HU217086B - Veterinary composition containing microelements and anthelmintic benzimidazole derivative and process for producing the same - Google Patents

Abstract

Micro-enriched, worm-borne, compressed, sodium-chloride-based lozenges, each containing 1 to 100 gbenzimidazole active ingredients, 1 to 100 mg of molybdenum and 1 to 100 mg of balm in physically primed inorganic salt flesh. In accordance with the present invention, the sodium-chlorite-crushed limestone-chelate is each firing gaseous 1 to 100 gbenzimidazole derivative, 2 to 200 mg of ammonium heptamate feed per dose of 4 to 600 mg of stone (II) gluten, mixed with 5 to 35 ml of water. Finally, the mixture is converted into a press die in a known manner. ŕ

Description

FIELD OF THE INVENTION The present invention relates to a wormicidal lichen enriched with trace elements and to a process for its preparation.

The micronutrient-enriched licking salt has an enhanced anthelmintic effect, a weight-increasing property, and positively influences the quality of the animal's fur and wool.

It is well known to those skilled in the art that the internal organs of animals are more or less infected with parasites. The infection is caused, among other things, by Cestodes (tapeworms), Fasciola (hepatitis), Ostertagia (gastrointestinal disease) and Dictyocalus viviparus (lungworm).

Because parasites also infect livestock, they cause severe indigestion and other lesions that can eventually lead to death and have a significant economic impact.

Many attempts have been made to control livestock infestation with parasites, but none of them have been satisfactorily successful.

This is primarily due to the fact that although the industry produces compounds of various structures with anthelmintic activity, their administration to animals is difficult or may not be solved and causes greater difficulty in grazing animals.

Requirements for the ideal anthelmintic are defined by MANGER and are as follows (Veterinary Applied Pharmacology and Therapeutics, Bailliere Tindall. London-Phyladelphia-Toronto-Sydney-Tokyo, 1991, 513-48).

- It should have a high therapeutic index, meaning that many times the effective amount of the parasite can only be toxic to the host.

- A broad spectrum of activity, preferably covering as many parasite species as possible, as well as eggs, larvae and adult forms.

- Short waiting time, especially for dairy and meat producing animals.

- Be free from any harmful effects on the user.

- Can be economically adjusted to production technologies (storage, sensitivity to light, humidity, temperature, etc.).

The above requirements are best met by anthelmintics of the benzimidazole and alkanesulfonic acid type when properly administered. When using benzimidazole and alkanesulfonic acid derivatives, the following characteristics must be taken into account:

- In ruminants and horses, they are more effective than other animal species due to slower passage.

Multiple bursts are more effective than a single major treatment because they require contact for a sufficient period of time to develop the antiparasitic effect.

- Slower metabolizing compounds are more effective.

- Low doses may also lead to the development of resistance.

Using the fact that the animals have a need for sodium chloride and, if possible, voluntarily satisfy that need, and taking into account the listed properties of the benzimidazole and benzenesulfonic acid derivatives, they have produced a licking salt mixed with benzimidazole or other anthelmintic drugs. (J. Kovács: Veterinary Pharmacy. Agricultural Publisher, Budapest, 1970, page 425). These licking salts are known preparations and are commercially available. Multiple dosing with this type of licking salt can be ensured, but in our experience it is not possible to obtain an effective amount of the parasite into the host so that only partial decontamination can be achieved which leads to the reproduction of the parasite in the animal. However, if the anthelminticum is administered in larger amounts effective to parasites, their larvae and their eggs, it may be harmful to the host.

It is an object of the present invention to provide a licking salt containing a benzimidazole derivative which is capable of allowing the host to utilize it without increasing the concentration of the anthelminticum, causing no damage to the animal and free of any deleterious effects on the human end of the food chain.

In our experiments, it has been found that when the benzimidazole-type anthelminticum is administered to infected host animals in combination with a physiologically acceptable salt of molybdenum and cobalt, the anthelmintic effect is greatly enhanced, synergistic effects are present, and other beneficial effects occur. the worm-blowing effect without any adverse side effects.

The micronutrient requirements of pasture-producing ruminants, in particular the effectiveness of rumen digestion, have been investigated by several researchers. Molybdenum is found in xanthine oxidase by DERENZO et al. (Arch. Biochem. Biophys. 953, 45, 236) and by RICHERT and WESTERFELD (J. Biol. Chem. 1953, 203, 915). The utilizable molybdenum content of feeds varies widely due to its multidirectional interaction. It is a "mobile" element and its concentration in the generative part of the plant may vary by several orders of magnitude depending on the fertilization and soil quality (KÁDÁR and BLEKE: Principles and methods of crop management, 1992 Research Institute of Soil and Agrochemistry, HAS). Molybdenum is part of several plant and animal enzymes (xanthine oxidase, aldehyde oxidase, sulfite oxidase) and its deficiency leads to serious disease (Trace elements in human and animal nutrition. Fifth ed. Academic Press. New York, London, Tokyo, 1986). , 439).

The cobalt requirement of ruminants is the same as that of rumen microorganisms. A portion of the added cobalt incorporated microorganisms -vitaminná B _12, so in the absence of acid (Primary supervening metabolic effect on vitamin B ₁₂ deficiency in the sheep., Nature, 1961, 190, 1085.) and homocysteine-methionine material marketed deteriorates (Folic acid metabolism in vitamin B ₁₂ deficient sheep. Biochem. J. 1974, 142, 119).

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There are reports in the literature that certain anthelmintics (oxfendazole, levamisol, oxaclozanid) have been used in combination with cobalt and selenium as trace elements, but these have not been administered in a practical formulation [Vet. Rec., 123 (9), 217-18 (1988). C. A. 109, 189171g].

It is clear from the above that animals are not only harmed by molybdenum and cobalt dosing, but that micronutrient administration of these elements is specifically required for their life processes.

However, it is not apparent from the known results, and it is not obvious to those skilled in the art, that the effect of molybdenum and cobalt on the anthelmintic activity of benzimidazole-type anthelmintics and the synergies we have experienced.

The present invention is based on the surprising discovery that when an anthelmintic benzimidazole derivative is co-administered with a physiologically acceptable inorganic molybdenum salt and a physiologically acceptable cobalt salt, the parasitic effect will be higher than if the individual compounds are administered separately. At the same time, there is a significant increase in weight gain and an improvement in the quality of the hair and wool, and we have been able to prove in vitro that the composition of the invention slows down the breakdown of protein in the rumen also develops.

For proper administration of the anthelminticum and trace elements, they are introduced into a sodium chloride-based licking salt to ensure that the parasite-infected animal will voluntarily and appropriately absorb the active ingredient and enhancer trace elements.

An anthelmintic can be a benzimidazole derivative. Such albendazole include oxfendazole, fenbendazole, fenbantel, netobimin, thiabendazole, trichlorobendazole. Particularly good results are obtained with albendazole, which is a methyl ester of [5- (propylthio) -1H-benzimidazol-2-yl] -carbamic acid.

Any physiologically acceptable inorganic molybdenum salt can be used as the molybdenum salt, especially ammonium heptamolybdate having the composition (NH ₄ ) ₆ MO ₇ O ₂₄ -4H ₂ O.

Kobaltsóként also any physiologically acceptable inorganic cobalt salt employed has been found particularly the COC1 ₂ -6 H ₂ O composition suitable cobalt (II) chloride.

All the ingredients of the composition of the invention are known and are commercially available.

According to the present invention, the natural, commercial sodium chloride is ground to a powder, homogenized with a powder of anthelmintic benzimidazole, molybdenum salt and cobalt salt in a few 100 kg portions. Water is added to the homogeneous mixture with constant stirring until it is just wet, and then weighed in portions of a few kilograms of the finished mixture to form a bulk.

The blocked licking salts are placed on pasture and barn. In both places the animals are happy to lick.

For the examination of the licking salt of the invention, comparative samples were prepared with the following ingredients:

- NaCI;

- sodium chloride, albendazole;

- sodium chloride, ammonium heptamolybdate, cobalt (II) chloride;

- sodium chloride, albendazole, ammonium heptamolybdate, cobalt (II) chloride.

The tests were performed on juvenile heifers and ewes with monthly measurements that included:

- weight measurement,

- faecal parasitological examination,

- examination of a sample of fur (wool).

The following methods were used for parasitological studies.

Detection and enumeration of hepatocellular carcinomas was performed by Benedek sedimentation using 10 g of faeces.

Detection and enumeration of gastrointestinal worms was performed by weighing 3 g of feces in a McMaster counting chamber.

Gastrointestinal worm and lungworm larvae were detected by larval isolation (glass method) using 10 g of faeces.

The cobalt and molybdenum content of the hair and wool samples were analyzed. To do this, the samples decontaminated with acetone, washed with sodium lauryl sulfate and hydrochloric acid, and then purified with hydroxyquinoline solution, were weighed in a porcelain crucible, moistened with 2 ml of 10% ammonium nitrate solution and ashed at 550 ° C. The ash was dissolved in 5 ml of a 1: 1 dilute solution of nitric acid and the solution was washed in a 25 ml volumetric flask and made up to the mark with water.

The molybdenum and cobalt concentrations of the resulting sample solutions were determined using a Perkin-Elmer 5000 atomic absorption spectrophotometer using a HGA-500 graphite furnace atomizer.

The statistical mean of the results of the comparative studies is summarized in the following tables.

In the first column of the tables, the study times were recorded over a six-month period.

Column 1 shows the leaching results from sodium chloride only, column 2 the leaching results from sodium chloride and albendazole, column 3 the leaching results from sodium chloride, ammonium heptamolybdate and cobalt (II) chloride, Column 4 contains the results of the leaching salt of the present invention consisting of sodium chloride, albendazole, ammonium heptamolybdate and cobalt (II) chloride.

Groups of 80-80 juvenile heifers and 130130 ewes were used for the studies.

The statistical mean of the tests is shown in Figures 1-8. are summarized in Table.

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Table 1

Test result for nematodes in juvenile heifer groups

examination see time- of First Second Third 4th group* +,% OPL P + L +% OPL P + L +,% OPL P + L +% OPL P + L 04/18/18 30 14 0.11 30 15 0.12 25 14 0.11 30 14 0.11 5/16/16 30 34 0.26 25 12 0.09 25 14 0.11 15 6 0.05 6/15/15 30 94 0.72 15 7 0.05 25 10 0.08 0 - - 07/18/18 25 86 0.66 10 3 0.02 20 9 0.07 0 - - 08/17 30 94 0.72 10 4 0.03 20 9 0.07 0 - - 9/16/16 30 95 0.73 5 2 0.02 20 8 0.06 0 - - 10/14 30 98 0.75 5 2 0.02 15 6 0.05 0 - -

* = Group 1: NaCl

Group 2: NaCl + Albcdazole

Group 3: NaCl + Co + Mo

Group 4: NaCl + Albcdazole + Co + Mo +,% = Positive of all Bcls tested,%

ÖPL = total number of eggs and larvae found in all (130 g) faeces P + L = average number of eggs and larvae per 1 g of faeces

Table 2

Test result for nematodes in ewes

INSPECTION gation time- of First Second Third 4th group* +,% OPL P + L +% OPL P + L +% OPL P + L +,% OPL P + L 04/18/18 25 19 0.15 30 18 0.14 30 20 0.15 30 20 0.15 5/16/16 30 52 0.40 25 16 0.12 30 21 0.16 15 9 0.07 6/15/15 30 174 1.34 20 9 0.07 25 17 0.13 5 1 0.01 07/18/18 35 432 3.32 10 5 0.04 25 12 0.09 5 1 0.01 08/17 35 487 3.75 10 5 0.04 20 10 0.08 5 1 0.01 9/16/16 45 889 6.84 5 4 0.03 20 11 0.08 5 2 0.02 10/14 50 1001 7.70 5 4 0.03 15 11 0.08 5 1 0.01

* = Group 1: NaCl

Group 2: NaCl + albendazole

Group 3: NaCl + Co + Mo

Group 4: NaCl + albendazole + Co + Mo +,% = positive of all faecal samples tested,%

ÖPL = total number of eggs and larvae found in all (130 g) faeces P + L = average number of eggs and larvae per 1 g of faeces

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Table 3

Lungworm test results in juvenile follicular groups

INSPECTION gala time- of First Second Third 4th group* +% EF L +% EF L +% EF L +% EF L 04/18/18 0 0 - 0 0 - 0 0 - 0 0 - 5/16/16 0 0 - 0 0 - 0 0 - 0 0 - 6/15/15 0 0 - 0 0 - 0 0 - 0 0 - 07/18/18 0 0 - 0 0 - 0 0 - 0 0 - 08/17 0 0 - 0 0 - 0 0 - 0 0 - 9/16/16 10 1 0.01 0 0 - 0 0 - 0 0 - 10/14 20 12 0.12 10 1 0.01 10 2 0.02 0 0 -

* = Group 1: NaCl

Group 2: NaCl + albendazole

Group 3: NaCl + Co + Mo

Group 4: NaCl + Albendazole + Co + Mo +,% = Positive of all bcls tested,%

LU - total number of larvae found in total 100 g faeces L = average larvae per 1 g bc larva

Table 4

Lungworm test result in sheep flocks

INSPECTION gala time- of First Second Third 4th group* +,% EF L +% EF L +% EF L +% EF L 04/18/18 20 10 0.10 20 11 0.11 20 10 0.10 20 9 0.09 5/16/16 30 16 0.16 10 10 0.10 20 11 0.11 10 3 0.03 6/15/15 30 17 0.17 10 3 0.03 20 9 0.09 0 0 - 07/18/18 30 16 0.16 10 1 0.01 20 9 0.09 0 0 - 08/17 30 19 0.19 0 0 - 10 7 0.07 0 0 - 9/16/16 40 43 0.43 0 0 - 10 7 0.07 0 0 - 10/14 50 54 0.54 0 0 - 10 8 0.08 0 0 -

* = Group 1: NaCl

Group 2: NaCl + albendazole

Group 3: NaCl + Co + Mo

Group 4: NaCl + Albendazole + Co + Mo +,% = Positive of all bcls tested,%

LU = total number of larvae found in total 100 g of faeces L = average number of larvae per 1 g of faeces

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Table 5

Laboratory test results for wool samples

Date First Second Third 4th group* Mo Co Mo Co Mo Co Mo Co μ / g 04/18/18 24.2 42.1 23.8 42.0 23.9 39.9 24.9 42.2 10/14 26.7 30.8 27.6 31.2 31.3 47.0 31.5 46.9

* = The first group: NaCl

Group 2: NaCl + albendazole

Group 3: NaCl + Co + Mo

Group 4: NaCl + Albendazole + Co + Mo

Table 6

Wool production and wool quality indicators

First Second Third 4th group* Average shear weight, kg “ 4.87 5.06 5.22 5.41 Average length of flirtation, cm “ 6.14 6.23 6.34 6.43 Average fiber diameter, micron ^b 25.30 24.20 23.40 21.80 Average rendement,% " 35.20 35.90 36.20 36.80 Our average assortment A / B A / B THE A / AA

* = Group 1: NaCl

Group 2: NaCl + albendazole

Group 3: NaCl + Co + Mo

Group 4: NaCl + Albendazole + Co + Mo a = the higher the value the better the quality b = the mincl the lower the value the better the quality c = order of values: A / AA, A, A / B

Table 7

Average individual body weight (kg) in the follicular groups

Date of weighing First Second Third 4th group* 04/18/18 296.86 297.13 ' 299.07 ' 299.74 ' 5/16/16 315.95 316.64 318.41 320.18 6/15/15 334.41 336.35 337.84 341.55 07/18/18 350.56 353.56 355.23 361.06 08/17 364.93 370.09 373.92 379.76 9/16/16 378.99 386.73 389.88 398.25

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Table 7 (continued)

Date of weighing First Second Third 4th group* 10/14 394.54 405.22 ^b 406.87 ^b 417.49 ' Avg one. ttgy., kg 97.68 108.09 ^b 107,80 " 117.75 ' Daily average e. ttgy., g 542.67 600.50 ^b 598.89 ' 654.17 '

* = The first group: NaCl

Group 2: NaCl + albendazole

Group 3: NaCl + Co + Mo

Group 4: NaCl + albendazole + Co + Mo a = ncm significantly different from group 1 b = significantly (p <0.05) from group 1

Table 8

Average individual body weight (kg) in the ewe groups

Date of weighing First Second Third 4th group* 04/18/18 42.92 42.89 43.00 43.03 5/16/16 43.67 43.73 43.69 43.71 6/15/15 43.71 43.79 43.82 43.98 07/18/18 43.62 43.92 43.96 44.42 08/17 43.59 44.19 44.23 44.87 9/16/16 43.58 44.28 44.37 45.02 10/14 43.63 44.46 44.51 45.24 Avg one. ttgy., kg 0.71 1.57 1.51 2.21

* = Group 1: NaCl

Group 2: NaCl + albendazole

Group 3: NaCl + Co + Mo

Group 4: NaCl + Albendazole + Co + Mo

The invention is illustrated by the following example, without limiting the scope thereof.

Example

The natural sodium chloride is ground in a ball mill to a powder grit. In a Lődige type mixer, 400 kg of powdered sodium chloride, 2 kg of albendazole, 14 g of powdered ammonium heptamolybdate and 24 g of powdered cobalt (II) chloride are weighed. The mixer was started and the mixture was homogenized with a stirring time of 4 minutes. To the homogeneous mixture is added 8 L of water while stirring, and the finished mixture is added to a 5 kg mold cabinet of an Amolds salt press via an automatic balance via an automatic balance. The salt press is then started and the wet mixture pressed to a pressure of 180 MPa.

Claims (6)

PATENT CLAIMS 1. Sodium chloride-based lichen-containing trace element, enriched with trace elements, each of 1 to 100 g of benzimidazole derivative and 1 to 100 mg of molybdenum and It contains 1-100 mg of cobalt in the form of a physiologically acceptable inorganic salt. Lichen salt according to claim 1, containing the methyl anthelmintic of [5- (propylthio) -1H-benzimidazol-2-yl] -carbamic acid as an anthelmintic. Lichen salt according to claim 1, containing molybdenum (NH ₄ ) ₆ Mo ₇ O ₂₄ -4H ₂ O (ammonium heptamolybdate). The licking salt of claim 1, wherein the cobalt is in the form of CoCl ₂ -6H ₂ O [cobalt (II) chloride]. HU 217 086 A 5. A process for the preparation of a trace amount of sodium chloride-based lime salt enriched in trace elements, characterized in that from 1 to 100 g of benzimidazole derivative, 2 to 200 mg of ammonium heptamolybdate per kg of powdered sodium chloride Cobalt (II) chloride (mg) was added, the mixture was homogenized, mixed with 5 ml to 35 ml of water and finally blended in a known manner using a press at 100-300 MPa. 6. The process according to claim 5, wherein the anthelmintic is methyl [5- (propylthio) 1H-benzimidazol-2-yl] -carbamic acid.