AU2009256444B2

AU2009256444B2 - Lasalocid compositions and methods

Info

Publication number: AU2009256444B2
Application number: AU2009256444A
Authority: AU
Inventors: Dirk Van Malcot
Original assignee: Zoetis Services LLC
Current assignee: Zoetis Services LLC
Priority date: 2008-06-03
Filing date: 2009-06-01
Publication date: 2015-09-03
Anticipated expiration: 2029-06-01
Also published as: AU2009256444A1; ZA201008384B; EP2285241A4; EP2285241A1; MY162336A; WO2009149011A1

Abstract

The present invention provides an animal feed additive composition comprising an effective amount of lasalocid sodium, a carrier, and a binder, methods of making the animal feed additive compositions, and the use of lasalocid sodium in the manufacture of an animal feed additive composition for controlling coccidiosis.

Description

WO 2009/149011 PCT/US2009/045834 LASALOCID COMPOSITIONS AND METHODS Background of the Invention [001] Coccidiosis is an intestinal disease that affects several animal species, presenting a particularly important problem in the raising of poultry and cattle. Coccidiosis is primarily a disease of the young where there is crowding, stress, and/or nonimmune animals. Older cows act as a reservoir and shed oocysts into the environment. Shipping, weaning, dietary changes, and steroid therapy can precipitate Coccidiosis. Even cattle immune to their own endemic species of coccidia can become ill when exposed to different species. Coccidiosis may result in death. [002] The causative agent of coccidiosis is a protozoan that has the ability to rapidly multiply. Damage is incurred by the rapid multiplication of the parasite in, and the subsequent rupture of, cells of the intestinal lining. Several species of coccidia occur in cattle but Eimeria zuemii and Eimeria bovis are the most frequently isolated species associated with the disease. [003] Bovine coccidia undergo various stages of development. Infection gives rise to a microscopic egg (called an oocyst), which is passed out in manure. Under proper conditions, the oocyst develops within three to seven days to form a sporulate oocyst, which is capable of infecting other cattle. The sporulated oocyst contains eight bodies (called sporozoites), each of which is capable of entering a cell in the animal's intestine. When sporozoites enter intestinal cells, they divide several times, and each resulting offspring is capable of entering another intestinal cell. Male and female cells are produced. The male fertilizes the female to produce an oocyst, which in turn ruptures the intestinal cell and is passed in the manure. Thousands of oocysts may be passed in the manure of an infected animal. [004] Lasalocid is an antibiotic that has been shown to prevent coccidiosis in chickens, turkeys, sheep, partridges, and rabbits. It is also used to control coccidiosis in cattle be an effective coccidiostatic and antibacterial agent. [005] Animal feedstuff compositions containing a prophylactic level of lasalocid 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 2 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, lasalocid is prepared by fermentation of organisms such as Streptomyces. [006) There remains a need for alternative feed additive compositions comprising lasalocid. 5 Brief Summary of the Invention [007] Advantageously, the above-described and other drawbacks may be alleviated by an animal feed additive composition comprising an effective amount of lasalocid sodium, a carrier, and a binder. [008] The present invention generally relates to the use of a lasalocid in the manufacture of a 10 feed additive for preventing coecidiosis. The feed additive comprises an effective amount of lasalocid sodium, a carrier, a binder, and optionally a colorant, [009] The present invention also generally relates to an animal feed composition comprises an animal foodstuff, and an effective amount of an animal feed additive composition comprising an effective amount of lasalocid sodium, a carrier, a binder, and optionally a colorant. is [010] The present invention also generally relates to a method of making an animal feed additive composition, comprising forming a mixture comprising from 0.1 wt-% to 30 wt-% of lasalocid sodium, from 69.9 wt-% to 99.8 wt-% of a carrier, from 0.1 wt-% to 10 wt-% of a binder, and 0 wt-% to 5 wt-% of a colorant, wherein all amounts are based on the total weight of the animal feed additive composition; and granulating the mixture to form a granulate. 20 [010A] In one aspect, the present invention provides an animal feed additive composition, comprising: from 0. 1 wt-% to 30 wt-% of lasalocid sodium as the only active ingredient, from 69.9 wt-% to 99.8 wt-% of calcium sulfate dihydrate, from 0.1 wt-% to 10 wt-% of a binder, and optionally a colorant, 25 wherein all amounts are based on the total weight of the animal feed additive composition. e:0S42 1 (GHaMnal Pa5637 AU VON:AM 14AW5 2a [01GB] In another aspect, the present invention provides the use of the animal feed additive composition as described above for controlling or preventing coccidiosis. [0 1 OC] In another aspect, the present invention provides, a method for controlling or preventing coccidiosis comprising administering the animal feed additive composition as described above. s [01 GD] In a further aspect, the present invention provides, an animal feed composition comprising an animal foodstuff, and an effective amount of an animal feed additive composition as described above. [010E] In yet a further aspect, the present invention provides a method of making an animal feed additive composition, comprising forming a mixture comprising: Sfrom 0.] w-% to 30 wt-% of lasalocid sodium as the only active ingredient, from 69.9 wt-% to 99.8 wt-% of calcium sulfate dihydrate, from 0. 1 wt-% to 10 wt=% of a binder, and optionally a colourant, wherein all amounts are based on tie total weight of the animal feed additive composition; and granulating the mixture to form a granulate. [0l ] 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. Detailed Description of the Invention [0 12] Disclosed herein are animal feed additive compositions comprising lasalocid sodium, a 20 binder, a carrier, and optionally a colorant. 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. 6800W542_1 jGHM rs) P$$537 A SONIAM 1410W15 WO 2009/149011 PCT/US2009/045834 3 [013] Since lasalocid sodium is the reference standard for lasalocid feed grade materials, all lasalocid concentrations and percentages stated herein, unless indicated otherwise, are calculated as the sodium equivalent, regardless of the form present (e.g., the free base, complexes or salts other than the sodium salt, etc.) Lasalocid sodium is typically prepared by fermentation of Streptomyces, followed by extraction to produce a fermentation product containing 80% or more lasalocid sodium. [014] The lasalocid sodium comprises from 0.1 wt-% to 30 wt-% of the total weight of the lasalocid animal feed additive composition, specifically from 12 wt-% to 24 wt-% lasalocid animal feed additive composition. [015] The lasalocid 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. In one embodiment, the binder comprises sodium carboxymethylcellulose. [016] The binder comprises from 0.1 wt-% to 10 wt-% of the total weight of the lasalocid animal feed additive composition, specifically from 0.2 wt-% to 5 wt-% of the lasalocid animal feed additive composition. [017] The lasalocid animal feed additive composition also comprises a carrier. Suitable carriers include, for example, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, calcium sulfate dehydrate, mannitol, sorbitol, calcium carbonate, and combinations comprising one or more of the foregoing carriers. In one embodiment, the carrier comprises calcium sulfate dihydrate. [018] The carrier comprises from 69.9 wt-% to 99.8 wt-% wt-% of the total weight of the lasalocid animal feed additive composition, specifically from 79 wt-% to 87.7 wt-% of the lasalocid animal feed additive composition. In one embodiment, the animal feed additive composition consists essentially of from 12 wt-% to 24 wt-% of the lasalocid sodium, from 79 wt-% to 87.7 wt-% of calcium sulfate dihydrate, and from 0.2 wt-% to 5 wt-% of sodium WO 2009/149011 PCT/US2009/045834 4 carboxymethylcellulose, wherein all amounts are based on the total weight of the animal feed additive. [019] In one embodiment, the composition has a colorant in an amount ranging from about 0.01% to about 2%. A specific colorant is Brillant Blue No. 1. [020] The compositions optionally comprise additional agents such as anti-caking agents, flow agents and combinations thereof, [021] The lasalocid sodium, carrier, and binder 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 pim. [022] In one embodiment, the lasalocid sodium, 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. [023] 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. [024] Several types of wet-granulation processes can be used to form lasalocid sodium 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 lasalocid sodium 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 lasalocid sodium 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 lasalocid sodium WO 2009/149011 PCT/US2009/045834 and/or carrier. The liquid is sprayed into the moving bed of particles, forming granules. 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. [025] In another embodiment, the particles are formed by extruding the liquid mixture into a solid mass followed by spheronizing or milling the mass. In 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 fonn 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. [026] 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. [027] The multiparticulates may also be made by a granulation process comprising the steps of (a) forming a solid mixture comprising lasalocid, a carrier, and a binder; 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). [028] 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. [029] 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 WO 2009/149011 PCT/US2009/045834 6 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. [030] The lasalocid animal feed additive compositions may be employed at any time for successfully protecting cattle, poultry or other target animals against coccidiosis. The animal feed additive compositions may 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 lasalocid animal feed additive compositions may be employed, in the case of poultry, continuously and before the outbreak of coccidiosis. The lasalocid animal feed additive compositions may, however, also be administered during short time intervals, i.e., a few days. [031] The lasalocid animal feed additive compositions may also be employed to control coccidiosis due to Eimeria bovis and Eimeria zuernii in cattle. Additionally, the lasalocid animal feed additive composition may be used to prevent coccidiosis due to Eimeria ovina, E. crandallis, E. ovinaoidalis, E.ninakohlyakimovae, E. parva, and E. intricate in sheep. The lasalocid animal feed additive compositions may also be used to prevent coccidiosis due to Eimeria meleagrimitis, E. gallopavonis, and . adenoeides in turkeys, Eimeria legionensis in Chukar Partridges, and F. stiedae in rabbits. The lasalocid animal feed additive compositions may further be used to improve weight gain and/or feed efficiency in animals. [032] The administration of lasalocid animal feed additive compositions and methods for combating coccidiosis are carried out in the normal manner. In accordance with the localization of the coccidia in the intestinal tract, an oral administration is primarily suitable. The lasalocid compositions may in this case be mixed with feedstuffs or with drinking water. [033] The lasalocid concentrations in feedstuffs or in drinking water may vary within certain limits, in general between 3 and 10 ppm of the lasalocid in the feedstuff or drinking water. [034] The lasalocid sodium 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 WO 2009/149011 PCT/US2009/045834 7 a normal practical fattening or rearing period. Because of special factors due to practical conditions, it may however happen that the cattle or poultry expert has to adjust these applied concentrations upwards if the poultry have to be supplied with different feed or water stocks. In that case, however, only a portion of the feed or water stocks contain lasalocid. [035] 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'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. [036] In one embodiment, an animal feed composition is prepared by adding a lasalocid animal feed additive composition to an animal foodstuff. The lasalocid animal feed additive composition may be added to the food in a number of ways. The lasalocid animal feed additive composition containing a given quantity of lasalocid 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 lasalocid 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. [037] The treatment method can also be extended to other methods for treating and feeding animals. Thus, for example, the lasalocid 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. A preferred combination is lasalocid sodium and chlortetracycline. [038] The invention also includes a method for treating coccidiosis in animals such as cattle or poultry, wherein the lasalocid animal feed additive compositions are administered orally ad lib, and in particular, either as feedstuff or by means of drinking water. [039] The invention is further illustrated by the following non-limiting examples.

WO 2009/149011 PCT/US2009/045834 8 Example [040] Batches of animal feed additives comprising lasalocid sodium were produced. The additives were produced by blending the lasalocid sodium, binder and carrier, followed by mixing, wet shear granulating and drying. The dried product was sieved to give particle sizes of 150-850 pm. The test formulation is given below: Lasalocid Sodium (alpha - as is), 20.0 %; Sodium carboxymethylcellulose, 2.0 %; Brillant Blue Colorant Dualake FD&C, 0.05 % CaSO4 - 2 H 2 0 (QSP 100.0 %), to 100 %. [041] The stability of three different lots of lasalocid feed additive stored either in a plastic or a paper bag was determined. For each lot, eight multi-layer paper bags and eight polyethylene bags containing 1.5 kg of sample were labeled and placed in a validated controlled climate chamber at 250 C and 60% Relative Humidity. For each lot, five multi layer paper bags and five polyethylene bags containing 1.5 kg of sample were labeled and placed in a validated controlled climate chamber at 400 C and 75% Relative Humidity. At each of the two test conditions, the required individual sample bags were taken from the environmentally controlled chamber and the door of the chamber was closed securely immediately following the removal of the sample. The amount of lasalocid sodium (as a percentage) was determined by HPLC Test Method TCA-020. The stability data for the test batch formulations are shown in Tables 1 to 3. As can be seen from Tables 1 to 3, through 6 months the lasalocid animal feed additive is stable. Table 1. Lot 1. Paper Bag Plastic Bag Paper Bag Plastic Bag Time 25'C/60% RH; 25 C/60% RH; 40 C/75% RH; 40 C/75% RH; (Months) % lasalocid % lasalocid % lasalocid % lasalocid sodium sodium sodium sodium i 0 19.4 19.4 19.4 19.4 3 19.0 18.9 18.5 19.0 6 18.8 18.9 18.7 19.0 WO 2009/149011 PCT/US2009/045834 9 Table 2. Lot 2 Paper Bag Plastic Bag Paper Bag Plastic Bag Time 25 C/60% RH; 250 C/60% RH; 40 C/75% RH; 400 C/75% RH; (Months) % lasalocid % lasalocid % lasalocid % lasalocid sodium sodium sodium sodium 0 20.0 20.0 20.0 20.0 .......... -- ------ --- - *- -- ----------- ------ -- 3 19.5 19.5 19.4 19.6 -------------- ---- ----- - - --- .. .. - - -- 6 19.6 19.7 19.7 19.7 Table 3. Lot 3 Paper Bag Plastic Bag Paper Bag Plastic Bag Time 250 C/60% RH; 250 C/60% RH; 400 C/75% RH; 400 C/75% RH; (Months) % lasalocid % lasalocid % lasalocid % lasalocid odiun sodium sodium sodium 0 20.8 20.8 20.8 20.8 3 20.4 20.4 20.1 20.3

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6 20.3 20.3 20.3 20.3 [042] Advantages of the animal feed additives disclosed herein are good particle size distribution, flowability, and stability. [043] 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 10 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 S used herein. [044] 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 front the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the 10 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 15 otherwise indicated herein or otherwise clearly contradicted by context. [045] All cited patents, patent applications, and other references are incorporated herein by reference in their entirety. (046] It is to be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general 20 knowledge in the art, in Australia or any other country. 6$00542 1 (G ote) PH6&37 AU SONIAM 14?'N8i

Claims

1. An animal feed additive composition, comprising: from 0. 1 wt-% to 30 wt-% of lasalocid sodium as the only active ingredient, from 69.9 wt-% to 99.8 wt-% of calcium sulfate dihydrate, s from 0. I wt-% to I0 wt-% of a binder, and optionally a colorant, wherein all amounts are based on the total weight of the animal feed additive composition.

2. The animal feed additive composition of claim 1, comprising: from 12 wt-% to 24 wt-% of lasalocid sodium, from 79 wt-% to 87.7 wt-% of calcium sulfate dihydrate, and ro from 0.2 wt-% to 5 wt-% of the binder, wherein all amounts are based on the total weight of the animal feed additive composition.

3. The animal feed additive composition of claim I or claim 2, in the form of a multiparticulate composition.

4. The animal feed additive composition of claim 3, wherein the multiparticulate composition is 15 a granulate.

5. The animal feed additive composition of any one of claims I to 4, wherein the binder is sodium carboxymethylcellulose.

6. Use of the animal feed additive composition as defined in any one of claims I to 5 for controlling or preventing coccidiosis. 20 7. A method for controlling or preventing coccidiosis comprising administering the animal feed additive composition as defined in any one of claims I to 5.

8. The use of claim 6 or the method of claim 7, wherein the coccidiosis is coccidiosis in poultry or cattle, PM00542 1 I(GHnv P5537 AU SOMAM 14VU1 5 9, The use or method of any one of claims 6 to 8, wherein the animal feed additive composition is administered either as feedstuff or by means of drinking water,

10. An animal feed composition comprising: an animal foodstuff, and an effective amount of an animal feed additive composition as defined in any one of claims I to 5. i1. The animal feed composition of claim 10, wherein the animal foodstuff is suitable for cattle or poultry.

12. A method of making an animal feed additive composition, comprising forming a mixture comprising: from 0.1 wt-% to 30 wt-% of lasalocid sodium as the only active ingredient, from 69.9 wt-% to 99.8 wt-% of calcium sulfate dihydrate, from 0.1 wt-% to 10 wt-% of a binder, and optionally a colourant, is wherein all amounts are based on the total weight of the animal feed additive composition; and granulating the mixture to form a granulate.

13. The method of claim 12, wherein the animal feed additive composition comprises: from 12 wt-% to 24 wt-% of lasalocid sodium, from 79 wt-% to 87.7 wt-% of calcium sulfate dihydrate, and 20 from 0.2 wt-% to 5 wt-% of the binder, wherein all amounts are based on the total weight of the animal feed additive composition.

14. The method of claim 12 or claim 13, wherein the binder is sodium carboxymethylcellulose.

15. The animal feed additive composition of claim 1, the use of claim 6., the method of claim 7, the animal feed composition of claim 10, or the method of claim 12; substantially as herein 25 described with reference to the example. 6600W21 (G;Mers) PB5537.AU SOMAM I4c/15S