BG2358U1 - An anthelmintics - Google Patents

Abstract

The utility model relates to an anthelmintic based on benzimidazole and carbamate compounds, which remains stable without sedimentation for up to two weeks and allows implementation into medical drinking water, thus making it useful for fighting off helminth infections in livestock. As an active components the anthelmintic includes benzimidazole carbamates, with a particle size of <500 nm, chosen from the group which includes fenbendazole, albendazole and flubendazole, compounds active on the surface, chosen from the group which includes- sodium docusate, sodium lauryl sulfate and polyoxol 35 castor oil; suspending compounds chosen from the group which includes Povidone and Hydroxy-propyl-methyl cellulose; sodium benzoate, included as a preservative; a pH regulator, chosen from the group which includes- 1M hydrochloric and citric acids and water

Description

The utility model relates to an anthelmintic for veterinary use, in particular to an agent for controlling helminthiasis in farm animals.

BACKGROUND OF THE INVENTION

Helminthiasis is a parasitic disease that is widespread in animals. They are caused by lower multicellular organisms that parasitize in various mammalian organs and are divided into three main groups - nematodes, trematodes and cestodes. Various agents are used in the fight against these diseases, of which the substances from the group of benzimidazoles containing as active component are especially widely used. The latter are characterized by a wide range of activity against nematodes and trematodes, and limited activity against cestodes.

The molecular effect of all benzimidazoles is based on the binding of tubulin 25 - a structural protein in important cellular organelles, microtubules, responsible for the motility, division and excretory processes of cells in all living organisms. Blockage of microtubules in parasites disrupts glucose uptake, leading to an imbalance of their entire energy mechanism, paralysis and death, and as cell division is also impaired, egg release and development are also blocked by benzimidazoles, i. they also have an ovocidal effect.

Fenbendazole is a benzimidazole carbamate compound used in veterinary medicine as an anthelmintic in many species of animals, including poultry, pigs and cattle. It is used to control nematodes such as Ascaridia, Heterakis and Capillaria in birds and pigs. It is often used in food in the form of ampoules with liquid preparation, food supplements, boluses, tablets, powders, etc., as well as in the form of sustained release agents, all for oral administration.

Fenbendazole is insoluble in water. The aqueous suspensions of the compound are unsatisfactory, as it settles. Accordingly, there is a need for stable aqueous suspensions of fenbendazole.

International patent application WO 9513065 discloses an aqueous suspension of fenbendazole having a particle size of about 1 micron. However, it is unsuitable for use with drinking water for animals, as it sediments after some time, which does not allow a homogeneous distribution of fenbendazole in the water supply systems on farms and leads to the risk of blocking all equipment.

International patent application WO 9516447 also discloses an oral anthelmintic composition comprising micronized particles of rafoxanide and fen bendazole, wherein more than 98% of the particles are smaller than 20 microns in size, but it is also inapplicable in drinking water systems used to distribute water on ₂₀ farms.

The object of the utility model is to propose an anthelmintic with the participation of benzimidazole carbamate compound as an active substance that satisfies the stability requirements of both the anthelmintic itself and the medicinal drinking water prepared with it, which is applicable in the fight against helminthiasis on farm animals.

Technical essence of the utility model

In essence, the utility model relates to an anthelmintic comprising (in% by weight): benzimidazole carbamates selected from the group consisting of fenbendazole, albendazole and flubendazole with a particle size <500 nm from 10.0 to 35.0; surfactants selected from the group consisting of sodium docusate, sodium lauryl sulfate and polyoxoyl 35 castor oil from 0.5 to 20.0; suspending agents selected from the group consisting of povidone and hydroxypropylmethyl cellulose from 0.5 to 10.0; sodium benzoate as a preservative from 0.1 to 1.0; narH correctors selected from the group consisting of 1M hydrochloric acid and citric acid in order to obtain a pH of 2.0 to 6.0 and water up to 100.

According to a preferred embodiment of the anthelmintic, according to the utility model, comprising as selected 50 benzimidazole carbamate, fenbendazole with an average particle size <500 nm; as

2358 Ul

Surfactant, causing wetting, dispersing and solubilization of the active substance, sodium docusate is used; Colidon (povidone) K25 was used as a suspending agent to increase the viscosity of the suspension; as a preservative - sodium benzoate; 1M hydrochloric acid and water were used as pH adjuster.

According to a second preferred embodiment of the anthelmintic, according to the utility model, comprising selected benzimidazole carbamate, flubendazole nanomized with an average particle size <500 nm; sodium lauryl sulfate is used as a surfactant; Colidon (povidone) KZO was used as a suspending substance; as a preservative - sodium benzoate; 1M hydrochloric acid and water were used as pH adjuster.

In another preferred embodiment of the anthelmintic according to the present utility, it includes, as selected, benzimidazole carbamate, albendazole with an average particle size <500 nm; Cremophor RH35 was used as a surfactant; hydroxypropylmethyl cellulose is used as the suspending agent; as a preservative - sodium benzoate; citric acid and water were used as a pH adjuster.

The advantages of the anthelmintic according to the present utility model over the existing ones are its stability without sedimentation for two weeks at temperatures of 2 ° C and 25 ° C due to the presence of active substance in nanomized form and the use of suitable solubilizing, suspending and viscosity stabilizing agents, which results in the stability of the medicated drinking water prepared with the suspension. The results of studies performed on pigs show that the administration of a suspension of selected benzimidazole carbamates, according to the utility model, using drinking water at a dose of 2.5 mg / kg body weight for 2 consecutive days, leads to statistically significant (p <0.05) reducing the number of adult and larval forms of helminths. Applied to drinking water in chickens at a dose of 1.0 mg / kg body weight for 5 consecutive days, resulted in a statistically significant (p <0.001) reduction in the number of adult forms of the parasite Heterakis gallinarum.

The utility model is illustrated by the following exemplary embodiments without limiting its scope.

Examples of implementation of the utility model

Example 1.

According to the present example, the anthelmintic contains (in g):

Fenbendazole with a particle size <500 nm 20.0

Sodium dosage 3.0

Povidone (Colidon K25) 0.5

Sodium benzoate 0.4

1M Hydrochloric acid - in an amount sufficient to achieve a pH of 2.0 - 6.0

Purified water up to 100.

Preparation of the suspension: To prepare the suspension, first prepare a solution of the excipients and the active substance by active stirring, carry out wet saturation with a multihomogenizer and nanomill to an average particle size of the active substance of less than 500 nm, and the resulting suspension is dosed in suitable packages for delivery to the relevant holding. The final product is a stable 20% suspension without sedimentation at 2 ° C to and at 25 ° C for a minimum of 14 days and a particle size of D _v (10) 0.0541 microm, D _v (50) 0.129 microm; D _v (90) 0.368 microm; D _v (99) 0.756 microm; where D _v denotes the percentage fraction of the particles less than the indicated value.

Example 2.

According to the present example, the anthelmintic contains (in g):

Flubendazole with a particle size <500 nm 10.0

Sodium lauryl sulfate 0.5

Povidone (Colidon KZO) 3.0

Sodium benzoate 0.1

1M Hydrochloric acid - in an amount sufficient to achieve a pH of 2.0-6.0

Purified water up to 100.

The final product is a stable suspension without sedimentation at 2 ° C and 25 ° C for a minimum of 14 days and a particle size D _v (10) of 0.0680 microns; D _v (50) 0.185 microns; D _v (90) 0.450 microm; D _v (99)

0.842 microm, where D _v denotes the percentage fraction of the particles less than the indicated value.

Example 3.

According to the present example, the anthelmintic contains (in g):

Albendazole with a particle size <500 nm 35.0

Polyoxoyl 35 castor oil 20.0

Hydroxypropylmethyl cellulose 10.0

Sodium benzoate 1.0

Citric acid - in an amount sufficient to achieve a pH of 2.0 to 6.0

Purified water up to 100.

The final product is a stable suspension without sedimentation at a temperature of 2 ° C and at 25 ° C for a minimum of 14 days and a particle size of DJ10) 0.060 microm,

D _v (50) 0.145 microns; D _v (90) 0.480 microm; Dv (99) 0.862 microm, where D _v denotes the percentage fraction of the particles less than the indicated value.

$ Example 4.

Experiments for the stability of the suspension depending on the hardness of the water containing the composition according to the utility model

IQ For the purposes of the study, medicated waters were prepared for pigs with a 20% suspension of fenbendazole from Example 1 in concentrations of 0.15 ml / l and 5 ml / l in hard and soft water. The visually obtained water does not show visible sediments for 24 hours. The resulting waters were tested for stability at 0 h (onset), 4 h and 24 h. The results of the study are presented below:

For a concentration of 0.15 ml / l water

Expected concentration 0.03 mg / ml : 0 hours 4 hours 24 hours ; Soft water 0.032 !! 0.032 0.031 ¹ Hard water 5 0.31 ј 0.032 0.03 For a concentration of 5 ml / 1 water

Expected concentration 0 h i1.0 mg / ml I; Soft water; 1,070 Hours; Hard water 1,065

The resulting suspensions with both hard and soft water are stable and do not settle for a period of 24 hours, which makes them applicable in watering plants.

Example 5.

Study of the effect of the anthelmintic, according to the utility model, against adult and larval forms (migratory and intestinal) of the parasite Ascaris suum.

A study was performed on 100 pigs at the beginning of the experiment about 6 weeks - 50% male and 50% female specimens, negative for the presence of Ascaris suum eggs in the feces and divided into 6 groups - 3 control and 3 experimental. All animals included in the experiment were artificially infected with 150 eggs of Ascaris suum, orally, by means of a gastrointestinal tube, and the experimental groups (G02, G04 and G06) were three! 4 hours! 24 hours —I -------------- ---------------------------. -------------- 1

Ϊ1,060 1,068

I1 056 1 061 tyrants with the anthelmintic according to Example 1 above, in the form of an oral suspension containing 200 mg fenbendazole / ml administered in an amount of 2.5 mg / kg body weight (B W) in drinking water for two consecutive days. At the end of the study, all pigs were euthanized and tested for the presence and absence of larvae in the migratory and intestinal stages (L4 and L5) and adult forms of Ascaris suum. The results are presented in Table 1 below.

After euthanasia, it was found that 100% of the pigs in group G02 were negative and 35% of group G01 were positive for the adult forms of the parasite Ascaris suum, which showed 100% reduction of infection in the group treated with anthelmintic suspension with the active substance fenbendazole. There was a statistically significant difference (p <0.005) in the absence and presence

2358 IU of adult forms of the parasite Ascaris suum in pigs of group G02 compared to those of group G01 (control).

It was also found that 60% of the pigs in group G04 were negative and 100% of GOS were positive for L4 larvae of the parasite Ascaris suum (migratory stage), which demonstrated a 99.5% reduction in infection in the group treated with anthelmintic suspension with active substance fenbendazole. A statistically significant difference (p <0.001) was found in the absence and presence of L4 larvae of the parasite Ascaris suum (migratory stage) in pigs from group G04 compared to those from group GOS (control).

It was also found that 100% of the pigs in group G06 were negative and 25% and 20% of those in group G05 were positive for larvae L4 and

L5 of the parasite Ascaris suum, which demonstrates 100% reduction of infection in the group treated with anthelmintic suspension with the active substance fenbendazole. A statistically significant difference was found (p <0.035 and p <0.040), respectively, in the absence and presence of larvae in stages L4 and L5 of the parasite Ascaris suum in pigs of group G06 compared to those of group G05 (control). 10 The results of the study presented in Table 1 below allow the conclusion that the administration of the suspension of Example 1 in an amount of 200 mg / ml by means of drinking water at a dose of 2.5 mg fenbendazole / kg body weight for 2 consecutive days of water to a statistically significant (p <0.05) reduction in the number of adult and larval forms of the parasite Ascaris suum.

Table 1

d stop D01 G02 GOZ ______. _ G04 G05 G06 'Total Number of animals 20 20 10 10 20 20 ј 100 I % 100 100 100 100 100 100 | L4 Absence I L. ... Number of animals 20 20 ---------------. . 6 15 20 % 100 100 60 75 100 I !! Availability Number of animals - 10 4 5 - % - ______ 100 40 , ²⁵ | Reduction % - . * _________ ...... 99.5 100 L5 Absence .... Number of animals 20 100 20 100 10 100 10 100 16 ________._. ... 80 20 100 Availability Number of animals * - 4 > o / o ²⁰ -. Reduction % - ... .... .. - - 100 Ages Absence Availability and Count animals 13 20 10 10 20 100 ------------------ ²⁰ % Number of animals 65 7 100 100 100 ............. 100 % 35 - • - - Reduction o / o - 100 - - - ^; -

Example 6.

Investigation of the effect of the anthelmintic, according to the utility model, applied in the drinking water of birds

The aim of the study was to confirm the efficacy of fenbendazole suspension 200 mg / ml administered with drinking water against an artificial infection with the nematode Heterakis gallinarum in laying hens. Heterakidosis is a helminthic disease in birds in industrial livestock.

The study included 39 clinically healthy day-old chicks. The chickens were divided into 2 groups (1 control and 1 experimental), respectively

W with 19 and 20 chickens. On day 0 of the study, all chickens included in the experiment were infected with 200 eggs of Heterakis gallinarum per bird, orally, using a gastrointestinal tube. The experimental group (G02) was treated with fenbendazole suspension by means of drinking water at a dose of 1.0 mg fenbendazole / kg body weight for 5 consecutive days.

At the end of the study (day 40), all chickens were euthanized and tested for the presence and absence of adult forms of Heterakis gallinarum. The results of the study are presented in Table 2 below.

Table 2

Indicators Groups D01 G02 Number of chickens per group _____________ ”_______ 20 Number of chickens with adult forms of Heterakis gallinarum at autopsy 19 4 Arithmetic mean 74.3 0.8 Geometrically average 68.2 0.3 Average 73.0 0.0 Minimally 20.0 0.0 Maximum 116.0 10.0

Percentage of reduction in the number of adult forms compared to the control group

The results of the study allow the conclusion that the application of fenbendazole suspension 200 mg / ml by drinking chicken water at a dose of 1.0 mg fenbendazole / kg body weight for 5 consecutive days, leads to a statistically significant (p <0.001) reduction in the number of adults. forms of the parasite Heterakis gallinarum. 4θ

Claims (1)

Claims An anthelmintic based on benzimidazole carbamates, characterized in that it comprises (in% by weight): - benzimidazole carbamates with a particle size <500 nm selected from the group consisting of fenbendazole, albendazole and flubendazole from 10.0 to 35.0; - surfactants selected from the group consisting of sodium docusate, sodium lauryl sulfate and polyoxoyl 35 castor oil from 0.5 to 20.0; - suspending agents selected from the group consisting of povidone and hydroxypropylmethyl cellulose from 0.5 to 10.0; - sodium benzoate from 0.1 to 1.0; - a pH adjuster selected from the group consisting of 1M hydrochloric acid and citric acid to achieve values of 2.0 to 6.0; and - water up to 100.