AU627444B2 - Rumen-stable pellets - Google Patents

Description

t i OPI DATE 25/08/89 AOJP DATE 28/09/89 APPLN- ID 29379 89 PCT NUMBER PCT/US89/00205 INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (51) International Patent Classification 4 (11) International Publication Number: WO 89/ 06909 A23K 1/00, A61K 9/52, 9/32 Al AC F 226/06 52 32 A (43) International Publication Date: 10 August 1989 (10.08.89) (21) International Application Number: PCT/US89/00205 (74) Agent: MONTGOMERY, Mark, Patent Department, Eastman Kodak Company, 343 State Street, (22) International Filing Date: 18 January 1989 (18.01.89) Rochester, NY 14650 (US).

(31) Priority Application Number: 150,180 (81) Designated States: AT (European patent), AU, BE (European patent), CH (European patent), DE (Euro- (32) Priority Date: 29 January 1988 (29.01.88) pean patent), FR (European patent), GB (European patent), IT (European patent), JP, LU (European pa- (33) Priority Country: US tent), NL (European patent), SE (European patent).

(71) Applicant: EASTMAN KODAK COMPANY [US/US]; Published 343 State Street, Rochester, NY 14650 With international search report.

Before the expiration of the time limit for amending the (72) Inventors: WU, Stephen, Hong-Wei 1104 Meadow claims and to be republished in the event of the receipt Lane, Kingsport, TN 37663 KIRK, Shane, Ki- of amendments.

pley 323 Dogwood Street, Route 6, Church Hill, TN 37642 PERRY, Kenneth, Paul 3840 Skyland Drive, Kingsport, TN 37664 SMITH, Ernest, Phillip Route 5, Box 4787, Blountville, TN 37617 CHANG, Yeong-Ho 306 Spring Lane, Apartment 7, Kingsport, TN 37663 JENKINS, Wayin, Lwewllyn ;2016 Lamont Street, Kingsport, TN t 37664 e (54) Title: RUMEN-STABLE PELLETS (57) Abstract Coating compositions and pellets coated therewith which are adaptable for oral administration to ruminants are disclosed. The coating protects the core material of the pellets in the rumen and releases it postruminally. The coating is a specific mixture of a film-forming polymeric material, hydrophobic material and flake material.

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1 2 i WO 89/06909 PCT/US89/00205

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i: -1- Description Rumen-Stable Pellets Application Serial No. 789,282 filed Oc r 18, 1985, which is a continuation-in-p Application Serial No. 498,445 filed 1983, now abandoned, and Serial N ,J387 filed January 2, 1985, now Technical Field This invention relates in general to pellets adapted to be orally administered to ruminants and which are beneficial to ruminants after passing the rumen and reaching the abomasum and/or intestines.

More particularly, this invention relates to pellets Ii having, in terms of structure, a core material such as i: a nutrient or medicament and a coating over the core i material which protects the core in the environment of the rumen, but which loses continuity under the more acidic conditions of the abomasum to render the core ii material available for utilization by the animal. 4 Background of the Invention In ruminants, beef and dairy cattle, sheep, etc., ingested feed first passes into the rumen, where it is pre-digested by fermentation. During this period of fermentation the ingested feed may be regurgitated to the mouth where it is salivated and ruminated. After a period of fermentation, absorption of digested nutrients starts and continues in the subsequent sections of the digestive tract. This r

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Z2^ digestive process is described in detail by D. C.

Church, "Digestive Physiology and Nutrition of iii 1 WO 89/06909 PCT/US89/00204 I Corvallis, Oregon.

The rumen serves as an important location of metabolic breakdown of ingested foodstuffs through the action of microorganisms which are present therein.

Ingested food is typically retained in the rumen for from about 6 to about 30 hours, during which time it is subject to metabolic breakdown by the rumen microorganisms. When the rumen contents pass into the abomasum and intestine, the microbial mass is digested, thus providing protein to the ruminant.

Thus, the natural nutritional balance of the ruminant animal is primarily a function of the microbial composition and population.

In preparing nutrients and medicaments intended for administration to ruminants, it is important to protect the active ingredients against the environmental conditions of the rumen, microbial degradation and the effects of a pH of about 5.5, so -i the active substance will be saved until it reaches the particular location where adsorption takes place.

It is well known that the rate of meat, wool and/or milk production can be increased if sources of growth 'f limiting essential amino acids, and/or medicaments, i are protected from alteration by microorganisms in the rumen and become available for direct adsoTption by the animal later in the gastrointestinal tract.

Materials which protect the core against degradation by the rumen contents should be resistant to attack by the rumen fluid but must make the active ingredient available rapidly in the more acidic fluid of the abomasum (postruminally) at a pH within the normal physiological range of about 2 to about i S WO 89/06909 PCT/US89/00205 1 i| i 1

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-3i 3 i Because proteins are subject to breakdown in the rumen, it has been suggested that protein-containing nutrients fed to ruminants be treated so as to permit passage without microbial breakdown through the rumen to the abomasum. Suggested procedures have included coating the protein material, for example, with fats and vegetable oils; heat treating of the protein material; reacting the protein material with various compounds such as formaldehyde, acetylenic esters, polymerized unsaturated carboxylic acid or anhydrides and phosphonitrilic halides, etc.

It is likewise well-known that some medicaments are more effective when they are protected from the environment of the rumen., See, for example, U.S.

Patent Nos. 3,041,243 and 3,697,640.

Compositions containing nutrient and medicaments for administration to ruminants must also exhibit adequate stability upon storage. In particular, such compositions must retain sufficient activity when stored in high humidity and/or heat so that the compositions will be effective for their intended purpose. In addition, such compositions must be I stable when in contact with moist feed.

In accordance with the present invention, a polymeric coating having a hydrophobic substance and a flake material dispersed therein, which coating is resistant to environmental conditions of the rumen but releases the core material under the environmental conditions of the abomasum, provides a very desirable utilization efficiency by ruminants. The core material may also contain a neutralizer to provide a pH above about The coating material has the ability to withstand environmental conditions of the rumen, and the ability WO 89/06909 PCT/US89/0020 i 4 environment of the abomasum. Thus, the coating material is resistant to pH conditions of about for at least about 24 hours. The coating material releases the core material upon exposure to postruminal environmental conditions having a pH of about after a time of about 5 minutes to about 6 hours.

The exposure of the core may occur by the coating becoming permeable to the fluids therein or by dissolving or disintegrating. Another requirement for the coating material is to have the ability to withstand feed environment or storage conditions of relatively high heat and/or humidity without a significant loss of rumen-stable and post-rumen release properties.

U.S. Patents of interest include Nos. 3,619,200; 3,880,990; 3,041,243; 3,697,640; 3,988,480; 3,383,283; 3,275,518; 3,623,997; 3,073,748; 3,829,564; 3,832,252; and 3,917,813.

Of particular interest are U.S. Patent Nos.

4,181,708; 4,181,709; and 4,181,710. The disclosure of U.S. Patent No. 4,181,708 is incorporated herein by reference. The '708 patent discloses rumen-stable pellets coated with a mixture of a polymeric material, a hydrophobic material, and a flake material, and the '710 patent discloses rumen-stable pellets coated with a mixture of polymeric material, hydrophobic material and inert filler. It has, however, been unexpectedly discovered that when the nutrients and/or medicaments of the core are highly water soluble (such as glucose and lysine which have a solubility of more than gm/100 gm water at 25 0 C) excellent results are obtained when the hydrophobic material and flake material are present in amounts as described herein.

carbon atoms, aluminum salts of fatty acids having from 12 to 32 carbon atoms, and ,WO 89/06909 PCT/US89/00205 5 In addition, it has been unexpectedly discovered that when the glass transition temperature (Tg) values of the coating compositions are as described herein, said compositions have increased stability to heat and/or high humidity.

Brief Description of the Drawings Figure 1 is a triangular coordinate graph illustrating the invention. The apex of the graph represents 100 weight polymeric material, exemplified by (80:20). The lower right corner of the graph represents 100 weight flake material, exemplified by talc/- aluminum flake (50:50). The lower left corner of the graph represents 100 weight hydrophobic material, exemplified by stearic acid. Compositions containing various concentrations of these three ingredients are represented graphically at A, B, C, D, and E, and the points labeled with a numerical figure. Such triangular coordinate graphs and their use are well known by those skilled in the art.

Figure 2 is an enlarged section of the graph of Figure 1 illustrating the present invention. The additional points not shown in Figure 1, B', F, G, and H also represent various concentrations of the three ingredients as in Figure 1. Lines of the graph representing major increments are also labeled.

Summary of the Invention According to the present invention, there are provided coating compositions and pellets adapted for oral administration to ruminants. The pellets comprise a core material beneficial to the ruminants postruminally abomasum and intestine), and a 1

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dispersed in said polymeric material selected from the group consisting of waxes, resins, polymers, fatty acids having from 12 to 32 /3 1 ;i WO 89/06909 PCTUS89/0020 1 ii 1,; if:ir 6 coating surrounding the core material which protects the core material in the rumen and releases it postruminally. The coating comprises a physiologically acceptable film-forming polymeric material comprising a polymer or a mixture of polymers, the polymeric material having basic amino groups the nitrogen content of which constitutes between about 2 and about 14% by weight of the polymeric material, between 1.5% and 121%, based on the weight of polymeric material, of a hydrophobic material dispersed in the polymeric material selected from the group consisting of waxes, resins, polymers, fatty acids having from 12 to 32 carbon atoms, aluminum salts of fatty acids having from 12 to 32 carbon atoms, and polyfunctional carboxylic acids having a ratio of from 10 to 22 carbon atoms per carboxyl group, and greater than about 200% and up to 485%, based on the weight of said polymeric material, of a physiologically acceptable flake material dispersed in the polymeric material.

The polymeric material in combination with the hydrophobic material and flake material is physiologically acceptable and resistant to a pH of greater than about 5 but capable of releasing the core of the pellets at a pH of less than about 3.5. The coating makes up about 5 to about 50% of the weight of the pellet. The coating has a glass transition temperature of not more than about 60 0 C and said coating is further defined in terms of weight of the polymeric material, hydrophobic material and flake

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,!a %n

B

%e ~rB i i1~ i of which constitutes between 2 ana 14; Dy weight of the polymeric material, between 1.5% and 121%, based on the weight of WO 89/06909 PCT/US89/00205 7 material by lines AB, BE, ED, DC, and CA of the tri-component graph of Figure 1.

Detailed Description of the Invention Pellets The pellets according to this invention are adapted for oral administration to ruminants. The pellets are of a suitable shape and size, such as cylindrical, having a diameter of about 1.0-2.0 mm and a length-to-diameter ratio of about 1-2.0:1. Also, the pellets must be of suitable density, a specific gravity of between about 1 and 1.7, have acceptable odor, taste, feel, etc. The pellets include a core and a continuous, film or coating completely encapsulating the core.

Core Material The core is of a material beneficial to the ruminant upon passing the rumen and reaching the abomasum and/or intestine. Normally, the core is a solid material which has been formed into particles, such as by pelletizing prior to being coated. The cores should have sufficient body or consistency to remain intact during handling, particularly during the jcoating operation. Suitable core materials include Svarious medicaments and nutrients such as, for example, antibiotics, relaxants, drugs, antiparasites, amino acids, proteins, sugars, carbohydrates, etc.

The core may also contain inert filler material such as clay and acid or base neutralizers.

The core material may be made ready for coating by the following method. The nutrient, medicament, or the like, and core neutralizer, if used, are mixed WO 89/06909 PCT/US89/00205 with water, binders, and sometimes inert organic substances added to adjust the specific gravity of the pellet and the resulting plastic dough-like mass is extruded or rolled to obtain suitable size particles.

Adhesive binders may be added to strengthen the pellets and can be nontoxic vegetable gums, starches, cellulose derivatives, animal gums and other similar substances well-known in the art of food thickening and tablet making. Inorganic additives used to adjust the specific gravity of the pellet include such substances as insoluble, nontoxic pigment-like materials such as metal sulfates, oxides and carbonates having a relatively high density. After creating suitable size pellets, the pellets are dried to remove the water. The pellets are then coated by contacting them with a solution of the protective coating material in a suitable solvent or mixture of solvents as hereinafter described.

Coating The coating material is capable of forming a continuous film around the core by the evaporation of solvent from the coating material. It has the ability to withstand environmental conditions of the rumen, and the ability to expose the core material of the pellet in the environment of the abomasum. Thus, the coating material should be resistant to pH conditions of greater than about 5 for from about 6 to about hours. The coating should release the core material after exposure to abomasum environmental conditions having a pH of about 2 to about 3.3.

Release should occur within the residence time in the abomasum or later in the intestinal track but at least within a time period of six hours after contacting pH 3.5 or less. The exposure of the core may occur by the coating becoming permeable to the contents of the i mixture of polymers, said polymeric material having basic amino groups the nitrogen content I WO 89/06909 PCT/US89/00205 1I i) -9rumen, such as by dissolving, disintegrating, or extensive swelling. The coating material is physiologically acceptable, the coating material should not interfere with the ruminants' healthy or normal body functioning.

Another requirement for the coating material is its ability to withstand abrasion in handling and storage conditions of relatively high heat and/or humidity without a significant amount of blocking or sticking. Also, the coating material is preferably soluble or dispersable in organic solvents having boiling points of between about 400 and 140 0 C to permit conventional coating processes such as spray coating to be used. Particularly suitable solvents include methylene chloride, chloroform, ethanol, methanol, ethyl acetate, acetone, toluene, isopropanol or mixtures of these.

Polymer, The polymeric substances include homopolymers, copolymers, terpolymers, polymers having more than three monomers, and mixtures thereof having basic amino groups in which the nitrogen content of the polymeric substance is between about 2 and about 14% and of a film-forming molecular weight. As used J; herein the term "polymer" encompasses homopolymers, copolymers, terpolymers, and polymers made from more than three monomers. The basic amino groups may be of the aliphatic type in which case they will contain from about 2% to about 10% by weight of nitrogen in the basic amino groups. The basic amino groups may also be of the aromatic type in which the basic amino groups are attached directly to the aromatic ring, or are part of the aromatic ring structure in which case they will contain from about 6% to about 14% nitrogen in the basic amino groups. The polymeric substances

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WO 89/06909 PCT/US89/00205' 10 are of sufficient molecular weight to have filmforming properties when the polymer is deposited from a solution or dispersion and after removal of a solvent or dispersing medium, or on cooling from a melt.

Polymeric substances having the characteristics defined herein include certain modified natural polymers, homo- and interpolymers obtained by addition polymerization methods, homo- and copolymers obtained by condensation polymerization methods and mixtures thereof. The polymeric material is comprised of at least one polymer or blend of polymers comprising cellulose derivatives such as cellulose propionate morpholino-butyrate; containing addition-type monomeric moieties such as acrylonitrile; vinylated derivatives of pyridine; styrene; methylstyrene; vinyl toluene; esters and amides of methacrylic acid; acrylic acid; such as a dialkylamino ethyl acrylate or i methacrylate in which the alkyl group contains from 1 to 6 carbon atoms, polymerizable ethylenically unsaturated aliphatic hyrocarbon monomers such as ethylene, propylene or butadiene; vinyl esters such as vinyl acetate, vinyl propionate or vinyl stearate; vinyl esters such as methyl, ethyl, propyl or stearyl, vinyl substituted heterocyclic ring or condensed ring compounds containing basic nitrogen configurations '"such as vinyl carbazole, vinyl quinoline, N-vinylpyrrole and 5-vinyl pyrozoline; containing condensation-type polymers wherein diacids such as phthalic, terephthalic, and succinic are combined with polyfunctional alcohols to form polyesters wherein either the acid or glycol moiety may contain basic nitrogen reactive to variable pH environments and wherein the same or similar diacids may be reacted with polyfunctional amines to form polyamide-type L L SWO 89/06909 PCT/US89/00205 11 polymers containing basic nitrogen not reacted in the polymerization process; and other basic nitrogen containing polymers such as polymers which have been formed by reacting an existing polymer with a nitrogen containing organic or inorganic moiety such as polybutadiene to which ammonia has been reacted with the remaining double bond. Especially preferred are poly(vinylpyridine), polymeric derivatives of vinylpyridine, and the copolymers of the various isomers and derivatives of vinylpyridine copolymerized with one or more of the above-mentioned addition type monomers.

Included among the especially preferred copolymers are 2-methyl-5-vinylpyridine and styrene, and in particular, the copolymer of about 75-85% by weight and about 15-25% by weight styrene, as well as the copolymer of 55-65% by weight and about 35-45% by weight acrylonitrile. Also especially preferred is the copolymer of 60-85 weight 2-vinylpyridine and 40-15 weight styrene. These copolymers are commercially available or may be produced by conventional techniques well known in the art. Other copolymers useful in the present invention include copolymers of 2-vinylpyridine and isoprene, butadiene, or acrylate.

Preferred novel polymers useful in the present invention that are made from three or more monomers comprise: 1. from about 50 to about 95 percent by weight of 2-vinylpyridine, and 2. from about 5 to about 50 percent by weight of two or more monomers selected from the group consisting of styrene, isoprene, butadiene, and an alkyl acrylate, wherein the polymer has a glass transition temperature, as styrene, and from 3 to 20 percent by weight of Ic.? L :I I

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-'1-;311 G~Xl;i, ii" i r- r- t-~

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WO 89/06909 PCT/US89/00205 12 measured by differential scanning calorimetry, of from about 50°C to about 100°C, a water transmission of from 0 to 2 about 29 g-mil/100 inches /24 hours when measured on a solvent-cast film, and an inherent viscosity of from about 0.3 to about A preferred novel terpolymer suitable for use in the present invention is a novel 2-vinylpyridine/styrene/acrylate or olefin terpolymer comprising from about 50 to about 95 percent by weight of 2-vinylpyridine, preferred is about 65 to about 85 percent; from about 45 to about 2 percent by weight of styrene, preferred is about 30 to about 5 percent; and from about 3 to about 20 percent by weight, preferred is about 5 to about 15 percent, of a monomer selected from the group consisting of isoprene, butadiene and an alkyl acrylate, said terpolymer having a glass transition temperature when measured by differential scanning colorimetry (DSC), of from about 500C to about 100 0 C, preferred is about 70 0 C to about and a water transmission of less than about 29 g.mil/100 inches2/24 hours, preferred is less than about 20 g.mil/100 incht- 2 /24 hours, when measured on a solvent-cast film, and an inherent viscosity about 0.3 to about 2.0, preferred is about 0.8 to about 1.7.

Tg by DSC can be measured by using the procedure disclosed by John Mitchell and Jen Chiu, Anal. Chem.

Annual Review, 43,267R (1971); M. J. O'Neill and R. L. Fyans, "Design of Differential Scanning Calorimeters and the Performance of a New System," paper presented at the Eastern Analytical Symposium, New York City, November, 1971.

WO 89/06909 PCf/US89/00205 13 1 K The inherent viscosities are determined according to ASTM D2857-70 procedure in a Wagner Viscometer of Lab Glass Inc., of Vineland, New Jersey, having an 0.4 mm capillary and a 1 ml bulb, using a polymer concentration of 0.25% by weight in dimethylforamide solvent. The procedure comprises dissolving the sample at 25 0 C, and measuring the time of flow at 0 C. The I.V. is calculated from the equation 1 0 ln s 1 0 0 C o 0.25% c wherein: Inherent viscosity at 25 0 C at a polymer concentration of 0.5 g/100 mL of solvent; In Natural logarithm; ts Sample flow time; to Solvent-blank flow time; and C Concentration of polymer in grams per 100 mL of solvent 0.25.

Water transmission can be determined by the methodology disclosed in ASTM Method F372.

When the novel polymers made from three or more Smonomers as disclosed herein are used as the polymeric material in the coatings of this invention, the Tg of the composition will be low enough so that the presence of a hydrophobic substance is no longer required. Therefore the present invention also encompasses binary coating compositions and pellets made therefrom which comprises such polymers made from three or more monomers as described hereinbefore and from about 186 to about 485 percent, based on the weight of polymer, of a physiologically acceptable flake material dispersed in said polymeric material, 4 i~ WO 89/06909 PCT/US89/00205, 14 preferably from about 186 to about 400 percent of said flake material.

The acrylate residues of the polymers made from three or more monomers useful in the coatings and pellets of the present invention are derived from an acrylate monomer having the formula

CH

2

C-COOR''

wherein R' is H or methyl and is a straight, branched or cyclic alkyl group of 1 to 20 carbon atoms. Preferred alkyl groups have 6 to 20 carbon atoms such as n-lauryl, 2-ethylhexyl, cyclohexyl, and iso-octyl. It is preferred that R' is H. Preferred acrylate monomers are n-lauryl acrylate, 2-ethylhexyl acrylate, cyclohexyl acrylate and iso-octyl acrylate.

All of the monomers used to prepare the novel polymers made from three or more monomers the preferred 2-vinylpyridine/styrene/acrylate or olefin terpolymer) are well known in the art and can be prepared by well known techniques. Polymers useful in the coatings and pellets of the present invention can be prepared by well known polymerization techniques such as solution or emulsion polymerization (see, for example, U.S. Patent 4,593,082). For example, three respective monomers in the desired proportions, with or without any desired additive, are placed in a reaction vessel in the presence of water and mixed with an emulsifier to form an emulsion. The emulsion is swept with an inert gas such as nitrogen or argon and heated to about 55°C. A polymerization initiator, such as sodium persulfate, is then added to the emulsion and said monomers are allowed to polymerize for a sufficient time to result in the desired terpolymer. After the terpolymer is formed, the temperature is typically adjusted to about 40 0 C and a I- I e~ WO 89/06909 PCT/US89/00205 15 suitable acid such as acetic acid is added to precipitate the terpolymer product. The terpolymer can then optionally be digested, for example, with heat, to obtain better-defined particles. The terpo.ymer can then be purified using standard procedures kwown in the art. The terpolymer can then be dissolved in a suitable solvent such as a mixture of 85% acetone and methanol by weight.

Hydrophobic Material Hydrophobic materials which are physiologically acceptable and have the correct degree of compatability with the polymer are commercially available.

It is important that the polymer and hydrophobic substance have a degree of compatability to permit the film to remain intact in the rumen environment, but to permit permeation of the abomasal fluid to the core while the pellet is in the abomasum.

A class of hydrophobic materials of value are fatty acids containing from 10 to 32 carbon atoms such as lauric, oleic, stearic, palmitic and linoleic.

These substances are well known to be water insoluble to the long hydrocarbon radical but to react to water due to the polar nature of the carboxyl group.

In the selected basic amino group-containing polymers, the carboxyl group of the fatty acid is able to react with the basic nitrogen group to form a weak salt-type linkage. This attachment to the polymer serves to cause the fatty acid to be fixed in the polymer matrix. The hydrophobic hydrocarbon chain of the fatty acid tends to render the matrix water resistant and thereby decreases swelling of the otherwise water suseptible polar film. Both the interior of the matrix film and the surface is now water resistant in aqueous environments at pH above about 5.0. However, WO 89/06909 PCT/US89/00205 16 at pH values below pH 4.5 and especially below about pH 3.5 the affinity of the basic nitrogen group for water and the hydrogen ion overcomes the increased water resistance. The film reacts with the acid environment and loses barrier properties sufficient to allow the core material to escape to the environment.

Polyfunctional carboxylic acids may be derived from natural products or obtained by organic synthesis but the ratio of carboxyl group to hydrophobic organic radical should be at least 1 to 10 based on the molecular weight of the organic radicals. The hydrophobic substance may be one or more polycarboxylic acids or salts thereof having a ratio of 10 to 22 carbon atoms per carboxyl group and a molecular weight of about 300 to about 1000. Also included in this class of synthesized organic hydrophobic acids are mono and polyfunctional acids containing silicone or fluorinated carbon groups located at least 4 atoms distant along the molecular chain from the position of the carboxyl group or groups. Also, included in the class of hydrophobic substances are the nontoxic multivalent metallic salts of the above acids such as the stearates, oleates, fatty acid diamerates, and palmitates of aluminum and iron and the calcium, magnesium and zinc salts of the higher molecular weight crystalline analogs of the above acids. When the cation is trivalent as for aluminum and ferric ion, the molar ratio of organic acid to metal ion is 2 to 1 or 3 to 1 and the acid can be any monofuhctional organic acid having one carboxyl group and at least carbon atoms in the organic radical attached to the carboxyl group. When the metal ion is divalent such as ferrous iron, calcium, magnesium or zinc the organic acid may be monocarboxylic or polycarboxylic and the ratio of metal ion to non-carboxylic carbon 1171:1111 WO 89/06909 PCT/US89/00205 i 17 atoms is at least 1 to 26. Natural and synthetic waxes and resins added at levels depending on the degree of hydrophobicity and compatibility in the matrix film are of value in the practice of the invention. Waxes and resins are useful that have a molecular weight of from 500 to 2000 and a critical surface tension of less than 31 dynes/cm as determined by the Zisman method described in "Contact Angle Wettability and Adhesion," Advances in Chemistry Series #43; Edited by Robert F. Gould; published by the American Chemical Society; 1963; Chapter 1; and have a solubility in the matrix film of less than Typical waxes and resins include beeswax, petroleum wax, dammar, hard manila, phenolic resins, rosin and maleated low molecular weight polyhydrocarbons. Also included in the hydrophobic substances are polymers having molecular weights of from 2000 to 10,000, a i1 critical surface tension of less than 31 dynes/cm measured by methods in the reference to Zisman described above. Of particular value are the polymers I and copolymers containing silicone groups in the main polymer chain or in a side chain and polymers and 11 copolymers containing flourinated carbon groups in a side chain. Regardless of the exact nature of the hydrophobic material it must be soluble or colloidally dispersible in the coating solvent when one is used.

It is not desired to be bound by any particular theory or mechanism; however, it is believed that the function of the hydrophobic material as a dispersed phase in the protective polymer layer is as follows: a. reduces wetting of the coating and therefore initial attack by water, b. reduces total volume of coating affected by water, and c. extends the length of permeable pathway the water must travel to core.

-i 1 L 1 WO 89/06909 PCT/US89/00205 ii 18 Functional Flake Material In accordance with this invention, a physiologically acceptable flake material is dispersed throughout the polymeric matrix. The flake material is substantially inert with respect to the ,J environment of the rumen.

Suitable inert flake materials include aluminum flake, talc, graphite, ground mica, and combinations thereof. Especially suitable are aluminum flake, talc and combinations thereof. Aluminum flake is produced by ball-milling the aluminum in a liquid medium in the presence of a lubricant such as stearic acid. It is available commercially from Alcan Metal Powders, Division of Alcan Aluminum Corporation.

Sizes of the flake are generally le.s than about 100 microns, preferably about 1-60 microns. Talc particle sizes are generally within the range of 0.5-40 microns. It is sometimes beneficial to subject the hydrophobic material and flake material to ball-milling operations such that they are brought ;i into rubbing contact for several hours, thereby increasing the efficiency of the coating.

The weight percentages of hydrophobic material and flake material according to this invention are shown in Figure 1 by the area defined by lines AB, BE, ED, DC and CA. Line AB is shown in greater r detail in Figure 2, where its relationship to U.S.

Patent 4,181,708 is also shown. The boundary of the disclosure of '708 is illustrated by broken line FG containing point H, which represents the specific disclosure of the '708 patent closest to applicants' present invention. Line AB is defined as follows: 1. based on percent hydrophobic material, 20% at A and 0.5% at B; L -1 -i

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:;a _i T"r~L WO 89/06909 PCT/US89/00205 19 2. based on polymeric material and flake material, straight, parallel, and juxtaposed to line FG.

By "juxtaposed" it is meant spaced from line FG an infinitesimal, or very small, distance but a distance sufficiently large that points on line AB are not graphically equivalent to points on line FG.

The coordinates for points A, B, C, D, E, F, G and H are given in the following table.

Coordinates Polymeric Material 28.09 32.47 31.5 (see below) (see below) 16.5 16.5 19.5 7 Hydrophobic Material 1 Flake Material 14.05 0.65 3.5 20 0.5 20 3.5 0.5 57.87 66.89 (see below) (see below) 63.5 line AB, B are as -sli i,: .i

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Within the definition given above for suitable coordinates for points A and follows: Polymeric Material 26 25.5 32.4 32 Hydrophobic Material 20 20 .5 .5 Flake Material 54 54.5 67.1 67.5 I Y LIU~~

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WO 89/06909 PCT/US89/0020 20 The boundary of the area disclosed by Dannelly '708 closest to the claimed invention is shown at line FG in Figure 2.

The '708 patent discloses hydrophobic material in amounts ranging from about 2% to about 50%, based on the weight of the polymeric material and flake material in amounts of about 10% to about 206%, based on the weight of polymeric material. These amounts are represented by the following, considering one unit of polymeric material: Case I Case II Case III Case IV Polymeric Material 1 1 1 1 Hydrophobic Material 0.02 0.02 0.5 Flake Material 0.10 2.06 0.10 2.06 Total 1.12 3.08 1.60 3.56 Converting to percentages based on composition weight rather than polymeric weight, the following percentages are found: Percentages in Case I: I

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Polymeric Material Hydrophobic Material 1 89.29% 1.12 0.02 1.12 0.10 1.12 1.78% Flake Material 8.93% 1 i-i WO 89/06909 PCr/US89/00205 i,:I j;r i I i:r i~B 1:;IIif: fii i jr 1~ 21 Percentages in Case II: Polymeric Material Hydrophobic Material Flake Material 1 32.47% 3.08 0.02 3.08 0.65% 2.06 3.08 66.88% Percentages in Case III: Polymeric Material Hydrophobic Material 1 1.6 62.50% 1.6 31.25% Flake Material 0.1 1.6 6.25% Percentages in Case IV: Polymeric Material Hydrophobic Material 1 28.09% 3.56 3.56 14.05% Flake Material 2.06 3.56 57.87% Obviously Cases II and IV, because of their high contents of flake material, represent the points on the graph closest to the area claimed by applicant.

These points are F and G respectively on the graph.

Point H illustrates the specific disclosure of the '708 patent in Example 14. Cases I and III represent points far removed from the present invention.

WO 89/06909 PCT/US89/00205 22 In all situations, the amount of flake material in the coatings of this invention is greater than about 200%, based on the weight of polymeric material; a preferred amount of flake material is greater than 206% and less than about 380%, based on the weight of polymeric material. In all situations, the amount of hydrophobic substance is between and 121%, based on the weight of polymeric material; a preferred amount is between about 5% and about based on the weight of polymeric material.

The Tg values of the coating compositions of the invention is not more than about 60 0 C, preferred is between about 30 0 C and about 60 0 C. It has been found that when the Tg value of the coating compositions are within the above-noted limit, an unexpected improvement in storage stability stability to high humidity and/or heat) is observed. Tg value of the coating compositions can be determined by using thermomechanical analysis (TMA). TMA can be measured on a Perkin-Elmer Model TMS-2 thermomechanical analyzer.

The coating compositions of the present invention L have an amount of flake material that is higher than that amount disclosed in the prior art. This increased amount of flake material greater than about 200%) contributes to better rumenprotection of the coatings and pellets of the invention and also contributed to better storage stability of the coating and pellets of the invention.

In addition, use of the novel polymers made from three or more monomers described herein as the polymeric material contribute to achieving the lower Tg values of the coatings5 of the invention.

The coatings of this invention can optionally contain a plasticizer which also can contribute to L e -r -i they will contain from about 6% to about 14% nitrogen i in the basic amino groups. The polymeric substances i-i WO 89/06909 PCT/US89/00205 23 achieving the lower Tg values of the coatings of the I invention. One or more plasticizers are present in an amount of from 0% to about 25%, based on the weight of polymeric material; preferred is from about 5% to about 25%. Typical plasticizers include, but are not limited to, fatty acids, esters of fatty acids, salts of fatty acids, esters of glycols, and polyglycols. Specific examples include triacetin, triethyl citrate, dimethyl adipate, and the like.

The pellets of the present invention preferably have postrumen release of core material of greater than 85%, more preferably greater than 90%. In addition, the pellets of this invention typically exhibit greater than 80% protection, preferably greater than 90%, when stored for 120 hours at 100 relative humidity and ambient temperature.

In the practice of this invention, the polymeric material may conveniently be dissolved in a suitable solvent which would be physiologically acceptable in the event there are residues upon evaporation of the solvent, as hereinbefore described. The hydrophobic substance and flake material are blended in the solution, wherein the polymeric substance is a continuous matrix and the additives are dispersed therein. The coating solution may be applied by various well known means such as, for example, brushing, dipping, spraying, fluidized bed, etc.

The examples which follow are submitted for a better understanding of the invention, but should not be construed as a limitation thereon.

Example I Rumen Studies While the following examples of Example 1 are based on in vitro tests, the in vitro experiments i-- WO 89/06909 PCT/US89/0020 24 i simulate conditions existing in ruminants thereby permitting the study of coated pellets without the use of live animals. It has been determined by actual in vivo tests using certain coating compositions that the testing of pellets in aqueous media simulating the environmental conditions of the rumen and abomasum with respect to temperature, pH, etc., provide reliable data concerning the protection offered by the coatings in the rumen, and releasability of the coatings in the abomasum. Nutrients such as amino acids and proteins which may be used in the core material are known to be beneficial to ruminants when positioned in the intestinal tract downstream from the rumen.

Generally, pellets are prepared from the nutrients indicated to a size of between about 8 and 12 sieve size. The nutrients are mixed with conventional additives such as microcrystalline cellulose, binders, inert consistency adjusting substances such as water, etc. The pellets are formed by a conventional pelletizer, dried, sieved, and coated using a coater as described herein. Upon application of the coating to the pellets, they are tested for resistance to pH conditions resembling those of the rumen and abomasum by agitating in buffer solutions of pH 2.9 for 0.5 hours and 5.4 for 24 hours.

Recovery and protection figures cited for active core ingredients herein contain in them all materials of the original coated pellet that are not completely dissolved in the pH 2.9 buffer, including any undissolved active ingredient in the original core.

For the sake of simplicity abbreviations are used in the examples as follows: AN acrylonitrile ST styrene r:l A :r !sill ia! qjti i i 'i:i

;.I

WO89/06909 PCr/US89/00205 25 Cylindrical smooth-edge glucose cores (-8/+12 mesh, U.S. standard mesh size) which consist of glucose and 10% microcrystalline cellulose are used in all experiments. In the process of preparing glucose cores, glucose powder and mirocrystalline cellulose are mixed thoroughly in a Hobart mixer-extruder; water is then added slowly to wet the dry solid mix until an extrudable dope was formed.

The moisture content of the final dope is about 18%.

The dope is extruded from the mixer-extruder through a die with 2-mm diameter holes and chopped with a rotating knife into small cylinders with a length/diameter ratio approximately equal to one.

Wet cores are tumbled to smooth the rough edges, and then dried in an oven at 60 0 C. Dry cores are screened to yield uniform size cores for all coating experiments.

In preparing the coating dopes, a mixture of copoly(2MSVP/ST 80:20) 1.30), stearic acid, and talc/aluminum flake (1:1 w/w) are mixed in acetone to make a series of coating dopes containing solids. The exact coating compositions are shown as dots in the tricompositional diagram in Figure 1.

The coordinates represent percentage of total composition weight of the polymeric material, hydrophobic material and flake material. Glucose cores are coated with the coatings dopes to desired coating levels using an air-suspension coater under the same operating conditions.

Rumen-protection and abomasal release are measured by extracting coated pellets in pH 5.4 buffer for 24 hours and pH 2.9 buffer for one hour respectively. Protection values are obtained for pellets with 6, 12, and 18% coating levels for each coating composition. The protection value at

V

[i, .4 L L

I

:Ljh~ :;i

B

WO 89/06909 PCT/US89/00205 i ~il:I ijt i i' .r ;j 26 coating weight for each coating composition is determined and indicated in at the respective coating compositions in Figure 1. For example, the rumen protection value of pellets coated with 20/70/10 (2M5VP/ST)/(Talc/Al)/stearic acid is 94%. All the coating compositions shown in Table 1 have abomosal release in excess of To illustrate the effect of coating amino acids with certain coating compositions, lysine and methionine are coated with compositions described as follows: Polymer Lysine 2M5VP/ST) 80:20%) Hydrophobic Material Flake Material Stearic Acid Aluminum Flake 18% Methionine 31.5% 2M5VP/ST 80:20% 5.0% Stearic Acid 63.5% Aluminum Flake Talc 14% 31.5% 26.0% 39.0% Coating Weight, Based on Weight of Coated Pellets The coated pellets are fed to calves for 140 days. The actual doses of methionine and lysine, were each between about 0.05% and about based on percent of diet on a dry matter basis. Over the entire trial, average daily weight gain increased flake material dispersed in said polymeric material, S WO 89/06909 PCT/US89/00205 27 about 6% when compared to the control groups which were fed no lysine and methionine, indicating rumen protection and delivery postruminally of the amino acids. Thus, the in vitro test results indicating effectiveness of the coatings are confirmed in vivo.

The coating compositions disclosed in this invention are also useful for other bioactive materials, particularly highly water-soluble amino acids such as lysine, carbohydrates, vitamins, antibiotics, hormones, and other pharmaceuticals. In general, a highly water-soluble active ingredient is much more difficult to protect less water-soluble bioactive compound and a successful rumen-stable coating for highly water-soluble materials is obviously useful for materials of low water solubility so that the coating compositions in this invention may be viewed as an universal coating which is independent of the solubility of the core material.

Unless otherwise specified, all parts, percentages, ratios, etc., are by weight. Molecular weights are given as weight averages.

Unless otherwise specified, the inherent viscosity of the polymers is determined at 25 0 C, using 0.25 gram polymer per 100 mL of a solvent composed of dimethylformamide.

Example II 1. This example illustrates the instability of a ternary rumen-stable coating formulation when subjected to 100% relative humidity to simulate feed contact for up to five days.

In an air-suspension coater, 200 grams of lysine.HCl and methionine containing pellets were coated with a rumen-stable coating formulation consisting of 31.5% 2-vinylpyridine/styrene ii be vewe as n uivesal oatng wichis ndepndet 1 ~f WO 89/06909 PCT/US89/00205 28 (65/35) copolymer, 63.5% talc, and 5.0% stearic acid to a coating level of -16.5% by weight. A sample of coated pellets (one gram) was extracted in 50 mL of pH 5.4 buffer solution for 24 hours to determine rumen stability. No significant amount of lysine-HC1 or methionine was detected in the extract. A sample of coated pellets was extracted in pH 2.9 buffer for 45 minutes followed by pH 7.0 buffer for 2.0 hours to test abomasal release. Analysis of the extracts showed greater than 95% release of the payload.

Coated samples (one gram) of the pellets were placed in a closed chamber at 100% relative humidity at room temperature (22 0 C) for 24, 48, and 72 hours. Following removal from the chamber, the coated samples were extracted in mL of pH 5.4 buffer solution for 24 hours to determine the effect of 100% relative humidity on the rumen stability. The effect of exposure to 100% relative humidity on the rumen stability (percent protection) is shown in the following table: Time in Protection 100% RH (Hours) Lysine.HCl Methionine 0 100 100 24 99 100 48 84 96 72 42 74 A very significant drop of lysine-HC1 protection was observed after 72 hours exposure at 100% RH. The glass transition temperature (Tg) of the coating composition measured by thermal mechanical analysis (TMA) was about S WO 89/06909 PCT/US89/00205 29 2. This example illustrates the use of an optimized ternary rumen-stable coating formulation to achieve improved feed stability of lysine-HCl and methionine containing pellets.

Using the same conditions as in Example II, 1, lysilne-HCl and methionine containing pellets were coated with a rumen-stable coating formulation consisting of 2-vinylpyridine/styrene (65/35) copolymer, 60% talc, and 20% stearic acid to a coating level of 16.5% by weight. Coated samples were extracted in pH 5.4 buffer solution for 24 hours to determine rumen stability. No significant amount of lysine-HCl or methionine was detected in the extract. A sample of coated pellets was extracted in pH 2.9 buffer for 45 minutes followed by pH 7.0 buffer for 2.0 hours to test abomasal release. Analysis of the extracts showed greater than 95% release of the payload.

Coated pellet samples were placed in a chamber at 100% relative humidity at room temperature (22 0

C)

for 24, 48, 72, 96, and 120 hours. Following removal from the chamber at 100% relative humidity, the coated samples were extracted in pH 5.4 buffer solution for 24 hours to determine rumen stability. The effect of 100% relative humidity on rumen stability (percent protection) is shown in the following table: Time in Protection 100% RH (Hours) Lysine-HCl Methionine 0 100 100 24 100 99 48 98 98 72 98 99 96 96 97 120 90 93 WO 89/06909 PCT/US89/00205 30 Coated pellet samples from Example 2 show a very significant increase in protection after 72 hours exposure to 100% relative humidity over that of samples from Example II, 1, a 56% improvement. The Tg of the coating composition i measured by TMA was about 50 0

C.

3. This example illustrates the incorporation of a plasticizer, triacetin, into a ternary composition to produce a quaternary composition which exhibits much improved feed stability characteristics compared to the ternary composition.

Using the same conditions as in Example II, lysine- HC1 an methionine containing pellets were coated with a rumen-stable coating composition comprised of essentially the same composition as given in Example II, 1 2-vinylpyridine/ styrene (65/35), 63.5% talc, and 5.0% stearic acid] and an additional amount of 20% triacetin by weight of the 2-vinyl-pyridine/styrene.

Coating weight applied to the pellets was 16.5% by weight. Coated pellet samples were extracted in pH 5.4 buffer solution for 24 hours to determine rumen stability. No significant amount of lysine-HCl or methionine was detected in the extract. A sample of coated pellets was extracted in pH 2.9 buffer for 45 minutes followed by pH 7.0 buffer for 2.0 hours to test abomasal release. Analysis of the extracts showed greater than 95% release of the payload.

Coated pellet samples were placed in a chember at 100% relative humidity at room temperature for 24, 48, 72, 96, and 120 hours. Following removal from the 100% relative humidity, the coated pellet samples were extracted in pH 5.4 buffer L'T~ WO 89/06909 PCT/US89/00205 i. i Jg 31 solution for 24 hours to determine rumen stability. The effect of 100% relative humidity on rumen stability is shown in the following table: Time in 100% RH (Hours) 0 24 48 72 96 120 Protection Lysine HCl 100 100 100 100 98 99 Methionine 100 100 100 99 99 99 The glass transition temperature of the coating composition measured by TMA was about 0

C.

4. This example illustrates the incorporation of a selected plasticizer, triethyl citrate, into a ternary composition to produce a quaternary composition which exhibits much improved feed stability characteristics compared to the ternary composition.

Using the same conditions as in Example II, 2, lysine-HCl and methionine containing pellets were coated with a rumen-stable coating composition comprised of essentially the same composition as given in Example II, 1 [31.5% 2-vinylpyridine/styrene (65/35), 63.5% talc, and stearic acid] and an additional amount of triethyl citrate by weight of the 2-vinylpyridine/styrene. Coating weight applied to the pellets was 16.5% by weight. Coated pellet samples were extracted in pH 5.4 buffer solution for 24 hours to determine rumen stability. No significant amount of lysine-HCl 1 WO 89/06909 PCT/US89/00205 32 or methionine was detected in the extract. A sample of coated pellets was extracted in pH 2.9 buffer for 45 minutes, 2.0 hours to test abomasal release. Analysis of the extracts showed greater than 95L release of the payload. Coated pellet samples were placed in a chamber at 100% relative humidity at room temperature for 24, 48, 72, 96, and 120 hours. Following removal from 100% relative humidity, the coated pellet samples were extracted in pH 5.4 buffer solution for 24 hours. The effect of 100% relative humidity on rumen stability is shown in the following table: Time in Protection 100% RH (Hours) Lysine-HCl Methionine 0 100 99 24 99 99 48 100 99 72 100 99 96 99 99 S120 99 99 The Tg of coating composition measured by TMA was about 45 0

C.

5. This example illustrates the use of a ternary coating composition containing an acid-sensitive terpolymer to improve feed stability characteristics.

Using the same conditions as in Example II, 2, lysine-HCl and methionine containing pellets were coated with a rumen-stable composition comprised of 31.5% 2-vinylpyridine/styrene/lauryl acrylate (65/25/10), 63.5% talc, and 5.0% stearic acid. Coating weight applied to the pellets was by weight. Coated pellet samples were WO 89/06909 PCT/US89/00205 33 extracted in pH 5.4 buffer solution for 24 hours to determine rumen stability. No significant amount of lysine-HC1 or methionine was detected in the extract. A sample of coated pellets was extracted in pH 2.9 buffer for 45 minutes followed by pH 7.0 buffer for 2.0 hours to test abomasal release. Analysis of the extracts showed greater than 95% release of the payload.

Coated pellet samples were placed in a chamber at 100% relative humidity at room temperature for 24, 48, 72, 96, and 120 hours. Following removal from the chamber at 100% relative humidity, the coated pellet samples were extracted in pH 5.4 buffer solution for 24 hours. The effect of 100% relative humidity exposure on the rumen stability is shown in the following table: Time in 7 Protection 100% RH (Hours) Lysine-HC1 Methionine 0 100 100 24 98 99 48 100 99 72 100 99 96 100 100 120 100 99 The Tg of the coating composition measured by TMA was about 520C.

6. This example illustrates the use of a binary coating composition containing an acid-sensitive terpolymer to improve feed stability characteristics.

Using the same conditions as in Example II, 2, lysine.HCl and methionine containing pellets were coated with a rumen-stable coating composition comprised of 28% L WO 89/06909 PCT/US89/00205 34 2-vinylpyridine/styrene/lauryl acrylate (65/25/10) and 72% talc. The coating weight applied to the pellets was 16.5% by weight.

Coated pellet samples were extracted in pH 5.4 buffer solution for 24 hours to determine rumen stability. No significant amount of lysine-HCl or methionine was detected in the extract.

Coated pellet samples were also extracted in pH 2.9 buffer for 45 minutes followed by pH buffer for 2.0 hours. Analysis of the extracts showed greater than 95% release of the payload.

Coated pellet samples were placed in a chamber at 100% relative humidity at room temperature for 24, 48, 72, 96, and 120 hours. Following removal from the chamber at 100% relative humidity, the coated pellet samples were extracted in pH 5.4 buffer solution for 24 hours. The effect of 100% relative humidity exposure on the rumen stability is shown in the following table: Time in Protection 100% RH (Hours) Lysine*HCl Methionine 0 100 100 24 100 99 48 99 99 72 90 98 96 76 120 SThe Tg of the coating composition measured by TMA was about 52 0

C.

7. This example illustrates the use of a binary coating composition containing an acid-sensitive terpolymer to improve feed stability characteristics.

Si i WO 89/06909 PCT/US89/00205 Using the same conditions as in Example II, 2, lysine-HCl and methionine containing pellets were coated with a rumen-stable coating composition comprised of 56% 2-vinylpyridine/styrene/lauryl acrylate (65/25/10) and 44% talc. The coating weight applied to the pellets was 16.5% by weight.

Coated pellet samples were extracted in pH 5.4 buffer solution for 24 hours to determine rumen stability. No significant amount of lysine-HCl or methionine was detected in the extract.

Coated pellet samples were also extracted in pH 2.9 buffer for 45 minutes followed by pH buffer for 2.0 hours. Analysis of the extract showed greater than 95% release of the payload.

Coated pellet samples were placed in a chamber at 100% relative humidity at room temperature for 24, 48, 72, 96, and 120 hours. Following removal from the chamber at 100% relative humidity, the coated pellet samples were extracted in pH 5.4 i buffer solution for 24 hours. The effect of 100% relative humidity exposure on the rumen stability is shown in the following table: Time in Protection 100% RH (Hours) Lysine-HCl Methionine 0 100 100 24 86 97 48 86 97 72 85 97 96 85 98 120 82 96 The Tg of the coating composition measured by TMA was about 52 0

C.

c WO 89/06909 PCT/US89/00205 feed contact. In an air-suspension coater, 180 grams of pellets containing lysine-HC1 and methionine were coated with a rumen-stable coating formulation consisting of 31.5% 2-vinylpyridine/styrene (80/20) copolymer, 63.5% talc, and 5.0% stearic acid to a coating level of 15.3% by weight. A sample of coated pellets (1.0 gram) was extracted in 50 mL of pH 5.4 buffer solution at 39 0 C for 24 hours to determine rumen stability. No significant amount of lysine-HC1 was detected in the extract.

Coated samples (1.0 gram) of the pellets were placed in a closed chamber at 100% relative humidity at room temperature (22 0 C) for 24, 48, an 72 hours. Following removal from the chamber, the coated samples were extracted in 50 mL of pH 5.4 buffer solution at 39 0 C for 24 hours to determine the effect of 100% relative humidity on the rumen stability. The effect of the 100% relative humidity on the rumen stability (percent protection) is shown in the following table: Time in Protection 100% RH (Hours) Lysine-HCl Methionine 0 98 100 24 94 100 48 68 91 72 10 66 The Tg of the coating composition measured by TMA was about 62 0

C.

9. This example illustrates the incorporation of a plasticizer into a ternary rumen-stable coating 1 K n* i l v^L 1

V.-

S'I WO 89/06909 PCT/US89/00205 37 to achieve improved feed stability of pellets containing lysine*HCl and methionine. Using the same conditions as in Example II, 8, pellets containing lysine-HCl and methionine were coated with a rumen-stable coating formulation consisting of 31.5% 2-vinylpyridine/styrene (80/20) copolymer, 63.5% talc, and 5.0% oleic acid to a coating level of 15.3% by weight. A sample of coated pellets (1.0 gram) was extracted in 50 mL of pH 5.4 buffer solution at 39°C for 24 hours to determine rumen stability. No significant amount of lysine-HCl was detected in the extract. Coated samples (1.0 gram) of the pellets were placed in a closed chamber at 100% relative humidity at room temperature (22°C) for 24, 48, and 72 hours. Following removal from the chamber, the coated samples were extracted in mL of pH 5.4 buffer solution at 39 0 C for 24 hours to determine the effect of 100% relative humidity on the rumen stability. The effect of the 100% relative humidity on the rumen stability (percent protection) is shown in the following table: Time in Protection 100% RH (Hours) Lysine-HCl Methionine 0 96 100 24 97 100 48 94 100 72 84 98 Coated pellet samples from Example 9 show a large increase in stability to 100% relative humidity over that of samples in Example 8.

The Tg of the coating composition measured by TMA was about 56 0

C.

L I I I I I I I I M MI WO 89/06909 PCT/US89/00205 38 This example illustrates the incorporation of a plasticizer into a ternary composition to produce a quaternary composition which exhibits much improved feed stability characteristics compared to the ternary composition. Using the same conditions as in Example II, 2, pellets containing lysine-HCl and methionine were coated with a rumen-stable coating formulation consisting of 30.25% 2-vinylpyridine/styrene (80/20) copolymer, 62.25% talc, 3.75% stearic acid, and 3.75% oleic acid to a coating level of 15.3% by weight. A sample of coated pellets gram) was extracted in 50 mL of pH 5.4 buffer solution at 39 0 C for 24 hours to determine rumen stability. No significant amount of lysine.HCl was detected in the extract. Coated samples (1.0 gram) of the pellets were placed in a closed chamber at 100% relative humidity at room temperature (22 0 C) for 24, 48, and 72 hours. Following removal from the chamber, the coated samples were extracted in 50 mL of B pH 5.4 buffer solution at 39 0 C for 24 hours to determine the effect of 100% relative humidity on the rumen stability. The effect of the 100% relative humidity on the rumen stability. The effect of the 100% relative humidity on the rumen stability (percent protection) is shown in the following table: Time in Protection 100% RH (Hours) Lysine-HCl Methionine 0 95 99 24 94 100 48 94 100 72 91 99 The Tg of the coating composition measured by TMA was about 50 0

C.

L i i~ S WO 89/06909 PCT/US89/00205 39 11. This example illustrates the stability of rumen-stable coatings in a moist feed environment. Ten grams of coated pellets were mixed with approximately 200 g of a typical dairy feed ration. The feed ration'contained 1,342 g of corn silage, 37 g corn meal, 24.8 g soybean meal, and 3.8 g of minerals. The moisture content of the feed was 43.2% and the pH of the feed was 5.1. Pellet samples were mixed into the feed at room temperature for 24 to 48 hours.

One gram of pellets was removed from the feed.

Following removal from the feed, the coated samples were extracted in 50 mL of pH 5.4 buffer solution for 24 hours to determine the effect of feed content on rumen stability. The effect of exposure to feed on rumen stability (percent protection is shown in the following table: 7 Protection Protection 24 Hours 48 Hours Sample Tg Lysine Methionine Lysine Methionine Example II, 1 88 0 C 54 97 28 98 Example II, 3 55 0 C 100 99 97 99 Example III 1. 65/25/10 Poly(2-vinylpyridine-co-styreneco-lauryl acrylate) To a 3,000-mL, three-neck flask equipped with condenser, mechanical stirrer, thermometer and a heating mantle are charged 2-vinylpyridine (260 g, 2.473 mol), styrene (100 g, 0.962 mol), lauryl acrylate (40 g, 0.177 mol), premixed sodium oleate (12 g, 0.039 mol) in water i, 1 i WO 89/06909 PCT/US89/00205' s4 40 (240 mL), 50% sodium hydroxide (20 g, 0.250 mol) and water (960 mL). The contents are swept with nitrogen and heated to 55 0 C. Sodium persulfate (3.6 g, 0.015 mol) is added and the reaction is agitated at 55°C with a heating mantle for 18 hours under nitrogen to give a white milky emulsion.

The batch temperature is adjusted to 40 0

C

and acetic acid (16 g, 0.267 mol) in water (960 mL) is added over 15 minutes to precipitate the product while allowing the batch temperature to drift downward. During this time, the milky emulsion breaks into a thick white paste which upon heating to 60 0 C over 1 hour turns into a thinner slurry with better-defined particles.

The batch is further digested at 60 0 C for minutes, cooled to room temperature and filtered. The cake is washed with water (4,000 mL) and then pulled with vacuum on a BUchner funnel. After drying in a 55°C oven, a total of 400.7 g (100% yield) of white powder is obtained. The dried polymer has a composition of 67 mol 2-vinylpyridine: 27 mol styrene: 6 mol lauryl acrylate by nuclear magnetic resonance (NMR) spectroscopy, a Tg of 88 0 C by differential scanning calorimetry (DSC), an I.V.

of 1.075 when determined in N,N-dimethylformamide (DMF) and a water transmission rate of 16.5 E-mil/100 in.2/24 hours when measured on a solvent-cast film. This solvent cast film is flexible and the polymer is suitable for coating amino acids when used in combination with standard filler and additives as demonstrated by the results in Examples II, 5; II, 6; and II, 7.

i consisting of 31.5% 2-vinylpyridine/styrene WO 89/06909 PCr/US89/00205 41 acrylate to give 398.7 g (99.7 yield) of dried polymer in the form of a white powder. The dried polymer has a composition of 66 mol 2-vinylpyridine 27 mol styidinren-e: 7 mol co-2-ethylhexyl acrylate by NMR a Tg of C by DSCThe procedure as described1.169 in DMFExample III, 1a water transmisis followed except that 2-ethylhexyl acrylate 16.5 g 0.217 ml) in. s used in place of measured on a acrys olvent-cast film. This solvent-cast film is flexible and the form of a white powder. The dried polymer has whena composition of 66 mol with standard fillers and additives.

viny3. 65/35 Polpyr2-vin 27 mol ylpyridinecostyrene: 7 mol ethylheA mixture of 2-vinylpyridine (650 g,C by 6.190 mol) and styrene (350 g, 3.365 mol) iswater washed twice with 5% NaOH (each 320 mL) then transmission rater (each 640 L) in a separatory 2 16.5funnel to remove/100 inhibi. /2 hours when meased 65/3on a 2-vinylpyridine/styrene, premixed sodium eatis (33 g 0.108 mol) in water (660 mL), 50% NaOH (30.0 g, 0.375 mol) and water (5,340 mL) are charged into a 10-litre, three-neck flask flexible and the polymer ismechanical suitable for coating thermometer. The contents are purged with nitrogen and sodium persulfate (5.0 g, 0.021 mol) amino acids when used in is hcombinated to 55 with standard fillbath under nitrogen and then maintained at 3. 65/35 Poly(2-vinylpyridine-co-styrene) 4 A mixture of 2-vinylpyridine (650 g, 6.190 mol) and styrene (350 g, 3.365 mol) is i washed twice with 51 NaOH (each 320 mL) then i| twice with water (each 640 mL) in a separatory funnel for 8 hours to give a milky emulsion. The65/35 35 batch is pyridivided into four equal parts,odium of whleatch (33 g 0.108 mol) in water (660 mL), 501 NaOH r "(30.0 g, 0.375 mol) and water (5,340 mL) are charged into a 10-litre, three-neck flask equipped with mechanical stirrer, condenser and thermometer. The contents are purged with nitrogen and sodium persulfate (5.0 g, 0.021 mol) is added. The reaction is heated to 55°C with a water bath under nitrogen and then maintained at for 8 hours to give a milky emulsion. The batch is divided into four equal parts, of which WO 89/06909 PCT/US89/00205 42 one is worked up as follows. An emulsion equivalent to 250 g polymer from above is added to an agitated solution of sodium chloride (48 g) and distilled water (600 mL) in a 5,000-mL three-neck flask equipped with a mechanical stirrer and a condenser. The emulsion breaks into a thick cottage-cheese like slurry. The reaction mixture is heated to and maintained at 0 C for 15 minutes. The batch is cooled to room temperature over 2-4 hours. The product is filtered on a BUchner funnel with house vacuum and washed with distilled water (6,000 mL). The wet cake is pulled on the funnel and dried in a 0 C oven to give 250.0 g white powder (100% yield). The dried polymer has a composition of 63 mol percent 2-vinylpyridine: 37 mol percent styrene by NMR, a Tg of 105 0 C by DSC, an I.V. of 1.169 in dimethylformamide (DMF) and a water 2 transmission rate of 29 g-mil/10 inches 24 hours when measured on a solvent-cast film.

This example represents the unmodified 2-vinylpyridine/styrene copolymer. Films of this polymer are brittle and the coated amino acids are less stable than those coated by the polymer d described in Examples III, 1 and III, 2.

The invention has been described in detail with particular reference to preferred embodiments thereof, but it will be understood that variations and modifications can be effected within the spirit and scope of the invention.

i lI

Claims (37)

1. A pellet adapted for oral administration to a ruminant comprising a core material beneficial to the ruminant postruminally, and a coating surrounding said core material which protects the core material in the rumen and releases it postruminally, said coating comprising a physiologically acceptable film-forming polymeric material comprising a polymer or mixture of polymers, said polymeric material having basic amino groups the nitrogen content of which constitutes between 2 and 14% by 15 weight of the polymeric material, between 1.5% and 121%, based on the weight of polymeric material, of a hydrophobic material dispersed in said polymeric material selected from the group consisting of waxes, resins, S 20 polymers, fatty acids having from 12 to 32 em e carbon atoms, aluminum salts of fatty acids having from 12 to 32 carbon atoms, and polyfunctional carboxylic acids having a ratio of from 10 to 22 carbon atoms per carboxyl 25 group, and greater than 200 and up to 485%, based on the weight of said polymeric material, of a physiologically acceptable flake material dispersed in said polymeric material, said polymeric material in combination with said hydrophobic material being physiologically acceptable and resistant to a pH of greater than but capable of releasing the core of the pellets at a pH of less than 3.5, and said coating making up to 50% of the weight of said pellet, said coating 44 having a glass transition temperatue of not more than 600 as measured by TMA and said coating being further defined in terms of weight of said polymeric material, hydrophobic material and flake material by lines AB, BE, ED, DC and CA of the tri- component diagram of Figure 1, wherein line AB is parallel to and juxtaposed to line FG.

2. A pellet according to Claim 1 wherein line AB is parallel to, and is in close proximity to but spaced from line FG.

3. A pellet according to Claim 1 wherein lines AB and FG are straight, parallel and juxtaposed.

4. A pellet according to Claim 1 wherein the composition is defined by lines A B BIE, ED, DC, and CA 1 S* 20 5. A pellet according to Claim 1 wherein the core comprises a substance having a solubility in water of greater than 60 gm/100 gm water at 25 0 C. i. 6. A pellet according to Claim 1 wherein the core 25 comprises lysine.

7. A pellet according to Claim 1 wherein said coating additionally containing from 0 to 25%, based on the weight of polymeric material, of a plasticizer.

8. A pellet according to Claim 1 wherein the glass transition temperature of said coating is between 0 C and r_ 1

9. A pellet adapted for oral administration to a ruminant comprising a core material beneficial to the ruminant postruminally, and a coating surrounding said core material which protects the core material in the rumen and releases it postruminally, said coating comprising a physiologically acceptable fili-forming polymeric material comprising a polymer, or mixture of polymers, said polymeric material i having basic amino groups the nitrogen content of which constitutes between 2 and 14% by weight of the polymeric material, between 1.5% and 121%, based on the weight of polymeric material, of a hydrophobic material dispersed in said polymeric material selected ""from the group consisting of waxes, resins, S" polymers, fatty acids having from 12 to 32 carbon atoms, aluminum salts of fatty acids having from 12 to 32 carbon atoms, and !I 20 polyfunctional carboxylic acids having a ratio of from 10 to 22 carbon atoms per carboxyl 0 0 group, and greater than 200 and up to 485%, based on the weight of said polymeric material, of a 25 physiologically acceptable flake material selected from talc, aluminum flake and combinations thereof dispersed in said polymeric material, said polymeric material in combination with said hydrophobic material being physiologically acceptable and resistant to a pH of greater than but capable of releasing the core of the pellets at a pH of less than 3.5, and said coating making up to 50% of the weight of said pellet, said coating having a glass transition temperature of not more -r 46 than 60 0 C as measured by TMA and said coating being further defined in terms of weight of said polymeric material, hydrophobic material and flake material by lines AB, BE, ED, DC and CA. of the tri-component diagram of Figure 1, wherein line AB is parallel to and juxtaposed to line FG. A pellet adapted for oral administration to a ruminant comprising a core material beneficial to the ruminant postruminally, and a coating surrounding said core material which protects the core material in the rumen and releases it postruminally, said coating comprising a physiologically acceptable film-forming 15 polymeric material comprising a polymer, or mixture of polymers, said polymeric material having basic amino groups the nitrogen content of which constitutes between 2 and 14% by weight of the polymeric material, 20 between 1.5% and 121%, based on the weight of t said polymeric material, of a hydrophobic 1: material dispersed in said polymeric material i selected from the group consisting of waxes, i resins, polymers, fatty acids having from 12 -4 to 32 carbon atoms, aluminum salts of fatty acids having from 12 to 32 carbon atoms, and polyfunctional carboxylic acids having a ratio of from 10 to 22 carbon atoms per carboxyl group, and greater than 200 and up to 485%, based on the weight of said polymeric material, of a physiologically acceptable flake material selected from talc, aluminum flake, graphite, ground mica and combinations thereof dispersed in said polymeric material, i ~i a41 j d' 47 said polymeric material combination with said hydrophobic material being physiologically acceptable and resistant to a pH of greater than but capable of releasing the core of the pellets at a pH of less than 3.5, and said coating making up to 50% of the weight of said pellet, said coating having a glass transition temperature of not more than 60 0 C as measured by TMA and said coating being further defined in terms of weight of said polymeric material, hydrophobic material and flake material by lines AB, BE, ED, DC and CA. of the tri-component diagram of Figure 1, wherein lineeee AB is parallel to and juxtaposed to line FG.

11. A composition adapted for use in coating pellets orally administrable to ruminants which protects ":the core material in the rumen and releases it postruminally, said composition comprising 20 a physiologically acceptable film-forming polymeric material comprising a polymer, or mixture of polymers, said polymeric material having basic amino groups the nitrogen content ii of which constitutes between 2 and 14% by 25 weight of the polymeric material, between 1.5% and 121%, based on the weight of polymeric material, of a hydrophobic material dispersed in said polymeric material selected from the group consisting of waxes, resins, polymers, fatty acids having from 12 to 32 carbon atoms, aluminum salts of fatty acids having from 12 to 32 carbon atoms, and polyfunctional carboxylic acids having a ratio of from 10 to 22 carbon atoms per carboxyl group, and I -48- greater than 200 and up to 485%, based on the 1 weight of said polymeric material, of a physiologically acceptable flake material dispersed in said polymeric material, said polymeric material in combination with said hydrophobic material and flake material being physiologically acceptable and resistant to a pH of greater than 5 but capable of releasing the core of the pellets at a pH of less than 3.5, said composition having a glass transition temperature of not more than 60 0 C as measured by TMA and said composition being further defined in terms of weight of said polymeric material, hydrophobic material and flake material by lines AB, BE, ED, DC and CA. of the tri-component diagram of Figure 1, wherein line AB is parallel to and juxtaposed to line FG.

12. A composition according to Claim 11 wherein line AB S: 20 is parallel to, and is in close proximity to but spaced from line FG.

13. A composition according to Claim 11 wherein lines AB and FG are straight, parallel and juxtaposed. wegto dplmrc aeil yrpoi

14. A composition according to Claim 11 wherein the composition is defined by lines AIB I BIE, ED, DC, 1 and CA 1 30 15. A composition according to Claim 11 wherein the core comprises a substance having a solubility in water of greater than 60 gm/100 gm water at 25 0 C.

16. A composition according to Claim 11 wherein the core comprises lysine. c2 an I II Il l jrl: A:~ r e r, r 49

17. A composition according to Claim 11 wherein said composition additionally contains from 0 to based on the weight of said polymeric material, of a plasticizer.

18. A composition according to Claim 11 wherein the glass transition temperature of the composition is between 30 0 C and 60 0 C.

19. A composition adapted for use in coating pellets orally administrable to ruminants which protects the core material in the rumen and releases it postruminally, said composition comprising a physiologically acceptable film-forming polymeric material comprising a polymer, or mixture of polymers, said polymeric material having basic amino groups the nitrogen content of which constitutes between 2 and 14% by weight of the polymeric material, between 1.5% and 121%, based on the weight of polymeric material, of a hydrophobic material dispersed in said polymeric material selected from the group consisting of waxes, resins, polymers, fatty acids having from 12 to 32 carbon atoms, aluminum salts of fatty acids having from 12 to 32 carbon atoms, and polyfunctional carboxylic acids having a ratio of from 10 to 22 carbon atoms per carboxyl group, and greater than 200 and up to 485%, based on the weight of polymeric material, of a physiologically acceptable flake material selected from talc, aluminum flake and combinations thereof dispersed in said polymeric material, [;q-~fW ii; 'w w Ii:iii i;i .i 50 o o o r I sc said polymeric material in combination with said hydrophobic material and flake material being physiologically acceptable and resistant to a pH of greater than 5 but capable of releasing the core of the pellets at a pH of less than 3.5, said composition having a glass transition temperature of not more than 60 0 C as measured by TMA and said composition being further defined in terms of weight of said polymeric material, hydrophobic material and flake material by lines AB, BE, ED, DC and CA. of the tri-component diagram of Figure 1, wherein line AB is parallel to and juxtaposed to 'line FG.

20. A composition adapted for use in coating pellets orally administrable to ruminants which protects the core material in the rumen and releases it postruminally, said composition comprising a physiologically acceptable film-forming 20 polymeric material comprising a polymer, or mixture of polymers, said polymeric material having basic amino groups the nitrogen content of which constitutes between 2 and 14% by weight of the polymeric material, between 1.5% and 121%, based on the weight of said polymeric material, of a hydrophobic material dispersed in said polymeric material selected from the group consisting of waxes, resins, polymers, fatty acids having from 12 to 32 carbon atoms, aluminum salts of fatty acids having from 12 to 32 carbon atoms, and polyfunctional carboxylic acids having a ratio of from 10 to 22 carbon atoms per carboxyl group, and _L L 72 91 99 The Tg of the coating composition measured by TMA was about 51 greater than 200 and up to 485%, based on the weight of said polymeric material, of a physiologically acceptable flake material selected from talc, aluminum flake, graphite, ground mica and combinations thereof dispersed in said polymeric material, said polymeric material in combination with said hydrophobic material and flake material being physiologically acceptable and resistant to a pH of greater than 5 but capable of releasing the core of the pellets at a pH of less than 3.5, said composition having a glass transition temperature of not more than 60 0 C as measured by TMA and said composition being further defined in terms of 15 weight of said polymeric material, hydrophobic material and flake material by lines AB, BE, ED, DC and CA. of the tri-component diagram of Figure 1, wherein line AB is parallel to and juxtaposed to line FG.

21. A composition adapted for use in coating pellets orally administrable to ruminants which protects the core material in the rumen and releases it postruminally, said composition comprising S 25 a polymer comprising from 50 to 95 percent by weight of a I 2-vinylpyridine residue, and from 5 to 50 percent by weight of two or more residues of monomers selected from the group consisting of styrene, isoprene, butadiene, and an alkyl acrylate, said polymer having a glass transition temperature when measured by 35 differential scanning calorimetry of from 50 0 C 52 0.3 to 2.0, and from 186 to 485 percent, based on the weight of said polymer, of a physiologically acceptable flake material dispersed in said polymer, said polymer in combination with said flake material being physiologically acceptable and resistant to a pH of greater than 5 but capable of releasing the core of the pellets at a pH of less than 3.5, and said composition having a glass transition temperature as measured by TMA of not 15 more than 60 0 C.

22. A composition according to Claim 21 wherein the core comprises lysine. 20 23. A composition according to Claim 21 wherein the glass transition temperature of the composition is between 300°C and 600C.

24. A composition according to Claim 21 wherein said 25 polymer has an acrylate residue derived from an acrylate monomer having the formula CH =-COOR' 2 wherein R' is H or methyl and is a straight, branched or cyclic alkyl group of 1 to carbon atoms. A composition according to Claim 24 wherein said acrylate monomer is selected from the group 4- I 53 consisting of n-lauryl acrylate, 2-ethylhexyl acrylate, cyclohexyl acrylate, and iso-octyl acrylate.

26. A composition adapted for use in coating pellets orally administrable to ruminants which protects the core material in the rumen and releases it postruminally, said composition comprising a 2-vinylpyridine/styrene/acrylate or olefin terpolymer comprising from 50 to 95 percent by weight of 2-vinylpyridine, from 45 to 2 percent by weight of styrene, and 15 from 3 to 20 percent by weight of isoprene, butadiene or alkyl acrylate, said terpolymer having a glass transition S* temperature when measured by differential scanning calorimetry of from 50 0 C 20 to 1000C and a water transmission of less than 29 g-mil/100 inches2/24 hours when measured on a solvent-cast film, and an inherent viscosity 0.3 to 2.0, and from 200 to 485 percent, based on the weight 25 of said terpolymer, of a physiologically acceptable flake material dispersed in said terpolymer, said terpolymer in combination with said flake material being physiologically acceptable and resistant to a pH of greater than 5 but capable of releasing the Jore of the pellets at a pH of less than 3.5, and said composition having a glass transition temperature as measured by TMA of not more than 600C. LUi OVi 54

27. A composition according to Claim 26 wherein the core comprises lysine.

28. A composition according to Claim 26 wherein the glass transition temperature of the composition is between 30 0 C and 60 0 C.

29. A composition according to Claim 26 wherein said terpolymer has an acrylate residue derived from an acrylate monomer having the formula 1 CH -COOR'' .wherein R' is H or methyl and is a straight, branched or cyclic alkyl group of 1 to 20 20 carbon atoms.

30. A composition according to Claim 29 wherein said acrylate monomer is selected from the group consisting of n-lauryl acrylate, 2-ethylhexyl S. 25 acrylate, cyclohexyl acrylate, and iso-octyl acrylate. e r

31. A composition according to Claim 29 wherein said terpolymer comprises from 65 to 85 weight percent 30 of component from 30 to 5 weight percent of component and from 5 to 15 weight percent of component

32. A polymer comprising from 50 to 95 percent by weight of a 2-vinylpyridine residue, and from 5 to 50 percent by weight of two or more residues of monomers selected from the group a-1- T ON UA L 55 consisting of styrene, isoprene, butadiene, and an alkyl acrylate, wherein the polymer has a glass transition temperature, as measured by differential scanning calorimetry, of from 50 0 C to 100 0 C, a water transmission of from 0 to 29 g-mil/100 inches2/24 hours when measured on a solvent-cast film, and an inherent viscosity of from 0.3 to

33. The polymer of Claim 32 which is a terpolymer comprising from 50 to 95 percent by weight of 2-vinylpyridine, from 45 to 2 percent by weight of styrene, and 15 from 3 to 20 percent by weight of a monomer selected from the group consisting of isoprene, butadiene, and an alkyl acrylate.

34. The polymer of Claim 32 wherein said alkyl acrylate is of the formula CH 2=C-COOR'' 25 25 }i wherein R' is H or methyl, and is a straight chain, branched or cyclic alkyl group of 1 to 30 20 carbon atoms.i The polymer of Claim 33 wherein said alkyl acrylate is of the formula CH 2 =-COOR'' wherein R' is H or methyl, and is a straight chain, branched or cyclic alkyl group of 1 to carbon atoms. I 56 6*b4 e C C S.. I 1 II 4C 5 *5*S

36. The polymer of Claim 33 wherein component is an alkyl acrylate.

37. The polymer of Claim 34 wherein is an alkyl group of 6 to 20 carbon atoms.

38. The polymer of Claim 35 wherein is an alkyl group of 6 to 20 carbon atoms.

39. The polymer of Claim 32 wherein said alkyl acrylate is selected from the group consisting of n-lauryl acrylate, 2-ethylhexyl acrylate, cyclohexyl acrylate, and isooctyl acrylate. 15 40. The polymer of Claim 33 wherein said alkyl acrylate is selected from the group consisting of n-lauryl acrylate, 2-ethylhexyl acrylate, cyclohexyl acrylate, and isooctyl acrylate. 20 41. The polymer of Claim 32 wherein component is present in an amount of from 65 to 85 weight percent, component is present in an amount of from 30 to 5 weight percent, and component is present in an amount of from 5 to 15 weight percent.

42. The polymer of Claim 32 wherein the Tg is from 70 0 C to 90 0 C, the water transmission is from 0 to g.mil/inches2/24 hours, and the inherent viscosity is from 0.8 to 1.7.

43. The polymer of Claim 33 wherein the Tg is from to 90 0 C, the water transmission is from 0 to g.mil/inches2/24 hours, and the inherent viscosity is from 0.8 to 1.7. I, ',i t; vl :h ~1 B OIL- i

44. A pellet of any one of claims 1, 9 or substantially as hereinbefore described with reference to any one of the examples or accompanying drawings.

45. A composition of any one of claims 11, 19; 20, 21 or 26 substantially as hereinbefore described with reference to any one of the examples or accompanying drawings.

46. A polymer of claim 32 substantially as hereinbefore described with reference to any one of the examples or accompanying drawings. DATED: 15 June 1992 PHILLIPS ORMONDE FITZPATRICK Attorneys for: EASTMAN KODAK COMPANY D- o e *eo e 0 e-e a ea 3 o ee° o *2 o *eeee e 4 57