BG2636U1 - Anticoccidials medium containing salinomycin - Google Patents

Abstract

The utility model relates to a micro-granule, dust free, freely flowing anticoccidials medium, containing salinomycin as an active ingredient in a concentration of 6 to 30 %, distinguished by its low content of improving fluidity ingredients and impurities, as waste materials, soaps and other water soluble waste, which finds application in veterinary medicine as a supplement. The anticoccidials medium containing salinomycin has the following composition in weight %: salinomycin biomass from 10 to 70%, containing an active substance salinomycin from 6 to 30%, filler 17- 85%, a medium, which improves fluidity 2-17 % and a medium for cleaning fats and waste compounds 3-15 %. 8 claims, 5 figures

Description

(54) ANTICOCIDAL PRODUCT CONTAINING SALINOMYCIN

(57) The utility model relates to a microgranular, dust-free, free-flowing anticoccidial agent containing salinomycin as an active ingredient in a concentration of 6 to 30%, characterized by a low content of flow-improving substances and impurities such as residual fats, soaps and other water-soluble residues, which is used in veterinary practice as a food supplement. The anticoccidial agent containing salinomycin has the following composition in% by weight: salinomycin biomass from 10 to 70%, containing active substance salinomycin from 6 to 30%, filler 17-85%, flow improver 2-17% and cleaning agent. fats and residues 3-15%.

claims, 5 figures

2636 UI (54) ANTICOCIDAL PRODUCT CONTAINING SALINOMYCIN

Field of technology

The utility model relates to an anticoccidial agent containing salinomycin, which is used in veterinary practice as a dietary supplement. It is applicable against all types of coccidiosis. It is active against gram-positive microorganisms, some anaerobes and Serpulina hyodysenteria.

BACKGROUND OF THE INVENTION

It is known that the biological activity of salinomycin is based on its ability to form complexes with monobasic metal ions, which make the cell membranes of coccidia permeable to said ions. In this way the intracellular concentration of ions in the cells of the parasites is disturbed and the anticoccidial effect of the antibiotic is manifested at the earliest stage of the development of coccidiosis.

The use of anticoccidials as dietary supplements is known. In order to achieve an anticoccidial effect against all types of causative agents of coccidiosis, small amounts of salinomycin, which is a polyether antibiotic from the group of iontophores, are added to food.

It is known that the size of the particles, their distribution, as well as the distribution of the active substance in the individual fractions of the granule is essential for ensuring uniform mixing of the agent with the food. Larger diameter particles are difficult to mix, at the same time there is a danger of their gravitational separation, both of which lead to violation of the specified dosage when ingested. No less important is the fact that the presence of a large amount of dust in the product does not meet toxicological and hygienic standards, creates a risk of contamination of production facilities and equipment with negative consequences for the safety and health of workers, complicates dosing and handling. product. The presence in the product of a large amount of residual vegetable oil, saponified substances, carbohydrates and proteins from the mycelial biomass contributes to its compaction, where it is possible to get lumps or too little coccidiostats in the food with the same negative consequences. This requires the addition of a large amount of anti-caking agents and flow-improving substances, which leads to an increase in the powder fraction in the product. Important for the uniform mixing of the product with food is the flow parameter, which determines the ability of the product to flow freely under the influence of gravity in granular form, thus ensuring its precise dosing, uniform mixing and ensuring the preservation of its properties for a long period. from time to time within the expiration date. All this determines the need to create a product formulation in which the preliminary purification of the mycelial biomass from the substances causing compaction of the dry product and preventing its flowability leads to a reduction in the amount of funds used to improve the flowability, while ensuring uniform distribution of the active substance in the individual fractions of the microgranule with a decrease in its size and in a wide range of concentrations of the active substance.

Various formulations of anticoccidial agents containing salinomycin as an active ingredient are known, providing to one degree or another some of the listed properties.

Patent EP 0035125 describes a process for the preparation of salinomycin culture broth from which biomass powder is obtained and then a granulate containing 6% by weight of salinomycin which is neither dust-free nor free-flowing.

The agglomerate obtained by this method has a residual fat content of 3.5% equal to 17.5% by weight in the dry mass of the culture broth. The disadvantage of this product is that it decomposes easily and forms a dust when the residual oil in the liquid biomass is completely decomposed.

Patent BG 60973 B1 describes a granulate of salinomycin biomass, free-flowing, dust-free and with unlimited availability of the active substance. The content of salinomycin biomass in the granule is in the range from 10 to 26% by weight at a concentration of

2636 IU antifungal agent (filler) from 30 to 40% by weight in relation to a flow improver from 3: 1 to 9: 1, as well as a cellulose ether content such as carboxymethyl cellulose in a concentration of 0.5 - 2.0%, relative to the weight of the culture broth. In addition, it is emphasized that the optimal residual fat content for the product is from 5.0 to 6.0% in the culture broth and from 24 to 30% in the dry biomass and this is important for the formulation. The addition of carboxymethyl cellulose helps to achieve good bioavailability of the active substance, hardens the granule, while reducing the powder fraction and increasing the flowability of the product. The particle size distribution in the product has a maximum in the range of 180 to 500 microns, where 50 to 80% of the particles fall and the powder fraction is up to 10%. In practice, this approach, although it meets some of the basic requirements for the formulation of salinomycin coccidiostats, is not good enough due to the high content of impurities and residual fats, high content of substances that improve fluidity, the need to add granulating and granulating agent, high powder fraction content and a relatively large microgranule, as well as a limited range of active substance content in which the product retains these properties. All this emphasizes the need for an alternative approach.

The composition and characteristics of all the obtained means described in the prior art have shortcomings with respect to one or another quality of the product. The main problem with salinomycin coccidiostats used as a food additive such as purity, compaction tendency, flowability, particle and active substance distribution profile and the preservation of these properties in a wide concentration range has not been satisfactorily solved.

Technical essence of the utility model

The essence of the utility model is a microgranular anticoccidial agent containing salinomycin and consisting of salinomycin biomass, filler, flow enhancer and aid to cleanse the fat and residues and characterized in that it contains in% by weight: salinomycin 10 to 70%, filler 17 to 85%, flow improver 2-17% and fat and residue scavenger 3-15%, the content of the active substance salinomycin being from 6 to 30%. The ratio of the sum of the filler and the cleaning aid and the flow aid is from 2: 1 to 44: 1. Up to 45% of residual fats, saponified substances and water-soluble side impurities are removed from salinomycin biomass. As fillers can be used finely dispersed calcium carbonate, chalk, kaolin, finely ground carbonate filler. Silica, natural and synthetic oxides of α-quartz and salts of silicic acids can be used as flow improvers. Perlite can be used as a means of purifying fats and residues from biomass. The size distribution of the granules has a maximum in the range between 100 and 300 micrometers, the product is dust-free, with a maximum powder content of 5%, at the same time the distribution of the active substance is uniform and its fluidity is over 100%, which practically means that the product gravitationally flows freely in the dry state. These characteristics of the product subject to the utility model are achieved without the separate addition of adhesive granulating substances and granulating hardening agents.

In the proposed formulation of the product in order to increase the filtration capacity of the liquid biomass to remove residual vegetable fats and impurities, increase the fluidity of the resulting microgranule and reduce the loss of active substance in the filtrate after treatment of the liquid mycelium containing active substance salinomycin about 65,000 - 70,000 pg / ml with liquid sodium hydroxide can be added to 3% perlite or other suspension of inert material as a filtration aid. The amount of filter aid agent can vary from 1 to 3% depending on the ability of the biomass to filter, which is checked in advance on

2636 UI laboratory filtration unit. Thus, for the separation of residual oil, soaps and impurities from the liquid biomass, a chamber or membrane filter press or separator can be used, in which the biomass containing the active substance is purified from a large part of the dissolved and suspended residues such as discarded fats, lipids, soaps, proteins and carbohydrates. A preferred type of equipment is a filter press, which can be provided with the possibility of membrane squeezing or rinsing of the cake with water or a separator with pre-concentration. The degree of purification of biomass from residues depends on their initial content in the biomass and its ability to filter, as well as on the quality washing of the mycelium after filtration. For example, when the fat content is about 2% and the total dry matter in the liquid biomass is between 18 and 20%, the fat content in the filtrate is in the range of 0.7 - 0.9%, and the total dry matter is in the range of 9 -10%, which means that practically more than 45% of all water-soluble and water-insoluble substances outside the micelle biomass leave the cake and are discarded through the filtrate. Thus, the content of residual fat in the product is in the range from 1.2 to 7.8% by weight. This helps to reduce the amount of flow improvers, and hence to reduce the powder fraction in the final product, as well as to reduce production costs and increase the competitiveness of the anticoccidial agent.

Fine substances containing finely dispersed calcium carbonate, for example chalk, kaolin in a concentration of 17 to 85%, can be used to carry out the liquid standardization of the resuspended heavy phase or cake containing the micellar biomass with the active substance in water and as a filler. weight Silicon dioxide or other synthetic silicic acid in a concentration of 2 to 17% by weight can be used as a flow improver. The ratio of the sum of the filler and the cleaning aid and the flow aid is from 2: 1 to 44: 1. It is not necessary to add adhesive granulating agents and substances separately, as well as the addition of granulating hardening agents.

The specific uniform distribution of the activity in the particles of the obtained microgranule, as well as their shape, size and strength can be achieved in a spray dryer - granulator with built-in internal fluidized bed, from where only the fraction with a certain particle size is taken out. classification by size in an external fluidized bed, the final sieving of the standardized microgranular agent is performed.

The advantages of the proposed composition of the anticoccidial agent containing salinomycin are as follows:

1. The use of a substance that increases the filtration and separation capacity of liquid biomass contributes to the quality removal of substances that impede the flow of the product and hence to a significant reduction in the amount of substances that improve flow, thus reducing the dust fraction.

2. The presence in the product of a filler (anti-compactor) and a flow-increasing agent and their application simultaneously and in a wide range of concentrations provides an opportunity for liquid standardization of the resuspended mycelial biomass cake and makes it possible to dry and granulate the product. carried out in the same plant sequentially, with an even distribution of the active substance, achieved without the separate addition of adhesive granulating substances or hardening granules, while the flowability of the product is over 100%.

3. The distribution of the particles in the microgranular anticoccidial agent with a maximum in the range between 100 and 300 micrometers achieves a uniform distribution of activity in the individual fractions of the obtained microgranule, as well as their specific shape, size, strength and low powder fraction.

Examples of implementation of the utility model

The essence of the utility model is illustrated in the following examples, and it cannot be assumed that they limit it in any way.

2636 UI

Example 1.

The present example describes the preparation of an anticoccidial agent containing salinomycin, in% by weight: salinomycin biomass 10%, containing the active substance salinomycin 6%, finely ground natural calcium carbonate as filler 85%, a flow improver SiO _{2 for} 2% and perlite purification of fats and residues 3%.

Liquid treated mycelial biomass from a fermentation process with post-treatment activity of 65,800 pg / ml, fat content 1.86%, total dry matter 18.99% and soluble dry matter 10.39% was used. The biomass is filtered on a pilot membrane filter press SH 500, equipped with a receiving vessel equipped with stirring for the liquid treated biomass, a piston feed pump, a pump for creating pressure in the membranes and a water tank with a pump for washing the cake. Polypropylene membrane combs with a chamber depth of 20 mm and filter sheets PPD 3140 with size 801 / dm ² / min are installed. 123 l of liquid treated mycelial biomass were loaded into the receiving vessel at a temperature of 60 ° C and pH 9.50. 0.6 kg /0.5%/ formalin for micelle preservation and 3.6 kg / 3% / perlite were added and the mixture was well homogenized. At the beginning of the filtration, the temperature in the receiving vessel was lowered to 42 ° C. Filtration was continued for 20 minutes to a pressure in the 8 bar chambers and a pressure in the cake squeezing membranes of 11 bar. The amount of filtered biomass is approximately 45 1. The amount of individual filtrate is 25 L without the water for rinsing the cake. After opening the press, a very well-shaped cake weighing 4.6 kg and a drying loss of 31.77% was observed. The fat content of the separated filtrate was 0.86%, the total dry matter 9.53%, the soluble dry matter 9.50% and the residual activity was 5000 pg / ml.

The resulting cake from wet biomass was resuspended in water in a vessel equipped with stirring up to 20% dry matter, 2% silica and 85% filler - natural calcium carbonate relative to the dry matter were added, calculating the activity of the dry product to be in the range of 60 - 65 pg / mg.

Drying and granulation were performed on a pilot spray dryer - granulator, equipped with internal and external fluid bed, from which 39.15 kg of microgranulated and standardized anticoccidial agent with activity 62 pg / mg and yield relative to the inserted mycelial biomass were obtained.

The study of the particle distribution of the obtained product was performed by sieve analysis and showed the following results:

Through a sieve with mesh sizes, pm Pass,% 300 95 100 5

The flow test of the obtained 6% product was performed by the QCDFPC-208 method when the product was included in the original package of an accelerated stability test and flow analysis every 30 days for a period of 6 months. The results obtained show the preservation of 100% fluidity for the entire storage period of the product.

Example 2.

The present example describes the preparation of an anticoccidial agent containing salinomycin in weight%: salinomycin biomass 23%, containing the active substance salinomycin 12%, finely ground natural calcium carbonate as a filler 70%, a flow improver SiO _{2 for} 4% and perlite purification of fats and residues 3%

Liquid treated mycelial biomass from a fermentation process with post-treatment activity 64700 pg / ml, fat content 1.76%, total dry matter 18.78% and soluble dry matter 10.53% was used. The biomass is filtered on a pilot membrane filter - press SH 500, equipped with a receiving vessel equipped with stirring for the liquid treated biomass, a piston charging pump, a pump for creating pressure in the membranes and a water tank with a pump for washing the cake. Polypropylene membrane combs with a chamber depth of 20 mm and filter sheets PPD 3140 with size 801 / dm ² / min are installed. 120 l of liquid treated mycelial biomass were loaded into the receiving vessel at a temperature of 62 ° C and pH 9.55. 0.6 kg (0.5%) of formalin and 3.6 kg (3%) of perlite were added and the mixture was homogenized well. At the beginning of the filtration, the temperature in the receiving vessel drops

2636 IU to 48 ° C. Filtration was continued for 25 minutes to a pressure in the 8 bar chambers and a pressure in the cake squeezing membranes of 11 bar. The amount of filtered biomass is approximately 46 1. The amount of individual filtrate is 25 L without the water for washing the cake. After opening the press, a very well-shaped cake with a weight of 4.6 kg and a drying loss of 35.70% was observed. The fat content of the separated filtrate was 0.9%, the total dry matter was 9.60%, the soluble dry matter was 9.50% and the residual activity was 4500 pg / ml.

The resulting cake from wet biomass was resuspended in water in a vessel equipped with stirring up to 20% dry matter and 4% silica and 70% natural calcium carbonate were added as filler by weight relative to the dry matter, calculating the activity of the dry product to be within 120 -125 pg / mg.

Drying and granulation were performed on a pilot spray dryer - granulator, equipped with internal and external fluid bed, from which 20.61 kg of microgranulated and standardized anticoccidial agent with activity 122 pg / mg and yield relative to the inserted mycelial biomass were obtained.

The study of the particle distribution of the obtained product was performed by sieve analysis and showed the following results:

Through a sieve with mesh sizes, pm Pass,% 300 96 100 4

The flow test of the obtained 12% product was performed by the QCD-FPC-208 method when the product was included in the original package of an accelerated stability test and flow analysis every 30 days for a period of 6 months. The results obtained show the preservation of 100% fluidity for the entire storage period of the product.

Example 3.

The purpose of the present example is to describe an anticoccidial agent containing salinomycin in weight%: salinomycin biomass 63% containing active substance salinomycin 30%, filler - finely ground natural calcium carbonate 17%, flow improver SiO ₂ 17% and permeability SiO 2 17% as a cleaning agent for fats and residues 3%.

Liquid treated mycelial biomass from a fermentation process with post-treatment activity of 69100 pg / ml, fat content 2.22%, total dry matter 19.12% and soluble dry matter 10.84% was used. The biomass is filtered on a pilot membrane filter - press SH 500, equipped with a receiving vessel equipped with stirring for the liquid treated biomass, a piston charging pump, a pump for creating pressure in the membranes and a water tank with a pump for washing the cake. Polypropylene membrane combs with a chamber depth of 20 mm and filter sheets PPD 3140 with size 801 / dm ² / min are installed. 123 l of liquid treated mycelial biomass were loaded into the receiving vessel at a temperature of 60 ° C and pH 9.60. 0.6 kg /0.5%/ formalin and 3.6 kg / 3% / perlite were added and the mixture was homogenized well. At the beginning of the filtration, the temperature in the receiving vessel drops to 50 ° C. Filtration was continued for 30 minutes to a pressure in the 8 bar chambers and a pressure in the cake squeezing membranes of 12 bar. The amount of filtered biomass is approximately 46 1. The amount of individual filtrate is 211 without the water for washing the cake. After opening the press, a very well-shaped cake weighing 4.85 kg and a drying loss of 33.60% was observed. The fat content of the separated filtrate was 1.0%, the total dry matter was 9.55%, the soluble dry matter was 9.84% and the residual activity was 5800 pg / ml.

The resulting cake from wet biomass was resuspended in water in a vessel equipped with stirring up to 20% dry matter and 17% silica and 17% natural calcium carbonate were added as filler by weight relative to the dry matter, calculating the activity of the dry product to be within 300 -310 pg / mg.

Drying and granulation were performed on a pilot spray dryer - granulator, equipped with internal and external fluid bed, from which 8.97 kg of microgranulated and standardized anticoccidial agent with activity 302 pg / mg and yield relative to the inserted mycelial biomass were obtained.

The study of the particle distribution of the obtained product was performed by sieve analysis and showed the following results:

2636 UI

Through a sieve with mesh sizes, pm Pass,% 300 97 100 3

The flow test of the obtained 30% product was performed by the QCD-FPC-208 method when the product was included in the original package of an accelerated stability test and flow analysis every 30 days for a period of 6 months. The results obtained show the preservation of 100% fluidity for the entire storage period of the product.

Comparison of an anticoccidial agent containing salinomycin subject to the utility model with the prior art

Microscopic examination of the obtained anticoccidial agents containing salinomycin at a magnification of 100 times of: microgranules of the anticoccidial agent according to the utility model - fig. 1; product obtained according to patent EP 0 035 125 - fig. 2; product obtained according to patent BG 60973 B1 - fig. 3 show the advantages of the product according to the proposed utility model compared to other granular coccidiostats.

The distribution of the particles and the activity in the separate fractions of the microgranule in an anticoccidial agent containing salinomycin, subject to the proposed utility model, is uniform, as can be seen in diagram 1 - fig. 4. This ensures excellent mixing of the product with the food.

In the other granular anticoccidial products the activity of the active substance is unevenly distributed in the individual fractions, as shown in diagram 2 - fig. 5.

The efficacy of an anticoccidial agent containing salinomycin, subject to the proposed utility model, remains consistently high during the shelf life of the product, as shown in the table:

Storage period, month Accelerated stability test Fluidity,% 1 100 2 100 3 100 4 100 5 100 6 100

The flowability of the granular anticoccidial product according to patent EP 0 035 125 is low from the very beginning with a tendency to decrease in the shelf life of the product, as shown in the table:

Storage period, month Accelerated stability test Fluidity,% 1 20-50 2 20-40 3 10-40 4 10-20 5 0-20 6 0-10

Claims (8)

An anticoccidial agent comprising salinomycin, comprising a salinomycin biomass, a filler and a flow improver, characterized in that it also comprises a cleaning agent for fats and residues in% by weight: salinomycin biomass of 10 to 70% with active substance salinomycin from 6 to 30%, filler 17-85%, flow improver 2-17% and cleanser for fats and residues 3-15%. An anticoccidial agent comprising salinomycin according to claim 1, characterized in that up to 45% of the residual fats, saponified substances and water-soluble impurities contained in the salinomycin biomass are removed. An anticoccidial agent comprising salinomycin according to claim 1, characterized in that the ratio of the sum of the filler to the fat and residue scavenger and the flow improver is from 2: 1 to 44: 1. An anticoccidial agent comprising salinomycin according to claim 1, characterized in that the filler is finely ground natural calcium carbonate. An anticoccidial agent comprising salinomycin according to claim 1, characterized in that the flow enhancer is silica. An anticoccidial agent comprising salinomycin according to claim 1, characterized in that the agent for cleaning fats and residues from the biomass is perlite. An anticoccidial agent comprising salinomycin according to claim 1, characterized in that its fluidity measured by the QCD-FPC-208 method is over 100% for the entire shelf life of the product. An anticoccidial agent comprising salinomycin according to claim 1, characterized in that it is microgranulated with a particle size distribution: 100 - 300 pm 95.00% - 97.00% below 100 pm 3.00% - 5.00%.