RU2413424C2 - Compositions of maduramicin, methods of production and application - Google Patents

Abstract

FIELD: food industry. ^ SUBSTANCE: composition of fodder additive for animals contains from 0.1 to 10 wt % of ammonium maduramicin, at the same time ammonium maduramicin has activity of maduramicin-alpha of more than 90%, from 75 to 99.8 wt % of carrier, from 0.1 to 10 wt % of binding substance. Method to prepare composition of fodder additive for animals consists in preparation of mix, containing ammonium maduramicin, carrier and binding substance, granulation of mixture to form granulate. ^ EFFECT: invention makes it possible to improve distribution of particle size, fluidity and stability, to provide for pH value in proper range for maduramicin. ^ 12 cl, 1 ex

Description

State of the art

Coccidiosis is a widespread disease in poultry that causes serious pathology in the intestines and cecum of poultry. It occurs due to infection by the simplest unicellular animals of the genus Eimeria; some of the most important protozoa of this species are E. tenella, E. acervulina, E. mitis, E. necatrix, E. brunetti, and E. maxima. This disease is usually spread by birds by ingestion at the stage of infection, through droppings on contaminated bedding or the ground, through food or drinking water. The disease manifests itself in the form of hemorrhage, accumulation of blood in the cecum, detection of blood in the litter, weakness and digestive disorders. The disease often ends with the death of an animal. Poultry that survive serious infections significantly lose their market value as a result of this infection. Therefore, coccidiosis is a disease that has significant economic impact, and extensive work has been done to find new and improved ways to control and treat coccidial infections in poultry.

Maduramycin is an antibiotic that has been shown to be an effective anticoccidial agent. It is used to treat coccidiosis caused, for example, by the microorganisms Eimeria acervulina, E. tenella, E. brunetti, E. maxima, E. necatrix and E. mivati. Maduramycin is used to treat coccidial infections in broilers, enhancing broiler growth, reducing morbidity and mortality. It is also useful for treating coccidiosis in turkeys, horses, pigs, cattle, and laying hens.

Animal feed compositions containing a therapeutic and / or prophylactic concentration of maduramycin were prepared by mixing the drug or its salt directly with the food or by mixing the supplement containing the drug with the desired food. Nutritional supplements are usually prepared by mixing a preparation or its salt, or a solution of the preparation or its salt with an edible substrate, for example, corn flour with cobs, soya feed, corn flour or the like. Usually, maduramycin is obtained by fermentation of microorganisms, for example, Actinomadura yumaensis.

The need for alternative compositions of feed additives, including maduramycin, remains.

SUMMARY OF THE INVENTION

The above and other symptoms are alleviated by the use of an animal feed supplement composition comprising an effective amount of ammonium maduramycin, a carrier, a binder, and optionally a pH adjuster.

Another embodiment of the invention includes the use of maduramycin for the preparation of a food supplement for the treatment of coccidiosis. The nutritional supplement contains an effective amount of ammonium maduramycin, a carrier, a binder, and optionally a pH adjuster.

In another embodiment, the animal feed composition comprises an animal feed and an effective amount of an animal nutritional supplement composition comprising an effective amount of ammonium maduramycin, a carrier, a binder, and optionally a pH adjuster.

In another example embodiment of the invention, a method for producing a food supplement composition for animals comprises forming a mixture containing from 0.1 to 10 wt.% Ammonium maduramycin, from 75 to 99.8 wt.% Of a carrier, from 0.1 to 10 wt.% Of a binder substances and from 0 to 5 wt.% pH regulator, where all amounts are given relative to the total weight of the feed additive; and also granulating the mixture to form granulate.

A person skilled in the art will appreciate and understand the above and other features from the following detailed description, drawing and appended claims.

A brief description of the graphic materials

The drawing shows the stability of the experimental batch according to the present description of the invention, stored in a plastic and paper bag. Stability is measured as the percentage of maduramycin alpha present in the test batch as a function of time.

DETAILED DESCRIPTION OF THE INVENTION

Animal feed compositions are disclosed herein, including ammonium maduramycin, a binder, a carrier, and optionally a pH adjuster. The composition "nutritional supplement" refers to a composition suitable for introduction into animal feed by introducing into the food and / or water for the animal. In one embodiment, the nutritional supplement is in the form of a granulate. Feed supplement formulations are also referred to as premix feed formulations.

Since ammonium maduramycin is the referenced standard for feed materials containing maduramycin, all maduramycin concentrations and percentages listed here, unless otherwise stated, are calculated as equivalent to ammonium maduramycin, irrespective of the form (e.g., free base, complexes or salts other than salt ammonium, etc.). Ammonium maduramycin is usually obtained by fermentation of Actinomadura yumaensis and subsequent extraction to obtain a fermentation product containing 90% or more of ammonium maduramycin. In one embodiment of the invention, ammonium maduramycin has an activity of maduramycin-alpha greater than 90 wt.%, In particular greater than 92 wt.%.

Maduramycin contains from 0.1 to 10 wt.% Of the total weight of the Maduramycin feed additive composition for animals, in particular from 0.5 to 2 wt.% Of the Maduramycin feed additive composition for animals.

The Maduramycin animal feed additive composition also contains a binder. The term "binder" is well known to specialists in this field as a substance that binds the components of the composition. Suitable binders include, for example, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, gelatin, polyvinyl pyrrolidone (PVP), polyvinyl alcohol, polyvinyl ether, hydroxypropyl cellulose, potassium alginate, sodium alginate, partially cellulose cellulose, cellulose granulose, cellulose cellulose comprising one or more than one prior binder. In one embodiment, the binder comprises sodium carboxymethyl cellulose.

The binder contains from 0.1 to 10 wt.% Of the total weight of the Maduramycin feed additive composition for animals, in particular from 0.2 to 5 wt.% Of the Maduramycin feed additive composition for animals.

The Maduramycin animal feed additive composition also contains a carrier. Suitable carriers include, for example, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, calcium carbonate, and combinations comprising one or more of the aforementioned carriers. In one embodiment, the carrier comprises calcium sulfate dihydrate.

The carrier contains from 75 to 99.8 wt.% Of the total weight of the Maduramycin feed additive composition for animals, in particular from 90 to 98 wt.% Of the Maduramycin feed additive composition for animals.

In one embodiment, the composition has a slightly alkaline pH, i.e. pH value from 7.4 to 9.

The Maduramycin animal feed additive composition also optionally contains a pH adjuster. Suitable pH adjusters include acids and bases suitable for adjusting the pH to a desired level. In one embodiment, the pH adjuster comprises a base, for example an alkali or alkaline earth metal hydroxide, including sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium bicarbonate, and combinations comprising one or more of the aforementioned pH adjusters.

An optional pH adjuster contains from 0 to 5 wt.% Of the total weight of the Maduramycin feed additive composition for animals, in particular from 0.05 to 2 wt.% Of the Maduramycin feed additive composition for animals.

The compositions optionally include additional agents, for example anti-caking agents, flow improvers, and combinations thereof.

Ammonium maduramycin, a carrier, a binder and an arbitrary pH regulator are combined to form a feed additive composition for animals. In one embodiment, the animal feed additive composition is a multi-particle composition. The term "multiparticulates" is intended to refer broadly to small particles, regardless of their composition or the method of their formation. Particles typically have an average diameter of from about 150 to 850 microns.

In one embodiment, ammonium maduramycin, a carrier, and a binder are granulated to form an animal feed additive composition. Granulation is a process in which relatively small particles form large granular particles. In wet granulation, liquid is used to increase the intermolecular forces between the particles, which leads to an increase in the integrity of the granule, called the "strength" of the granule. Often, pellet strength is defined as the amount of fluid that is present in the gaps between particles during the granulation process. Examples of liquids that have been found to be effective wet granulation liquids include water, ethanol, isopropyl alcohol, and acetone.

In a typical granulation process, the components of the feed additive form a mixture, and the mixture is granulated to form granulate.

Several types of wet granulation processes can be used to form multiparticulates containing maduramycin. Examples include fluid bed granulation, rotary granulation, and high speed mixers. When granulating in a fluidized bed, air is used to mix or "fluidize" the particles of ammonium maduramycin and / or the carrier in the fluidization chamber. The liquid is then sprayed into this fluidized bed to form granules. During rotational granulation, horizontal disks rotate at high speed, forming a rotating “belt” of maduramycin and / or carrier particles on the walls of the granulation vessel. Liquid is sprayed into this belt to form granules. High speed mixers comprise a stirrer blade or impeller for mixing particles of maduramycin and / or carrier. The liquid is sprayed into a moving bed of particles to form granules. In these processes, the liquid preferably contains a binder and optionally a pH adjuster. Also in these processes, all or part of the carrier can be dissolved in the liquid before the liquid is sprayed onto the particles. Thus, in these processes, the stages of formation of the liquid mixture and the formation of particles from the liquid mixture occur simultaneously.

In another embodiment, particles are formed by displacing a liquid mixture into a solid mass, followed by spheronization or grinding of the mass. In this process, a liquid mixture, which is in the form of a paste-like plastic suspension, is squeezed through a perforated plate or an extrusion die to form a solid mass, often in the form of elongated, solid rods. This solid mass is then pulverized to form multiparticulates. In one embodiment, a solid mass, with or without an intermediate drying step, is placed on a rotating disk having protrusions that break the material down to spheres, spheroids, or rounded rods consisting of multiparticulates. The multiparticles thus formed are then dried to remove any remaining liquid. This process is sometimes referred to in the pharmaceutical industry as an extrusion / spheronization process.

After the formation of particles, part of the liquid is removed, usually at the drying stage, with the formation, thus, of multiparticulates. Preferably, at least 80% of the liquid is removed from the particles, more preferably at least 90% and most preferably at least 95% of the liquid is removed from the particles during the drying step.

Multiparticulates can also be obtained using a granulation process comprising the steps of (a) forming a solid mixture comprising maduramycin, a carrier, a binder and optionally a pH adjuster; and (b) granulating the solid mixture to form multiparticulates. Examples of such granulation processes include dry granulation and melt granulation, both well known in the art. See Remington's Pharmaceutical Sciences (18th Ed. 1990).

An example of a dry granulation process is rolling. In the rolling process, the solid mixture is pressed between the rollers. The rollers can be designed so that the resulting compressed material is in the form of small beads or granules of the desired diameter. On the other hand, the pressed material may be in the form of a tape that can be pulverized to multiparticulate using methods known in the art.

In the melt granulation processes, the solid mixture is fed to a granulator, in which the carrier can be heated or melted. Equipment suitable for use in this process includes high-speed granulators, as well as single or multi-screw extruders, for example, those described above for melting and solidification processes. In the melt granulation processes, the solid mixture is placed in a granulator and heated until the solid mixture is sintered. The solid mixture is then triturated or mixed until the desired particle size is achieved. The granules thus formed are then cooled, removed from the granulator and fractions of the desired size are separated by sieving to form multiparticulates.

Maduramycin animal feed additives can be used at any time to successfully protect poultry or other target animals from coccidiosis. Compositions of a feed additive for animals can, in particular, find application in poultry farms or in the rearing of young poultry, where the costs of combating infections that arise in poultry due to the constant forms of coccidiosis (oocyst) that are constantly excreted in bedding are high. Since there is always a risk of an outbreak of coccidiosis under these circumstances, the compositions of Maduramycin feed additives for animals can be used for poultry constantly and before an outbreak of coccidiosis. However, Maduramycin feed additives for animals can also be prescribed for short periods of time, that is, several days.

The administration of the Maduramycin feed additive compositions for animals and methods for controlling coccidiosis are carried out in the usual manner. In accordance with the localization of coccidiosis in the intestinal tract, oral administration is particularly suitable. In this case, the compositions of maduramycin can be mixed with feed or drinking water.

The concentrations of maduramycin in feed or in drinking water can vary within certain limits, usually from 3 to 10 ppm. Maduramycin in feed or drinking water.

The concentrations of ammonium maduramycin in the anti-coccidiosis preparation are based on the consumption of feed or drinking water as desired, that is, for free feeding or consumption of drinking water during normal feeding in practice or in the growing period. Due to special factors due to practical conditions, it may, however, happen that a poultry specialist will need to increase these practical concentrations if the poultry should be provided with a variety of feeds or water. In this case, however, only part of the feed or water contains maduramycin.

The resulting animal feed, such as cattle, pigs and poultry, is usually supplied in the form of granules or similar particulate material. Pellets are usually made by combining a grain base with components, for example oil and protein, conditioning the mixture with steam (for example, at 70 ° C for 5 minutes), extruding through an annular extrusion die (usually from 2 mm to 15 mm in diameter), cutting into pieces of appropriate size (e.g. 5-20 mm) and drying. Finished granules are usually in the form of cylinders and have a relatively smooth surface.

In one embodiment, an animal feed composition is prepared by adding a maduramycin animal feed additive composition to an animal feed. The animal maduramycin feed additive composition can be added to the feed in a variety of ways. An animal maduramycin feed additive composition containing a predetermined amount of maduramycin can be added to a predetermined amount of feed and ground or mixed to provide a substantially homogeneous feed composition containing a drug substance. Thus, large batches of feed can be obtained to treat a large number of animals. Alternatively, batches of food containing food for a single animal or a separate food can be obtained by mixing a predetermined amount of the Maduramycin animal feed additive composition with animal feed or adding a predetermined amount of premix to the animal feed as the main feed.

The method of treatment can also be extended to other methods of treatment and feeding of poultry. Thus, for example, animal maduramycin feed additive compositions can be combined with other active substances, for example, with other anti-coccidiosis preparations, growth promoting substances, anti-parasitic substances or antibiotics.

Although the Maduramycin feed additive compositions are to some extent aimed at protecting poultry (e.g., chickens and turkeys) from coccidial infections, however, they can also be applied similarly to other domestic and beneficial animals, such as other birds, rabbits, pigs and ruminants.

The invention also includes a method of treating coccidiosis in animals, for example poultry, where the maduramycin feed additive composition for animals is administered to poultry orally "at will" and, in particular, as feed or drinking water.

The invention is further illustrated by the following non-limiting examples.

Examples

Received a batch of feed additives for animals containing maduramycin ammonium. Ammonium maduramycin had an activity of maduramycin-alpha of 92.6% and a water content of 0.8%. Additives were prepared by mixing maduramycin ammonium, a binder and a carrier, followed by stirring, wet granulation and drying. The dried product was sieved with the formation of particles with a size of 150-850 microns. The test formulation is given below.

Cygro® 10% G

Ammonium Maduramycin (alpha activity as indicated), 1.0%; 5.4 g

Sodium carboxymethyl cellulose, 2.0%; 10.0 g

CaSO ₄ · 2H ₂ O (a sufficient amount up to 100.0%); 484.6 g

The stability of two different batches of the Maduramycin feed additive stored in a plastic or paper bag was determined. Data on the stability of the experimental batches of the composition shown in the drawing. As can be seen in the drawing, the Maduramycin feed additive for animals is stable for 12 months.

The advantages of the animal feed additives disclosed herein are good particle size distribution, pH in a good range for maduramycin, fluidity and stability.

The use of terminology in the singular (especially in the context of the following claims) should be considered both the use of the singular and plural, unless otherwise specified here or clearly does not contradict the context. The terms “first,” “second,” etc., as used herein. they are not intended to denote any particular order, but simply for the convenience of denoting a set. The terms “including,” “having,” “including,” and “consisting” should be construed as open terms (that is, meaning “including, but not limited to), unless otherwise indicated. The enumeration of ranges of values is intended merely to serve as a shorthand notation when referring specifically to each individual value within the range, unless otherwise specified here, and each individual value is included in the description as if it were mentioned separately here. The endpoints of all ranges are included within the range and connected independently. All methods described herein may be performed in any suitable order, unless specifically stated herein or clearly contrary to the context. The use of any and all examples or the language of examples (for example, “for example”) is intended merely to better illustrate the invention and does not impose limitations on the scope of the invention, unless otherwise specified. No language in the description should be considered as an indication of an element that is not in the claims, essential and applied in the practice of inventions.

While the present invention has been described with reference to a typical embodiment of the invention, one skilled in the art will recognize that various changes can be made and its elements can be replaced with equivalents without departing from the scope of the invention. In addition, many modifications can be made to adapt a particular situation or material to the idea of the invention without departing from its essential capabilities. Therefore, it is understood that the invention is not limited to the particular disclosed embodiment as the best method selected for implementing this invention, but that the invention will include all embodiments within the scope of the appended claims. Any combination of the above elements in all possible variants is encompassed by this invention, unless otherwise specified or clearly contrary to the context.

All patents, applications, and other references cited herein are hereby incorporated by reference in their entirety.

Claims (12)

1. The composition of a feed additive for animals, containing:
from 0.1 to 10 wt.% of maduramycin ammonium, characterized in that maduramycin ammonium has an activity of maduramycin-alpha more than 90%,
from 75 to 99.8 wt.% media,
from 0.1 to 10 wt.% a binder, and
however, all quantities are given relative to the total weight of the feed additive for animals. 2. The feed additive composition for animals according to claim 1, characterized in that the binder is sodium carboxymethyl cellulose, and the carrier is calcium sulfate dihydrate. 3. The composition of the feed additive for animals according to claim 2, characterized in that the sodium carboxymethyl cellulose is about 2% of the composition. 4. The composition of the feed additive for animals according to claim 2 or 3, characterized in that ammonium maduramycin is about 1% of the composition. 5. The composition of the feed additive for animals according to claim 1, characterized in that it further comprises a pH regulator in an amount up to 5 wt.% Of the total weight of the feed additive. 6. The composition of the feed additive for animals according to any one of claims 1 to 4, characterized in that the composition has a pH from 7.4 to 9. 7. The composition of the feed product for animals containing a feed product for animals and the composition of the feed additive for animals according to any one of claims 1 to 6. 8. The composition of the feed product for animals according to claim 7, characterized in that the feed product is suitable for poultry. 9. A method of obtaining a feed additive composition for animals according to any one of claims 1 to 6, comprising preparing a mixture containing ammonium maduramycin, a carrier and a binder, granulating the mixture to form a granulate. 10. The method according to claim 9, characterized in that the granulate contains particles with a size in the range from 150 to 850 microns. 11. The method according to any one of claims 9 to 10, characterized in that it further comprises a pH regulator in preparing the mixture. 12. A sustainable composition of a feed additive for animals, containing:
1 wt.% Of ammonium maduramycin, characterized in that the ammonium maduramycin has an activity of maduramycin-alpha more than 90%;
97 wt.% Calcium sulfate dihydrate,
2 wt.% Sodium carboxymethyl cellulose, and
however, all quantities are given relative to the total weight of the feed additive.