MADURAMICIN COMPOSITIONS AND METHODS

BACKGROUND

[0001] Coccidiosis is a widespread poultry disease that causes severe pathology in the intestines and ceca of poultry. It is produced by infections with protozoans of the genus Eimeria; some of the most significant of these species are E. tenella, E. acervulina, E. mitis, E. necatrix, E. brunetti, and E. maxima. This disease is generally spread by the birds picking up the organism at its infectious stage in droppings on contaminated litter or ground, or by way of food or drinking water. The disease is manifested by hemorrhage, accumulation of blood in the ceca, passage of blood in the droppings, weakness and digestive disturbances. The disease often terminates in the death of the animal. The fowl that survive severe infections have had their market value substantially reduced as a result of the infection. Coccidiosis is, therefore, a disease of great economic impact and extensive work has been done to find new and improved methods for controlling and treating coccidial infections in poultry.

[0002] Maduramicin is an antibiotic that has been shown to be an effective anticoccidial agent. It is used to treat coccidosis caused, for example, by Eimeria acervulina, E. tenella, E. brunetti, E. maxima, E. necatrix, and E. mivati. Maduramicin has been used to treat coccidial infections in broilers, increasing broiler growth, reducing morbidity and decreasing mortality. It is also useful for treatment of coccidosis in turkeys, horses, swine, cattle and layers.

[0003] Animal feedstuff compositions containing a therapeutic and/or prophylactic level of maduramicin have been prepared by admixing the drug or a salt thereof with the feedstuff directly or by admixing an additive containing the drug with the desired feedstuff. Feed additives are normally prepared by admixing the drug or salt thereof, or a solution of the drug or a salt thereof with an edible substrate such as corn cob grits, soybean feed, corn meal or the like. Typically, maduramitfln is prepared by fermentation of organisms such as Actinomadura yumaensis.

[0004] There remains a need for alternative feed additive compositions comprising maduramicin.

BRIEF SUMMARY

[0005] The above-described and other drawbacks are alleviated by an animal feed additive composition comprising an effective amount of maduramicin ammonium, a carrier, a binder, and optionally a pH regulator.

[0006] Another embodiment includes the use of a maduramicin in the manufacture of a feed additive for treating coccidiosis. The feed additive comprises an effective amount of maduramicin ammonium, a carrier, a binder, and optionally a pH regulator.

[0007] In another embodiment, an animal feed composition comprises an animal foodstuff, and an effective amount of an animal feed additive composition comprising an effective amount of maduramicin ammonium, a carrier, a binder, and optionally a pH regulator.

[0008] In another embodiment, a method of making an animal feed additive composition, comprises forming a mixture comprising 0.1 wt% to 10 wt% of a maduramicin ammonium, 75 wt% to 99.8 wt% of a carrier, 0.1 wt% to 10 wt% of a binder, and 0 wt% to 5 wt% of a pH regulator, wherein all amounts are based on the total weight of the animal feed additive; and granulating the mixture to form a granulate.

[0009] The above-described and other features will be appreciated and understood by those skilled in the art from the following detailed description, drawings, and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figure 1 shows the stability of a test batch according to the present disclosure stored in a plastic and a paper bag. Stability is measured as the percentage of maduramycin alpha present in the test batch as a function of time.

DETAILED DESCRIPTION

[0011] Disclosed herein are animal feed additive compositions comprising a maduramicin ammonium, a binder, a carrier, and optionally a pH regulator. A "feed additive" composition refers to a composition suitable for incorporation into the diet of an animal through incorporation into the animal's food and/or water. In one embodiment, the animal

feed additive is in the form of a granulate. Feed additive compositions are also referred to as feed "pre-mix" compositions.

[0012] Since maduramicin ammonium is the reference standard for maduramicin feed grade materials, all maduramicin concentrations and percentages stated herein, unless indicated otherwise, are calculated as the ammonium equivalent, regardless of the form present (e.g., the free base, complexes or salts other than the ammonium salt, etc.) Maduramicin ammonium is typically prepared by fermentation of Actinomadura yumaensis, followed by extraction to produce a fermentation product containing 90% or more maduramicin ammonium. In one embodiment, the maduramicin ammonium has an alpha maduramicin activity of greater than 90 wt%, specifically greater than 92 wt%.

[0013] The maduramicin comprises 0.1 wt% to 10 wt% of the total weight of the maduramicin animal feed additive composition, specifically 0.5 wt% to 2 wt% maduramicin animal feed additive composition.

[0014] The maduramicin animal feed additive composition also comprises a binder. The term "binder" is well known to those of skill in the art as an agent that holds the components of the formulation together. Suitable binders include, for example, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, gelatin, polyvinylpyrrolidone (PVP), polyvinylalcohol, polyvinylether, hydroxypropylcellulose, potassium alginate, sodium alginate, ethyl cellulose, methylcellulose, microcrystalline cellulose, starch such as partially pregelatinized corn starch, and combinations comprising one or more of the foregoing binders, hi one embodiment, the binder comprises sodium carboxymethylcellulose.

[0015] The binder comprises 0.1 wt% to 10 wt% of the total weight of the maduramicin animal feed additive composition, specifically 0.2 wt% to 5 wt% of the maduramicin animal feed additive composition.

[0016] The maduramicin animal feed additive composition also comprises 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 foregoing carriers. In one embodiment, the carrier comprises calcium sulfate dihydrate.

[0017] The carrier comprises 75 wt% to 99.8 wt% wt% of the total weight of the maduramicin animal feed additive composition, specifically 90 wt% to 98 wt% of the maduramicin animal feed additive composition.

[0018] In one embodiment, the composition has a slightly alkaline pH, that is, a pH of 7.4 to 9.

[0019] The maduramicin animal feed additive composition also optionally comprises a pH regulator. Suitable pH regulators include acids and bases suitable to adjust the pH to the desired level. In one embodiment, the pH regulator comprises a base such as an alkali metal or alkaline earth metal hydroxide, including sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium bicarbonate, and combinations comprising one or more of the foregoing pH regulators.

[0020] The optional pH regulator comprises 0 wt% to 5 wt% of the total weight of the maduramicin animal feed additive composition, specifically 0.05 wt% to 2 wt% of the maduramicin animal feed additive composition.

[0021] The compositions optionally comprise additional agents such as anti-caking agents, flow agents and combinations thereof.

[0022] The maduramicin ammonium, carrier, binder and optional pH regulator are combined to form the animal feed additive composition. In one embodiment, the animal feed additive composition is a multiparticulate composition. The term multiparticulate is intended to refer broadly to small particles regardless of their composition or the manner in which they are formed. The particles generally are of a mean diameter of about 150 to 850 μm.

[0023] In one embodiment, the maduramicin ammonium, carrier and binder are granulated to form the animal feed additive composition. Granulation is a process by which relatively small particles are built up into larger granular particles. In wet-granulation, a liquid is used to increase the intermolecular forces between particles, leading to an enhancement in granular integrity, referred to as the "strength" of the granule. Often, the strength of the granule is determined by the amount of liquid that is present in the interstitial spaces between the particles during the granulation process. Examples of liquids found to be effective wet-granulation liquids include water, ethanol, isopropyl alcohol and acetone.

[0024] In an exemplary granulation process, the components of the animal feed additive are formed into a mixture and the mixture is granulated to form the granulate.

[0025] Several types of wet-granulation processes can be used to form maduramicin- containing multiparticulates. Examples include fluidized bed granulation, rotary granulation and high-shear mixers. In fluidized bed granulation, air is used to agitate or "fluidize" particles of maduramicin ammonium and/or carrier in a fluidizing chamber. The liquid is

then sprayed into this fluidized bed, forming the granules. In rotary granulation, horizontal discs rotate at high speed, forming a rotating "rope" of maduramicin and/or carrier particles at the walls of the granulation vessel. The liquid is sprayed into this rope, forming the granules. High-shear mixers contain an agitator or impeller to mix the particles of maduramicin and/or carrier. The liquid is sprayed into the moving bed of particles, forming granules. In these processes, the liquid preferably comprises the binder and optional pH regulator. Also in these processes, all or a portion of the carrier can be dissolved into the liquid prior to spraying the liquid onto the particles. Thus, in these processes, the steps of forming the liquid mixture and forming particles from the liquid mixture occur simultaneously.

[0026] In another embodiment, the particles are formed by extruding the liquid mixture into a solid mass followed by spheronizing or milling the mass, hi this process, the liquid mixture, which is in the form of a paste-like plastic suspension, is extruded through a perforated plate or die to form a solid mass, often in the form of elongated, solid rods. This solid mass is then milled to form the multiparticulates. In one embodiment, the solid mass is placed, with or without an intervening drying step, onto a rotating disk that has protrusions that break the material into multiparticulate spheres, spheroids, or rounded rods. The so- formed multiparticulates are then dried to remove any remaining liquid. This process is sometimes referred to in the pharmaceutical arts as an extrusion/spheronization process.

[0027] Once the particles are formed, a portion of the liquid is removed, typically in a drying step, thus forming the 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 particle during the drying step.

[0028] The multiparticulates may also be made by a granulation process comprising the steps of (a) forming a solid mixture comprising maduramicin, a carrier, a binder, and optionally a pH regulator; 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).

[0029] An example of a dry granulation process is roller compaction. In roller compaction processes, the solid mixture is compressed between rollers. The rollers can be designed such that the resulting compressed material is in the form of small beads or pellets of the desired diameter. Alternatively, the compressed material is in the form of a ribbon that may be milled to for multiparticulates using methods well known in the art.

[0030] In melt granulation processes, the solid mixture is fed to a granulator that has the capability of heating or melting the carrier. Equipment suitable for use in this process includes high-shear granulators and single or multiple screw extruders, such as those described above for melt-congeal processes. In melt granulation processes, the solid mixture is placed into the granulator and heated until the solid mixture agglomerates. The solid mixture is then kneaded or mixed until the desired particle size is attained. The so-formed granules are then cooled, removed from the granulator and sieved to the desired size fraction, thus forming the multiparticulates.

[0031] The maduramicin animal feed additive compositions may be employed at any time for successfully protecting poultry or other target animals against coccidiosis. The animal feed additive compositions may, in particular, find application in broiler farms or poultry rearing houses for pullets, where a high burden of infection is produced for the poultry population because of the permanent forms of the coccidia (oocysts) which are constantly being excreted in the droppings. Since the risk of a coccidiosis outbreak always exists under these circumstances, the maduramicin animal feed additive compositions may be employed, in the case of poultry, continuously and before the outbreak of coccidiosis. The maduramicin animal feed additive compositions may, however, also be administered during short time intervals, i.e., a few days.

[0032] The administration of maduramicin animal feed additive compositions and methods for combating coccidiosis are carried out in the normal manner, hi accordance with the localization of the coccidia in the intestinal tract, an oral administration is primarily suitable. The maduramicin compositions may in this case be mixed with feedstuffs or with drinking water.

[0033] The maduramicin concentrations in feedstuffs or in drinking water may vary within certain limits, in general between 3 and 10 ppm of the maduramicin in the feedstuff or drinking water.

[0034] The maduramicin ammonium concentrations of the coccidiocidal agents are based on the feed or drinking water preparations ad lib, i.e., for free feed or drinking water consumption during a normal practical fattening or rearing period. Because of special factors due to practical conditions, it may however happen that the poultry expert has to adjust these applied concentrations upwards if the poultry have to be supplied with different feed or water stocks, hi that case, however, only a portion of the feed or water stocks contain maduramicin.

[0035] Manufactured foodstuffs for animals such as cattle, pigs, and fowl are usually provided in the form of pellets or similar particulate material. Pellets are typically manufactured by combining a cereal base with ingredients such as oil and protein, steam conditioning the mixture (for example at 70 ⁰ C for 5 minutes), extruding through a circular die (typically between 2 mm and 15 mm in diameter), cutting into appropriately sized lengths (e.g., 5-20 mm), and drying. The finished pellets are generally cylindrically shaped and have a relatively smooth surface.

[0036] In one embodiment, an animal feed composition is prepared by adding a maduramicin animal feed additive composition to an animal foodstuff. The maduramicin animal feed additive composition may be added to the food in a number of ways. The maduramicin animal feed additive composition containing a given quantity of maduramicin may be added to a given quantity of feed and mixed or blended to provide a substantially homogeneous medicated feed composition. Large feed lots may be prepared in this manner for treating a large number of animals. Alternatively, feed batches containing feed for a single animal or single meal may be prepared either by mixing a predetermined quantity of maduramicin animal feed additive composition with the animal feed or by adding a predetermined quantity of premix to an animal's feed as a top dressing.

[0037] The treatment method can also be extended to other methods for treating and feeding poultry. Thus, for example, the maduramicin animal feed additive compositions may be combined with other active substances, such as, for example, with other anti- coccidiodal agents, growth-promoting agents, antiparasitics, or antibiotics.

[0038] Although the maduramicin feed additive compositions are to a particular extent directed at the protection of poultry (e.g., chickens and turkeys) against coccidial infections, they can, however, also be applied analogously to other domestic and useful animals, such as, for example, other birds, rabbits, pigs and ruminants.

[0039] The invention also includes a method for treating coccidiosis in animals such as poultry, wherein the maduramicin animal feed additive compositions are administered orally ad lib to poultry, and in particular, either as feedstuff or by means of drinking water.

[0040] The invention is further illustrated by the following non-limiting examples.

EXAMPLES

Batches of animal feed additives comprising maduramicin ammonium were produced. The maduramicin ammonium had an alpha maduramicin activity of 92.6% and a water content of 0.8%. The additives were produced by blending the maduramicin ammonium, binder and carrier, followed by mixing, wet shear granulating and drying. The dried product was sieved to give particle sizes of 150-850 μm particles. The test formulation is given below:

Cygro® 10%G

Maduramicin ammonium (alpha - as is), 1.0%; 5.4 g

Sodium carboxymethylcellulose, 2.0%; 10.0 g

CaSCWH ₂ O (QSP 100.0%); 484.6 g

[0041] The stability of two different lots of maduramicin feed additive stored either in a plastic or a paper bag was determined. The stability data for the test batch formulation are shown in Figure 1. As can be seen from Figure 1, through 12 months the maduramicin animal feed additive is stable.

[0042] Advantages of the animal feed additives disclosed herein are good particle size distribution, pH in good range for maduramicin, flowability, and stability.

[0043] The use of the terms "a" and "an" and "the" and similar referents (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms first, second etc. as used herein are not meant to denote any particular ordering, but simply for convenience to denote a plurality. The terms "comprising", "having", "including", and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to") unless otherwise noted. Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are included within the range and independently combinable. All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as"), is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be

construed as indicating any non-claimed element as essential to the practice of the invention as used herein.

[0044] While the invention has been described with reference to an exemplary embodiment, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from the essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims. Any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0045] All cited patents, patent applications, and other references are incorporated herein by reference in their entirety.