WO2009026115A1

WO2009026115A1 - Palatable microgranules for acidifying feed rations

Info

Publication number: WO2009026115A1
Application number: PCT/US2008/073237
Authority: WO
Inventors: Steven Andrew Webb; Gavin Bowman
Original assignee: Novus International Inc.
Priority date: 2007-08-17
Filing date: 2008-08-15
Publication date: 2009-02-26

Abstract

The present invention provides a palatable microgranule for acidifying the feed rations of mammals. In particular, the microgranule comprises a core material having a mixture of anionic salts and a shell wall that encapsulates the core material.

Description

PALATABLE MICROGRANULES FOR ACIDIFYING FEED RATIONS

FIELD OF THE INVENTION

[0001] The present invention relates to microgranules for acidifying animal feed rations. The microgranules comprise a core material having a mixture of anionic salts encapsulated by a shell wall.

BACKGROUND OF THE INVENTION

[0002] Dairy cattle are prone to several diet related metabolic disorders.

Milk fever, for example, is an economically important metabolic disorder of dairy cattle that results when a cow's calcium homeostatic mechanisms fail to maintain normal plasma calcium concentrations at the onset of lactation. It has been estimated that milk fever may effect up to 10% of cows at calving at a cost of approximately $334 per occurrence (Guard, C. (1996) Fresh cow problems are costly: culling hurts the most. Page 100 in Proc. 1994 Ann. Conf. Vet., Cornell Univ., Ithaca, NY). As cows age, the incidence of milk fever increases dramatically, likely due to the decline in the ability to mobilize calcium from bone store, and a decline in the active transport of calcium in the intestine. If left untreated, milk fever may result in a disruption of neuromuscular function, and ultimately, mammal death in severe cases.

[0003] One treatment for milk fever is to infuse calcium borogluconate solutions into the affected mammal. Although this treatment is usually effective, it is relatively expensive, and may cause overly high concentrations of plasma calcium. High concentrations of plasma calcium, in turn, may trigger cardiac arrest in some mammals.

[0004] Various dietary strategies for treating or preventing milk fever have been utilized. Feeding acidifying diets prior to calving has been shown to significantly reduce the incidence of milk fever. The aim of each dietary strategy is to maintain an appropriate dietary cation/anion difference (DCAD) at the onset of lactation. One approach is to feed inorganic acids, such as a combination of sulphuric and hydrochloric acids, to postpartum cows. Although this approach is effective, inorganic acids are dangerous and difficult to use on a farm in their concentrated liquid form. Alternatively, another approach is to adsorb strong acids (e.g., hydrochloric acid) onto organic dry material, such as beet pulp and canola, which can be consumed by the mammal. Adsorbing strong acids onto organic carriers, however, is generally not cost effective. For example, the chloride fraction cannot be highly concentrated on organic substrates, which makes transporting the product, particularly for long distances, uneconomical. Another option for treating or preventing milk fever is to supplement the diet of dairy cattle with anionic salts. Commonly used sources of anions include the chloride ion or sulfur containing ion salts of calcium, ammonium, and magnesium. These anionic salts, however, are often not palatable to mammals, which in turn, can reduce dietary feed intake and limits the therapeutic value.

[0005] A need, therefore, exists for a treatment option for milk fever that can effectively acidify the diet of dairy cattle in a cost effective manner. In addition, the treatment option, when combined with the feed ration, needs to be palatable and acceptable to the animal.

SUMMARY OF THE INVENTION

[0006] One aspect of the invention encompasses a microgranule. The microgranule comprises a core material consisting essentially of at least two anionic salts and a shell wall that encapsulates the core material.

[0007] Another aspect of the invention provides a method for acidifying the diet of a mammal without negatively impacting the palatability of the diet. The method comprising combining the mammal's feed ration with a microgranule. The microgranule comprises a core material consisting essentially of at least two anionic salts and a shell wall that encapsulates the core material.

[0008] A further aspect of the invention provides a method for treating a metabolic disorder in a mammal. The metabolic disorder results from a failure of the mammal's calcium homeostatic mechanisms. The method comprises administering to the mammal a microgranule comprising a core material consisting essentially of at least two anionic salts and a shell wall that encapsulates the core material. [0009] Still another aspect of the invention encompasses a ruminant feed ration. The feed ration comprises a grain portion, a forage portion, and a microgranule. The microgranule comprises a core material consisting essentially of at least two anionic salts and a shell wall that encapsulates the core material.

[0010] Other aspects and features of the invention are described in more detail herein.

FIGURES

[0011] Figure 1 depicts a schematic of an embodiment of a microgranule of the invention.

DETAILED DESCRIPTION OF THE INVENTION

[0012] The present invention provides microgranules that comprise a core material having a mixture of anionic salts encapsulated by a shell wall. Because the shell wall encapsulates the core material, the anionic salts are generally not released until they reach the gastrointestinal tract of the mammal after their passage through the mammal's oral cavity. As such, the microgranules provide a means to acidify the diet of a mammal without negatively impacting the palatability of the mammal's feed ration. The microgranules may be utilized to treat or prevent several dietary-related metabolic disorders including clinical and subclinical milk fever, hypocalcaemia, and ketosis.

/. Microgranules

[0013] The microgranule of the present invention generally comprises a core material comprising at least two anionic salts and a shell wall that encapsulates the core material.

(a) core material

[0014] The core material comprises at least two different anionic salts.

Alternatively, the core material may comprise three, four, or five or more different anionic salts. As utilized herein the term "anionic" includes salts that have at least one negatively charged ion. Generally speaking, the anionic salts will comprise chloride ions and/or sulfate ions. In an exemplary embodiment, the anionic salts will comprise at least one chloride and at least one sulfate. Suitable anionic salts include ammonium chloride, ammonium sulfate, calcium chloride, calcium sulfate, magnesium sulfate, and magnesium chloride. In an exemplary embodiment, the anionic salts are ammonium chloride, ammonium sulfate, and calcium chloride.

[0015] The concentration of anionic salts comprising the core material can and will vary without departing from the scope of the invention. In some embodiments, the concentration of anionic salts in the core material is from about 1 % to about 99% by weight of the microgranule. In additional embodiments, the concentration of anionic salts in the core material is greater than about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or greater than about 90% by weight of the microgranule. In yet another embodiment, the concentration of the anionic salts in the core material is from about 40% to about 60% by weight of the microgranule. In one exemplary embodiment, the microgranule comprises from about 25% to about 35% by weight ammonium chloride, from about 5% to about 15% by weight ammonium sulfate, and from about 5% to about 15% by weight calcium chloride. In another exemplary embodiment, the microgranule comprises about 29% by weight ammonium chloride, about 11 % by weight ammonium sulfate, and about 10% by weight calcium chloride.

[0016] Typically, the anionic salts are solids, such as crystals or powders.

In an exemplary embodiment, the anionic salts are ground to form a powder of an appropriate particle size. The particle size of the anionic salt may be an important factor that can effect bioavailability, blend uniformity, segregation, and flow properties. In general, smaller particle sizes increase the bioabsorption rate of the anionic salts by increasing the surface area. In various embodiments, the average particle size of the powder of the anionic salts is less than about 100 microns in diameter, or less than about 90 microns in diameter, or less than about 80 microns in diameter, or less than about 70 microns in diameter, or less than about 60 microns in diameter, or less than about 50 microns in diameter, or less than about 40 microns in diameter, or less than about 30 microns in diameter, or less than about 20 microns in diameter, or less than about 15 microns in diameter, or less than about 10 microns in diameter, or less than about 5 microns in diameter, or less than about 1 microns in diameter.

(b) shell wall

[0017] The shell wall generally "encapsulates" the core material comprising anionic salts. As used herein, the term "encapsulate" means that the shell wall coats and surrounds the core material. In this manner, the shell wall generally is constructed such that it protects the core material during storage, but that upon ingestion by the mammal, the shell wall will be compromised to permit release of the core material in the mammal's gastrointestinal tract. In this context, the shell wall substantially prevents release of the anionic salts comprising the core material in the mammal's oral cavity and thereby acidifies the diet without negatively impacting palatability of the feed ration. The microgranule may comprise one shell wall layer or many shell wall layers, of which the layers may be of the same material or different materials. Typically, the shell wall will comprise materials that are substantially water impermeable. Suitable materials for forming the shell wall are described below.

[0018] In one embodiment, the shell wall material may comprise a polysaccharide or a mixture of saccharides and glycoproteins extracted from a plant, fungus, or microbe. Non-limiting examples include corn starch, wheat starch, potato starch, tapioca starch, cellulose, hemicellulose, dextrans, maltodextrin, cyclodextrins, inulins, pectin, mannans, gum arabic, locust bean gum, mesquite gum, guar gum, gum karaya, gum ghatti, tragacanth gum, funori, carrageenans, agar, alginates, chitosans, or gellan gum.

[0019] In another embodiment, the shell wall material may comprise a protein. Suitable proteins include, but are not limited to, gelatin, casein, collagen, whey proteins, soy proteins, rice protein, and corn proteins.

[0020] In still another embodiment, the shell wall material may comprise an edible wax. Edible waxes may be derived from mammals, insects, or plants. Non- limiting examples include beeswax, lanolin, bayberry wax, carnauba wax, and rice bran wax. The shell wall material may also comprise a mixture of biopolymers. As an example, the shell wall material may comprise a mixture of a polysaccharide and a fat.

[0021] In yet another embodiment, the shell wall material may comprise a semi-synthetic polymer. Semi-synthetic polymers include, but are not limited to, semisynthetic celluloses and semi-synthetic starches. The semi-synthetic celluloses include methylcellulose, ethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sulfonated cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimelitate, cellulose ethyl phthalate, and viscose. Suitable semi-synthetic starches include water-soluble starch, carboxymethylated starch, dialdehyde starch, hydrophobically modified starch, oxidized starch, etherified starch, and esterified starch.

[0022] In an exemplary embodiment, the shell wall will comprise a lipid material. The lipid material can be derived from animal or vegetable origins, such as, for example, palm kernel oil, soybean oil, cottonseed oil, canola oil, and poultry fat. Generally, the lipid is preferably hydrogenated, and can be saturated or partially saturated. Examples of suitable lipid materials include, but are not limited to, monoglycehdes, diglycehdes, fatty acids, esters of fatty acids, phospholipids, salts thereof, and combinations thereof.

[0023] Monoglycehdes and diglycehdes can be formed naturally in a biological system, as well as by partial or complete hydrolysis of triglycerides and distillation in commercial manufacturing. These methods are known to those skilled in the art. Monoglycerides, also known as monoacylglycerols, are molecules made up of a glycerol and a fatty acid bound as an ester. Diglycerides (i.e., diacylglycerols) are molecules made up of a glycerol and two fatty acids, each fatty acid is bound to the glycerol as an ester. Depending upon the nature of the fatty acid molecule(s) contained in the mono- or diglyceride, the properties of the lipid material may vary.

[0024] Phospholipids can be, for example, monoacyl and diacyl phospholipids. Examples of phospholipids include, but are not limited to, phosphatidic acid, phosphatidyl choline, phosphatidyl ethanolamine, phosphatidyl inositol, phosphatidyl serine, phosphatidyl glycerol, and diphosphatidyl glycerol. [0025] The fatty acids can have a carbon chain length of about 4 carbon atoms to about 24 carbon atoms. In an exemplary embodiment, the fatty acid will have a carbon chain length from about 12 carbon atoms to about 18 carbon atoms. The fatty acid can be saturated or unsaturated (e.g., partially saturated), in free form or estehfied to glycerol. Examples of such fatty acids include, but are not limited to lauric acid, myhstic acid, palmitic acid, stearic acid, palmitoleic acid, oleic acid, ricinoleic acid, and linoleic acid.

[0026] The fatty acid esters can be mono- or diglycerol esters formed from fatty acids having from 4 to 24 carbon atoms, such as for example glyceryl distearate, glyceryl monostearate, glyceryl dipalmitate, glyceryl monopalmitate, glyceryl dilaurate, glyceryl didocosanoate, glyceryl monodocosanoate, glyceryl monocaprate, glyceryl dicaprate, glyceryl monomyhstate, glyceryl dimyristate, glyceryl monodecenoate, or glyceryl didecenoate.

[0027] The lipid material is preferably a food grade lipid material. Some examples of food grade lipid materials include sorbitan monostearates, sorbitan tristearates, calcium stearoyl lactylates, and calcium stearoyl lactylates. Examples of food grade fatty acid esters that are lipid materials include acetic acid esters of mono- and diglycerides, citric acid esters of mono- and di-glycehdes, lactic acid esters of mono- and di-gylcerides, polyglycerol esters of fatty acids, propylene glycol esters of fatty acids, and diacetyl tartaric acid esters of mono- and diglycerides.

[0028] The shell wall may comprise from about 1 % to about 99% by weight of the microgranule. More typically, the shell wall will comprise about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, or about 20% by weight of the microgranule. In one exemplary embodiment, the shell wall will comprise from about 40% to 60% by weight of the microgranule. In another exemplary embodiment, the shell wall will comprise about 50% by weight of the microgranule. (c) physical properties of the microgranule

[0029] The size and shape of the microgranules can and will vary without departing from the scope of the present invention. Generally, their size may be measured in terms of the diameter of a sphere that occupies the same volume as the microgranule being measured. The characteristic diameter of a microgranule may be directly determined, for example, by inspection of a photomicrograph. Typically, a microgranule of the present invention may have an average diameter from 10 to about 10,000 microns. More typically, the microgranule will have an average diameter of about 5000, about 4500, about 4000, about 3500, about 3000, about 2500, about 2000, about 1500, about 1000, about 500, or less than about 100 microns. In an exemplary embodiment, the microgranule will have an average diameter from about 100 to about 1500 microns.

[0030] The size distribution of a sample of microgranules may be measured using a particle analyzer by a laser light scattering technique. Generally, particle size analyzers are programmed to analyze particles as though they were perfect spheres and to report a volumetric diameter distribution for a sample on a volumetric basis. An example of a suitable particle analyzer is the Malvern Zeta Sizer (Malvern Instruments, Worcestershire, UK).

[0031] The thickness of a microgranule shell wall may be an important factor in some instances. Shell walls that are too thin may have insufficient integrity to withstand mechanical forces and may not remain intact. Shell walls that lack mechanical integrity may be prone to defects and destruction, thereby allowing access of water to the core material. Shell walls that are too thick may be uneconomical and may delay release of the core materials in the digestive tract. The thickness of a microgranule shell wall of the present invention may be expressed as a percentage representing the ratio of the weight of the shell wall to the weight of the core material. Accordingly, the weight ratio of shell wall to core material may be less than about 65% (e.g., between about 1 % or 5% and about 65%). Alternatively, the weight ratio may be less than about 35% (e.g., between about 1 % and 35%). In still another embodiment, the weight ratio is less than about 15% (e.g., between about 1 % and 15%). Generally then, for microgranules having a shell wall to core material weight ratio between about 5% and about 15%, the equivalent thickness of shell wall is between about 1.5% and about 5% of the diameter of a microgranule. By way of example, the equivalent shell wall thickness of a microgranule having a diameter between about 0.1 and about 60 microns may typically be between about 0.001 and about 4 micrometers microns. Likewise, for microgranule diameters between about 1 and about 30 microns, the equivalent shell wall thickness may be between about 0.01 and about 2 microns. For microgranule diameters between about 1 and about 6 microns, the equivalent shell wall thickness may typically be between about 0.01 and about 0.4 microns.

(d) methods of encapsulation

[0032] As will be appreciated by a skilled artisan, the encapsulation method can and will vary depending upon the compounds used to form the core material and shell wall, and the desired physical characteristics of the microgranules themselves. Additionally, more than one encapsulation method may be employed so as to create a multi-layered microgranule, or the same encapsulation method may be employed sequentially so as to create a multi-layered microgranule. Methods of encapsulation may include spray drying, spinning disk encapsulation (also known as rotational suspension separation encapsulation), supercritical fluid encapsulation, air suspension encapsulation, fluidized bed encapsulation, spray cooling/chilling (including matrix encapsulation), extrusion encapsulation, centrifugal extrusion, coacervation, alginate beads, liposome encapsulation, inclusion encapsulation, colloidosome encapsulation, sol-gel encapsulation, and other methods of encapsulation known in the art.

[0033] In one exemplary embodiment, a spray drying encapsulation process may be used. Methods of spray drying encapsulation are well known in the art. For instance, see S. Gouin (2004) Trends in Food Science and Technology 15:330-347 and Langrish and Fletcher (2001 ) Chemical Engineering Process 40:345-354. Spray drying encapsulation may include aqueous two-phase systems (Millqvist et al., (2000) J. Colloid and Interface Science 225:54-61 ) and multiple layered microgranules (Edris and Benrgnstahl (2001 ) Nahrung/Food 45:133-37).

[0034] In another exemplary embodiment, a spinning disk process of encapsulation may be utilized. Methods of encapsulation utilizing the spinning disk method are known in the art (see U.S. Patent Application No. 20060078598). The spinning disk method typically uses an emulsion or suspension including the ingredient and the coating composition. The emulsion or suspension is fed to the disk surface where it can form a thin wetted layer that, as the disk rotates, breaks up into airborne droplets from surface tension forces that induce thermodynamic instabilities. The resulting encapsulated ingredients may be individually coated in a generally spherical shape or embedded in a matrix of the coating composition. Because the emulsion or suspension is not extruded through orifices, this technique permits use of a higher viscosity coating and allows higher loading of the ingredient in the coating.

[0035] In another exemplary embodiment, an air suspension process may be utilized for encapsulation. Methods of encapsulation utilizing an air suspension process are well known in the art (see WO 1997/14408). Generally speaking, the core material is coated with the shell wall while suspended in an upward-moving air stream. The core materials are typically supported by a perforated plate having different patterns of holes inside and outside a cylindrical insert. The holes are generally of a size such that sufficient air is permitted to rise through the outer annular space to fluidize the settling core materials. Most of the rising air, which is generally heated, flows inside the cylinder, causing the core materials to rise rapidly. At the top, as the air stream diverges and slows, the core materials settle back onto the outer bed and move downward to repeat the cycle. Generally, the core materials pass through the inner cylinder many times in a few minutes until the encapsulation process is completed. Methods of fluidized bed encapsulation are also well known in the art. (See S. Gouin, (2004) Trends in Food Science and Technology 15:330-347 for review).

[0036] In a further exemplary embodiment, a fluidized bed process for encapsulation may be employed. Fluidized bed encapsulation may be a top-spray, Wurster, or rotational fluidized bed encapsulation. //. Acidified Feed Rations

[0037] The microgranules of the invention are generally utilized to acidify the diet of a mammal. In the context of the present invention, the term "acidify" generally means that a feed ration to which the microgranules are added will have a lower DCAD compared to the same feed ration not having the microgranules. Because the microgranules acidify the feed ration, generally mammals consuming the feed ration will have a lower urinary pH. The extent to which either a diet's DCAD and/or a mammal's urinary pH are lowered can and will vary depending upon the concentration of microgranules added to the diet. As will be appreciated by a skilled artisan, the concentration of microgranules added to a diet can and will vary depending upon the condition and/or disorder being treated and the species of mammal. By way of non- limiting example, the condition and/or disorder may include conditions and/or disorders resulting from a failure of the mammal's calcium homeostatic mechanisms. Alternatively, the condition and/or disorder may include a condition and/or disorder benefited by lowering a mammal's urinary pH. Each of the foregoing conditions and/or disorders is described in more detail below.

(a) disorders resulting from failure of calcium homeostatic mechanisms

[0038] The microgranules may be administered to a mammal to treat or prevent a disorder and/or condition resulting from a failure of the mammal's calcium homeostatic mechanisms that generally occurs at the onset of lactation. For example, such a failure can occur when a mammal gives birth and a tremendous amount of calcium is put into colostrum and milk. This is particularly true for mammals that produce large quantities of milk, such as dairy cattle, dairy goats or lactating sows. In severe cases, milk fever may result. In less severe cases, the mammal may have a depressed appetite that may result in ketosis. As such, the present invention provides a method for treating disorders or conditions resulting from a failure of the mammal's calcium homeostatic mechanisms, such as hypocalcaemia, milk fever and ketosis.

[0039] Typically, the method comprises administering to the mammal a therapeutically effective amount of the microgranules. It is believed, without being bound to any particular theory, that administering the microgranules increases calcium mobilization and absorption and facilitates the reestablishment of proper blood calcium levels. The microgranules are generally administered to a pregnant dairy mammal from one day to several weeks or months before parturition. In an exemplary embodiment, the microgranules are administered to a pregnant dairy cow for at least 5 days, at least 10 days, at least 15 days, at least 20 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, at least 50 days, at least 55 days, or at least 60 or more days before parturition. In another exemplary embodiment, the microgranules will be administered to a dairy cow from about 1 day to about 21 days before parturition. [0040] The amount of microgranules administered to the mammal can and will vary without departing from the scope of the invention. Generally speaking, the amount administered will lower the DCAD of the feed ration to about 0 to about -300 meq/Kg. More typically, the DCAD of the feed ration will range from about -20 to about -200 meq/Kg. The amount of microgranules administered per mammal per day may be about 50 g, 100 g, 200 g. 300 g, 400 g, 500 g, 750 g, 1000 g, 2000 g, 3000 g, 4000 g, or 5000 g. Stated another way, the amount of microgranule administered to the mammal will generally result in an average urinary pH from about 5.5 to about 6.5.

(b) conditions benefited by lowering urinary pH

[0041 ] Because the microgranules of the invention generally lower urinary pH, they may be utilized to treat or prevent a disorder or condition that is benefited by lowering the pH of the mammal's urine. By way of non-limiting example, one such condition is urinary calculi. Urinary calculi occur when undissolved minerals (especially calcium) form stones that can block the urinary tract of the mammal. It may be caused when mammals are provided diets that are high protein, such as feedlot finishing rations, or by unbalanced diets, such as diets not having a proper balance of minerals. Without being bound by any particular theory, it is believed that the microgranules of the invention lower the pH of the mammal's urine and facilitates dissolution of the stone resulting from urinary calculi. It is also believed that, when administered to the mammal in an effective amount, the microgranules will also aide in preventing the formation of a stone. While certain types of mammals have a higher incidence of developing urinary calculi, such as mammals on high protein diets, the method of the invention may be effective in a variety of mammals including for the treatment or prevention of urinary calculi in companion mammals, such as dogs and cats. A skilled artisan can readily determine the amount of microgranule to administer to a particular mammal for treatment or prevention of urinary calculi.

[0042] The microgranules, irrespective of the condition and/or disorder being treated, may be administered to a mammal by adding them directly to a total feed ration. Alternatively, the microgranules may be administered to the diet of a mammal by mixing them in a premix and then adding the premix to the total feed ration. Suitable premixes and total feed rations are detailed below.

(c) premix

[0043] Another aspect of the invention comprises an animal feed premix comprising the microgranules of the invention. Typically, the premix will be added to various formulations of grain concentrates and forages to formulate a total feed ration. As will be appreciated by the skilled artisan, the particular premix formulation can and will vary depending upon the feed ration and mammal that the feed ration will be fed to. In addition to the microgranules, the premix may further optionally include one or more of a mixture of natural amino acids, analogs of natural amino acids, such as a hydroxyl analog of methionine ("HMTBA"), vitamins and derivatives thereof, enzymes, animal drugs, hormones, effective microorganisms, organic acids, preservatives, flavors, and inert fats.

[0044] In one embodiment, the feed premix will include one or more amino acids. Suitable examples of amino acids, depending upon the formulation, include alanine, arginine, asparagines, aspartate, cysteine, glutamate, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. Other amino acids usable as feed additives include, by way of non-limiting example, N-acylamino acids, hydroxy homologue compounds, and physiologically acceptable salts thereof, such as hydrochlorides, hydrosulfates, ammonium salts, potassium salts, calcium salts, magnesium salts and sodium salts of amino acids.

[0045] In one exemplary embodiment, the microgranules will be combined with a hydroxy analog of methionine ("HMTBA") to form a feed pre-mix. Suitable hydroxyl analogs of methionine include 2-hydroxy-4(methylthio)butanoic acid (sold by Novus International, St. Louis, Mo under the trade name Alimet^®), its salts, esters, amides, and oligomers. Representative salts of HMTBA include the ammonium salt, the stoichiometric and hyperstoichiomethc alkaline earth metal salts (e.g., magnesium and calcium), the stoichiometric and hyperstoichiomethc alkali metal salts (e.g., lithium, sodium, and potassium), and the stoichiometric and hyperstoichiometric zinc salt. Representative esters of HMTBA include the methyl, ethyl, 2-propyl, butyl, and 3- methylbutyl esters of HMTBA. Representative amides of HMTBA include methylamide, dimethylamide, ethylmethylamide, butylamide, dibutylamide, and butylmethylamide. Representative oligomers of HMTBA include its dimers, trimers, tetramers and oligomers that include a greater number of repeating units.

[0046] In still another embodiment, the feed premix will include vitamins or derivatives of vitamins. Examples of suitable vitamins and derivatives thereof include vitamin A, vitamin A palmitate, vitamin A acetate, β-carotene, vitamin D (e.g., D₂, D₃, and D₄), vitamin E, menadione sodium bisulfite, vitamin B (e.g., thiamin, thiamin hydrochloride, riboflavin, nicotinic acid, nicotinic amide, calcium pantothenate, pantothenate choline, pyridoxine hydrochloride, cyanocobalamin, biotin, folic acid, p- aminobenzoic acid), vitamin K, vitamin Q, vitamin F, and vitamin C.

[0047] In yet another embodiment, the feed premix will include one or more enzymes. Suitable examples of enzymes include protease, amylase, lipase, cellulase, xylanase, pectinase, phytase, hemicellulase and other physiologically effective enzymes.

[0048] In still another embodiment, the feed premix will include a drug approved for use in animals. Non-limiting examples of suitable animal drugs include antibiotics such as tetracycline type (e.g., chlortetracycline and oxytetracycline), amino sugar type, ionophores (e.g., rumensin, virginiamycin, and bambermycin) and macrolide type antibiotics.

[0049] In an additional embodiment, the feed premix will include a hormone. Suitable hormones include estrogen, stilbestrol, hexestrol, tyroprotein, glucocorticoids, insulin, glucagon, gastrin, calcitonin, somatotropin, and goitradien.

[0050] In a further embodiment, the feed premix will include an effective microorganism. Examples of suitable effective microorganisms include live and dead yeast cultures, which may be formulated as a probiotic. By way of example, such yeast cultures may include one or more of Lactobacillus Acidophilus, Bifedobact Thermophilum, Bifedobat Longhum, Streptococcus Faecium, Sacchromyces cerevisiae, Bacillus pumilus, Bacillus subtilis, Bacillus licheniformis, Lactobacillus acidophilus, Lactobacillus casei, Enterococcus faecium, Bifidobacterium bifidium, Propionibacterium acidipropionici, Propionibacteriium freudenreichii, Aspergillus oryzae, and Bifidobacterium Pscudolongum.

[0051] In yet another embodiment, the premix will include an organic acid.

Suitable organic acids include malic acid, propionic acid and fumaric acid.

[0052] In still another embodiment, the premix will include a preservative.

Examples of preservatives include natural and synthetic antioxidants. By way of example, natural antioxidants include vitamins E and C. Synthetic antioxidants include ethoxyquin, butylated hydroxytoluene, and butylated hydroxyanisol. In a preferred embodiment, the antioxidant is ethoxyquin.

[0053] In an additional embodiment, the feed premix will include a substance to increase the palatability of the feed ration. Suitable examples of such substances include natural sweeteners, such as molasses, and artificial sweeteners such as saccharin and aspartame.

[0054] In a further embodiment, the feed premix will include an inert fat, such as a ruminally inert fat. Suitable examples of ruminally inert fats include megalac, alifet, and carolac. Some commercially available bypass fats are described, for example, in U.S. Pat. Nos. 5,182,126; 5,250,307; 5,391 ,787; 5,425,963; and 5,456,927 which disclose Ci₄ to C22 fatty acids, their glycerides, or their salts including, but not limited to, palmitic, oleic, linoleic, stearic, and lauric compounds.

[0055] As will be appreciated by the skilled artisan any of the substances that may be included in the premix of the invention can be used alone or in combination with one another. The concentration of these additives will depend upon the application but, in general, will be between about 0.0001 % and about 10% by weight of the dry matter, more preferably between about 0.001 % and about 7.5%, most preferably between about 0.01 % and about 5%.

(d) total feed ration

[0056] A further aspect of the invention encompasses an animal feed ration that will typically contain the microgranules or a premix containing the microgranules. The feed ration may be formulated to meet the nutritional requirements of a variety of mammals including ruminants (e.g., cattle, goats, and sheep), monogastrics (e.g., pigs), or companion animals (e.g., dogs and cats). Those of skill in the art can readily formulate a feed ration to meet the energy demands of a particular mammalian species. Non-limiting examples of typical feed formulations for dairy cattle are detailed below.

[0057] In one embodiment, the feed ration will be formulated for a ruminant and in particular, a dairy cow. In practice, ruminants are typically fed as a ration, commonly referred to as a total mixed ration (TMR), which consists of a forage portion and a grain concentrate portion. The forage portion generally consists of hay, haylage, or silage. The grain concentrate portion is generally prepared by mixing grains such as corn, soy, and alfalfa with any of a variety of premix items such as those identified above (i.e., vitamins, minerals, molasses, fat sources, synthetic amino acids and a variety of other feedstuffs). These ingredients may be prepared using conventional milling techniques that include augehng, mixing, expanding, extruding, and pelleting.

[0058] In one exemplary embodiment, the feed ration is formulated for a dairy cow. As will be appreciated by a skilled artisan, a feed ration for a dairy cow can and will vary greatly depending upon the cow's stage of production. In this context, stage of production not only refers to whether a dairy cow is dry or lactating, but also the duration of time the cow has been in the dry cycle or the lactation cycle. Milestones in the stage of production include the first 35 days dry, known as "far off;" the last 21 days dry, known as "close-up;" day 0 to day 14 of lactation, known as "fresh;" day 14 to day 80 of lactation, known as "peak milk;" days 80 to 200 of lactation, known as "peak intake;" and days 200 to 330 of lactation. Suitable rations for dairy cattle for the first 35 days dry, day 0 to 14 of lactation and day 14 to 80 of lactation are detailed below. In an exemplary embodiment, the microgranules of the invention are typically administered to a pregnant dairy cow from about 10 days to about 60 days before parturition.

[0059] An example of a suitable dairy cow feed ration for a cow in the first

35 days of the dry cycle is as follows:

Percent by Weight (DM basis) Ingredient of Total Feed Composition

Steamrolled Corn 8.0

Wheat straw 8.5

Alfalfa hay 38.0

Corn silage 41.0

Trace Mineral Salts 4.5

[0060] A suitable example of a dairy cow feed ration for a cow at day 0 to

14 of the lactation cycle is as follows:

Percent by Weight (DM basis) Ingredient of Total Feed Composition

Steamrolled Corn 8.0

Soybean meal (44%) 7.5

Alfalfa hay 17.0

Corn silage 47.0

Trace Mineral Salts 4.5

[0061] An example of a suitable dairy cow feed ration for a cow at day 14 to 80 of the lactation cycle is as follows: Percent by Weight (DM basis)

Ingredient of Total Feed Composition

Steamrolled Corn 15.0

Soybean meal (44%) 13.0

Alfalfa hay 22.0

Corn silage 21.0

Distillers grains 8.0

Whole Cottonseed 10.0

Soybean hulls 6.5

Trace Mineral Salts 4.5

[0062] A feed ration may also be formulated to meet the nutritional requirements of non-dairy cattle, and in particular, feedlot cattle. The percentage of each type of component in the cattle diet (i.e. grain to roughage ratio) depends upon the dietary requirements of the particular animal. By way of example, a feed composition typically fed to feedlot cattle on an intermediate or growing diet would include:

Percent by Weight of Ingredient Total Feed Composition

Dehydrated Alfalfa Meal 25.0

Cottonseed Hulls 5.0

Steamrolled Corn 60.0

Soybean meal (44%) 3.0

Calcium Carbonate 1.0

Sodium Thpolyphosphate 0.5

Cane Molasses 5.0

Trace Mineral Salts 0.5

[0063] The intermediate diet contains a moderate energy to roughage ratio and is fed to cattle during their growth stage. After the intermediate diet, a higher energy finishing diet is substituted until the cattle are ready for slaughter. A typical finishing diet would include: Percent by Weight of Ingredient Total Feed Composition

Dehydrated Alfalfa Meal 5.0

Cottonseed Hulls 10.0

Steamrolled Corn 74.8

Soybean meal (44%) 3.0

Calcium Carbonate 0.7

Sodium Thpolyphosphate 0.3

Cane Molasses 5.0

[0064] Standard feed formulations are described in E. W. Crampton et al.,

Applied Animal Nutrition, W. H. Freeman and Company, San Francisco, Calif., 1969 and D. C. Church, Livestock Feeds and Feeding, O & B Books, Corvallis, Oreg., 1977, both of which are incorporated herein by reference.

DEFINITIONS

[0065] The term "DCAD" is an abbreviation for dietary cation/anion difference. DCAD may be calculated by the following formula:

(Na + K) - (Cl + S).

[0066] The term "mammal" includes fur-bearing animals that lactate.

Representative non-limiting examples include humans, cattle, sheep, goats, swine, horses, dogs and cats.

[0067] "DM" is an abbreviation for dry matter.

EXAMPLES

[0068] The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples that follow represent techniques discovered by the inventors to function well in the practice of the invention. Those of skill in the art should, however, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention, therefore all matter set forth or shown in the accompanying drawings is to be interpreted as illustrative and not in a limiting sense.

Example 1. Process for Making The Microgranules.

[0069] Microgranules comprising coated anionic salts may be made by a process that involves the use of a mixer and a heated liquid metering system equipped with at least one spray nozzle. The process begins with the "melting" of the coating substance in a heated tank to a temperature about 10° F (-6° C) higher than its melting point to create a fluid capable of being circulated and sprayed. For example, stearic acid would be heated to a temperature of about 75.6° C. The process continues with the blending of the dry ingredients. For this, the appropriate amounts of the dry components (i.e., ammonium chloride, ammonium sulfate, and calcium chloride powders) are placed into the mixing vessel of a mixer and mixed to form a homogenous mixture. The loading of the mixer should be sufficient to obtain efficient mixing, while allowing for an increase in mass and decrease in bulk density of the overall mixture associated with the addition of the coating.

[0070] Next, the coating substance is metered into the blend of dry ingredients while the mixer is running. The selection of the spray pattern is made based on the mixing environment to minimize "overspray" and control flow rate. The flow rate is variable based on the mixing technology used to provide adequate absorption and the hardening time to create a coated product. To assist in the hardening process, the mixing vessel may be swept with cool air.

[0071] After the required amount of coating is added to the blend of anionic salts, the mixture is mixed for a short period of time to allow for "complete" hardening of the product prior to discharge. To assist in that process, the mixing vessel may be swept with cool air. The product may then be discharged and prepared for packaging. Example 2. Feed Trial To Test The Acceptability of The Microgranules.

[0072] The acceptability of the microgranules may be tested with a feed trial in a sample of dairy cows. The cows will be fed a basal diet for a period of time and them switched to a treatment diet comprising microgranules for a second period of time. Differences in the dry matter intake between the two time periods reflect the acceptability of the microgranules.

Animals

[0073] Twenty multiparous far off dairy cows (4 cows per treatment) may be used in a randomized design. To be included in the study, an individual cow's projected calving date will be preferably at least 30 days away from the start of the study. A time course of the study is presented in Table 1.

Table 1. Timetable for Treatment Administration.

Diets

[0074] All cows will be fed a normal close up cow total mixed ration (TMR)

(as described above in section Md). The same forage and grain sources will be used for all diets. Diets may be formulated with Cornell Penn Miner (CPM) dairy ration software and the DCAD balanced at about -6 meq/100g. The treatments (see Table 2) will be mixed into the TMR. Samples of TMR may be taken daily and a representative composite sample sent to a contract laboratory for proximate and mineral analysis.

Pre-treatment phase

[0075] Prior to treatment, the cows will generally receive the basal diet from day 1 through day 6. Dry matter intake may be monitored to determine ad libitum intake. From day 7 through day 8, the cows may be fed the basal diet at 95% of their ad libitum intake. Cows may receive their daily feed allotment in two feedings.

Treatment phase

[0076] The treatment phase may commence on day 9 and continue for 7 days (days 9-16). Cows may be fed 95% of their ad libitum intake during the treatment phase. Cows may receive their daily feed allotment in two feedings. The treatment conditions may be: A) Control (no anionic supplementation), B) Anionic Salts (calcium chloride and ammonium chloride), C) Microgranules, D) Microgranules-HCI (microgranules with HCI), and E) Current Market DCAD product (e.g., BioChlor or SoyChlor).

Table 2. Treatment conditions

Determining the acceptability of the microqranules

[0077] The acceptability of the microgranules may be determined by the sustained voluntary intake of feed during the treatment phase. Feed intake may be expressed as the percent of ad libitum intake and plotted against time with standard deviations. The acceptability of the microgranules may be demonstrated if the feed intake of cows receiving the microgranule-supplemented feed does not differ significantly from the control group.

Example 3. Feed Trial To Determine Whether the Microgranules Acidify the Urine.

[0078] Because the microgranules acidify the feed ration, the urinary pH of animals consuming the microgranules may be reduced. To test this, a feed trial similar to that described above in Example 2 may be performed, and urine samples may be collected. Urine samples may be collected near the end of the basal diet phase (days 7 and 8), and again near the end of the treatment diet phase (days 13-16).

Urine sampling procedure

[0079] Urine samples may be collected on the days listed in Table 3 in a clean dry container during the voluntary void of the urine by the cow. A minimum of 8 urine samples should be obtained throughout the 24-hour cycle from each cow. If the duration of time between samples is greater than 3 hours, manual stimulation may be required to obtain the sample. Upon sampling, the time of collection will be recorded, and the pH of the sample will be measured and recorded. After the pH is recorded, the sample may be discarded. Determining the ability of the microqranules to reduce urinary pH [0080] The ability of the microgranules to acidify the urine of cows may be determined by measuring the urinary pH before and after treatment with microgranule- supplemented feed rations. The pH of the urine may be plotted as a function of time, along with the standard deviations. The ability of the microgranules to acidify the urine may be demonstrated if the microgranule treatment groups show a statistically significant reduction in pH compared to their respective pre-treatment phase.

Claims

CLAIMSWhat is Claimed Is:

1. A microgranule comprising a core material consisting essentially of at least two anionic salts; and a shell wall that encapsulates the core material.

2. The microgranule of claim 1 , wherein one of the anionic salts is a chloride and one of the anionic salts is a sulfate.

3. The microgranule of claim 1 , wherein the anionic salts are selected from the group consisting of ammonium chloride, ammonium sulfate, calcium chloride, calcium sulfate, magnesium sulfate, and magnesium chloride.

4. The microgranule of claim 1 , wherein the anionic salts are ammonium chloride, ammonium sulfate, and calcium chloride.

5. The microgranule of claim 1 , wherein the shell wall is substantially water impermeable.

6. The microgranule of claim 1 , wherein the shell wall is a material selected from the group consisting of a biopolymer, a semi-synthetic polymer, edible wax, and a mixture thereof.

7. The microgranule of claim 1 , wherein the shell wall comprises a lipid material comprising from about 12 to about 18 carbon atoms or mixtures thereof.

8. The microgranule of claim 1 , wherein the microgranule has an average diameter ranging from about 1 micron to about 1500 microns.

9. The microgranule of claim 1 , wherein the microgranule comprises from about 40% to about 60% by weight of anionic salts and from about 40% to about 60% by weight of the shell wall.

10. The microgranule of claim 1 , wherein the anionic salts are ammonium chloride, ammonium sulfate, and calcium chloride; and the shell wall comprises a lipid material comprising from about 12 to about 18 carbon atoms or mixtures thereof.

11. The microgranule of claim 10, wherein the microgranule comprises from about 25% to about 35% by weight of ammonium chloride, from about 5% to about 15% by weight of ammonium sulfate, from about 5% to about 15% by weight of calcium chloride, and from about 40% to about 60% by weight of the lipid material.

12. The microgranule of claim 10, wherein the microgranule comprises about 29% by weight of ammonium sulfate, about 11 % by weight of ammonium sulfate, about 10% by weight of calcium chloride, and about 50% by weight of the lipid material.

13. The microgranule of claim 10, wherein the anionic salts are substantially a powder, and the microgranule has an average diameter ranging from about 1 micron to about 1500 microns.

14. A method for acidifying the diet of a mammal without negatively impacting the palatability of the diet, the method comprising combining the mammal's feed ration with a microgranule comprising a core material consisting essentially of at least two anionic salts; and a shell wall that encapsulates the core material.

15. The method of claim 14, wherein the anionic salts are ammonium chloride, ammonium sulfate, and calcium chloride; and the shell wall comprises a lipid material comprising from about 12 to about 18 carbon atoms or mixtures thereof.

16. The method of claim 15, wherein the microgranule comprises from about 25% to about 35% by weight of ammonium chloride, from about 5% to about 15% by weight of ammonium sulfate, from about 5% to about 15% by weight of calcium chloride, and from about 40% to about 60% by weight of the lipid material; the anionic salts are substantially a powder, and the microgranule has an average diameter ranging from about 1 micron to about 1500 microns.

17. The method of claim 14, wherein the anionic salt added to the feed ration is an amount such that the dietary cation-anion difference is from about -20 to about -200 meq/kg.

18. The method of claim 14, wherein the average urinary pH of a mammal that has consumed the feed ration is from about 5.5 to about 6.5.

19. The method of claim 14, wherein the mammal is pregnant and the microgranule is administered to the mammal for at least 10 days before parturition.

20. The method of claim 14, wherein the mammal is pregnant and the microgranule is administered to the mammal from about 10 days to about 60 days before parturition.

21. The method of claim 14, wherein the mammal is a pregnant dairy cow.

22. The method of claim 14, wherein the mammal is a pregnant dairy cow, the microgranule is administered to the dairy cow from about 10 days to about 60 before parturition, and the anionic salt added to the feed ration is an amount such that the dietary cation-anion difference is from about -20 to about -200 meq/kg.

23. The method of claim 22, wherein the average urinary pH of the dairy cow is from about 5.5 to about 6.5.

24. The method of claim 14, wherein the average daily feed intake of the mammal is substantially the same when the microgranule is present in the feed ration compared to when the microgranule is absent from the feed ration.

25. The method of claim 14, wherein the mammal is selected from the group consisting of a cow, a goat, and a sheep.

26. A method for treating a metabolic disorder in a mammal that results from a failure of the mammal's calcium homeostatic mechanisms, the method comprising administering to the mammal a microgranule comprising a core material consisting essentially of at least two anionic salts; and a shell wall that encapsulates the core material.

27. The method of claim 26, wherein the disorder is selected from the group consisting of milk fever, hypocalcaemia, and ketosis.

28. The method of claim 26, wherein the anionic salts are ammonium chloride, ammonium sulfate, and calcium chloride; and the shell wall comprises a lipid material comprising from about 12 to about 18 carbon atoms or mixtures thereof.

29. The method of claim 28, wherein the microgranule comprises from about 25% to about 35% by weight of ammonium chloride, from about 5% to about 15% by weight of ammonium sulfate, from about 5% to about 15% by weight of calcium chloride, and from about 40% to about 60% by weight of the lipid material; the anionic salts are substantially a powder, and the microgranule has an average diameter ranging from about 1 micron to about 1500 microns.

30. The method of claim 26, wherein the anionic salt is administered to the mammal in an amount such that the dietary cation-anion difference is from about -20 to about -200 meq/kg.

31. The method of claim 26, wherein the average urinary pH of a mammal that has consumed the microgranule is from about 5.5 to about 6.5.

32. The method of claim 26, wherein the mammal is pregnant and the microgranule is administered to the mammal for at least 10 days before parturition.

33. The method of claim 26, wherein the mammal is pregnant and the microgranule is administered to the mammal from about 10 days to about 60 days before parturition.

34. The method of claim 26, wherein the mammal is a pregnant dairy cow.

35. The method of claim 26, wherein the mammal is a pregnant dairy cow, the microgranule is administered to the dairy cow from about 10 days to about 60 before parturition, and the anionic salt is administered in an amount such that the dietary cation-anion difference is from about -20 to about -200 meq/kg.

36. The method of claim 35, wherein the average urinary pH of the dairy cow is from about 5.5 to about 6.5.

37. The method of claim 26, wherein the mammal is selected from the group consisting of a cow, a goat, and a sheep.

38. A ruminant feed ration, the feed ration comprising a grain portion, a forage portion, and a microgranule comprising a core material consisting essentially of at least two anionic salts; and a shell wall that encapsulates the core material.

39. The feed ration of claim 38, wherein the forage portion is selected from the group consisting of hay, haylage, silage, and a combination thereof.