SE437602B - PELLET FOR IDISCELLANEOUS INCLUDING A NUCLEAR MATERIAL AND A COVER INCLUDING A MOVIE-MAKING POLYMER MATERIAL AND A DISPERSED HYDROPHOBIC SUBJECT - Google Patents

Description

7809224-4 2 rumen, where it was digested or precipitated by fermentation. tation. During this fermentation period, it can be ingested the food is pushed through the retina to the mouth, where the food saliva and ruminants. After a fermentation period, 5 which are regulated by natural processes and vary on the animal and the food, starts the absorption of inmates nutrients and continues in subsequent sections of ruminants' digestive system. This process is described in detail by D.C. Church, "Digestive Physiology and Nutri- 10 tion of Ruminants ", vol l, O.S.U. Book Stores, Inc., of Corvallis, Oregon, USA.

The rumen, which is the largest of the four abdominal spaces in ruminants, serves as an important place for metabolism. degradation of ingested food by the effect of 15 enzymes and microorganisms (bacteria and protozoa), which Is there. Ingested food is typically retained in the rumen below about 6-30 hours, or longer in some cases, including food subjected to metabolic degradation by microorganisms in the rumen. Much of the ingested protein material is broken down Down into the rumen to soluble peptides and amino acids and utilized by the microorganisms in the rumen for their own growth and reproduction. When the rumen contents pass the gastrointestinal tract and intestines, the microbial mass is digested, whereby the ruminant is supplied with protein. The ruminant The animal's natural nutritional balance is thus primarily one function of the microbial composition and population , lations.

In the manufacture of nutrients and drugs, which are intended for administration to ruminants, it is Important and protect the active ingredients against environmental conditions in the rumen, ie microbial degradation and the effect of a pH of about 5.5, so that they the active ingredients are retained until they reach the different places, where absorption takes place. It is known that The production rate for meat, wool and / or milk can be increased on sources of essential amino acids and / or drugs protected from alteration by micro-organisms, which the rumen, and is made available for direct absorption 780922441 3 tion of the animal later in the digestive tract.

Previous proposals for the treatment of protein content nutrients, given to ruminants, in order to provide passage without microbial degradation through the rumen to Running stomach, has included the coating of protein with, for example, fats and vegetable oils, heat treatment of the protein material, as well as treatment of the protein material by reaction with various compounds, such as formaldehyde, acetylenic esters, polymerized Unsaturated carboxylic acids or anhydrides, and phosphonic trilhalides.

Previous proposals for the protection of medicines from the rumen includes the U.S. patents 3,041,243, 3,275,518, 3,619,200 and 3,697,640. Polymeric material containing at least one basic amino acid group and which has a nitrogen content of 3-14% of the polymer molecular weight, such as cellulose propionate morpholinobutyrate and copolymers of styrene and 2-methyl-5-vinylpyridine, are effective as coatings for core materials, which consist of 20 nutritional and medicinal products for ruminants and which have a pH value of more than 5.5. These polymeric materials are too loose in the rumen medium and they do not create sufficient protection for the core materials in the rumen so that the core materials can be utilized jas in the running stomach and / or intestines. The present invention provides pellets for oral use administration to ruminants, which include pellets an iron material and a protective coating, which creates adequate protection of the core material in the rumen environment.

In accordance with the present invention Thus a pellet for oral administration to ruminants, which pellet comprises a core material having a pH value of more than 5.5 and is healthy for the ruminant after ruminant, as well as a coating, which surrounds the core material, wherein the pellet is characterized in that the coating comprises: A) a film-forming polymeric material containing at least a basic amino group, wherein the nitrogen of the polymeric material content is 3-14% of the molecular weight of the polymeric material and the polymeric material is soluble within 24 hours in aqueous ruminant medium in ruminants, which medium has a pH value 38092244; 10 15 20 äs 30 35 of more than 5.5 b) a hydrophobic substance dispersed in polymeric material and selected from fatty acids with 12-32 carbon atoms, aluminum salts of fatty acids with 12-32 carbon atoms, and polycarboxylic acids with 10 ~ 22 carbon atoms per carboxyl group and a molecular weight of 400-1000, and possibly c) a physiologically acceptable flake material, wherein the hydrophobic material is present in the coating in an amount of 2-75% by weight of the polymeric material, and the coating constitutes 5-50% of the weight of the pellet and has one sticking temperature of at least SOOC.

The pellets according to the invention are adapted for oral administration to a ruminant. The pellets have suitable size, such as between 1.27 and 19 mm in diameter.

They should have an acceptable smell, taste and feel. The shape is usually not critical, but is usually spherical for to facilitate transfer.

The core material is healthy for a ruminant then it has passed the rumen and reaches the stomach and / or intestines.

Normally, the core material is solid and has been formed into tiklar, eg by pelleting. These particles can rounded, if desired, by conventional means, such as by tumbling.The pellet core should have sufficient firmness or consistency to remain intact during operation, especially during the transfer operation. the ability of the coated material to protect the core material is associated with the core pH and solubility in water. The cores to which the present invention is applicable, are those with a pH value of more than 5.5.

Suitable core materials include various drugs and nutrients, such as drugs, such as antibiotics, relaxants and anti-parasitic materials, amino acids, proteins, sugar and other carbohydrates. The core may also contain inert filler material, such as clay.

Some amino acids, which are suitable for use as core material is set forth below together with information on their pH and solubility: 10 15 20 30 '7809221 + ~ l + 5 AMINO ACIDS, THEIR SOLUBILITY AND pH ~ VALUE OF SATURATED SOLUTIONS Solubility (g / 100 g water at 25 ° C) pH DL - Alanine ~ 16.7 6.2 L - Arginine 21.6 11.8 DL - Methionine 4.0 5.7 L (-) - Tyrosine 0.05 7.3 Proteins from various sources are valuable material for use in the invention. Proteins are ampho- substances which are soluble or suspensible in aqueous containing medium, which is either more acidic or more than the protein in question.

The core material can be prepared for coating according to the following method. The core material is mixed with water, binders and sometimes one or more inert inorganic substances, and the resulting plastic, dough-like mass extruded or rolled or otherwise treated to give pellets of suitable size. One or more adhesive binders are added to increase the pellets strength and the binder may consist of non-toxic plant gums, starches, cellulose derivatives, animal gums and others similar substances, which are well known in the art of thickening food preparation and tablet production. Alter- natively, the various powdered ingredients can be mixed together before adding water. Inorganic additives agents used to adjust the pH or density the pellet content of the pellet, including such substances as non-toxic, pigment-like materials, such as metal relatively high density sulphates, oxides and carbonates.

Other minor ingredients, required for special properties, can be added, as is common practice at tablet manufacture. The desired end range for density the density of the rumen-protected pellets is 1.0-1.4.

The pH value of the core materials can be raised in predetermined extent by mixing a basic neutral by coating the core with a basic neutralizing agent. The acidity is modified by the addition of non-toxic, soluble basic substances, .arma Quaf 78092244! 10 15 20 25 30 35 6 such as oxides, hydroxides, carbonates or basic salts of alkaline earth metals, in particular mag- magnesium and calcium, to the core material before the pellet shaped the step. Basic compounds of aluminum, such as the various forms of hydrated alumina and alumina nium hydroxide, and. dibasic aluminum salts of organic acids having less than 6 carbon atoms, such as dibasic aluminum acetate, can also be used. These basic substances is added to the pellets by mixing the core material, the basic substance. and adhesives, as described above, before adding water. The amount used depends on both on the solubility and the relatively acidic nature of nuclear the material, the time required for rumen protection, the time required for release in the tummy, on the coating composition which used to provide rumen protection, as well as on the thickness of the applied coating. Normally it is basic the weight of the substance, if such substance is used, 1-20% of the core total weight. The pH of the core is at least 5.5 and preferably show up to 7.

Water is removed from the pellets by drying them under ambient conditions or 5.heated ovens or fluidized beds. The dry pellets are therefore ready for subsequent transfer operations, carried out by any method, such as plate drawing, fluidized bed coating, spray coating, or combinations thereof. The pellets are preferably transmitted by contacting them with a solution of the protective coating material in a suitable solvent or mixture of solvents agents, as described below. Typical solution agents which are useful include lower alcohols, ketones, esters, hydrocarbons and chlorinated hydrocarbons.

Another method of neutralizing the core is based on the principle that while the cover is permeable for water and acidic, water-borne molecules, it is not required that the interior of the entire pellet be neutralized.

The non-toxic, inorganic, basic substances can be deposited on the surface of the core material before applying the final _ lO 15 20 25 30 35 78092244 » 7 the cover. In practice, they are placed HRS] * örfcrmade pellet- in a fluidized bed or other transfer bed apparatus, and a dispersion of an oxide, hydroxide, a carbonate or basic salt of magnesium, calcium or aluminum in water or an organic liquid is sprayed on the pellets. The dispersion of basic substance contains usually an adhesive and may also contain protective colloidal substance, the weight ratio of binder plus protective colloidal substance and alkaline substance is less than 1: 3. If basic substance is used, the amount is thereof, which is transferred to the pellet normally from 1 to 20% of the weight of the core material. The binder and the protective the colloidal substance may be the same substance or different substances and are preferably soluble or dispersible in water and in the organic liquid used to pend the basic substance. Such binder materials, such as relatively low molecular weight cellulose derivatives, synthetic polymers, and natural rubbers, which are known in the art for tablet manufacture, are suitable for carrying out of the invention. The organic liquid can be any one which has the appropriate solvent capacity and boils in the range 40-140 ° C. the coating material has the ability to form a conti- nuclear film around the core by evaporation of solvent from a solution or dispersion thereof. coating material alet has the ability to withstand the environmental conditions of rumen and the ability to expose the core material of the search in the abdomen. the coating material should thus be resistant to pH conditions of more than 5.5 below 6-30 h. It is preferably resistant for at least 24 hours at a pH of 5.5. the coating material should release the core material after exposure to the conditions in the tummy tuck, which has a pH of 2-3.3. The release should occur during the residence time in the tummy tuck or later 1 the intestinal tract, but at most within a period of 6 hours, for example, within a period of from 10 minutes to 6 hours after can of a pH of 3.5 or lower. g The exposure of the nucleus can occur by transferring c 7809224-4 10 15 20 25 30 35 8 goat becomes permeable to the contents of the tummy tuck, such as by dissolution or decomposition or by catching swelling. 7 the coating material is physiologically acceptable, ie the coating material should not interfere with the health of the ruminant or normal body function.

Another requirement for the coating material is its ability to withstand storage conditions with relatively high heat and / or humidity without significant blockage, ie without the coated pellets sticking together in significant extent. the coating should have a tack temperature turn of more than 50 ° C. The stick temperature is defined as the temperature at which sufficient expansion occurs stapling to cause tearing of the cover in case of forced separation of coated particles when an applied force of 0.25 kp / cm2 keeps the particles in pace for 24 hours. the coating material is preferably soluble or dispersible in organic solvents, such as those with a boiling point of 40-140 ° C, to allow the use of conventional coating procedures, such as spray transfer drawing. Particularly suitable solvents include methylene chloride, chloroform, ethanol, methanol, ethyl acetate, acetone, toluene, isopropanol, and mixtures thereof.

The coating or film-forming material used used in the invention includes a mixture of at least a polymeric substance and at least one hydrophobic substance. The poly- _more the substance is a continuous matrix and constitutes 25-95%, preferably 50-95% of the cover weight. General applies that more acidic and more soluble core materials require greater proportion of hydrophobic substance to polymeric substance, while more and less soluble core materials require less proportion of hydrophobic to polymeric substance within that content range.

The hydrophobic substance is normally dispersed in the polymer matrix. and is present in an amount of 2-75%, calculated on the weight of the additional material. In preferred embodiments of the invention contains the hydrophobic substance in an amount of 2-40% and 5-75%, based on the weight of the polymeric material. lO 15 20 25 30 35 780922144! 9 The polymeric substances useful in the coatings according to the invention, include those substances which in combination with the hydrophobic substance described below, are physiologically acceptable and resistant to one pH of more than 5.5, but capable of releasing the core of the pellets at a pH of less than 3.5 at the normal body temperature of ruminants (37 ° C). The The polymeric substances include polymers, copolymers and mixtures of polymers and / or copolymers, which have basic amino groups, wherein the nitrogen of the polymeric substance content is 3-14% of the molecular weight, which is 5000-300 000.

The basic amino groups may be of the aliphatic type, in which case they contain 3-10% by weight of nitrogen in the basic the amino groups. The basic amino groups can also be of the aromatic type, in which case the basic amino acids the groups are attached directly to the aromatic ring or forms part of the aromatic ring structure, wherein they contain 6-14% nitrogen in the basic amino groups.

Polymeric substances with the properties defined here includes certain modified natural polymers, homo- and interpolymers obtained by addition polymers processes, homo- and copolymers obtained by condensation polymerization processes, as well as mixed thereof. The polymeric material comprises at least one polymeric more, copolymer, or blend of polymers, selected among cellulose derivatives, such as cellulose propionate morpholino- butyrate; copolymers in which one of the monomers is acrylic nitrile, vinylpyridine, vinylcarbazole, vinylquinoline, N-vinyl- pyrrole or 5-vinylpyrazoline; copolymers of nitrogen containing monomers with comonomers such as styrene, methyl styrene, vinyltoluene, esters and amides of methacrylic acid, esters of amides of acrylic acid, ethylene, propylene, butadiene, vinyl acetate, vinyl propionate and vinyl stearate; polymers of condensation type in which a dicarboxylic acid, such as phthal acid, terephthalic acid or succinic acid, is combined with polyfunctional alcohols to form polyesters, wherein either the acid or glycol moiety may contain basic nitrogen which is not reactive in the polymerization process, ___, -.-, »- ~ - ~ --- ~ -.-" '" 10 15 20 25 30 35 78092244 » 10 but which is reactive for variable_pH environments and vari the same or different dicarboxylic acids can be reacted with functional amines to form polymers of poly- amide type containing basic nitrogen, which did not react in the polymerization process; and other polymers, such as contains basic nitrogen, such as preformed polymers, which have been formed by reacting an existing poly- more with a nitrogen-containing organic or inorganic part, such as polybutadiene where ammonia has reacted with the remaining double bond. Particularly preferred the copolymers of the various isomers and derivatives of vinyl pyridine, which has been copolymerized with one or more of the the above-mentioned monomer types, such as 65% by weight of 2-methyl-5-vinyl- pyridine and 35% by weight of acrylonitrile.

Also particularly preferred are copolymers of 2-methyl- -5-vinylpyridine and styrene, and in particular a copolymer of 80% by weight of 2-methyl-5-vinylpyridine and 20% by weight of styrene.

These copolymers are commercially available or can prepared by known conventional methods.

Hydrophobic substances, which are physiologically acceptable and which has the correct degree of compatibility with the polymer, is commercially available. It is important that the polymer and the hydrophobic substance has a certain degree of compatibility for the film to remain intact in the rumen environment, but allow penetration of the gastric fluid into the nucleus when the pellets are in the stomach.

Without limiting the invention to any particular one theory as to why the covers, which contain it hydrophobic substance, has better protective properties, The function of the hydrophobic substance is generally to be that reduce the overall availability of polymer matrix the films or coatings for aqueous, slightly acidic surroundings. In other words, the hydrophobic substance decreases wetting of the coating and consequently original infestation of water. The hydrophobic substance also reduces the total volume of the coating affected by water and extends the distance of the penetration path the water must move to the core. Furthermore, it is assumed 10 15 20 25 30 35 '7809224-4 ll that, given the inherent nature of polymers containing sufficient basic groups of nitrogen for to be functional with respect to the differences in pH value of the rumen and runny stomach, a reduction in water availability of the film is required, especially when the material is acidic and / or very water soluble. Although the general theory is presumed to be correct, as described white above, there are subtle variations in the exact manner in which the hydrophobic substance functions. Suitable hydrophobic substances include fatty acids, dimer acid and trimer acid, and certain polymers, such as polymers containing highly hydrophobic chemical groups, such as siloxane and some polyvalent cationic soaps.

Dimeric acid is a dibasic acid, which is produced by dimerization of unsaturated fatty acids at the center of the molecule and usually contains 36 carbon atoms. Trimic acid, which contains three carboxyl groups and 54 carbon atoms, smiles in a similar way.

A class of hydrophobic substances that can be used includes contains fatty acids having 10 to 32 carbon atoms, such as lauric acid, oleic acid, stearic acid, palmitic acid and linolenic acid. Des- said acids are known to be water insoluble due to their long hydrocarbon radicals, but react with water on due to the polar nature of their carboxyl groups.

In the selected polymers, which contain basic amino groups per, the carboxyl group of the fatty acid has the ability to react with the basic nitrogen group to form a weak bond salt type. This anchoring to the polymer allows the fatty acid is fixed in the polymer matrix. The fatty acid hydro- foba hydrocarbon chain tends to make the matrix waterproof thereby reducing the swelling of the otherwise aqueous available polar film. Both the interior of the matrix film and its surface is now waterproof in aqueous environments at pH values above 5.5. At pH values below 4.5 and spe- below 3.5, however, the basic nitrogen the affinity of the group for water and the hydrogen ion standing against water. The film reacts with the acid environment and loses its barrier properties sufficiently to _ å * N ._, _..... _- lläw fi il fi ifft fi . ..._. ,, _._.- \; ...._._, -. 78Û9224 ~ ëß 10 15 20 25 30 35 12 the core material must be released to the environment.

Polyfunctional carboxylic acids, which are derived from natural products or obtained by organic thesis, can be used. In the class of synthesized poly- functional carboxylic acids include mono- and poly- functional acids containing siloxane or fluoro- carbon groups, which are located on at least 4 atoms distance along the molecular chain from the carboxyl group or the position of the groups. Other suitable hydrophobic substances are those non-toxic polyvalent metal salts of the abovementioned acids, such as stearates, oleates, fatty acid dimerates, and palmitic aluminum and iron, as well as calcium, magnesium and and the zinc salts of the high molecular weight crystalline analyte the lodges of the abovementioned acids. Mixtures of these acids and / or salts are also useful. When the cation is trivalent, such as aluminum and trivalent iron, are molar the ratio between organic acid and metal ion 2: 1 or 3: 1 and the acid can be any monofunctional organic acid, which has a carboxyl group and at least 10 carbon atoms at the organic radical attached to the carboxyl group.

When the metal ion is divalent, such as divalent iron, calcium, magnesium or zinc, the organic acid may be one monocarboxylic acid or polycarboxylic acid and the ratio between metal ion and non-carboxylic carbon atoms is least 1:26.

Natural and synthetic waxes and resins can also present in the cover. Useful waxes and resins have ' a molecular weight of 500-2000 and a critical surface tension of less than 31 dynes / cm, determined by the Zisman method, which described in "Contact Angle Wettability and Adhesion", Advances in Chemistry Series No. 43; edited by Robert F. Gould; published by the American Öhemical Society; 1963, Chapter 1, and has a solubility in the coating of less than 5%. These waxes and resins are dispersed in drawn in an amount at least equal to twice the and up to 30% of the total weight of the polymer in the cover. Typical waxes and resins include beeswax, petroleum wax, ponds, hard manilla copal, phenolic resins, lO 15 20 25 30 vso9224 ~ 4 13 rosin and low molecular weight polycarbonate maleate.

Other suitable hydrophobic substances are polymers with a molecular weight of 2000-10000 and a critical surface tension of less than 31 dynes / cm, measured as described above Zisman methods.

Useful polymers have a solubility or compatibility slightly less than 5% by weight, and present in the coating in a concentration of at least equal to twice the solubility and up to 30% by weight of the cover. Particularly valuable are the polymers and polymers containing siloxane groups in the main polymer chain or in a side chain, and polymers and copolymers merers, which contain fluorinated carbon groups in a chain.

Regardless of the exact nature of the hydrophobic substance, it must be soluble or colloidally dispersible in the coating solvent if used.

When a polycarboxylic acid is used as the hydrophobic substance, it should have 10-22 carbon atoms per carboxyl group and a molecular weight of more than 300. the coating may also contain a physiological acceptable flake material, which is dispersed in the drawn. The flake material is substantially inert in the rumen environment. ningen. Suitable flake materials include metal flakes, mineral flakes and crosslinked organic polymers. Special Particularly suitable flake materials are aluminum flakes, talc, graphite and ground mica.

The following examples are provided to facilitate understanding the invention. The examples are based on in vitro test, which simulates the conditions of ruminants, var- through coated pellets can be studied without use of live animals. Through similar experiments using actual fluids from the rumen and runny stomach, which liquids obtained from a ruminant, it has been found that testing of pellets in the aqueous medium which used in the examples and which simulate environmental in the rumen and tummy with respect to temperature and pH value, provides reliable data regarding it we-LJ-ngu.

Iïk fi ïë fi ï fl 7809224-4 10 15 20 25 30 35 14 protection which the coatings create in the rumen and the performance in the tummy tuck.

Unless otherwise stated, all parts refer to conditions and percentages weight. Measurements of viscosity the limit was made at 25 ° C using 0.25 g of polymer per 100 ml of a solvent, which consisted of 60% by volume phenol and 40% vol. tetrachloroethane.

The liquid used to simulate the environment the conditions in the rumen (at pH 5.5), were prepared by mixing 11.397 g of sodium acetate with 1.322 g of acetic acid and diluting the mixture with demineralized water l liter.

The liquid used to simulate the environment conditions in the gastric stomach (at pH 2.9), were prepared by mixing 7.505 g of glycine with 5.85 g of sodium chloride and dilute the mixture with demineralized water to 1 liter. Eight parts by weight of this solution were mixed with two parts by weight. parts 0.1 N hydrochloric acid for the test liquid.

EXAMPLE 1 (Comparative) 600 g finely divided lysine monohydrochloride, 60 g micro- crystalline cellulose and 6ç; gum arabic were dry mixed, whereby a substantially homogeneous mixture was obtained. 195 g water was mixed with the powder mixture until a homogeneous, plastic, dough-like consistency was obtained. This plastic dough was extruded and cut into cylindrical pellets, which had a length of 2.4 mm and a diameter of 2.4 mm.

These pellets were rounded by tumbling in a rotary drum for 5 min and then dried at 6000.

Detorrapellets were intended to remove dust and was passed through a spray zone, which contained finely divided droplets of polymer dissolved in a volatile solvent. coating- had the ability to recycle the pellet through a coating zone, a drying zone and a storage zone, and was thus able to impose multiple coatings of polymer on each pellet. In the present case was the polymer of cellulose propionate morpholinobutyrate contains countries 3.0% organic solvents such as ketones, esters, mixtures alkaline nitrogen. This polymer is soluble in 10 15 20 25 30 35 7809224- 15 of aromatic hydrocarbons and alcohols, mixtures of halogenated aliphatic hydrocarbons and alcohols, and aqueous at a pH of less than 3.0. The polymer was dissolved in acetone at a concentration of 6% by weight, based on total weight. the transfer operation was continued for the period necessary to transfer the essential all the pellets with a 0.15 mm thick layer of dry polymer, which layer accounted for 17-20% of the final the weight of the coated pellet. During the transfer sampling operation, samples were taken from the coated pellets. then with coatings, which accounted for 5, 10 and 15% by weight of it the total weight of the coated pellet.

These pellets were tested for resistance against dissolution at pH 5.5 and at pH 3.0 as a function of the cover weight. The test at pH 5.5 was performed for 24 hours and the test at pH 3.0 was performed for 1 hour. then was stable to aqueous media at pH None of the pellets from 3.0 to 8.0. The pellets were also unstable in the rumen in sheep and cattle.

EXAMPLE 2 The lysine monohydrochloride pellets prepared from according to the procedure of Example 1, was coated with a mixture of 60% by weight of cellulose propionate morpholinobutyrate and «M)% by weight monobasic aluminum dioleate. The mixture was used in a 4% by weight solution in 90% by volume of methylene chloride and 10% by volume of nol. The pellets were coated in the manner described in Example 1. and the final coating on the pellets was 20% ' of the weight of the coated pellets. 65% of the lysine monohydrochloride was retained in pellets, exposed to aqueous medium at pH 5.5 below 24 h. All this substance was removed from the pellets by treatment in a hydrogenated medium at pH 3.0 for 1 n.

EXAMPLE 3 730 g of lysine monohydrochloride, 91 g of basic magnesium carbonate, 73 g of microcrystalline cellulose and 73 g of rubber Arabica was dry blended to create a substantially homogeneous gent powder. 250 g of water were mixed with the powder mixture until a plastic dough-like consistency was obtained. This vsoszza-a M ...-, ....... _. . § ¥ ß = ~ iYfff -Fr, FCC » g-É lO 15 20 25 30 35 16 dough was extruded, cut, rounded and dried, as described in Example 1. The pellets were then coated with the polymer blend described in Example 2.

The pellets, which contained 20% by weight of dry coating, were resistant to dissolution upon exposure to an aqueous medium having a pH of 5.5, such as shown by a recovery of 94% of lysine monohydrochloride after exposure for 24 hours. Upon exposure to aqueous medium with a pH of 3.0 or lower, was removed lysine monohydrochloride from the pellet for 1 hour.

EXAMPLE 4 (Comparative) The pellets described in Example 3, which contained lysine monohydrochloride and basic magnesium carbonate, was drawn with 20% by weight of cellulose propionate morpholinobutyrate. 7 When tested for stability at pH 5.5 85% of the lysine monohydrochloride was leached from the pellets.

Thus, the pellets were not stable at pH values such as fl are typical of the environment in the rumen fi EXAMPLE 5 40 g of cellulose propionate morpholinobutyrate and 13 g oleic acid (0.047 equivalents) was dissolved in a solvent mixture containing 900 ml of trichlorethylene, 100 ml of zero and 100 ml of dichloromethane. The solution was coated with 150 g pellets, which were composed of 83% lysine monohydrochloride, 6% calcium carbonate and 11% suitable binders, with use of a fluidized bed process.

The coated pellets retained 48% of the lysine mono- the hydrochloride after stirring for 24 hours in an aqueous solution. pH 5.5, and released all this substance during the stirring for 1 hour in an aqueous solution of pH 2.9.

EXAMPLE 6 The procedure of Example 5 was repeated using 0.094 equivalents of oleic acid in the coating composition tion.

The coated pellets retained 54.5% of the lysine the monohydrochloride after treatment for 24 hours at pH 5.5 and released all this substance in 1 hour while stirring at pH 2.9 » 10 15 20 25 780922444 17 EXAMPLE 7 The procedure of Example 5 was repeated using 0.047 equivalents of stearic acid instead of oleic acid. 71% of the pellet sample remained intact after stirring for 24 hours in an aqueous solution of pH 5.5.

EXAMPLE 8 The procedure of Example 5 was repeated using 0.094 equivalents of Empol 1010 Dimer Acid (a aliphatic dibasic acid with 36 carbon atoms from Emery Industries, Inc., Cincinnati, Ohio, USA) instead of the oleic acid.

The coated pellets retained 90% of the lysine mono- the hydrochloride after treatment for 24 hours with an aqueous containing solution with a pH of 5.5, and released all this substance for 1 hour with stirring at pH 2.9.

EXAMPLE 9 Methionine pellets were coated with a copolymer of 80% 2-methyl-5-vinylpyridine / 20% styrene and a variety of lauric acid, which was calculated to be equivalent to the present basic function. The copolymer and the acid were dissolved in trichlorethylene, although other suitable solvents may be used. The obtained coated pellets constituted one useful nutrient composition for ruminants.

EXAMPLES 10-37 In the examples in Table 1, the coverage was approximately 20% of the weight of the pellets. The pellets in each example treated for 24 hours in aqueous solutions with one 30 pH of 5.5, and up to 6 hours in aqueous solutions with a pH value of 2.9. The amounts of active nuclear materials that were retained and released during these, respectively conditions are given as percentages in both tables last columns. 78092244 » 18 Åm fl v muæmc fi umwum ooñ mm ß fl nowua I \ -> m «« H ° om \ om Am fl v om fl m Gwøowuwz ^ mov u fi øoudmm umwHo «wE =«: «E: ~ < Goa wm Gmdo fl umz ñomv uwdouuwm Amv muhmnwummum oo fi mm fiflfi m fl m æn ænwm I Aomv mußmuoëwn oo fl mm = fi = ° Hu @: 1 AQNV mpßwu fifi o , fi æv ANV ^ u & «> Hmuou Amcäz unououuhn m. ~ mm w «> m.m mm w«> muuwmuunm> m mm mn fi m Hm fi uwumaumsa fi om S Q ma = QN ~ @ u «@ umønmx M umøxmu Nux fi> V mm Umuxm fl NOW» «> v unommwum umH fl m: Hm> M adam u> «ux <fi wumë fifi hm fi m fi umumå unomouwhm H A fl mmd fi uosß fl om fi mm | øwu> um \ d «w« nhm | H> = fl> | m | H> u @ a | ~ mH \ mw nmäæ fl omëmm |: wu> um \ n «w« u> m L fi> = «> | m | H> @@ a | ~ m ~ \ mß Hmäß fl omämm | cwumum \ = fl w «u> m 1H »=«> «m | H> u @ E1N m ~ \ mß umëß fi omamm |: mH> um \ = «u« u> a H> = «> 1m | ~» u @ s | ~ ¶mH \ mw uuah fl omämw , | nuu> um \ c «v« u> m | ~> = «>« M »~>» «E» ~ o ~ \ ow .n fl wk flfl d fi hüí fl Oß fl üä ma NH Have O fi | Bmxm 7809224-4 19 oo fi mm moxs fl w Aoov muwA ^ ~ v muhwcwuwa fi mm oø fi em HUm.cmmhA | A Åmmv mama Amv mummd fi umuum oøa ßm moxn fl w Amov umdounmm mmv muhwdwhmwum OOH mm Hum.d «mhA | A Ammv moomu Amv mummd fi nmwuw oo fi am Hu=.c@m> A | A 1 Ammv »~ uH °« va: «=« a = H < ANV ANV ^ ux «> Hmuou Aucñm unomouwhn m.N mm fl «> m.m mm ww> wuøwmuwum> æ mm m flfi a fl m fl umumsumñh fl om 5 m mm n QN uuumm Gmdumx M um fi xmu Nux «> v mm umcxmn Nux«> v uua fi w fl nm uu fi Hw & um> M odäm u> «uM <fl wumñ fifi mm Hm fi uwumñ usowouwmm E35 ummuuøwv H Aqmmå. uvah fl omsmw | ßuumum \ u «¶wumm | H> = M> | m | H »u @ s-« o ~ \ ow uøaæ fl omamm \ nwu> um \ G «vwu> m | H> = «> 1m | ~» »@ s» ~ m fi \ mw Hm fi ß fl omamw | = mumum \ G «w fl n> m | H> = «> | m« ñ> »@ e | ~ m ~ \ m ~ umsh fi oaamw | fi mu> um \ Gw¶ «u> m -H> = «> | n | H> ~ @ a1 ~ om \ o ~ umäh fl omamw | ømu> um \ G «w« uma | ~> ø «> 1m | H» »@ e | ~ mH \ mw fi mwuwumëuwsh fl om ma wa NH wa ma x fi uxm Il fi u 78ü9 fi2 lvli 20 Ao fi v Aowv oo fi wa ø fi couua øwuwx fl mx u fi mz umw ~ o «uE =« ø «EnH < oo fl ma = «@ Uw> u ÅNNV muw fl AWNV m»> m-a «n oø fi om Hmm ~. = ~ m> Q | A 1 Aomv «~> m-a« q em mm fi wcowuuä I ^ oNv wuhmmw fl o ñm fl v oo fi Nm Hom.n «v« um «m Aonv mnw fl umuHo« uuE: «=« E = H4 ANV ^ Nv ^ ux «> Hmuou Amcäm unomouwßn m.N mm ¶ «> m.m mm w«> muuwmuvuo> m ma m flfl m Hm fi umumsuwëh fl on S w mn n em uøumw ømøamx M um fi xmu Nux «> v mm um fi xmu Nuxw> v u fi o fi m fi ßm »~ HHmn ~«> M wusw u> fl »x <Hw fl wa flfl æm Hw fl uwuwe upomo fl wßm Aw fi c fi wwuuouv H .Smmës Hmsh fi omawm | «« HuHcHmuxm \ c «w« Hhm | H> = «> | m | H>» ~ e | ~ o «\ oN <~ uuäh fi omåmm | H «uu« = Hæuxm \ c fi w «u> m »H> =«> | m | fl> u «s | ~ m ~ \ m ~ n ~ umäß fl omñmm | H fl uu «GH> nxm \ G fi w fl H% m | H> ø «> | m | H> u @ e | ~ m ~ \ mw NN mø fiøvcm fl ßøwuæum | maom \: «w« nhm fl mdw> | m | fl> u @ e | ~ |> H ° @ mH \ mw HN umëh fl omamm x = wumum \ c «u« uhm 1 ~> G «> | m | HmuøE | ~ m fl \ mæ om Hm fl umumauwaz fl om dum lâmxw m _ hrs w 7809224-4 21 umaæ fl oañmmum fi hhxmumë | H% uwE \ umHmu3muuE fl äuo 3 ä fi no fi zš 88 8.3 ä fl oäas fififi sš <| on fl å fl ßuw fifl iz.z 33. » Anmëß fl omämw fi wuu fififi æuxm | \ G «w« u% a | Hæ: fl> | m | HhuwElN øm \ 0mv \ ^ HwEh ~ omEmmH «uu« ø | H> uxm \ c @ v «n% mHhc«> | m | 03 ä fl ššw SS änoëå mä fl ma fifi LÜQFN minä 030m nwah fi omamm | fl wuuwdHhuxm \ fi «vwuhm QOH mm fi wowuuwumm | AOHV muäm fi wumoum | H% fl «> | m | H% umElN o« \ Oo mu v ^ Nv ^ u ¥ fi> Hmuou Amdäm unowouwßn fl wwuøumënmñm fl om Hmm m.N mm u «> m.m mm w«> muuwmuwHo> w mm m flfi m Hmwumuwsumäm fl om 5 o mm S qw uuuwm cmcuwx m uwnxmu Nux «> v mm umcxmn Nux«> v uuowwwnm uwH ~ mnum> M unam u> «ux <fi onw flfifi mm fl wwuwumä unowouwæm Awøwduum 3.83 H Émm fi now mu now lüwww 22 w Oo fl cm d «: owHH ^ omv muw fl ^ cv muæmc fi uduuw: wHhum \ c« u «Hhnw>: w> | N O ~ \ 0æ Nm í = w fl m «umumEmwGmwu: w w> m> & o = «Em uumë fl nm nuo v fi uo fl x um fi oñ uw fi wumm mm uw fl xmn .uuoxw | uw> w = «Emmuucw fl> um« w N fl oä m uuw: oo x fl øxuumcomummwumsh fi om luuæwømuw> m wuw: udm> dm wmå d fl swwuu fl w fl muwwv wmü w fi uo fl x l fi h fifl uosm mnwwmwu uum Eo fl mw oo fl _ mo ø flfl o fi umä Aomv u fl couøøn umwHo «wE:« = «E: fi <, wu fifi wumemuw Ewm .u fl ëmm fl om, Hn umumusnumuuom _ | mmo fi nH fi mo \ Hoxh fi mca fl ßmoumlw.H wmë w fl nwmnømmaæwd fi oamä now lmøm fi mnmHoEw> xm muuwcmm fl uum V Eoøww u fi amumamuw uwummh fl om '780922lr-Ä mm ßß_ = «: o« uu2 Aoøv umcoaavm uwwHo «vE:« n «En fl <co flfl wu uxswumc fifl ouuoë m ~ \ mß om ANV ANV ^ u & «> fi muou Amøsm unowonuhn Hm fl umumshwsæ fl cm Hmm m.N mm w «> m.m mm w«> muuwmuuuw> m wa mn fi m Hm «nwumEumE> Hom, lamxu n w mm s em uwuww mucnmx «uwcxmu Nux fi> v mm uwcxmu Nux«> v uuoww fl um umH ~ m: um> ¥ unam u> «ux <Hwwøä fifl ßm fi m fi uwum fi unououußm Awc fi bummuuoä H Qummš 7809224-4 23 : Qq fi wøvël dww «nænHæm«> | N mn Ne Gwdowua Aoov mum fl ^ C fl v muæmcwnwuum \ fl oNmnumxA% G «> m fl xmæ Nm Gmu> um \ fl «fl« u> m mm Om fl wdowuæ Aoøv uw fi ouøum AOHV umuwmumwhhmm | Hßdw> Im | HhuwElN m fi xmw en fi o fi v øwumum \ ø «u fl uhm mn ææ øwdo fl uwz Amwv u fi counmm umummumss fl wmdwmä | H> fi H> | m | HhuwE | N m ~ \ mw mn W Ao fl v ~ o.o u.>. H umaænxm fi huøß dmu> um \ c «u« u% m en mm cmco fl uwz AONV mama lß fi om uwuuuoä fi mumm: Hh: «> Im | HhumEIN o ~ \ Oæ en fi osuon wuummm fl un nm = ~ ouHhn «> Û AND wa ldmmouuomwæa, Aomv wumn Amv wuhmnwu fl muw \ nww «n> nH% fi«> | «oN \ ow mm _ ANV ^ Nv ^ ~ x fl> H ~ uou ^ maam upomouwhn Hm fi H ~ uwa ~ wa> H ° mämm a.N mm © w> m.m mm u «> uumwmHwHw> w mm w flfi m Hwwumumsuwäh fl om Iäwkm n Q mm s qw Hmumw umu fl mx H ~ «= xw ~ Nux«> v mm ~ «= ~ mH N» «fi> v uuo fi w «um_ uuHHm: nm> M ø fl aw u>« u & <fl mww flfifl hm Hm fi uwum fi unomonwßm _ ^ w = fl ø ~ umm »~ °« v H AAum <@ 780922144; 24 In the following examples, pellets were formed using of a conventional pelletizer, was dried, was targeted and transferred by means of an air suspension coating device, wherein the specified components Dissolved or suspended in acetone was used at a fixed substance content of 5%.

The coated pellets were then tested for on resistance to pH conditions similar to those of rumen and runny stomach, by stirring in buffer solutions With pH 5.5 for 24 hours and pH 2.9 for 0.5 hours. Indicated values of recycling and protection of active core services refer to all materials in the original coated the pellet that was not completely dissolved in the buffer with pH 2.9, including any undissolved active ingredients 15 in the original core. _ ' In the case of the transfer ratios in Table 2, the the number of parts of "60/40 2M5VP / AN" copolymer, where the abbreviations mean 2-methyl-5-vinylpyridine res- respectively acrylonitrile, the second number refers to the number of parts Hydrophobic substance (Dimer Acid 1010), and the third number refers to the number of parts of inert flake material, which was aluminum in Examples 38-43 and graphite in Example 44. 25% of the chloride of lysine.HCl was neutralized using calcium carbonate. In Table 3, a coating ratio was used. 70/30/10, the flake material being aluminum or graphite. ._. ~ .n 10 15 20 25 30 35 7809224-L 25 TABLE 2 Achieved protection for lysine.HC1 pellets with cover combinations of 60/40 2M5VP / AN- copolymer, DimerAcidl0l0ochfling material § Recovered from Eczema- cover combination-% gelation ratio coating pH 2.9 pH 5.5 38 70/20/10 18.8 24.3 83.7 39 70/20/20 19.8 23.3 84.2 40 70/20/30 19.8 23.1 88.5 41. 70/30/10 20.0 ---- 82.9 42 70/30/20 19.9 «--- 89.9 43 70/30/30 21.2 17.6 90.3 44 70/30/30 19.1 20.6 79.0 TABLE 3 Recovery of coated glucose pellets Eczema- Ratio%% Recovered from 2Él__ 2M5VP / AN coating pH 2.9 pH 5.5 45 85/15 15.6 12.8 87.7 46 80/20 l7.8 ~ 20.8 95.5 47 75/25 16.2 14.5 95.2 48 70/30 16.6 13.3 88.8 49 60/40 16.2 12.2 92.3 so so / so 16.7 10.4 'ao, s Table 4 compares the results obtained with the use of real fluid from the tummy and duodenum the intestine by extraction from a ruminant, as well as by reversal of artificial test fluids. In the examples it was use the polymeric material an 80/20 copolymer of 2-methyl- -5-vinylpyridine and styrene with a viscosity limit of 1.23. The core material was 90.9% methionine, 3.6% sodium carboxylmethylcellulose and 5.5% sucrose. The pellets produced was prepared by first dry mixing 500 g of methionine, 20 g sucrose and 10 g of sodium carboxymethylcellulose. Water (135 g) was added and mixed to give a 2 ".. 780922h-4 10 26 compressible, wet powder. The mixture was extruded and cut into pellets. 10 g of sucrose and 10 g of sodium carboxymethylcellulose was dry blended and added to the wet pellets. The pellets were then tumbled to create a uniform cover. The tumbling continued in the warm air to produce dry pellets.

In the examples in Table 4, the coverage comprised 31.5% polymeric material, 3.5% stearic acid and aluminum flakes and talc, as indicated. the covers were prepared using of an air suspension coating device, wherein the the ingredients were dissolved or suspended in acetone a solids content of 5%. the amount of cover was 10%, nat on the weight of the core. The release was measured after 1 h periods. ? 8Û922lr-4 27 w _ ä i E 3 ä oá mä mn om 3. 2 2 2 || 3 oá wå 3 3 mm _ å i 2 S. 3. oá wá om 2 .ä í å E ä 3 ä mä wá mm S 3 m 2 i $ 2 å. Mä mä S m ä ä. 2 3 .ä Nm QN wd 3 o S Qv š š äÉE A5 15 EE ECT š ss l fi wm fi w m2 "ou Cuñumu um fi umu mxwum> mxmumk / umwu ms fl m nmwmëmm fi luwwnw w fi nou mxmumš lumw fi mkåou mxmum> uomc flfi w | uwwuEo> lwmmämm fi .m: mmm mxmuw> cmnu mxmum> Lwmmämw fi ..H Gmuu wxwum> lwwmënw fl LEAG .Hmm w Råå w fi äw fl ß M w fi äw fi ä M w fi ä fi ä w fi gmw fi ä wïäwš w fi åms .nå åešä na fl ä .w AAMMÉH. 780922Ä ~ lr I 28 To be useful and practical as food for ruminants are considered to be at least 60% and preferably at least 75% of the active ingredients of the core of the pellets to which the invention relates should be - 5 stable in the rumen and released in the tummy. 'f ... ÉÛ-QÉiQššNIQÉ-'TY

Claims (10)

Pellet for oral administration to ruminants, which pellet comprises a core material having a pH value of more than 5.5 and is healthy for the ruminant after ruminating, and a coating which surrounds the core material, characterized in that the coating comprises a) a film-forming polymeric material containing at least one basic amino group, the nitrogen content of the polymeric material being 3-14% of the molecular weight of the polymeric material and the polymeric material being soluble within 24 h of aqueous rumen medium, which medium has a pH value of more than 5.5, b) a hydrophobic substance dispersed in the polymeric material and selected from fatty acids having 12-32 carbon atoms, aluminum salts of fatty acids having 12-32 carbon atoms, and polycarboxylic acids having 10-22 carbon atoms per carboxyl group and a molecular weight of 400-1000, and optionally c) a physiologically acceptable flake material, the hydrophobic material being present in the coating in an amount of 2-75% of the weight of the polymeric material, and the coating constitutes 5-50% of the weight of the pellets and has a tack temperature of at least 50 ° C. The pellet according to claim 1, in that the hydrophobic material is present in the supernatant in an amount of 2-40% by weight of the polymeric material. The pellet according to claim 1, wherein the hydrophobic material is present in the supernatant in an amount of 5-75% by weight of the polymeric material. 4. The pellet according to claim 3, in that the hydrophobic material is present in the coating in an amount of 5-50% by weight of the polymeric material. Pellet according to any one of claims 1 to 4, characterized in that the polymeric material comprises at least one polymer, copolymer or mixture of polymers selected from cellulose propionate morpholinobutyrate, aromatic polymers with basic amino groups, dialkylaminoethyl acrylates and methacrylates, wherein the alkyl group contains 1-6 carbon atoms, condensation polyesters and polyamides. 6. The pellet according to claim 5, characterized in that the polymeric material is cellulose propionate morpholinobutyrate. 7. The pellet according to claim 5, characterized in that the polymeric material is a copolymer of vinyl-pyridine and styrene. ' Pellet according to one of Claims 1 to 7, characterized in that the hydrophobic substance is aluminum dioleate, stearic acid or dimer acid. 9. The pellet according to claim 1, characterized in that the flake material consists of aluminum flakes, talc, graphite or ground mica. Pam »“ ft '.-.-.-..._._..-....