AU666394B2 - A method for the preparation of a veterinary remedy and processing of same - Google Patents

Description

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Us &1( 1 1 A Method for the Preparation of a Veterinary Medicament and Processing of Same Description The present invention relates to the preparation of a veterinary medicament 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 medicament, which can be applied orally as well as parenterally to fight endoand ecto-parasites of oxen, sheep, goats and pigs. Such a medicament, 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 medicament with such properties and possibilities of application will satisfy a need in veterinary practice. Blood-sucking roundworms (nematodes) are a severe threat to livestock, but with the known remedies against these the larvae of several 15 arthropods which also appear could not be fought at the same time.

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 medicament 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 Distomatosis (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 30 and causes injuries to the liver, but also Toxacara vitulorum, Trichuris ovis, Trichostrongylides, Haemonchus, Nematodirus and Strongyloides and the gadfly species Oestrus ovis, Hypoderma bovis and Hypoderma lincatum, Dermatobia hominis, Boophilus decoloratus, Chorioptes bovis and Psoroptes bovis in cattle, Cochliomya hominivorax in sheep and Metastrongylus elongatus, Ascaris and the larvae of these, Hyostrongylus rubidus, Oesophagostomum dentatum and several others could now be fought with success.

According to a first embodiment of this invention, there is provided a method for the preparation of a veterinary medicament for the oral and parenteral therapeutic and Spreventive fight against endo- and ectoparasites with cattle, sheep, goats and swine, [N:\LIBC100147:TCW P I-, 1A characterised in that a suspension of pure 2,3,5,6-tetrahydro-6-phenyl-imidazo-2,1thiazole-hydrochloride and of N- [5-chloro-4a-chlorophenyl-a-cyanomethyl-2methylphenyl]-2-hydroxy-3,5-diiodobenzamide in a weight ratio of 2:1 in propylene-glycol is made with addition of minor-amounts of methyl-4-hydroxybenzoate, propyl-4hydroxybenzoate, sodium disulfite, polyvinylpyrrolidone, citric acid with buffer of sodium citrate, and colloidal silicic acid, and that this stable mixture is worked up into an appropriate form for pharmaceutical administration.

According to a second embodiment of this invention, there is provided a veterinary medicament for fight against parasites upon and inside the bodies of cattle, characterised in that it comprises a composition of L-2,3,5,6-tetrahydro-6-phenyl-imidazo-2,1-thiazolehydrochloride and N- [5-chloro-4a-chlorophenyl-a-cyanomethyl-2-methylphenyl]-2hydroxy-3,5-diiod6benzamide.

According to a third embodiment of this invention, there is provided a bolus for antiparasitical treatment of cattle, characterised in that said bolus comprises a medicament according to the second embodiment.

According to a fourth embodiment of this invention, there is provided a capsule for :antiparasitical treatment of cattle, characterised in that said capsule comprises a medicament according to the second embodiment.

According to a fifth embodiment of this invention, there is provided a liquid for injection for antiparasitic treatment of cattle, characterised in that said liquid comprises a medicament according to the second embodiment.

S A According to a sixth embodiment of this invention, there is provided a method for the treatment of parasitic infections in a mammal requiring said treatment or prophylaxis, which method comprises administering to said mammal an effective amount of a 25 medicament according to the second embodiment.

S C The veterinary medicament against parasites of cattle according to the invention, S ,which is suitable for oral, subcutaneous and parenteral application both for therapy and for i prophylaxis, consists of a stable mixture of the components 2,3,5,6- N:\LIBC00147:TCW [N:\LIBC]00147:TCW

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2 tetrahydro-6-phenyl-imidazo-2, 1 -thiazole hydrochloride of the formula: N iS 4t Ct l and N-[5-chloro-4-chlorophenyl-a-cyanomethyl-2-methylphenyl]-2-hydroxy-3,5diiodobenzamide of the formula: O H CN

H

1 OH CH 3 with some solvent and stabilising compounds, which are used for stabilising the pH of the liquid suspension mixture.

The phenylimidazothiazole derivative is a pure 1-isomner of tetramisole as the hydrochloride, and it is prepared by the reaction of o-phenylenediamine with o-thiopropionic acid amide by heating under reflux-cooling, with ring closure.

The molecular formula is C 11

H

1 2N 2 S.HC1.

The molecular weight of the pure compound is 240.8.

The second component, the diiodobenzamide derivative, is a salicylanilide.

It is prepared by reduction of 2-nitro-4-chlorotoluene with chlorobenzyl-4-cyanide in 15 alkaline medium, reduction of the reaction product to 4-amino-2-chloro-a-4-chloropheny1which is reacted with phosphorus trichloride to phosphate, which reacts with 3,5-diiodosalicylic acid to N-[5-chloro-4-a-chlorophenyl-c-cyanomethyl- 2-methylphtnyl]-2-hydroxy-3,5-diiodobenzamide.

Formula: C2 2

H

14 C1 2 1 2

N

2 0 2 hiolecular weight: 663.08.

The p:2paration of the .#p4 ii according to the invention is carried out as follows:

V

Example 1 Into a reactor of stainless steel with a stirrer and a volume of about 300L 100kg of propylene glycol is poured, and, with continuous stirring, the following substances are subsequently added: 250g methyl-4-hydroxybenzoate, propyl-4-hydroxybenzoate, 12500g polyvinyl pyrrolidone, e' 3o 25000g 2,3,5,6-tetrahydro-6-phenyl-imidazo-2, 1-thiazole hydrochloride, 2 IN:\1ibCi00147:JOC2 of 6 I 3 100000g water for injection, 2500g citric acid, 250g sodium bisulfite.

Then sodium citrate is added as a buffer substance, in an amount such that the pH of the solution is exactly The solution obtained is then sterilised and filtered through a membrane filter with pores of <0.22[pm.

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

The stirring is continued intensively during 30 minutes, so that a homogeneous suspension is obtained.

The concentration of the preparation in liquid form is obtained by adding water for injection so that 1 litre of the liquid composition contains 100g of 1-tetramisole and 50g of the diiodobenzamide derivative.

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

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

It is suitable for oral and subcutaneous administration.

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

A third presentation of thecofpositia 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 litre of the suspension contains: 100.0g 1-tetramisole, diiodobenzamide derivative, methyl-4-hydroxybenzoate, 0.lg propyl-4-hydroxybenzoate, 1.0g sodium bisulfite, 50.0g polyvinyl pyrrolidone, 100.Og citric acid (buffered with sodium citrate, so that the pH of the solution will be S400.0g propylene glycol, ii t Itr 1 i~ 1

P-'

1 .4 41 IN:\libC100147:JOC 3 of 6 S4 colloidal silica gel, made up to 1 litre with demineralised sterile water.

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

s The analytical determination of the two active components can be done by highpressure liquid chromatography with a column packing of Nucleosil RP 18 (particle size Jtm).

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=r I The detection of the 1-tetramisole in methanolic solution appears in the ultraviolet spectrum at 225nm.

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

The keeping quality of thep#epaeati@ and the stability of the concentrations of the active components have been experimentally demonstrated with a tolerance of The diiodobenzamide derivative can be analytically determined furthermore by a potentiometric titration in a non-aqueous bath, by dissolving 0.3g of the composition in 60mL of N,N-dimethylformamide and titration is carried out with 0.1molar tetrabutylammonium hydroxide solution, analytical grade. A consumption of lmL of 0.1molar tetrabutylammonium hydroxide corresponds to 0.06631g of N-[5-chloro-4-(4chlorophenyl)-cyanomethyl-2-methylphenyl]-2-hydroxy-3,5-diiodobenzamide.

Acute, subacute and subchronic toxicity tests were carried out orally and subcutaneously on warm-blooded animals, showing that the subcutaneous LD 5 o-value was higher than 40mg/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 ee ipositio showed excellent activity also in tests against Haemonchus species, which had shown resistance against other benzimidazole preparations of known composition.

-/01 IN:\libCl00147:JOC 4 o7 6

Claims (9)

1. A method for the preparation of a veterinary medicament for the oral and parenteral therapeutic and preventive fight against endo- and ectoparasites with cattle, sheep, goats and swine, characterised in that a suspension of pure 2,3,5,6-tetrahydro-6- phenyl-imidazo-2,1-thiazole-hydrochloride and of N- [5-chloro-4a-chlorophenyl-a- cyanomethyl-2-methylphenyl]-2-hydroxy-3,5-diiodobenzamide in a weight ratio of 2:1 in propylene-glycol is made with addition of minor-amounts of methyl-4-hydroxybeinzoate, propyl-4-hydroxybenzoate, sodium disulfite, polyvinylpyrrolidone, citric acid with buffer of sodium citrate, and colloidal silicic acid, and that this stable mixture is worked up into an appropriate form for pharmaceutical administration.

2. A veterinary medicament made according to claim 1, characterised in that as a liquid it comprises 10% wt/vol of pure 2,3,5,6-tetrahydro-6-phenyl-imidazo-2,1-thiazole- hydrochloride and 5% wt/vol of N- [5-chloro-4a-chlorophenyl-a-cyanomethyl-2- methylphenyl]-2-hydroxy-3,5-diiodobenzamide with stabilising additives in propylene- 15 glycol and that it is worked up in a form suitable for administration.

3. A veterinary medicament for fight against parasites upon and inside the bodies of cattle, characterised in that it comprises a composition of L-2,3,5,6-tetrahydro-6-phenyl- imidazo-2,1-thiazole-hydrochloride and N- [5-chloro-4a-chlorophenyl-a-cyanomethyl-2- methylphenyl]-2-hydroxy-3,5-diiodobenzamide. 20

4. A bolus for antiparasitical treatment of cattle, characterised in that said bolus comprises a medicament according to claim 3.

5. A capsule for antiparasitical treatment of cattle, characterised in that said capsule comprises a medicament according to claim 3.

6. A liquid for injection for antiparasitic treatment of cattle, characterised in that 25 said liquid comprises a medicament according to claim 3.

7. The veterinary medicament of claim 3, wherein said medicament is bottled in small vials of brown glass.

8. A veterinary medicament, substantially as hereinbefore described with reference to any one of the examples.

9. A method for the treatment of parasitic infections in a mammal requiring said treatment or prophylaxis, which method comprises administering to said mammal an effective amount of a medicament according to any one of claims 2 to 8. Dated 28 November, 1995 Barend Willem Hak Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON [N:\LIBC100147:TCW if ;.i -l~llll-rl--l;; I I A Method for the Preparation of a Veterinary Remedy and Processing of Same Abstract 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 2,3,5,6- tetrahydro-6-phenyl-imidazo-2,1-thiazole hydrochloride of the formula: and N-[5-chloro-4c-chlorophenyl-a-cyanomethyl-2-methylphenyl]-2-hydroxy-3,5- diiodobenzamide of the formula: I CI 0 H CN -C-NO C C H I OH CH 3 with some solvent and stabilising compounds, which are used for stabilising the pH of the liquid suspension mixture. I It IC ''AC a I 'CACAO II 4 t 0 i, ,o IN:\LIBC100147:JOC 0 of 6