HU210693B - Process for producing pharmaceutical compositions for injections without tissue damages, containing sulfamethoxazol and trimetoprime - Google Patents

Description

FIELD OF THE INVENTION The present invention relates to a process which is free from local tissue damaging adverse reactions, comprising 3- (4-aminobenzenesulfonamido) -5-methylisoxazole (sulfamethoxazole) and 2,4-diamino-5- (3 ', 4', 5'-trimethoxybenzyl) ) -pyrimidine (trimethoprim) for the manufacture of an injectable veterinary medicinal product by adding water, ethanol, polyethylene glycol, organic acid, polyvinylpyrrolidone and additive (s) to the active compounds. The composition can be used in the veterinary treatment of various bacterial infections.

The synergism between trimethoprim and sulfonamides has long been known. Hungarian Patent Specification]. As sulfonamides, sulfamethoxazole is very commonly used and there is a wide variety of oral formulations containing the above components.

In veterinary medicine, especially for the treatment of large animals such as cattle, pigs, sheep, the use of injectable solutions is required. In contrast, it is essential that they be free of both local and general side effects, i.e., that they do not cause irreversible tissue changes at or near the injection site.

A major concern when preparing stable solutions containing the active ingredient trimethoprim and sulfamethoxazole is the need to combine a weak acid (sulfamethoxazole) with a weak base (trimethoprim), usually in a ratio other than stoichiometry. No. 156,391. According to the Hungarian patent, the problem is solved by combining an aqueous solution of the water-soluble salt of sulfamethoxazole with a solution of trimethoprim in an organic solvent such as ethanol, polyethylene glycol or dimethylacetamide. A solution of pH 8-11 is obtained which is detrimental to tissue.

Given that near neutral pH, insoluble sulfamethoxazole-trimethoprim complex may be precipitated from the solution, while sulfonamide is often oxidized upon heat sterilization of a basic sulfamethoxazole solution, the problem of preparing a stable injectable solution is described in U.S. Pat. According to the Hungarian patent, a solution of pH 4-6, preferably 4.5-5.5 is used. For this purpose, the active compounds are dissolved in a mixture of various organic solvents in the presence of an organic acid. This known formulation is also highly tissue damaging.

No. 37,501. According to the published European patent application, the water-soluble sulfamethoxazole salt and trimethoprim are dissolved in water together with an aldehyde such as formaldehyde. A complex compound is formed which is present in a solution having a pH of 8.69,6. This is also an excessively alkaline pH with respect to a physiological pH of about 7.4 and therefore exhibits tissue irritation when administered to the known formulation.

No. 2,538,678. According to the German patent application, lyophilized trimethoprim is dissolved in an organic solvent solution of sulfamethoxazole, which also contains polyvinylpyrrolidone, before use. Although a solution of pH 7.2 to 7.6 is obtained, it is only stable for a short time, so it is generally not possible to store the solution for more than 12 hours.

No. 180,740. According to the Hungarian patent, the active compounds are dissolved in Ν, Ν-dimethylacetamide and the solution is mixed with polyethylene glycol and ethyl oleate. Although the resulting injectable solution has a pH of 7.5 to 8 and provides a relatively sustained action on ethyl oleate, it is disadvantageous that a large amount of Ν, Ν-dimethylacetamide is highly tissue damaging and therefore has a haemorrhagic, inflammatory causes a focal point that usually dies or abscesses. The lesion causes severe pain, slows down the normal rate of development, and reduces weight gain. And in the case of slaughter animals, muscle changes have serious meat hygiene consequences.

No. 2,631,780. German Patent Publication No. 4,198,198 discloses an aqueous solution containing sulfonamide and trimethoprim in which the active ingredients are kept in solution in an extremely high amount, usually 20-80 g / 100 ml, by a special process polyvinylpyrrolidone. The examples show a maximum active ingredient content of only 12 g / 100 ml (which is the combined concentration of trimethoprim and sulfamoxol) at 50 g / 100 ml of polyvinylpyrrolidone for viscous ear drops. In a single example of an injectable solution, the combined concentration of sulfamoxol and trimethoprim is 4.8 g / 100 ml and a concentration of 30 g / 100 ml polyvinylpyrrolidone is required to maintain this small amount in the solution. Increasing the drug content requires a disproportionate amount of polyvinylpyrrolidone, which significantly increases the viscosity of the solution. The active ingredient content of about 20 g / 100 ml for the treatment of animals with a higher body weight is no longer available at the rate of 2,631,780. in the preparation known from German patent application.

In summary, known solutions containing sulfamethoxazole and trimethoprim as active ingredients have either very limited stability over time or are tissue damaging due to their pH and / or excipient content or too little active ingredient content.

It is an object of the present invention to provide an injectable veterinary composition containing sulfamethoxazole and trimethoprim as the active ingredient, having an active ingredient content of at least 20%, having the stability required by the injectable formulations and causing no local tissue damage upon injection.

It has now been found that 3.5-5 parts by weight of 2,4-diamino-5- (3 ', 4', 5'-trimethoxybenzyl) pyrimidine and 17.5-25 parts by weight of 3- (3-dimethylbenzyl) pyrimidine can be achieved. 4-aminobenzenesulfonamido) -5-methylisoxazole with 7-10 parts ethanol, 35-50 parts polyethylene glycol, 3-30 parts water, 3-10 parts polyvinylpyrrolidone, 0 7-1.2 parts by weight of hexamethylenetetramine, 3-10 parts by weight of urea, 0.2-4 parts by weight of additive (s), preferably an antioxidant, and mono-, di- or tricarboxylic acid substituted with C 3-6 hydroxy or amino; and converting the mixture into an injectable pharmaceutical preparation in a manner known per se.

It is surprising to those skilled in the art that the invention

The process according to EN 210 693 B provides a stable, non-tissue injectable solution containing from 21 to 30% by weight of active ingredient, since the composition of the known injectable formulations does not at all indicate that 3-10% by weight urea and 0.7-1.2% by weight in the presence of% hexamethylene tetramine, the active compounds form a stable solution free of toxic side effects in a mixture of 330% water, 7-10% ethanol, 35-50% polyethylene glycol and 3-10% polyvinylpyrrolidone .

In our experiments, an attempt was made to prepare a solution similar to that of the present invention without the use of hexamethylene tetramine, whereby the amount of polyethylene glycol was increased by the amount of abandoned hexamethylene tetramine, otherwise as in Example 2. It was found that the solution had become opaque by 1 hour after preparation and by the next day the active ingredients had partially precipitated. Our experiment is illustrated by a comparative example.

In the process of the invention, the additive is generally one or more substituted with one or more antioxidants, such as potassium pyrosulfite, reduced glutathione [gamma-L-glutamyl-L-cysteinylglycine], etc., and one or more C 3-6 hydroxy or amino groups. mono-, di- or tricarboxylic acids such as lactic acid, citric acid, glutamic acid, epsilonaminocaproic acid and the like.

According to the invention, it is preferable to dissolve hexamethylenetetramine and / or polyvinylpyrrolidone in water, and also the carboxylic acid, add ethanol and polyethylene glycol or the organic compounds listed therein. a portion of the solvents, dissolve the trimethoprim in the resulting mixture, and add to the solution one or more antioxidants, urea, sulfamethoxazole, and the remaining ingredients. After complete dissolution, the solution is filtered, filled into vials or ampoules and, after sealing, heat-sterilized.

The order of administration of the individual ingredients may vary, however, it is preferable to dissolve the trimethoprim first and add the sulfamethoxazole to an aqueous solution of the organic solvent which already contains it.

The resulting injectable solution has a pH of between 6.5 and 7. The tissue-damaging effect of the injectable solution of the present invention has been investigated and surprisingly has been found to be extremely low in contrast to known tissue-inducing effects.

Healthy white meat pigs weighing 24-34 kg were treated intramuscularly with the composition according to the invention according to Example 1 and 180,740 lbs. U.S. Patent No. 5,198, which is an injectable preparation of the same active ingredient which served as a comparator. Injections were given at a dose of 1 ml / 16 kg body weight in the long back muscle. The animals were observed for 14 days after treatment and then bleeded, the long back muscles of the animals were transversely sliced and histological examination was performed on the lesions.

At the site of injection of the injectable solution of the present invention, a very small area of about a lens area developed after 6 hours. The lesion did not increase in the next few days, became fully organic after 14 days and was replaced by a so-called. an apprentice inscription left.

At the site of administration of the solution prepared by the known method, approximately a bean area of necrosis occurred after 6 hours, which continued to increase on day 1. Within 14 days, myocardial infarction did not develop.

Thus, our study clearly confirms that the injectable solution of the present invention does not damage tissue at or near the site of injection.

The injectable solution of the present invention is characterized by relatively prolonged elimination, i.e., its therapeutic effect is sustained over time, while elimination from the body occurs within a short period of time. The studies were performed on suckling boars administered a dose of 1 ml / 10 kg body weight of the composition of Example 1, and at regular intervals the animals were sampled, their sulfamethoxazole and trimethoprim concentrations were on the 6th day after administration, the size of the residual. The results are shown in Table 1.

/. spreadsheet

Elimination half-life and residual suckling calves

agent Elimination half-life Reziduum 6 days after administration sulfamethoxazole 850 minutes 0.1 mg / kg trimethoprim 485 minutes 0.05 mg / kg

Table 1 shows that the intramuscular injection of the composition of the present invention provides a therapeutic effect for a relatively long time, since half of the administered amount is eliminated within 14 and 8 hours, however, after a therapeutic effect, clearance is rapid because the amount of residual fluid measured on the 6th day after administration is only about one-hundredth of the amount initially administered.

Thus, the injectable preparation of the present invention has no significant acute or permanent pathological side effects, nor does it delay the development or weight gain of the animals and does not have any adverse meat hygiene consequences. The preparation is easy to prepare and does not require the use of any special excipients.

The invention is illustrated in detail by the following examples.

/. Example 5 To 5 g of distilled water is added 5 g of polyvinylpyrrolidone, 1.4 g of lactic acid, 10 g of 96% ethanol and 4 g of trimethoprim are dissolved in the mixture. For the clear solution, 49.8 g of polyethylene glycol (degree of polymerization 300),

HU 210 693 B

Reduced glutathione (0.15 g), potassium pyrosulfite (0.05 g) and urea (3 g) were added followed by dissolution of sulfamethoxazole (20 g) and hexamethylenetetramine (0.75 g). The solution is filtered, filled into vials or ampoules, sealed and heat-sterilized at 120 ° C for 20 minutes.

The vials were stored for 2 years at room temperature. No opalescence, discoloration or color change was observed.

Example 2

A solution of the following composition was prepared as described in Example 1:

4.00 g trimethoprim

20.00 g of sulfamethoxazole

4.00 g lactic acid

5.00 g Polyvinylpyrrolidone

10.00 g ethanol (96%)

0.15 g reduced glutathione

37.00 g poly (ethylene glycol) (degree of polymerization: 300)

0.005 g of potassium pyrosulphate

6.00 g of urea

0.75 g of hexamethylenetetramine are added in 100 ml of water

The resulting solution is filtered, filled into ampoules, sealed and heat-sterilized at 120 ° C for 20 minutes.

The resulting injectable solution had a pH of 6.8 at the time of preparation. The solution samples were stored for 8 weeks at 40 ° C. The color of the solution did not change and the pH was 6.89. No opalescence or material precipitation was observed.

Comparative example

The procedure described in Example 2 was followed, except that 0.75 g of hexamethylene tetramine was replaced by the same amount of polyethylene glycol. Only a slight heating gave a clear solution which became opaque 1 hour after heat sterilization.

after an hour, a precipitate was observed.

Thus, it can be stated that the solution does not have sufficient stability.

Example 3 Dissolve 1.4 g of lactic acid in g of distilled water, add 4 g of polyvinylpyrrolidone, 55 g of polyethylene glycol (degree of polymerization 300), 10 g of 96% ethanol. and dissolving 5.3 g of trimethoprim in the solution. To the clear solution were added 0.05 g of potassium pyrosulfite, 6.5 g of urea, 0.25 g of reduced glutathione, 26.5 g of sulfamethoxazole and 1.1 g of hexamethylenetetramine. Hereinafter referred to as

The procedure of Example 1 is followed.

Example 4 To g of poly (ethylene glycol) (degree of polymerization 300) was added 1 g of epsilonaminocaproic acid, 6 ml of distilled water, 8 g of polyvinylpyrrolidone and 10 g of 96% ethanol. 4 g of trimethoprim are dissolved in the mixture and 0.1 g of reduced glutathione, 10 g of urea, 0.08 g of potassium pyrosulphite, 20 g of sulfamethoxazole and 0.9 g of hexamethylene tetramine are added. In the following, the procedure of Example 1 is followed.

Example 5 0.8 g of glutamic acid and 10 g of polyvinylpyrrolidone are dissolved in g of distilled water and 53.1 g of polyethylene glycol (degree of polymerization 200) and 10 g of 96% ethanol are added. , 4 g of trimethoprim are dissolved in the resulting solution, 0.08 g of potassium pyrosulfite, 0.15 g of reduced glutathione, 3 g of urea, 20 g of sulfamethoxazole and 1 g of hexamethylene tetramine are added. In the following, the procedure of Example 1 is followed.

Claims (1)

Patent Claim Point Injectable veterinary medicinal product containing no local tissue damaging agent containing 3- (4-aminobenzenesulfonamido) -5-methylisoxazole and 2,4-diamino-5- (3 ', 4', 5'-trimethoxybenzyl) pyrimidine as active ingredient by adding water, ethanol, polyethylene glycol, organic acid, polyvinylpyrrolidone and additive (s) to the active compounds, characterized in that 3.5-5 parts by weight of 2,4-diamino-5- ( 3 ', 4', 5'-trimethoxybenzyl) pyrimidine and 17.5-25 parts by weight of 3- (4-aminobenzenesulfonamido) -5-methylisoxazole with 7-10 parts by volume of ethanol, 35-50 parts by weight of poly (ethylene glycol), 3-30 parts water, 310 parts polyvinylpyrrolidone, 0.7-1.2 parts hexamethylenetetramine, 3-10 parts urea, 0.2-4 parts additive / substances, preferably an antioxidant and a mono-, di- or tricarboxylic acid substituted with C 3-6 hydroxy or amino, and the mixture is itself in injectable converted in a known manner.