JPH0683640B2 - Feed additive composition for ruminants - Google Patents

Description

TECHNICAL FIELD The present invention relates to a feed additive composition for ruminants, and more particularly, when amino acids are orally administered to ruminants, they are decomposed in the rumen. And a feed additive composition for ruminants, which is protected against digestion and absorption in the digestive organs of the abomasum and above with high efficiency.

In ruminants, protein amino acids in feed are generally rumen, and a considerable part is decomposed into ammonia and carbon dioxide by microbial fermentation. Bacteria and protozoa in the lumen utilize ammonia for their own growth and proliferation, and the microbial proteins that are grown and formed are delivered to the abomasum, which corresponds to the stomach of monogastric animals, and partially in this gastric chamber. Be digested by. This process is completed and absorbed in the small intestine.

(Prior art and problems) Therefore, in order to improve absorption efficiency in the small intestine, in order to suppress decomposition in the rumen, a method of coating the core of a basic amino acid such as lysine with various coating agents has been proposed. Although proposed, in both cases, a mineral acid salt of a basic amino acid (typically, a hydrochloride salt) is used as a nucleating agent (JP-A-SHO)
54-46824, JP-A-61-88843).

However, the use of mineral acid salts such as mineral acid salts of basic amino acids as a source of basic amino acids has been problematic in that the material is susceptible to metal corrosion in the manufacturing process.

As a coating agent, for example, the above-mentioned publication proposes a synthetic polymer such as morpholinobutyric acid cellulose propionate or polyvinyl pyridine.

However, especially L-lysine monohydrochloride has a very high solubility in water and dissolves 70 g in 100 g of water at 25 ° C., and the acidity of its saturation is pH 5.5, and the pellet containing this substance is propionic acid. When it was coated with a sensitive polymer such as cellulose morpholinobutyrate or polyvinyl pyridine, it could not prevent elution in the rumen environment, and the protection rate in the buffer solution corresponding to rumen fluid In order to maintain the dissolution rate in the buffer solution corresponding to the abomasum at a level useful as a ruminant feed, it is necessary to use it in combination with a basic substance such as basic magnesium carbonate or magnesium hydroxide. .

(Means for Solving Problems) The inventors of the present invention have diligently studied to solve these problems, and by using a salt of a basic amino acid and an acidic phosphate as a nucleating agent, minerals such as hydrochloric acid and sulfuric acid can be obtained. Protective properties in the rumen are improved as compared with the case where an acid salt is used or the basicity of the nucleus is increased by using a basic substance such as basic magnesium carbonate or magnesium hydroxide. It was found to be extremely effective in solving problems. Examples of the basic amino acid used in the present invention include amino acids such as lysine, arginine, histidine, ornithine and hydroxylysine. Two or more kinds of these basic amino acids may be used in combination.

Examples of the acidic phosphates include phosphoric acid, sodium monophosphate, potassium monophosphate, calcium monophosphate, ammonium monophosphate, sodium acid pyrophosphate, and potassium acid pyrophosphate.

The salts of these basic amino acids and acidic phosphates can be used as a nucleating agent, as a source of amino acids, and as a source of phosphates.

These nucleating agents are usually binders for granulation, excipients, disintegrating agents, various additives for adjusting specific gravity, etc., as long as they are substances that are biologically acceptable to ruminants as additives for feed. It can be used in combination with these, which is convenient.

As a method for preparing a salt of a basic amino acid with acidic phosphates, a method of performing a neutralization reaction in the presence of water at room temperature or under heating is convenient. The salts obtained by these reactions may be used alone or in combination with other biologically active substances.

In the present invention, the biologically active substance is a substance which shows some activity such as weight gain, increase in milk production, prevention or treatment of diseases when administered to animals, particularly ruminants. In particular, when the substance is orally administered directly to a ruminant, a substance which is easily decomposed and deactivated by gastric juice in the rumen or a microorganism present in the gastric juice is targeted. As biologically active substances, amino acids such as methionine, lysine, threonine and tryptophan, N-acyl amino acids such as N-
Stearoylmethionine, N-oleylmethionine, etc.,
Amino acid derivatives such as N-hydroxymethylmethionine calcium salt and lysine hydrochloride, 2-hydroxy-4
-Hydroxy analogs of amino acids such as methylmercaptobutyric acid and its calcium salt, feather powder, fish powder, proteins such as casein, potato protein, vitamin A. vitamin A-acetate salt, vitamin A-palmitate salt, vitamin D _3, vitamin E, nicotinic acid, nicotinamide, calcium pantothenate, such as β- carotene, vitamins, enzymes such as acid proteases, carbohydrates such as glucose, antibiotics such as penicillin,
Examples thereof include tetracycline and the like, and anthelmintic drugs such as veterinary drugs such as Negfuon.

As the binder, polyvinylpyrrolidone, hydroxypropylcellulose, polyvinyl alcohol, gum arabic, guar gum, sodium alginate, sodium fibrin glycolate, sodium polyacrylate, etc., as the excipient, lactose, mannitol, crystalline cellulose, etc. The agent may contain potato starch, corn starch, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, crystalline cellulose, various additives for adjusting specific gravity, and the like.

In addition, binders, excipients, disintegrants, lubricants, coloring agents, flavoring agents, and odors described in the Pharmaceutical Manufacturing Method (1) Pharmaceutical Development Basic Course XI (pp133-154) issued by Jishin Shokan Known additives such as agents can be used as necessary.

The ratio of the coating agent used to the core containing the salt of a basic amino acid and an acidic phosphate-like acid protects the nuclear material in a stable state during the long residence time in the rumen of ruminants and It is necessary to quickly elute the nuclear material within a relatively short residence time in the abomasum, and the required amount varies depending on the size of the particles used for coating and the type of coating agent used, but , 10 to 200 wt% of the particles before coating, preferably 15 to 100 wt%.

Substances that are stable under the weakly acidic or weakly alkaline conditions corresponding to rumen gastric juice, but disintegrate, swell, or elute under the strongly acidic conditions corresponding to rumen gastric juice Examples of benzylaminomethylcellulose, dimethylaminomethylcellulose, piperidylethylhydroxyethylcellulose, cellulose acetate diethylaminoacetate, cellulose acetate dibutylaminohydroxypropyl ether, ethylcellulose-N, N-diethylaminohydroxypropyl ether, ethylcellulose pyridinohydroxypropyl ether, diethylamino Cellulose derivatives such as methyl cellulose, piperidyl ethyl hydroxyethyl cellulose, N, N-diethyl vinyl amine-vinyl acetate copolymer, vinyl pipe Peridine-vinyl acetate copolymer, vinyldiethylamine-vinylacetate copolymer, vinylbenzylamine-vinylacetate copolymer, polyvinyldiethylaminoacetoacetal, polyvinylbenzylaminoacetoacetal, vinylpiperidylacetoacetal-vinylacetate copolymer, polyvinyl Acetate derivatives such as acetal diethylaminoacetate, polydiethylaminomethylstyrene, polydiethanolaminomethylstyrene, polydimethylaminoethyl (meth) acrylate, dimethylaminoethyl acrylate-methyl (meth) acrylate copolymer, dimethylaminoethyl methacrylate-methyl ( (Meth) acrylate copolymer, poly 2-methyl-5-vinyl pyridine, poly 2-ethyl-5-vinyl Pyridine poly Arue kill vinylpyridine, such as, poly 2-vinylpyridine, poly 4-vinylpyridine, polyvinyl pyridine, such as 2-vinylpyridine-styrene copolymer, 4-vinylpyridine-styrene copolymer,
Vinyl pyridine-styrene copolymer, such as 2-ethyl-5-vinyl pyridine-styrene copolymer,
2-methyl-5-vinylpyridine-styrene copolymer,
Such as vinylalkylpyridine-styrene copolymer, 2-vinylpyridine-acrylonitrile copolymer, vinylpyridine-acrylonitrile copolymer, vinylethylpyridine-acrylonitrile copolymer, methylvinylpyridine-acrylonitrile copolymer, 2 -Vinyl pyridine-methyl methacrylate copolymer,
4-vinyl pyridine-methyl methacrylate copolymer,
Such as vinylpyridine-methylmethacrylate copolymer, 2-vinylpyridine-butadiene copolymer, 2-vinylpyridine-butadiene-styrene copolymer, vinylpyridine-styrene copolymer, 2-vinylpyridine-styrene-methylmethacrylate. Copolymers, such as vinyl pyridine or alkyl vinyl pyridine polymers or copolymers with other vinyl compounds, N, N-dimethylaminopropyl (meth) acrylamide-acrylonitrile copolymers, N, N-dimethylaminopropyl (Meth) acrylamide-styrene copolymer, N,
N-dialkylaminoalkyl (meth) acrylamide-acrylonitrile copolymer, vinylpyridine-acrylonitrile copolymer, methylvinylpyridine-acrylonitrile copolymer, methylvinylpyridine-polyvinyl derivative such as styrene copolymer, styrene-dimethylfumarate Or N, N-diethylethylenediamine derivative of styrene-maleimide copolymer, reaction condensate of terephthalic acid or maleic acid and N-n-butyldiethanolamine, benzylamine adduct of propylene glycol-maleic acid polyester and the like. .

The coating agent is a synthetic polymer that dissolves in water in the acidic range of pH 5 or less, but it also contains anti-fusion agents such as talc, aluminum, mica, silica, stearic acid, aluminum stearate, magnesium stearate, etc. You can do it.

The synthetic polymer for coating is usually used in a state of being dissolved in a solvent, but it may be used as an emulsion by using an emulsifier.

Suitable solvents for coating include methylene chloride, chloroform, isopropanol, ethyl alcohol, methyl alcohol, ethyl acetate, acetone, methyl ethyl ketone, toluene or mixtures thereof.

At the time of coating, the raw materials for coating may be supplied in a state in which the anti-fusion agent and the like are suspended, or may be supplied separately.

Various methods are known as coating methods for granules, and for example, any general coating method such as centrifugal granulation coating method, fluidized coating method and pan coating method may be used. Besides this, chemical modification methods,
Microencapsulation methods are also conceivable.

(Examples) Hereinafter, typical examples of the method of the present invention will be shown.
A more specific description will be given. It should be noted that these are merely examples, and the present invention is not limited by these examples.

In order to be useful and practical as a feed additive for ruminants, at least 60%, preferably at least 75% of the amino acids or amino acid salts in the coated particles of the present invention are stable in the rumen and It is believed that it must be released in the stomach. Therefore, the following examples were evaluated according to the above-mentioned criteria.

[Example 1] 67 g of potassium primary phosphate of L-lysine, 17.5 g of talc and 3.5 g of polyvinylpyrrolidone (K-90) were mixed in a mortar to obtain a substantially homogeneous mixture. 16 g of water was thoroughly kneaded with this powdery mixture to form a putty. this
It was extruded from an extruder having a hole diameter of 2.2 mmφ and cut to obtain a cylindrical pellet having a diameter of about 2.0 mm. The pellet was rolled with a marumerizer and dried at 60 ° C. The dried pellets are sieved to 8-9 mesh (2.00-2.38 mm).
Particles in the range of φ) were obtained.

The solution used for coating the particles thus obtained was prepared by the following method.

That is, a copolymer of 70 wt% 4-vinylpyridine and 30 wt% styrene (reduced viscosity at 0.5 g / dl in ethanol: η _{sp / c} = 0.75) 3.0 g, aluminum powder 3.25 g, talc powder 3.25 g Then, 60 g of ethyl alcohol was added to a mixture of 0.5 g of stearic acid and the mixture was stirred at room temperature for 3 hours to obtain a suspension for coating. The particles were coated with the coating suspension described above until the weight of the coating layer was 29.4 wt% of the total coated particles.

The potassium monophosphate of L-lysine was retained at 93.6% after shaking in McDougall buffer solution at 39 ° C. for 24 hours. Further, by shaking in a Clark-Lubs buffer solution at 39 ° C. for 3 hours, 94.3% of L-lysine monobasic potassium phosphate salt was eluted.

Example 2 L-lysine monobasic sodium salt 70 g, talc 17.5 g,
A substantially homogeneous mixture was obtained by mixing 3.5 g of polyvinylpyrrolidone (K-90) in a mortar. This powdery mixture was kneaded well with 16.5 g of water to form a putty. Granulation was performed in the same manner as in Example 1 to obtain pellets in the range of 8 to 9 mesh. The same coating suspension as in Example 1 was coated until the weight of the coating layer was 29.8 wt% of the total coated particles.

The monobasic sodium phosphate salt of L-lysine was retained at 85.3% after shaking in McDougall buffer solution at 39 ° C. for 24 hours. Further, by shaking in a Clark-Lubs buffer solution at 39 ° C. for 3 hours, 77.2% of potassium primary phosphate of L-lysine was eluted.

[Example 3] 67 g of potassium primary phosphate of L-lysine and 17.5 g of talc and 3.5 g of polyvinylpyrrolidone (K-90) were mixed in a mortar to obtain a substantially homogeneous mixture. This powdery mixture was kneaded well with 16.5 g of water to form a putty. Granulation was performed in the same manner as in Example 1 to obtain pellets in the range of 8 to 9 mesh.

The solution used for coating the particles thus obtained was prepared by the following method.

That is, a copolymer of 70 wt% 2-vinylpyridine and 30 wt% styrene (reduced viscosity at 0.5 g / dl in ethanol: η _{sp / c} = 0.47) 3.0 g, aluminum powder 3.25 g, talc powder 3.25 g Then, 60 g of ethyl alcohol was added to a mixture of 0.5 g of stearic acid and the mixture was stirred at room temperature for 3 hours to obtain a suspension for coating. The particles were coated with the coating suspension described above until the weight of the coating layer was 30.2 wt% of the total coated particles.

The monobasic sodium phosphate salt of L-lysine was retained at 97.1% after shaking in a McDougall buffer solution at 39 ° C. for 24 hours. Also, by shaking in a Clark-Lubs buffer solution at 39 ° C. for 3 hours, 85.4% of L-lysine monobasic potassium phosphate salt was eluted.

[Comparative Example 1] A substantially homogeneous mixture was obtained by mixing 100 g of L-lysine monohydrochloride, 10 g of microcrystalline cellulose, and 1 g of gum arabic in a mortar. Add 3 parts of water to this powdered mixture.
5.0 g was well kneaded to form a putty. Granulation was performed in the same manner as in Example 1 to obtain pellets in the range of 8 to 9 mesh. The solution used for coating the pellet was prepared by the following method. That is, a copolymer of N, N-dimethylaminoethylmethacrylate and methylmethacrylate (Rohm Pharma (West Germany), trademark "Eu
dragit E100 ") 3.0 g, aluminum powder 3.5 g, and talc powder 3.5 g were added to a mixture of 60 g of ethyl alcohol and stirred at room temperature for 3 hours to obtain a suspension for coating. The suspension was coated until the weight of the coating layer was 30.8 wt% of the total coated particles.

L-Lysine monohydrochloride was added to McDougall buffer solution at 39 ° C for 24 hours.
Only 43.5% was retained after shaking for an hour. Further, by shaking in a Clark-Lubs buffer solution at 39 ° C. for 3 hours, 100.0% of L-lysine monohydrochloride was eluted.

Comparative Example 2 By mixing 100 g of 2-L-lysine / sulfate, 25 g of microcrystalline cellulose and 5.0 g of polyvinylpyrrolidone (K-90) in a mortar, an almost homogeneous mixture was obtained.
The powdery mixture was kneaded well with 28.5 g of water to form a putty. Granulation was performed in the same manner as in Example 1 to obtain pellets in the range of 8 to 9 mesh. The weight of the coating layer with the same coating suspension as in Example 1
Coated to 29.5 wt%.

2L-lysine sulphate was only retained at 37.7% after shaking for 24 hours at 39 ° C in McDugall buffer solution. Moreover, 100.0% of 2L-lysine sulfate was eluted by shaking in a Clark-Lubs buffer solution at 39 ° C. for 3 hours.

[Comparative Example 3] By mixing 50.0 g of lysine base, 10.0 g of aluminum hydroxide and 5.0 g of polyvinylpyrrolidone (K-90) in a mortar, a substantially homogeneous mixture was obtained. Granulation was carried out in the same manner as in Example 1 to obtain pellets in the range of 7-8 mesh (2.38-2.83 mmφ).

The same coating suspension as in Example 1 was coated until the weight of the coating layer was 30.3 wt% of the total coated particles. Only 25.6% of L-lysine was retained after shaking in McDougall buffer solution at 39 ° C for 24 hours. Also Clar
By shaking in a k-Lubs buffer solution at 39 ° C. for 3 hours, 91.0% of L-lysine was eluted.

[Comparative Example 4] Lysine base 50.0 g, calcium carbonate 45 g, gum arabic 5 g
Were mixed in a mortar to obtain an almost homogeneous mixture. Granulation was carried out in the same manner as in Example 1 to obtain pellets in the range of 7-8 mesh (2.38-2.83 mmφ). Example 1
The same coating suspension was coated until the weight of the coating layer was 22.8 wt% of the total coated particles. L-lysine was dissolved in McDougall buffer solution at 39 ° C. for 24 hours after shaking, then 46.8.
Only% was retained. Further, by shaking in a Clark-Lubs buffer solution at 39 ° C. for 3 hours, 86.5% of L-lysine was eluted.

〔Test method〕

McDougall corresponding to rumen fluid was prepared by adding 1 g of the ruminant nutrient obtained in Example to an Erlenmeyer flask with an internal volume of 300 ml.
^{* 1} Clark-Lubs for artificial saliva or abomasum
^{* 2} Add 200 ml of artificial gastric juice respectively, and in a constant temperature bath at 39 ± 0.5 ° C, while applying reciprocating vibration 91 times per minute with an amplitude of 4 cm,
Shaken.

The elution rate of the basic amino acid salt after 24 hours using the McDougall buffer solution and after 3 hours using the Clark Lubs buffer solution was determined using high performance liquid chromatography. ^{* 1} McDougall buffer solution sodium bicarbonate 7.43g, disodium phosphate dodecahydrate
7.0 g, sodium chloride 0.34 g, potassium chloride 0.43 g, magnesium chloride hexahydrate 0.10 g, and calcium chloride 0.05 g were dissolved in water 1 to adjust by saturating carbon dioxide. (PH 6.
8). ^{* 2} Clark-Lubs buffer solution 0.2N potassium chloride 50ml and 0.2N hydrochloric acid 10.6ml with water 139.4m
Adjusted in addition to l. (PH 2.0).

(Effects of the Invention) As is clear from the above-mentioned Examples and Comparative Examples, the feed additive composition for ruminants of the present invention is compared with a conventional composition in which a biologically active substance and a protective substance are mixed and granulated. The elution rate of biologically active substances from the artificial saliva of McDougall, which corresponds to the gastric juice of the rumen, is extremely low, and Clark Lapse (Cl), which corresponds to the gastric juice of the abomasum, is suppressed.
The elution rate of the biologically active substance with respect to the pH 2 buffer solution of Ark-Lubs) is extremely high.

That is, it shows that when orally administered to a ruminant, the biologically active substance is effectively digested and absorbed in the digestive organs after the abomasum without being decomposed and inactivated in the rumen.

The present invention suppresses the decomposition of a biologically active substance in the rumen during oral administration of the biologically active substance to ruminant animals, and digests and absorbs it at a high rate in the digestive organs after the abomasum. To provide a feed additive composition for ruminants that can be
Its industrial significance is extremely large.

 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Hiroyuki Sato 2-89 Shinmei-cho, Saiwai-ku, Kawasaki-shi, Kanagawa

Claims (6)

[Claims] 1. A core comprising a salt of a basic amino acid and acidic phosphates is coated with at least one coating agent of a synthetic polymer which dissolves or swells in water in an acidic range of pH 5 or less. A feed additive composition for ruminants. 2. The animal feed according to claim 1, wherein the basic amino acid comprises one or more selected from lysine, arginine, histidine, hydroxylysine and ornithine. Additive composition. 3. The method according to claim 1, wherein the acid phosphate is one or more selected from alkali metal salts, alkaline earth metal salts and ammonium salts of phosphoric acid. The animal feed additive composition. 4. The use ratio of the coating agent is 10 to 2 with respect to 100 parts by weight of the core.
The animal feed additive composition according to claim 1, which is 00 parts by weight. 5. The animal feed additive composition according to claim 1, wherein the ruminant is cow, sheep or goat. 6. A coating agent comprising dimethylaminoethyl methacrylate and (meth) acrylic acid alkyl ester, or 2
-Methyl-5-vinylpyridine, 2-vinylpyridine,
Vinyl pyridines selected from the group of 4-vinyl pyridine, 2-vinyl-6-methyl pyridine, 2-vinyl-5-ethyl pyridine, and alkyl (meth) acrylate, (meth) acrylic acid, acrylonitrile The animal feed additive composition according to claim 1, which is a copolymer with an acrylic compound or styrene.