JP2670844B2 - Coatings for bioactive substances for ruminant feeding and additives for ruminant feed - Google Patents

Description

Description: FIELD OF THE INVENTION The present invention relates to a coating of a ruminant breeding additive having a nucleus composed of a physiologically active substance and a coated ruminant breeding additive.

2. Description of the Related Art The pH of the rumen of the rumen is about 5.5, and microorganisms are present and fermenting is performed. The food is, for example, about 6-
It is known to stay in the rumen for 30 hours. As a result, when a veterinary-acceptable physiologically active substance such as an amino acid (hereinafter referred to as an active substance) is orally administered to ruminants such as cows and sheep, the active substance is decomposed in the rumen. In the gastrointestinal tract after 4 stomachs (pH about 3), the desired active substance cannot be effectively absorbed.

In order to solve this drawback, a material (hereinafter referred to as a coating agent) that inhibits the decomposition of the active substance in the rumen but does not prevent the effective absorption in the digestive tract after the rumen is used,
For example, attempts have been made to protect nucleated active substances.

For example, resins that are emulsified with triglycerides such as hydrogenated vegetable and animal fats, waxes, bile salts, and / or dissolved with intestinal lipase.
Capsule-shaped feed additive (JP-A-48-12785) using a coating agent composed of a wax mixture, an active substance and a basic substance (for example, magnesium oxide, magnesium carbonate, calcium carbonate, aluminum hydroxide, etc.) Feed pellets coated with a coating agent containing a polymer (for example, cellulose propionate morpholinobutyrate, a copolymer of dialkylaminoethyl acrylate and methacrylate, etc.) (JP-A-54-46824). Gazette), the active substance is a polymer substance (for example, morpholinobutyric acid cellulose propionate, a copolymer of vinylpyridine and styrene, a copolymer of 2-methyl-5-vinylpyridine and styrene or acrylontolyl, N, Copolymer of N-diethylaminoethyl methacrylate and methyl methacrylate, etc.) and a hydrophobic substance ( (Leic acid, stearic acid, palmitic acid, timer acid, etc.) and a feed additive coated with a coating agent (JP-A-54-46825), a saturated or unsaturated monocarboxylic acid having 14-22 carbon atoms, A feed additive coated with a coating agent containing chitosan and one or more of hardened vegetable fat and hardened animal fat (JP-A-58)
-175449 gazette), saturated or unsaturated monocarboxylic acid having 14 to 22 carbon atoms, one or more of hardened vegetable fat and hardened animal fat, chitosan and a feed additive coated with a coating agent containing inorganic salts. (Japanese Patent Laid-Open No. 59-66843), p
A feed additive coated with a coating agent containing ethyl cellulose and a synthetic polymer compound that dissolves in water at H5 or less (Patent Document 1)
61-88843), a first component consisting of a synthetic polymer compound that dissolves in water at pH 5 or lower, and fat, wax, carbon 14-
32 saturated or unsaturated fatty alcohols and 14-37 carbon atoms
Feed additive coated with a coating agent containing a second component comprising one or more of saturated or unsaturated fatty acids of JP-A-61-88844.
Gazette) has been proposed.

However, in general, of these known coatings, the first
If the protective effect in the stomach is too strong, the disintegration in the abomasum is slow, and if it disintegrates early in the abomasum, the protective effect in the rumen tends to be weak, so there is still room for improvement. .

The present invention is disclosed in JP-A-61-88 by adding a substance that is solid at room temperature and is soluble in organic solvents but not water.
It is based on the finding that the protective effect of the coating agent described in Japanese Patent No. 843 can be significantly improved.

SUMMARY OF THE INVENTION It is an object of the present invention to provide improvements in animal feed additives containing active substance coatings of this type and coated physiologically active substances.

Means for Solving the Problems As an active ingredient provided by the present invention for coating a nucleus containing a physiologically active substance, its ability to be stable in the rumen and effectively disintegrated in the abomasum of a ruminant animal. A coating agent containing a veterinary-acceptable water-soluble synthetic polymer compound and ethyl cellulose further has a compatibility with the polymer compound and ethyl cellulose as an active ingredient, but does not dissolve in water. It is characterized by the fact that it contains a substance that is acceptable from a scientific point of view.

Protecting the nucleus with the coating according to the invention provides a ruminant feed additive with excellent protective capacity.

 Next, the present invention will be described in detail.

For the purposes of the present invention, various known, veterinary-acceptable physiologically active substances for animal rearing, for example, amino acids, derivatives or peptides thereof (e.g. methionine, lysine, tryptophan, threonine, glutamic acid, glutamine,
Asparagine, dopa, glutathione), vitamins (eg vitamin A), enzymes (eg acid protease), sugars such as glucose, antibiotics such as penicillin, anthelmintic agents (eg levamisole) etc. are used alone or in combination. . The type of active substance is outside the scope of the invention.

The coating composition according to the invention can be used, for example, in ruminant feed additives for cattle, sheep, goats and the like.

In the present invention, as the veterinarily acceptable polymer compound, known types of compounds having moisture proof properties in a neutral region and dissolving in water at a pH of 5 or less as exemplified below can be used. .

(1) Polyvinyl acetal diethylaminoacetate.

Practically, the molecular weight is 30,000 to 150,000 and the nitrogen content is 1.0 to 5.5.
(W / w), for example, AEA [trade name of Sankyo Co., Ltd.] is used.

(2) A copolymer comprising dimethylaminoethyl methacrylate and one or more of methacrylic acid alkyl ester and acrylic acid alkyl ester.

Practically, the molecular weight is 50,000 to 500,000 and the nitrogen content is 3 to 8%.
(W / w) inclusions, eg Eudragit E1 which is a copolymer of dimethylaminoethylmethacrylate, methylmethacrylate and butylmethacrylate
00 (solid), 12.5 (12.5% solution) [trade name, West Germany, Rohm Pharma Co.] is used.

(3) A copolymer consisting of 2-methyl-5-vinylpyridine and one or more of acrylic acid alkyl ester, methacrylic acid alkyl ester, methacrylic acid and acrylic acid.

Practically, the molecular weight is 5,000 to 400,000, and nitrogen is 2 to 15% (w /
Those containing w) such as MPM-47 [trade name of Tanabe Seiyaku Co., Ltd.], which is a copolymer of 2-methyl-5-vinylpyridine, methyl acrylate, methacrylic acid, is used.

Among the above-mentioned monomers, as the alkyl of the alkyl ester, linear or branched alkyl having 1 to 8 carbon atoms, such as ethyl, i-propyl, n-butyl, 2-ethylhexyl and the like are practical.

As ethyl cellulose, one containing 2.0 to 2.8% (w / w) of ethoxy groups in one glucose unit is practical.

In order for the coating agent to effectively disintegrate in the abomasum, as the water-insoluble substance used in the present invention, those having compatibility with the above-mentioned polymer compound and ethyl cellulose are used.

When the water-insoluble substance is in a solid state at room temperature, it is easy to handle. Further, solubility in organic solvents such as isopropanol, ethanol, dichloromethane, acetone, ethyl acetate, ethyl cellosolve and the like is advantageous for forming a strong film. For this reason,
Examples of practical water-insoluble substances include saturated fatty acids having 14 or more carbon atoms, higher aliphatic alcohols having 12 or more carbon atoms, hardened animal oils, hardened vegetable oils, natural resins or synthetic resins.

Examples of practical saturated fatty acids having 14 or more carbon atoms are myristic acid, palmitic acid, and stearic acid.

Examples of practical higher aliphatic alcohols having 12 or more carbon atoms are lauryl alcohol, myristyl alcohol, cetyl alcohol, and stearyl alcohol.

Examples of practical animal oils and vegetable oils are hydrogenated tallow oil and hydrogenated castor oil.

Examples of practical natural resins and synthetic resins are, for example, shellac and vinyl acetate.

The polymer compound and ethyl cellulose in the coating agent can be used in a weight ratio of, for example, 1: 0.5 to 1:10 (especially 1: 1 to 1: 7). When ethylcellulose is less than 1: 0.5, biologically active substances such as amino acids are eluted significantly in the rumen and decomposed by fermentation of microorganisms. When it is more than 1:10, active substances are eluted in the rumen. Not done, fourth
It was found that even if it enters the stomach, it is not effectively eluted.

The practical weight ratio of the water-insoluble substance in the coating agent and ethyl cellulose is, for example, 1: 0.1 to 1:20 (particularly 1: 0.5 to 1:
2) can be

A practical coating is solids, in addition to the polymer,
Various known plasticities such as polyethylene glycol,
An anti-agglomeration agent such as triacetin, mybaset, and the like, such as talc and magnesium stearate, may be contained. , The total of these other components is practically 30% (w / w)
Is less than.

The practical weight ratio of the total of the polymer compound and the water-insoluble substance in the coating agent can be 50% or more, for example, 1: 0.7 or more.

The nucleus is usually solid, and if desired, various known
Binders (eg hydroxypropyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol), excipients (eg lactose, mannitol, crystalline cellulose), disintegrating agents (eg potato starch, corn starch, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, crystalline cellulose) May be included.

The amount of the coating agent used for the core containing the active substance has a great influence on the utilization rate of the active substance. For example, 10 cores by weight
0 to 5 coating agents can be used. If the weight ratio is less than 5 parts, the coating amount is insufficient, and there is a risk of excessive decomposition (disintegration) in the rumen. If it is larger than 100 copies,
Absorption in the digestive tract after the abomasum may not be sufficient.

An example of producing an animal feed composition using the coating material according to the present invention will be described below.

The oral composition according to the invention is obtained by drying the granules containing one or more active substances and then coating the dried granules with a coating according to the invention.

The granules are prepared by dissolving the binder in a solvent and adding 1 to the resulting binding solution.
It is obtained by adding one or more active substances and kneading them. Alternatively, it is obtained by coating one or more active substances with a binder liquid.

When two or more kinds of active substances are used, they are bound to the first active substance, that is, on the nucleus containing one or more first physiologically active substances having higher solubility in water than the second physiologically active substance. The desired granules can be obtained by adding the drug solution, then adding the second active substance having a lower solubility in water on the core, and repeating this operation.

The solid content concentration of the binder liquid is, for example, 3 to 20% w / w. The granules are prepared by a conventional method, for example, a method using a cylindrical granulator and a spherical granulator.

For example, when producing granules containing lysine and methionine, crystalline lysine or granulated lysine, for example, centrifugal fluidized granulation coating equipment (CF-granulator, CF-
360, Freund Sangyo) and seed crystals, and while adding methionine powder and a binder dissolved in water to the seed crystals, coat them into granules. The particle size of the seed crystal of the active substance having a high solubility in water is preferably 0.5 to 3.0 mm. Thereafter, the obtained granules are treated at a suitable temperature for a suitable time (for example,
Dry at 30 to 70 ° C for 30 to 90 minutes) (for example, hot air).
The practical particle size after drying is, for example, 1.4 to 3.2 mm.

The active substance used may be the active substance itself or a mixture of other substances (for example, an excipient, a disintegrant).

Next, a suitable solid content concentration of the granules is, for example, 1 to 10%.
The (w / w) coating liquid is protected by, for example, spray coating. The organic solvent used for preparing the coating liquid is, for example, dichloromethane, ethanol, isopropanol, acetone, ethyl acetate, and is used alone or in combination.

For a more effective absorption of the active substance, it is necessary to increase the dissolution rate of the active substance in the abomasum. However, in the case of a coating agent to which no water-insoluble substance is added, even if the pH-dependent synthetic polymer is dissolved in the low pH range, the ethylcellulose membrane does not collapse, which delays the elution of the active substance in the abomasum. There is. Further, the excessive addition of the water-insoluble substance has a drawback that after the swelling of the polymer compound, the strength of the coating material is sharply lowered and the coating material is rapidly disintegrated, and the active substance is dispersed too fast.

According to the present invention, the protective coating is moisture-proof in the neutral range and disintegrates in the low pH range. In addition, since a water-insoluble substance compatible with the synthetic polymer compound and the ethylcellulose is used, for example, the disintegration of the film-like coating agent starts in a relatively low pH range. As a result, the active substance is stable in the rumen and is effectively eluted in the abomasum.

The use of the water-insoluble substance according to the invention enhances the moisture resistance,
Not only does it make it possible to reduce the dose of coating agent, but it also makes it possible to improve the utilization of the active substance.

 The invention is illustrated by the following examples and test examples.

Example 1 To 2000 g of DL-methionine, 400 g of 20% (w / w) aqueous polyvinyl alcohol solution was added as a binder and kneaded. The material is extruded using a cylindrical granulator having a screen with a diameter of 2.0 mm, and further mulmelized [Fuji Paudal Co., Ltd.
The product was spheroidized, and sieved with 8-10 mesh, and dried with hot air at 60 ° C. for 1 hour to obtain granules having a particle size of 1.7-2.4 mm.

Ethyl cellulose: Stearic acid: AEA (4: 2: 3w / w) 15
0 g and 30 g of glycerin fatty acid ester were dissolved in 3000 g of isopropanol: acetone (2: 1 v / v), and 25 g of magnesium stearate was added as an anticoagulant to prepare a coating liquid. Using a fluidized bed device,
Spray coated to 1000 g. 100 parts by weight of the granules were coated with 10 parts by weight of the coating agent (as a solid content) to obtain granules having a methionine content of 90% (w / w).

Example 2 150 g of ethyl cellulose: vinyl acetate: AEA (3: 3: 3 w / w)
Further, 30 g of glycerin fatty acid ester was dissolved in 3000 g of ethanol: acetone (3: 1 v / v), and 25 g of magnesium stearate was added as an anti-agglomeration agent to prepare a coating solution. The particle size obtained by the same operation as in Example 1 was 1.7 to
100 parts by weight of 2.4 mm granules were spray-coated with 10 parts by weight of the coating liquid as a solid content. Coating-coated granules with a methionine content of 90% (w / w) with slightly increased particle size were obtained.

Comparative Example 1 Ethyl cellulose: AEA (6: 3 w / w) 150 g and glycerin fatty acid ester 30 g were mixed with ethanol: acetone (3: 1 v / v) 3
It was dissolved in 000 g and 25 g of magnesium stearate was added as an anti-agglomeration agent to prepare a coating liquid.

Particle size 1.7 to 2.4 mm obtained by the same operation as in Example 1.
100 parts by weight of the granules were spray-coated with 10 parts by weight of the coating liquid as a solid content. Methionine content 90% (w /
Granules protected with the coating agent of w) were obtained.

Example 3 To 2000 g of lysine hydrochloride, 700 g of a 6% (w / w) hydroxypropylcellulose / water / ethanol (water: ethanol = 1: 1 v / v) mixed liquid was added as a binder and kneaded. The kneaded product was extruded with a cylindrical granulator using a 2.0 mm screen, further spheroidized with a marmellaizer, sieved with 8 to 10 mesh, and then dried with hot air at 60 ° C. for 1 hour to obtain a particle size of 1.7 to 2.4 mm. Granules of

Ethyl cellulose: Stearic acid: Eudragit E1
00 (3: 2: 1w / w) 150g and glycerin fatty acid ester 30g
Was dissolved in 3000 g of ethanol: acetone (3: 1 v / v), and 25 g of magnesium stearate was added as an anticoagulant to prepare a coating agent. Using a fluidized bed apparatus, 100 parts by weight of the above granules were spray-coated as a solid content in an amount of 100 parts by weight.

Granules protected with coating with a lysine content of 90% (w / w) were obtained.

Comparative Example 2 Ethylcellulose: Eudragit E (5: 1w / w) 150g
Was dissolved in 3000 g of ethanol: acetone (3: 1 v / v), and 25 g of magnesium stearate was added as an anticoagulant to prepare a coating agent.

Particle size of 1.7 to 2.4 mm obtained by the same operation as in Example 3
100 parts by weight of the granules were spray-coated with 10 parts by weight of the coating liquid as a solid content. Granules protected with coating with a lysine content of 90% (w / w) were obtained.

Example 4 To 2000 g of lysine hydrochloride, 700 g of a mixed solution of 6% (w / w) hydroxypropylcellulose / water / ethanol (water: ethanol = 1: 1 v / v) was added as a binder and kneaded. The kneaded product was extruded by a cylindrical granulator using a screen having a diameter of 2.0 mm, further spheroidized by a marumerizer, and sieved with 8-10 mesh,
Then, it was dried with hot air at 60 ° C. for 1 hour to obtain granules having a particle size of 1.7 to 2.4 mm. Ethyl cellulose: Vinyl acetate: AEA (5: 1: 3w
/ w) 150g dichloromethane: ethanol (3: 3v / v) 3000
The coating liquid prepared by dissolving in 100 g by weight of the granules,
As a solid content, 10 parts by weight was spray coated to obtain coated granules having a lysine content of 90% (w / w).

Comparative Example 3 A coating liquid was prepared by dissolving 150 g of ethyl cellulose: AEA (6: 3 w / w) in 3000 g of dichloromethane: ethanol (1: 1 v / v).

Particle size 1.7 to 2.4 mm obtained by the same operation as in Example 4.
100 parts by weight of the above granules were spray coated with 10 parts by weight of the coating solution as a solid content to obtain coated granules having a lysine content of 90% (w / w).

Example 5 1500 g of lysine crystals having a particle size of 1.5 to 2.0 mm was added to a CF-granulator (CF-360, Freund Sangyo). Powder methionine 1500g, polyvinyl alcohol 90g, water 510g
Coating with the binder dissolved in 60 ℃
And dried with hot air for 1 hour to obtain granules having a particle size of 1.5 to 3.0 mm. 100 parts by weight of the granules were spray-coated with 10 parts by weight as a solid content using the coating material shown in Example 2 using a fluidized bed apparatus.

Granules protected with a coating agent having lysine and methionine contents of 44% (w / w) each were obtained.

Comparative Example 4 1500 g of powder lysine and 1500 g of powder methionine were mixed, and 90 g of polyvinyl alcohol was mixed with water 4 using a ribbon type kneader.
The binder liquid dissolved in 50 g was added and kneaded for 10 minutes. The mixture was extruded and granulated by using an extrusion granulator with a screen of 20 mm in diameter, spheroidized with a marumerizer, and dried with hot air at 60 ° C. for 1 hour to obtain granules having a particle diameter of 1.5 to 3.0 mm. Using a fluidized bed apparatus, the same coating material as in Example 2 was spray coated to obtain granules protected with a coating material having lysine and methionine contents of 44% (w / w) each.

Test Example 1 Dissolution Test With respect to the methionine granules, lysine granules, and lysine / methionine mixed granules obtained in Examples 1 to 5 and Comparative Examples 1 to 4, pH 3.0 corresponding to the rumen and pH 6 corresponding to the rumen were used. A dissolution test was performed at 0.0.

(1) Test conditions Test solution: pH3.0: first potassium citrate-hydrochloric acid pH6.0: first potassium citrate-sodium hydroxide Liquid amount: 500 ml Liquid temperature: 37 ° C Sample 500 mg Detection method: methionine: HPLC method , Detection wavelength 210nm column Nucleosyl C18 [manufactured by Nippon Gasclo Industry Co., Ltd.] Lysine: Ninhydrin color development, OD method, 565nm Test method: JP11, General test method, Dissolution test method, Paddle method Rotation speed 100rpm (2) Result No. It is shown in Tables 1-3.

The additive of the present invention was used in Comparative Example 1 in Test Example 1 above.
Elution at pH 3.0 was quicker than that of ~ 4, and suppression of elution at pH 6.0 was also excellent.

Test Example 2 Animal Test An absorption test of the active substance was carried out using sheep (body weight: 50-60 kg, 10 animals) with cannulated anterior mesenteric vein, hepatic portal vein and carotid artery.

During the test period, an orchard glass (dried product) and a basic feed consisting of 300 g of bran each are used twice a day, 600 g each time.
Was paid at 7:00 and 17:00. As samples (A) control (no methionine added), (B) uncoated DL-methionine granules, (C) coated as obtained in Example 1 above.
DL-methionine granules were used. The amount of granules added is 30 bran
Methionine in 0 g was 1.5% (4.5 g).

Seven days after the start of the test, blood was collected from the carotid artery at 11 o'clock and 16 o'clock and the plasma methionine concentration was measured. The results are shown in Table 4.

In Test Example 2, the additive of the present invention significantly increased the plasma methionine concentration as compared with the case of the control product B. From these results, it was found that the present invention can significantly improve the utilization rate of the active substance in the additive.

EFFECTS OF THE INVENTION The coating material of the physiologically active substance for feeding ruminant and the additive for animal feed according to the present invention effectively protects the active substance and remarkably improves the utilization rate thereof.

Claims (17)

(57) [Claims] 1. A veterinarily acceptable water-soluble substance which is stable in the rumen of a ruminant and has the ability to be effectively disintegrated in the abomasum to coat a nucleus containing a physiologically active substance. A coating agent containing a synthetic polymer compound and ethyl cellulose, further comprising a veterinary-acceptable substance that is miscible with the polymer compound and ethyl cellulose but is insoluble in water. . 2. The coating composition according to claim 1, wherein the ruminant is cow, sheep or goat. 3. The coating agent according to claim 1, wherein the synthetic polymer compound is a compound soluble in water at pH 5 or lower. 4. The above synthetic polymer compound comprises: (a) a polyvinyl acetal diethylaminoacetate, (b) a copolymer comprising dimethylaminoethyl methacrylate and at least one of alkyl methacrylate and alkyl acrylate, and (c) A compound selected from the group consisting of 2-methyl-5-vinylpyridine and a copolymer of alkyl acrylate, alkyl methacrylate, one or more of methacrylic acid and acrylic acid. The coating material according to 3 above, 5. The coating agent according to claim 1, wherein the weight ratio of the polymer compound to ethyl cellulose is 1: 0.5 to 1:10. 6. The coating agent according to claim 1, wherein the water-insoluble substance is solid at room temperature. 7. The water-insoluble substance is a saturated fatty acid having 14 or more carbon atoms, a higher aliphatic alcohol having 12 or more carbon atoms, a hardened animal oil, a hardened vegetable oil, a natural resin or a synthetic resin.
The coating agent according to claim 6, which comprises at least one species and is soluble in an organic solvent. 8. The water-insoluble substance is myristic acid, palmitic acid, stearic acid, lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, hydrogenated tallow oil, hydrogenated castor oil, shellac, or vinyl acetate. The described coating agent. 9. The coating agent according to claim 1, wherein the weight ratio of the water-insoluble substance to the ethyl cellulose is 1: 0.1 to 1:20. 10. The coating material according to claim 1, wherein the total weight ratio of the polymer compound and the water-insoluble substance in the coating material is 50% or more. 11. A veterinary-acceptable water-soluble substance having a nucleus containing a physiologically active substance as an active ingredient, which is stable in the rumen of a ruminant and has the ability to be effectively disintegrated in the abomasum. In an additive for ruminant feeding, which is protected by a coating agent containing a synthetic polymer and ethyl cellulose, the coating agent is further added as an active ingredient,
A composition containing a veterinary-acceptable substance that is miscible with the polymer compound and ethyl cellulose but is insoluble in water 12. The composition according to claim 11, wherein the core has a protective film formed by spray coating the protective agent. 13. The weight ratio of the coating material to the core is 10
The composition according to claim 11, which is 0: 5 to 100: 100. 14. A method for producing an animal feed composition, comprising drying granules containing one or more physiologically active substances, and then coating the dried granules with a coating agent having the following composition. Composition of coating agent (1) Ethyl cellulose and (2) (a) Polyvinyl acetal diethylaminoacetate, (b) Copolymer of dimethylaminoethyl methacrylate and one or more of methacrylic acid alkyl ester and acrylic acid alkyl ester, and (c) One or more compounds selected from the group consisting of 2-methyl-5-vinylpyridine and one or more of acrylic acid alkyl ester, methacrylic acid alkyl ester, methacrylic acid and acrylic acid (3) Saturated fatty acids having 14 or more carbon atoms, higher aliphatic alcohols having 12 or more carbon atoms, hardened animal oil, hardened vegetable oil,
A composition comprising a natural resin or a synthetic resin and (4) a solvent. 15. The granule obtained by adding a binder solution obtained by dissolving a binder in a solvent to one or more physiologically active substances and kneading the mixture. The manufacturing method described. 16. The method according to claim 14, which is a granule obtained by coating one or more physiologically active substances with a binder. 17. The granule contains (a) first and second bioactive substances, and (b) one or more first bioactive substances having higher water solubility than the second bioactive substance. 15. The method according to claim 14, which is a granule obtained by adding a binder onto the core containing the granules, and then adding the second physiologically active substance and the binder.