LT3063B - Injectable veterinary composition free from side toxic effects and process for the preparation thereof - Google Patents

Abstract

An injectable veterinary composition that is free from toxic side effects contains 0.8 - 6 parts by weight of 2,4-diamino-- 5-[3',4',5'-trimethoxybenzyl]-pyrimidine 4 to 30 parts by weight of 3-[4-aminophenylsulfonamido]-5-methylisoxazole 25 to 65 parts by weight of one or more organic solvent(s) being miscible with water, 1 to 40 parts by weight of water, 3 to 12 parts by weight of one or more solubilising agent(s), 2 to 10 parts by weight of urea and 0.2 to 4 parts by weight of one or more additive(s).

Description

The present invention relates to an injectable veterinary composition which has no adverse toxic effects, wherein the active ingredient is 2,4-diamine-5-; [3 *, 4 ', 5'-trimethoxybenzyl] -pyrimidine and 3- / 4-amino-5-phenylsulfonamide / -5-methyl-oxazole, and a process for preparing this composition.

The injectable veterinary composition of the invention may be used in veterinary therapy

1Q for the treatment of infections of bacterial origin.

There is widespread knowledge that sulfonamide is known to enhance the action

2,3-DIAM-5- / 3 ', 4 ^1, 5 ¹ -trimetoksibenzil / -pyrimidine (trimethoprim)' (British Patent No. 117 6395).

One of the most commonly used sulfonamides is 3- / 4-aminophenylsulfonamide / -5-methylsulfoxazole '(sulfamethoxazole)' - and '' a fairly common oral pharmaceutical formulation containing trimethoprim and 'sulfamethoxazole.

In veterinary medicine, the treatment of 'particularly large body animals such as cattle, pigs and sheep requires injection' compositions. The basic requirement is that the injectable composition should have no undesirable toxic effects, i.e., that it does not cause irreversible changes at the injection site or its vicinity.

When preparing stable solutions containing trimethoprim and sulfamethoxazole, an active ingredient, it is important that the weak acid (i.e., sulfamethoxazole) is mixed with a weak alkali (i.e., trimethoprim) in a ratio generally different from that required by stoichiometry. Under · British Patent No. 1176395 ·; an attempt was made to solve this problem by adding an aqueous solution of the sulfamethoxazole salt to a solution of trimethoprim in an organic solvent such as ethyl alcohol, polyethylene glycol,. or dimethylcei amide. However, the resulting solution has a .pH y of 8 µg II. .In the way: · after use: this known injection solution contains: damaged tissue; '

If the pH of the solution is' adjusted to a lower value close to neutral, it is an insoluble complex consisting of sulfamethoxazole. and '' trimethoprim may be released from solution. On the other hand ^ by sterilizing the solution ,. - with a pH value of alkaline, -. sulronamide at high temperature * ..commonly oxidized. To avoid such drawbacks, according to • British Patent No. 1469521, a solution having a pH of from 4 to € and preferably pS from 4 to 10 was prepared

4.5 to 5.5. for this purpose the active substances are dissolved in a mixture of various organic solvents in the presence of - an organic acid. - But. veterinary injections thus obtained. composition. is also 'toxic to tissues.

According to EP .No. 37501, the water-soluble, s-ulfamethoxazole salt and triraethoprirase are dissolved in water together with an aldehyde such as formaldehyde. A complex is formed in a solution having a pff of 8.6 to 9.6. This pH is also too high, since the physiologically acceptable pH is about 7.4. Animal tissue is also irritated when using this solution for injection.

According to the 'German' patent no. 2538678, i'iophylized trimethoprim, before use, is dissolved in a solution of sulfamethoxazole-organic acid, which also contains. ' polyvinylpyrrolidone. The resulting solution is stable for only a short time. This solution should not be stored for more than 12 hours.

According to British patent no. 2066068, the active substances are dissolved in N, N-dimethylacetamides in the

polyethylene glycol and ethyl oleate are added to the solution. Although the pH of the resulting solution for injection ranges from 7.5 to 8 and quite. long lasting due to ethyl oleate · but N, N-dimethylacetamide present in solution is. toxic to tissues. This results in the formation of a bloody inflammatory foci at the site of injection, with tissue necrosis or abscess. The lesion is accompanied by fiber pain, reduced animal growth and weight gain. In addition, muscle damage has serious hygiene implications for meat. -.

It is an object of the present invention to provide and prepare a non-toxic, injectable veterinary composition comprising sulfamethoxazole and trimethoprim.

The object was achieved by creating a composition in which the ratio of components, by weight, is as follows: Y _; //// '^; 7 / <W _; .

2,4-Diamine-5- / 3 *, 4 ', 51-trimethoxybenzyl / pyrimidine 3- / 4-aminophenylsulfonamide / -5-methylisoxazole one' 'or more organic solvents miscible

Ytsai / yafideniu Y ·. / j · '/// Y' /.: .-- /// Y /: / water one or more solubilizing agents' /////kazb^idas''/;///..,/'/ // - / '\ /, /// ..//-- - /.v/Y/one or more attachments

Ethyl alcohol and / or polyethylene glycol is provided in the composition of the invention in an organic solvent miscible with water. Polyvinylpyrrolidone and / or hexamethylene, tetramine used as the solubilizing agent // In general, the additive contains any atoxidant such as potassium redsulfite, · .glutathion · · (gamma-L-glutamyl-L-cysteinyl-glycine) and so on. and / or any mono, di- or tricarboxylic acid containing

0.8-6

4-30

25-65

1-40 3-12

2 10 0.2 Y / /.kuris from 3 to 6 carbon atoms with -hydroxyl or amino group, such as., Pien®, acid _r citric acid, glutamic acid, s-aminocaproic acid and '1.1. The invention-composition may also have more than

5- '. one antioxidant and more than one of the above-mentioned organic acids of this type.

Then, in the composition of the invention, the ratio by weight of the components is as follows:

1 °

2,4-Diamine-5- / 3 ', 475 * -trimethoxybenzyl / pyrimidine 1,5-5,5

3- / 4-aminophenylsulfonamide / -5-methylisoxazole 8-27 'ethyl alcohol y 8-10 polyethylene glycol 48-55 water 1-40 polyvinylpyrrolidone 4-10 hexamethylene tetramine - 0.7-1.1 urea 3-1D antioxidant G, 08-0.3 Mono, di- or tricarboxylic acid with 3-6 carbon atoms, hydroxy or amino 0.4-1.5

The composition of the present invention is prepared by mixing the components as follows; 0.8-6 parts by weight of 2,4-diamino5- / 3/4/5 * -trimethoxybenzylZ-pyrimidine, 4-30 parts by weight

15 'parts of 3- / 4-aminophenylsulfonamide / -5-methylisoxazole, 2565 parts by weight of one or more organic solvents mixed with water, 1 to 4 parts by weight of water, 3 to 12 parts by weight of one or more stabilizing agents, from 2 up to 10 parts by weight of urea and from 0.2 to 4 parts by weight of one or more additives.

- A solubilizing agent is proposed, e.g. _r palivinylpyrrolidone or part thereof, the more organic acid, dissolved in water.

·

A.,, A, S-A

Then, to the resulting solution is added an organic 'solvent ©,: or a portion thereof, miscible with water.-' / Trimethoprim is dissolved in the resulting mixture, then added to the resulting solution ''; '·'. '? ', - / - .. ·' ·. *. · '·. ·' 'A A A A A,; -. / · .- -. ·. / · '·' A '' '/,,' -'A · ·· ...-. A.

compound .athoxidant, urea, sulfamethoxazole. 5 and the remainder of the dissolving agent. When the materials are completely dissolved, the solution is filtered and the clear filtrate is dispensed into bottles which are sealed and sterilized at high temperature.

The order of adding some -'components may be changed, but - it is suggested - · first to be solved: yAA ^? / A // i ^ r: lHiėtp ^ rdma / Aš'd /// withFamambkspzbf; A _; salty water // joey / \ aqueous / - ///: / ^; : ////: bi: a / paią / ASAScreatingY.r-is / ;;: /: © rgahiriis ^; / - / '/ t'irpikIis, ^(ICCE;;; Air:

t rime t op r imam. '

.... '·' ·· '· · -' ···· •• ^! «- ^{<Then -} ''^'S'iūlOma''-išradimo' kompozicija- ^one prepared by mixing from 1.5 to 5.5 parts by weight of 2,4-DIAM ~ 5- / 3 ', 4', 5 ' - frimethoxybenzyl / pyrimidine, from '8 to 27 parts by weight • 3- / 4-aminophenylsulfonamide / -5-methylisoxazole, from 8 to '10 parts by weight of ethyl alcohol, from 48 to 55 parts by weight of polyethylene glycol, from 1 to 40 parts by weight water, 4 to 10 parts by weight polyvinylpyrrolidone, -0.7 to 1.1 parts by weight h'examethylenootetramine, 3 to 10 parts by weight urea, 0.08 to. 0.3 parts by weight of an antioxidant and 0.4 to '1.5 parts by weight of any mono-, di- or tricarboxylic acid with' 3-6 carbon atoms having a hydroxyl or amino group, and the resulting 'injectable veterinary composition is filtered, bottled bottles or ampoules that are sealed and sterilized at high temperature.

The composition of the invention has a pH value of 6 to 7. The injectable veterinary composition of the invention has been tested for tissue damage and has been found to have very minor tissue lesions, unlike other known injectable veterinary compositions which even cause tissue necrosis.

In this way, healthy, white-eyed gilts of 27> -36r kg body weight were treated by intramuscular administration of the composition of Example I of the invention. The control material was British patent no. 2066-068 A composition of Example I which was identical. quantities of active ingredients. Doses; 1 ml per 16 kg body weight was

7./.'/./,-'7/. '''i ·· /; ·' ·. -'I-- '..' y ·: - / -Į '.- //'. // - // / - (-././-7.-/ ^.: · :: // 5 '/ 55i -.... 7 /// 7 /: /: //,.> - / l-.v -' / y- / · '/ //' 5 /-/./- // : / '- /: -' / '/.Injected into the thoracic longissimus muscle-sv The animals were observed for 14 days after treatment and then sacrificed., -Blooding .. Longitudinal thoracic (longitudinal) ) the muscles were transversely cut, - o - areas with lesions - histologically examined.

After administration of the composition of the invention, a small change of approximately the size of the lens was observed after 6 hours. Change - did not increase too. the following 'days. After 14 days, the lesions' completely healed. leaving muscle scar-tissue '..-

After administration of a known control composition, after '6 hours. a bean-size necrotized area was observed.- On the first day the necrotized area increased. Muscle necrosis developed within 14 days did not heal.

Thus, the above tests clearly demonstrate that the injectable veterinary composition of the invention is practically unaffected, at the site of tissue injection and in its vicinity.

Injectable veterinary composition of the invention. characterized by · relatively prolonged elimination, i.e..

735 therapeutical activity lasts for the long time, but the elimination of IS7; _ ^ organism (one / ⁷ -within a short time. The characteristics of compositions of the invention 7 .buvo? 77..y / Z? //'.,/ '/ Tested with suckling calves. 71 example Compositions. was injected calves intramuscularly with 1 ml per 10 kg bodyweight. Blood samples were _t taken · the animal at appropriate times' were determined sulfamethoxazole trimethoprim quantities then calculated active ingredients elimination half-life and amount of residues at day 6; ρ © injected.

'Residues of active ingredients and elimination half-life in suckling calves.

 Active ingredient- enth Elimination half-life, min. Residues 6 mg / kg after injection Sulfamethylxazole 7; / 77 // 77 //// τ5Ο, '? 7/71 /:? 7? / Ϊ́ 0.1 Trimethoprim y? <7: yy / 7: / 7? 4 ₈ 5 - //: z7: /, j /? / f | - 0.05

Table 1 shows that the intramuscular injections of the veterinary composition of the invention have a therapeutic effect

C. relatively long, since 'half of the injected active ingredients are eliminated from the body in 14 and 8 hours, respectively. At the same time, the active ingredients are rapidly removed after therapeutic action. This is evident from the amount of residues on Day 6, which represents only about one-hundredth of the injected volume.

Thus, the injectable veterinary composition of the invention has no significant acute or chronic side effects, does not reduce the growth and weight gain of the animals, and the meat has no adverse hygienic consequences after the slaughter of the treated raccoon. Compound '7 of the invention can be prepared without the use of special carriers.

8th

To 20 g of distilled water are added 5 g of polyvinylpyrrolidone, 1.4 'g of lactic acid and 10 g of 96% ethyl alcohol, and 4 g of trimethoprim are dissolved in the resulting mixture. 49.8 g of polyethylene glycol are added to the clear solution. with a degree of polymerization of 300, 0.15 g of reduced glutathione, 0.05 g of potassium pyrosulphite and 3 g of urea, and the resulting mixture is dissolved in 20 g of sulfamethoxazole and 0.75 g of hexamethylene tetramine. The resulting solution is filtered and bottled. in bottles or ampoules / which are sealed and sterilized for 20 minutes at 120 ° C. ,

The ampoules thus prepared were stored at room temperature for two years. No opalescence, fading or deposition of substances was observed.

example.

Dissolve 1 g of polyvinylpyrrolidone and 0,42 g of citric acid in 30 g of distilled water. 8 g of 96% ethyl alcohol and 55 g of polyethylene glycol are added with a degree of polymerization. 200 and 1.6 g 'of trimethoprim is dissolved in the resulting mixture. The resulting clear solution is dissolved in 4 g of urea, 0.08 g of reduced glutathione, 0.1 g of potassium red sulfite, '8 g of sulfamethoxazole and 0.9 g of hexamethylene tetramine.

Following is the procedure described in Example 1.

example

1, 4 g 'of milk: .. ···. Acid is dissolved in 4 g of distilled water, 4 g of polyvinylpyrrolidone, 5.5 g of polyethylene glycol having a degree of polymerization of -300 and -10 g of 96% ethyl alcohol are added and the resulting solution

0.25 g of reduced glutathione, 26.5 g of sulfamethoxazole and 1-, 1-g hexamethylene tetramine. The following follows

5 · 'The procedure described in Example 1.

example.

grade 300, add »ε-aminocaproic acid, 6 ml distilled water, 8 g polyvinylpyrrolidone and 10 g

96% ethanol. Dissolve 4 'g of trimethoprim in the resulting mixture and add 0.1 g of reduced glutathione, 10 g of urea, 0.08 g of potassium pyrosulphite to the resulting solution. 20th g. sulfamethoxazole and 0.9 g of hexamethylene tetramine. The procedure described in Example Ί follows.

example.

'G, 8 g of glutamic acid and 10 g of polyvinylpyrrolidone are dissolved in 12 g of distilled water and 53.1 g of polyethylene glycol with degree of polymerization are added. 200, and '10 g of 96% ethyl alcohol.' To the resulting solution was dissolved 4 g of trimethoprim 25 ', followed by the addition of 0.08 g' of potassium pyrosulphite, 0.15 g of reduced glutathione, 3 g of urea, 20 g of sulfamethoxazole and 1 g of hexamethylene tetramine. Next. is followed by the procedure described in Example 1.

Claims (11)

1. An injectable veterinary composition which is free of side effects and contains active ingredients Materials 5 2,4-DIAM-5- / 3 ^r 475 * -trimetoksibenzil / pyrimidine. and 3- / 4-aminophenylsulfonamide / -5-methylisoxazole, b .e -sis k. additionally containing one or more organic solvents miscible with water, 10 water, one or more solubilizing agents, urea and one or more additives in such proportion by weight; 2,4-Diamine-5- / 3 ^T , 4 *, 5 * -trimethoxybeftzyl / pyrimidine 0.8-6 3- / 4-aminophenylsulfonamide / -5-methylisoxazole 4-30 one or more organic solvents miscible with water 25-65 water '. 1-40 one or more dissolving agents 3-12 urea 2-10 one or more additives 0.2-4 15 '2. The injectable veterinary composition according to claim 1, wherein the one or more organic solvents are ethyl alcohol and / or polyethylene glycol. 3. An injectable veterinary composition according to claims 1 and 2 wherein one or more solubilizing agents is / polyvinylpyrrolidone and / or hexamethylene tetramine. ~ ₅ A ^; l7x ^^^^ a'- ' ^: v ^ err0ąri ^ yykompozlgia according to claims 1-3 ··'. ·>', Characterized in that the additive is an antioxidant and / or mono-, di- or tricarboxylic acid with 3-6 carbon atoms, with a hydroxyl or amino group. //, 7/11 5. An injectable veterinary composition according to claims 1-4, wherein the component ratio is by weight; - 2,4-DIAM-5- / ¹ 3, 4 ', 5' -trimetoksibenzil / pyrimidine 3- / 4-Aminophenylsulfonamide-5-methylisoxazole. Ethyl alcohol Poly / ethylene glycol. - water j '.poli / vinylpyrrolidone ¹ hexamethylene t-etramine - urea • antioxidant mono-, di- or. tricarboxylic acid with 3-6 7 carbon atoms with hydroxyl-o - or ¹ amino group 8-27 8-10 48-55 1-40 4-10 0.7-1.1 3-10 · 0.08-0.3 0.4-1.5 '10 6- Injectable veterinary compositions having no adverse 'toxin effect; preparation - a method involving - active substances in admixture, bes i's Kir it on is / are mixed in the ,, 0.8 to 6 weight- parts of 2,4-DIAM-5 ~ / 3 '/ d 4 ^T 5'-trimethoxybenzyl / -pyrimidine, 4- 30 weight ⁴ , -parts ^; 3 * / 4-aminophenylsulfonamide / -5-ethylisoxazole _J , 2565 parts by weight of one or more organic solvents mixed with water, -1 to 40 parts by weight of water, 7 // 7 \ // 7 / 7-: 7-7777 / 7- · 7/7 / 7ΐν: / '. 7/7 /// ^{; '7/7/77/7} // 77 / 7-7 / 1/7 · / 7 ·?: ·· ^{/:,: J} - / /// · - ·' /// - // 7 ' 77 // /·../ i / b, · ///. · /;-.--/:- 7/7 /.- 77- · ^,; - 3-12 parts by weight of one or more dissolving agents, 2'10 parts by weight, parts by weight of urea and 0.2-4 parts by weight by one or more additives, and the resulting compositions are filtered and filtered. The process according to claim 6, wherein the organic solvent is ethyl alcohol and / or polyethylene glycol. The preparation method according to claims 6 and 7, characterized in that the 'dissolving agents are 25 poly / vinylpyrrolidone and / or hexamethylene tetraminase. Method of preparation according to claims 6-8, b. It is claimed that the additive contains an antioxidant and / or mono-, di- or tricarboxylic acid with 3-6 carbon atoms with hydroxyl or amino. 5 gsupev A process according to claims 6 to 9, characterized in that the following components are mixed with 1.55.5 parts by weight of 2,4-diamin-5- / 3 *, 4 *, 5'-trimethoxy10 benzyl / pyrimidine ^ 8-; 27 parts by weight of 3- / 4-aminophenylsulphonamide / -5-methylisoxazole / 8-1 δ parts by weight of ethyl alcohol, 48-55 parts by weight of polyethylene glycol, 1-40 parts by weight of water, 4-10% by weight parts by weight of polyvinylpyrrolidone, 0.7-1.1 parts by weight of bexamethylene 15 parts by weight of tetramine, 3 parts by weight of urea, -0.08 to 0.3 'parts by weight of any oxidant and 0.4 to 1.5 parts by weight of mono-, di- or tricarboxylic acid with 3-6 carbon atoms hydroxyl or amino group, and the resulting composition is filtered and sterilized.