IE60375B1 - A method for producing a veterinary curative and for processing it into a pharmaceutically acceptable form - Google Patents

Abstract

Compsns. for control of endo- and ectoparasites in livestock contain l-tetramisol (I) and N-(5-chloro- 4-(4-chloro-alpha-cyanobenzyl)- 2-methylphenyl)-2-hydroxy- 3,5-diiodobenzamide (II). (I) is l-2,3,5,6-tetrahydro -6-phenylimidazo (1,2-c) thiazol.HCl.

Description

Title:- A Method for producing a veterinary curative and for processing it into a pharmaceutically acceptable form Descri pti on The present invention relates to the preparation of a veterinary curative against parasites of cattle, and to its processing into a pharmaceutical form. With regard to the many different kinds of parasites of cattle there exists a need for a preventive and therapeutic preparation, which can be applied orally as well as parenterally to fight endo- and ectoparasites of oxen, sheep, goats and pigs.

Such a preparation, being stable, easy to apply and having a broad spectrum activity, was hitherto unknown.

Since infection with ectoparasites through the skin often causes the appearance of endoparasites, and since the point of time for necessary therapy is difficult to discern in many animals, a composition with such properties and possibilities of application will satisfy a need in veterinary practice. Blood-sucking roundworms (nematodes) are a severe threat to live-stock, but with the known remedies , against these the larvae of several arthropods which also appear could not be fought at the same time. - 2 In particular it was difficult to fight trematodes and larvae of arthropods side by side with nematodes, and difficult to provide a preventive treatment against several groups of said parasites. { The composition prepared according to the present invention meets the said requirements and it can be used for prophylaxis as well as for therapy of cows, sheep, goats and pigs, In infections by adult worm species and by larval stages of worm species and of arthropoda.

Many parasites have a growth cycle in several host animals, where their metabolic system demonstrates considerable adaptive power.

It is therefore an advancement that with the present composition Intestinal nematodes, lungworm species, liverworms, as well as the larvae of various dangerous and irritant arthropods could be fought with demonstrable success.

Not only the originator of Distomatosls (liverworm disease), which appears In the liverworm slug in the larval stage, encysts in the grass and is swallowed with the grass by cattle and sheep, where the sucking worm subsequently penetrates into the bile passages and causes Injuries to the liver, but also Toxacara vltulorum, Trichuris ovls, Trichostron25 gylides, Haemonchus, Nematodlrus and Strongyloides and the gadfly species Oestrus ovls, Hypoderma bovis and Hypoderma lincatum, Dermatobia hominis, Boophilus decoloratus, Chorioptes bovis and Psoroptes bovis in cattle, Cochllomya hominivorax in sheep and Metastrongylus elongatus, Ascaris and the larvae of these, Hyostrongylus rubidus, f Oesophagostomum dentatum and several others could , now be fought with success. * The veterinary medical preparation against parasites of cattle according to the invention, which is suitable for oral, subcutaneous and parenteral application both for therapy and for prophylaxis, consists of a stable mixture of the components z 2,3,5,6-Tetrahydro-6-phenyl-imidazo-2,l-thi azol e hydrochloride (Formula I) and N-[5-Chloro-4«chl orophenyl -ot-cyanomethy 1 -2-methyl phenyl ]-2hydroxy-3,5-diiodobenzamide (Formula II) with some solvent and stabilizing compounds, which are used for stabilizing the pH-value of the liquid suspension mixture.

The phenylimidazothiazole derivative is a pure 1-lsomer of Tetramisole as the hydrochloride, and it is prepared by the reaction of ortho-phenylene diamine with ortho-thiopropionic acid amide by heating under reflux-cooling, with ring closure.

The molecular formula is cnHi2N2S,HC1 ’ The molecular weight of the pure compound Is 240.8. The second component, the diiodobenzamlde derivative, is a salicyl-anil 1de.

It is prepared by reduction of 2-Nitro-4chlorotoluene with Chiorobenzyl-4-cyanide in alkaline medium, reduction of the reaction product to 4-Amino-2-chioro-ot-4-chl orophenyl -5methyIphenyl-acetonitrile, which is reacted with phosphorus trichloride to phosphate, which reacts with 3,5-D11odosalicyllc acid to N-[5-Chloro-4-cv chlorophenyl-ctcyanomethyl-2-methylphenyl]-2hydroxy-3,5-diIodobenzamide.

Formula: C22H14C12I2M2°2Molecular weight: 663.08.

The preparation of the composition according to the invention is carried out as follows: r Into a reactor of stainless steel with a stirrer and a volume of about 300 liters 100 kg of propylene glycol is poured, and, with continuous stirring, the following substances are subsequently added: 250 g Methyl-4-hydroxybenzoate, g Propyl-4-hydroxybenzoate, 12500 g Polyvinyl pyrrolidone, 25000 g 2,3,5,6-Tetrahydro-6-phenylimidazo-2,1-thiazole hydrochloride (1evo-tetrami sole), 100000 g water for injection, 2500 g citric acid, 250 g sodium bisulphite.

Then sodium citrate 1s added as a buffer substance, in an amount such that the pH of the solution is exactly 3.0.

The solution obtained is then sterilized and filtered through a membrane filter with pores of <0.22 pm.

With continuous stirring of the solution the following substances are then added: 12500 g N-[5-Chloro-4-(4-chlorophenyl)-cyanomethyl-2methylphenyl]-2-hydroxy-3,5-d1iodobenzamide. 1250 g colloidal silica gel.

The stirring is continued Intensively during 30 minutes, so that a homogeneous suspension 1s obtained. f ί The concentration of the preparation in liquid form is obtained by adding water for injection so that 1 liter of the liquid composition contains 100 g of 1-Tetramisole and 50 g of the diiodobenzamide derivative.

The liquid composition is subsequently filled into brown glass bottles, or into brown glass vials of 100 ml content.

It should be stored protected against light and is shelf-stable for several years.

It 1s suitable for oral and subcutaneous admi ni strati on.

The suspension can also be mixed, however, with an inert unguent-forming supporting substance, and then applied, 1n the form of a cream or ointment, to the exposed parts of the skin or hide.

A third presentation of the composition of the invention is as follows: The suspension is mixed with an inert solid pulverulent supporting material, ground down to a fine homogeneous mass of suitable concentration, and then compressed to pills, tablets, suppositories and boluses.

The composition of the suspension is analytically examined, and should preferably be as follows: One liter of the suspension contains: 100.0 g 1-Tetramisole, 50.0 g di 1odobenzamide derivative, 1.0 g methyl-4-hydroxybenzoate, 0.1 g propyl-4-hydroxybenzoate, 1.0 g sodium bisulphite, 50.0 g polyvinyl pyrrolidone, J 100.0 g citric acid (buffered with sodium citrate, so that the pH-value of the solution will be 3.0), 400.0 g propylene glycol, .0 g colloidal silica gel, made up to 1 liter with demineralized sterile water.

The composition is a white low-viscosity homogeneous aqueous suspension, with a specific gravity of 1.1.

The analytical determination of the two active components can be done by high-pressure liquid chromatography with a column packing of Nucleosil RP (particle size lOjim).

The detection of the 1-Tetramisol in methanolic solution appears in the ultraviolet spectrum at 225 nm.

The detection of the diiodobenzamide derivative, dissolved in acetonitrile, 1s done by fluorescence spectrometry, excitation at 336 nm and emission at 506 nm.

The keeping quality of the preparation and the stability of the concentrations of the active components have been experimentally demonstrated with a tolerance of -0.6 %.

The diiodobenzamide derivative can be analytically determined furthermore by a potentiometric titration in a non-aqueous bath, by dissolving 0.3 g of the composition in 60 ml of N,N-d1methylformamide and titration is carried out with 0.1 molar Tetrabuty1 ammonium hydroxide solution, analytical grade.

A consumption of 1 ml of 0.1 molar Tetrabutylammonium hydroxide corresponds to 0.06631 g of N-[5-Chloro-4-(4-chlorophenyl)- r cyanomethyl-2-methylphenyl]-2-hydroxy-3,5- , diiodobenzamide. t Acute, subacute and subchronic toxicity tests were carried out orally and subcutaneously on warmblooded animals, showing that the subcutaneous LDgQ-value was higher than 40 mg/kg body weight.

The combination of both active components according to the present invention against nematodes, trematodes and other parasitic worms and against larvae of arthropods showed a fast paralysing activity resulting from the blocking of adenosine triphosphate, whereby the metabolism of the parasite in question no longer functions and the parasite is killed and excreted.

Mammals do not meet with any harm whatsoever, because in their blood and digestive tract an inactive metabolite is formed.

The composition showed excellent activity also in tests against Haemonchus species, which had shown resistance against other benzimidazole preparations of known composition.

The formulae of the active compounds, as referred to on page 2, are as follows: H H-C-CN Formula II

Claims (8)

1. A method for the preparation of a veterinary remedy for the oral and parenteral therapeutic and preventive combatting of endo- and ecto05 parasites 1n cattle, sheep, goats and swine, characterized in that a suspension of pure

2. ,3,5,6-Tetrahydro-6-phenylimi dazo-2,l-th1azolehydrochloride (1-tetramlsol e) and of N-(5Chl oro-4-d-chlorophenyl -c^-cyanomethyl -210 methyl phenyl)-2-hydroxy-3,5-di1odobenzamide in a weight ratio of 2:1 1n propylene glycol is made with the addition of small amounts of methyl-4-hydroxybenzoate, propyl-4hydroxybenzoate, sodium disulphite, polyvinyl 15 pyrrolidone, citric acid buffered with sodium citrate, and colloidal silicic acid, and that this stable mixture 1s worked up Into an appropriate form for pharmaceutical admini stration. 20 2. A veterinary remedy made according to the method of claim 1, characterized in that as a liquid it comprises 10% wt/vol of pure 1-tetramisole and 5% wt/vol of N-(5-Chloro-4-al-chlorophenyld-cyanomethyl -2-methylphenyl )-2-hydroxy-3,525 dilodobenzamide with stabilizing additives in propylene glycol, and that it is worked up into a form suitable for administration. !

3. A veterinary remedy for combatting parasites upon and inside the bodies of cattle, characterized in that it comprises a composition of 1-2,3,5,6-Tetrahydro-6-phenylimidazo-2,105 thiazole hydrochloride and N-(5-Chloro-4-ochlorophenyl-o-cyanomethyl-2-methylphenyl )-2hydroxy-3,5-di1odobenzami de.

4. A bolus for the antiparasitic treatment of cattle, characterized in that said bolus 10 comprises a composition according to claim 3.

5. A liquid for Injection for the antiparasitic treatment of cattle, characterized in that said liquid comprises a composition according to claim 3. 15

6. Pharmaceutically applicable Items of the veterinary remedy according to claim 2, characterized in that they are bottled In small vials of brown glass.

7. A method for the preparation of a veterinary 20 remedy, substantially as herein described.

8. A veterinary remedy substantially as herein described, or when prepared by the method of claim 1.