WO2009149012A1

WO2009149012A1 - Laidlomycin compositions and methods

Info

Publication number: WO2009149012A1
Application number: PCT/US2009/045837
Authority: WO
Inventors: Dirk Van Malcot
Original assignee: Alpharma, Inc.
Priority date: 2008-06-03
Filing date: 2009-06-01
Publication date: 2009-12-10
Also published as: BRPI0915219A8; BRPI0915219A2

Abstract

The present invention provides an animal feed additive composition comprising an effective amount of a laidlomycin, a carrier, a binder, and optionally a pH regulator, methods of making the animal feed additive compositions, and the use of a laidlomycin in the manufacture of an animal feed additive for increasing the efficiency of feed utilization in domestic animals.

Description

LAIDLOMYCIN COMPOSITIONS AND METHODS

&ckgroundj)f the ^_.Invention

[001] There are many different species of ruminant animals found around the world. Ruminants include cattle, sheep, goats, buffalo, deei, and elk. These animals have a digestive system uniquely different from other animals (including humans, chickens, and pigs). Instead of having only one compartment to the stomach, ruminants have four compartments. The rumen is the largest section of the stomach and is the main digestive area. T ie rumen is filled with billions of microorganisms that are able to break down grass and other coarse vegetation that animals having one stomach cannot digest.

[002] Laidlomycin is an antibiotic that has been showed to inhibit the growth of Gram positive bacteria. Laidlomycin has also been shown to increase the efficiency of feed utilization in domestic animals, especially meat-producing and milk-producing animals, such as cattle. Carbohydrates form a large part of these animals' diets, and the efficiency of carbohydrate utilization is desirably increased by treatment, which encourages intraruminal production of propionate rather than acetate from carbohydrates. Additionally, laidlomycin suppresses rumen lactic acid production, thereby assisting in the prevention or treatment of bloat in ruminant animals.

[003] Animal feedstuff compositions containing a therapeutic and/or prophylactic level of laidlomycin 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, laidlomycin is prepared by fermentation of organisms such as Streptoverticillium eurocidicum.

[004] There remains a need for alternative feed additive compositions comprising laidlomycin.

Brief Summary of the Invention

[005] The above-described and other drawbacks are alleviated by an animal feed additive composition comprising an effective amount of laidlomycin, a carrier, a binder, and optionally a pH regulator. [006] Another embodiment includes the use of a laidlomycin in the manufacture of a feed additive increasing the efficiency of feed utilization in domestic animals. The feed additive comprises an effective amount of laidlomycin, a carrier, a binder, and optionally a pH regulator.

[007] 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 laidlomycin, a carrier, a binder, and optionally a pH regulator.

[008] In another embodiment, a method of making an animal feed additive composition, comprises forming a mixture comprising from 0.1 wt-% to 24.9 wt-% of a laidlomycin, from 75 wt-% to 99.8 wt-% of a carrier, from 0.1 wt-% to 10 wt-% of a binder, and from 0 wt-% to 5 wt-% of a pH regulator, wherein all amounts are based on the total weight of the animal feed additive composition; and granulating the mixture to form a granulate.

[009] 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

[010] Disclosed herein are animal feed additive compositions comprising laidlomycin, 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.

[011] Since laidlomycin propionate potassium is the reference standard for laidlomycin feed grade materials, all laidlomycin concentrations and percentages stated herein, unless indicated otherwise, are calculated as the propionate potassium equivalent, regardless of the form present (e.g., the free base, complexes or salts other than the propionate potassium salt, etc.). Laidlomycin is typically prepared by fermentation ol Streptoverticillium eurocidicum, followed by extraction to produce a fermentation product containing 90% or more laidlomycin. In one embodiment, the laidlomycin has an alpha laidlomycin activity of greater than 90 wt-% and a beta laidlomycin activity of less than 20 wt-%. [012] The laidlomycin comprises from 0.1 wt-% to 24.9 wt-% of the total weight of the laidlomycin animal feed additive composition, specifically from 0.1 wt-% to 15 wt-% laidlomycin animal feed additive composition.

[013] The laidlomycin 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, e.g., sodium carboxymethylcellulose, calcium lignosulfonate, 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 or calcium lignosulfonate.

[014] The binder comprises from 0.1 wt-% to 10 wt-% of the total weight of the laidlomycin animal feed additive composition, specifically from 0.2 wt-% to 5 wt-% of the laidlomycin animal feed additive composition.

[Ul 5] The laidlomycin animal feed additive composition also comprises a carrier. Suitable carriers include, e.g., 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.

[016] The carrier comprises from 75 wt-% to 99.8 wt-% wt-% of the total weight of the laidlomycin animal feed additive composition, specifically from 90 wt-% to 98 wt-% of the laidlomycin animal feed additive composition.

[017] In one embodiment, tLe composition has a slightly alkaline pH, i.e., a pH of 8 to 10.

[018] The laidlomycin 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. [019] The optional pH regulator comprises from 0 wt-% to 5 wt-% of the total weight of the laidlomyciπ animal feed additive composition, specifically from 0.05 wt-% to 2 wt-% of the laidlomycin animal feed additive composition.

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

[021] The laidlomycin, 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 250 to about 850 μm.

[022] In one embodiment, the laidlomycin, 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] Seveial types of wet-granulation processes can be used to form laidlomycin- containing multiparticulates. Examples include fiuidized bed granulation, rotary granulation and high-shear mixers. In fiuidized bed granulation, air is used to agitate or "fluidize" particles of laidlomycin and/or carrier in a fiuidizing chamber. The liquid is then sprayed into this fiuidized bed, forming the granules. In rotary granulation, horizontal discs rotate at high speed, forming a rotating "rope" of laidlomycin 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 laidlomycin 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.

[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 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.

[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 laidlomycin, 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).

[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 described above for melt-congeal processes. In melt granulation processes, the solid mixture is placed into the granulatoi 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 laidlomycin animal feed additive compositions may be employed at any time for improving average daily weight gain and feedlot efficiency in cattle and other target animals. The laidlomycin animal feed additive compositions may, however, also be administered during short time intervals, i.e., a few days.

[031] The administration of laidlomycin animal feed additive compositions and methods for increasing the efficiency of feed utilization in domestic animals are carried out in the normal manner. An oral administration is primarily suitable. The laidlomycin compositions may be mixed with feedstuffs or with drinking water.

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

[033] The laidlomycin concentrations are based on the feed or drinking water preparations ad lib, i.e., for free feed or drinking water consumption during a normal practical fatte iing or rearing period.

[034] Manufactured foodstuffs for animals such as cattle, pigs, and fowl are usually provided in the form of pellets or similar particulate material. Pellets are manufactured, e.g., by combining a cereal base with ingredients such as oil and protein, steam conditioning the mixture (e.g., at 70⁰C 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 mrn), and drying. The finished pellets are generally cylindrieally shaped and have a relatively smooth surface.

[035] In one embodiment, an animal feed composition is prepared by adding a laidlomycin animal feed additive composition to an anin al foodstuff. The laidlomycin animal feed additive composition may be added to the food in a number of ways. The laidlomycin animal feed additive composition containing a given quantity of laidlomycin 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 laidlomycin 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.

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

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

Examples

[038] Four different samples of animal feed additives were produced comprising laidlomycin having an alpha laidlomycin activity of 81.33%, a beta laidlomycin activity of 10.27%, and a water content of 8.4%. The additives were produced by blending the laidlomycin, binder and carrier, followed by mixing, wet shear granulating and drying. The dried product was sieved to give particle sizes of about 250 to about 850 μm.

Example 1 :

Laidlomycin; 60.0 g

Sodium carboxymethylcellulose; 20.0 g

CaSO₄ • 2H₂O (QSP 100.0%); 430.0 g

Example 2:

Laidlomycin; 60.0 g

Sodium carboxymethylcellulose; 10.0 g

Ca(OH)₂; 0.5 g

CaSO₄ • 2H₂O (QSP 100.0%); 429.5 g

Example 3:

Laidlomycin; 60.0 g Calcium lignosulfonate; 20.0 g CaSO₄ • 2H₂O (QSP 100.0%); 420.0 g Example 4:

Laidlomycin; 60.0 g

Calcium lignosulfonate; 20.0 g

Ca(OH)₂; 0.5 g

CaSO₄ • 2H₂O (QSP 100.0%); 419.5 g

[039] The stability of the above four samples of laidlomycin feed additive was determined under stress conditions of 6O⁰C and 75% relative humidity for eight (8) weeks. The amount (wt-%) of laidlomycin was measured by HPLC analysis. The stability data for the test batch formulation are shown in Table 1. As can be seen from Table 1 , the laidlomycin animal feed additive is stable through 8 weeks under stress conditions. Table 1 shows that that the formulation of Example 1 is the best choice and is stable. Examples 3 and 4 show that using calcium lignosulfonate as a binder does not give the same stability as using sodium carboxymethylcellulose. Comparing Example 1 to Example 2, adding Ca(OH)₂ to the formulations may not improve stability.

Table 1.

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

[041] 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.

[042] 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.

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

Claims

What is claimed is:

1. An animal feed additive composition, comprising: an effective amount of a laidlomycin, a carrier, a binder, and optionally a pH regulator.

2. The animal feed additive composition of claim 1, comprising: from 0.1 wt-% to 24.9 wt-% of the laidlomycin, from 75 wt-% to 99.8 wt-% of the carrier, from 0.1 wt-% to 10 wt-% of the binder, and from 0 wt-% to 5 wt-% of the pH regulator, wherein all amounts are based on the total weight of the animal feed additive composition.

3. The animal feed additive composition of claim 1 or 2, in the form of a multiparticulate composition.

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

5. The animal feed additive composition of any one of claims 1 to 4, wherein the laidlomycin is in the form of laidlomycin propionate potassium.

6. The animal feed additive composition of any one of claims 1 to 5, wherein the composition has a pH of 8 to 10.

7. The animal feed additive composition of any one of claims 1 to 6, wherein the binder is sodium carboxymethylcellulose or calcium lignosulfonate, and the carrier is calcium sulfate dihydrate.

8. Use of a laidlomycin in the manufacture of an animal feed additive composition for increasing the efficiency of feed utilization in domestic animals, wherein the animal feed additive comprises: an effective amount of a laidlomycin, a carrier. a binder, and optionally a pH regulator.

9. The use of claim 8, wherein the animal feed additive comprises: from 0.1 wt-% to 24.9 wt-% of the laidlomycin, from 75 wt-% to 99.8 wt-% of the carrier, from 0.1 wt-% to 10 wt-% of the binder, and from 0 wt-% to 5 wt-% of the pH regulator, wherein all amounts are based on the total weight of the animal feed additive composition.

10. The use of claim 8 or 9, wherein the laidlomycin animal feed additive composition is administered either as feedstuff or by means of drinking water.

11. The use of any one of claims 8 to 10, wherein the laidlomycin is in the form of laidlomycin propionate potassium.

12. The use of any one of claims 8 to 11, wherein the binder is sodium carboxymethylcellulose or calcium lignosulfonate, the carrier is calcium sulfate, and the composition has a pH of 8 to 10.

13. An animal feed composition comprising: an animal foodstuff, and an effective amount of an animal feed additive composition comprising an effective amount of laidlomycin, a carrier, a binder, and optionally a pH regulator.

14. The animal feed composition of claim 13, wherein the animal foodstuff is suitable for cattle.

15. The animal feed composition of claim 13 or 14, wherein the laidlomycin is in the form of laidlomycin propionate potassium.

16. The animal feed composition of any one of claims 13 to 15, wherein the animal feed additive composition has a pH of 8 to 10.

17. The animal feed composition of any one of claims 13 to 16, wherein the binder is sodium carboxymethylcellulose or calcium lignosulfonate, and the carrier is calcium sulfate dihydrate.

18. A method of making an animal feed additive composition, comprising forming a mixture comprising: from 0.1 wt-% to 24.9 wt-% of a laidlomycin, from 75 wt-% to 99.8 wt-% of a carrier, from 0.1 wt-% to 10 wt-% of a binder, and from 0 wt-% to 5 wt-% of a pH regulator, wherein all amounts are based on the total weight of the animal feed additive composition; and granulating the mixture to form a granulate.

19. The method of claim 18, wherein the laidlomycin is in the form of laidlomycin propionate potassium.

20. The method of claim 18 or 19, wherein the binder is sodium carboxymethylcellulose or calcium lignosulfonate, the carrier is calcium sulfate dihydrate, and the composition has a ρH of 8 to 10,