions |
| DE2631780C3 (en) * | 1976-07-15 | 1981-11-19 | Basf Ag, 6700 Ludwigshafen | Sulfonamide trimethoprim solutions |
| DE2631779A1 (en) * | 1976-07-15 | 1978-01-19 | Basf Ag | Clear aqueous sulphonamide-trimethoprim solutions - contg. a water-soluble sulphonamide salt, trimethoprim and polyvinyl pyrrolidone of K-value 10-18 |
-
1979
- 1979-07-27 EP EP79102682A patent/EP0009559B1/en not_active Expired
- 1979-07-27 DE DE7979102682T patent/DE2963584D1/en not_active Expired
- 1979-07-30 CA CA000332815A patent/CA1134747A/en not_active Expired
- 1979-07-30 AR AR277526A patent/AR229570A1/en active
- 1979-07-31 AU AU49394/79A patent/AU530816B2/en not_active Ceased
- 1979-07-31 ZA ZA00793928A patent/ZA793928B/en unknown
- 1979-07-31 DK DK323579A patent/DK323579A/en not_active Application Discontinuation
- 1979-08-01 JP JP9860479A patent/JPS5522693A/en active Pending
- 1979-08-08 IE IE1455/79A patent/IE48608B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0009559B1 (en) | 1982-08-25 |
| JPS5522693A (en) | 1980-02-18 |
| DK323579A (en) | 1980-02-02 |
| IE791455L (en) | 1980-02-01 |
| DE2963584D1 (en) | 1982-10-21 |
| IE48608B1 (en) | 1985-03-20 |
| AU530816B2 (en) | 1983-07-28 |
| AU4939479A (en) | 1980-02-07 |
| ZA793928B (en) | 1980-08-27 |
| EP0009559A1 (en) | 1980-04-16 |
| AR229570A1 (en) | 1983-09-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2008113483A2 (en) | Stabilization of vitamin b12 | |
| CA1134746A (en) | Medicinal formulation | |
| CN101269072A (en) | Pharmaceutical composition containing beta-lactamase restrainer and piperacillin sodium with steady content and preparation method thereof | |
| EP0137627B1 (en) | Pour-on formulation for the control of parasites | |
| CA1134747A (en) | Medicinal formulation | |
| DE2311214A1 (en) | INGREDIENTS COMBINATION | |
| BG65673B1 (en) | Veterinary formulation for administration to an animal in need of a water-insoluble drug through a water distribution system | |
| CN103417478B (en) | Water based ivermectin O/W injection and preparation method thereof | |
| Zilversmit et al. | Fate of intravenously administered glycerol. | |
| JPS59139316A (en) | Anticoccidial drug | |
| US3065133A (en) | Imidazoles for the control of histomoniasis | |
| NZ209100A (en) | Topical compositions for control of endoparasites | |
| CN101690547B (en) | Liquid multi vitamin and production method thereof | |
| NZ188912A (en) | Prevention or treatment of copper deficiency by topical application of copper | |
| US3728452A (en) | Water-soluble composition comprising sulfadimidine and pyrimethamine | |
| CN104171407A (en) | Application of sodium butyrate to preparation of feed or feed additive of promoting flaudio-videoonoid secretion | |
| JPS6242924A (en) | Vermifuge and fungicide composition | |
| US3781422A (en) | Therapeutic solution of iron and liposoluble vitamins | |
| EP0084516A1 (en) | Anthelmintics | |
| US3954996A (en) | Water-soluble composition comprising a robenidine salt | |
| JPS60260510A (en) | Injection solution for ketonemia | |
| AU619004B2 (en) | Water-soluble preparations of coccidiostats | |
| JPH0118051B2 (en) | ||
| DE2102889C3 (en) | Use of SuIf adimidine and pyrimethamine | |
| US2812282A (en) | Stabilized aqueous solution of nitrofurazone |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |