JP2004254530A - Method for producing lumen bypass pharmaceutical - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for efficiently and stably producing a coated-type lumen bypass pharmaceuticals excellent in a lumen bypassing property. <P>SOLUTION: The method for producing lumen bypass pharmaceuticals comprises heat-mixing (A) a mixture of a nuclear pharmaceuticals containing (a) biological active substance, (b) fatty acid salt, (c) a bonding agent comprising at least one kind selected from aliphatic monocarboxylic acid, aliphatic alcohol, aliphatic dicarboxylic acid and tricarboxylic acid, and having a water content of ≤1 wt.%, and (B) a coating agent at a temperature higher than the melting point of (c) the bonding agent but lower than the melting point of (B) the coating agent using a mixer so as to coat the surface of the nuclear pharmaceuticals preparation (A) with the coating agent (B). <P>COPYRIGHT: (C)2004,JPO&NCIPI

Description

【００７３】
第１表から、比較例に比して、実施例では生物学的活性物質であるメチオニンの濃度の高い製剤が得られたことがわかった。
【００７４】
ナイロンバック試験
乳量４０ｋｇ／日の第１胃フィステラル装着した搾乳牛２頭のルーメン中に、２００メッシュのナイロン袋に詰めた製剤（比較例１及び実施例１〜４で得られた製剤）を浸漬し、一定時間（８Ｈｒ、１６Ｈｒ、２４Ｈｒ）後に取り出した時のメチオニン残存率（製剤中の、浸漬前のメチオニンに対する浸漬後のメチオニンの重量（％））を算出した。結果（２頭に行った試験の平均）を第２表に示す。
【００７５】
【表２】

【００７６】
第２表から、実施例で得られた各製剤（Ｃ１〜Ｃ４）は、比較例で得られた製剤（Ｃ５）に比較して、ルーメンにおけるメチオニン残存率が高いことが分かった。特に２４時間後の残存率が高く、長時間のルーメンバイパス性がより優れている。また、比較例１、実施例１及び実施例２を比較したとき、水分含有量が少ない程ルーメンバイパス性が良好となる傾向があることが分かった。
また、実施例で得られた製剤は、つややべたつき等の見かけだけではなく、ルーメンバイパス性も優れた製剤であることが分かった。
【００７７】
【発明の効果】
本発明によれば、表面につやがあり、べたつきがなく、かつ、ルーメンバイパス性に優れるルーメンバイパス製剤を効率よく製造することができる。
【図面の簡単な説明】
【図１】図１は、本発明の製造方法に用いる連続生産用加熱撹拌装置の一例を示す図である。（ａ）は側面から見た断面図、（ｂ）は正面から見た断面図である。
【図２】図２は、本発明の製造方法に用いる連続生産用加熱撹拌装置の他の例を示す図である。（ａ）は側面から見た断面図、（ｂ）は正面から見た断面図である。
【符号の説明】
１…撹拌容器、１’…回転ドラム、２…撹拌翼、３…クリアランス、４，４’…ジャケット、５…シャフト、５’…固定軸、６…掻取り板、６’…スクレーパー、７…推進羽根、８…ローター、９…投入口、１０…取出口、１１…突起部[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a method for producing a ruminal bypass preparation, which comprises coating a surface of a core preparation containing a biologically active substance, a fatty acid salt and a binder having a low melting point with a coating agent.
[0002]
[Prior art]
BACKGROUND ART Conventionally, a rumen (ruminal) bypass preparation for ruminants having a coating layer around a core preparation containing a biologically active substance (hereinafter sometimes referred to as a “coating type rumen bypass preparation”) is known. Has been. For example, Patent Literature 1 discloses a lumen bypass preparation obtained by coating the surface of a core preparation comprising a substance derived from a natural product such as fats and oils and a wax and a biologically active substance with a fatty acid calcium salt or the like, and a method for producing the same. I have. This document also discloses that this lumen bypass preparation can be produced by mixing a powder of a coating agent and a core preparation, and heating and stirring the mixture in a rotary container.
[0003]
Such a ruminal bypass preparation contains a high concentration of a biologically active substance such as methionine (50-90% by weight based on the nuclear preparation), and dissolves the biologically active substance in the rumen of the ruminant and removes the microorganism. It has the function of suppressing the degradation by the gastrointestinal tract and increasing the elution and absorption efficiency of the biologically active substance in the digestive tract after the abomasum (lumen bypass property). However, some of the preparations manufactured by the above-mentioned manufacturing method include those having stickiness on the surface, poor gloss on the surface, and poor lumen bypass property. Therefore, there has been a demand for the development of a production method capable of efficiently and stably producing a coated-type lumen bypass preparation exhibiting excellent lumen bypass properties.
[0004]
Further, in Patent Document 2, a mixture of a solid substance and a thermoplastic substance having a low softening point is heated and stirred at a temperature higher than the softening temperature of the thermoplastic substance, and the thermoplastic substance is heated and melted by the heating action of the solid substance. Thus, a method for immobilizing a thermoplastic material on the surface of a solid material has been disclosed. However, since the melting point of fatty acids and the like constituting the core preparation is generally lower than the melting point of the coating agent in many cases, it is difficult to apply this technique to a method for producing a coated-type lumen bypass preparation. In addition, since the melting point of the coating agent used for the coating type lumen bypass preparation is generally the same as or higher than each component of the core preparation, it is not possible to heat the mixture of the coating agent and the core preparation to a temperature higher than the softening temperature of the coating agent. It is impossible.
[0005]
[Patent Document 1]
JP-A-10-215789
[Patent Document 2]
Japanese Patent Application No. 4-160366
[0006]
[Problems to be solved by the invention]
The present invention has been made in view of the above-mentioned circumstances of the related art, and has as its object to provide a method for efficiently and stably producing a coated-type lumen bypass preparation having excellent lumen bypass properties.
[0007]
[Means for Solving the Problems]
Means for Solving the Problems In order to solve the above-mentioned problems, the present inventors have intensively studied a method for producing a coated-type lumen bypass preparation. As a result, the mixture of the core preparation and the coating agent having a water content of 1% by weight or less is heated and stirred at a temperature higher than the melting point of the binder and lower than the melting point of the coating agent using a stirrer. It has been found that a high quality rumen bypass preparation can be produced efficiently.
[0008]
In addition, a stirring device having a stirring blade, a stirring container, and a heating means is used as a stirring device, and a clearance between the stirring blade and the wall surface of the stirring container is set to a condition not more than 5 times the particle diameter of the obtained lumen bypass preparation. Heating and stirring the mixture within, or using a rotating drum-type stirring device in which a stirring vessel having a scraper mounted therein and a heating means, and rotating the stirring vessel, heats and stirs the mixture in the stirring vessel. As a result, it has been found that a high-quality rumen bypass preparation can be efficiently produced.
[0009]
Furthermore, by using a stirrer having an inlet for a mixture of a core preparation and a coating agent and an outlet for a manufactured lumen bypass preparation as a stirrer, a high-quality preparation can be efficiently and continuously produced. And completed the present invention.
[0010]
Thus, according to the invention, it comprises a biologically active substance (a), a fatty acid salt (b) and at least one selected from aliphatic monocarboxylic acids, aliphatic alcohols, aliphatic dicarboxylic acids and aliphatic tricarboxylic acids. Using a stirrer, a mixture of the core preparation (A) and the coating agent (B), which contains the binder (c) and has a water content of 1% by weight or less, is melted at a melting point of the binder (c). A method for producing a lumen bypass preparation, wherein the surface of the core preparation (A) is coated with a coating agent (B) by heating and stirring at a higher temperature and a temperature lower than the melting point of the coating agent (B). Is provided.
In the production method of the present invention, it is preferable to use a core preparation (A) having a water content of 0.5% by weight or less as the core preparation (A).
[0011]
In the production method of the present invention, as the stirring device,
(I) a stirrer, a stirrer, and a heating means; and a stirrer that rotates and stirs the mixture in the stirrer to rotate and stir the mixture. Heating and stirring the mixture under the condition that the clearance of the wall is 5 times or less the particle diameter of the manufactured lumen bypass preparation, or
(Ii) It is preferable that the mixture is heated and stirred by using a rotating drum type stirring device in which a stirring container having a scraper mounted therein and a heating means are used, and the stirring container rotates.
[0012]
BEST MODE FOR CARRYING OUT THE INVENTION
Hereinafter, the method for producing the rumen bypass preparation of the present invention will be described in detail.
The production method of the present invention comprises a biologically active substance (a), a fatty acid salt (b), and at least one selected from aliphatic monocarboxylic acids, aliphatic alcohols, aliphatic dicarboxylic acids and aliphatic tricarboxylic acids. A lumen bypass including a step of heating and stirring a mixture of a core preparation (A) containing a binder (c) and having a water content of 1% by weight or less and a coating agent (B) using a stirrer. This is a method for producing a preparation.
[0013]
1) Nuclear preparation (A)
The core preparation (A) used in the present invention comprises a biologically active substance (a), a fatty acid salt (b), and at least one selected from aliphatic monocarboxylic acids, aliphatic alcohols, aliphatic dicarboxylic acids and aliphatic tricarboxylic acids. It comprises one kind of binder (c).
[0014]
Biologically active substance (a)
The biologically active substance (a) used for the nuclear preparation (A) is not particularly limited as long as it is a substance that exhibits a biological activity when administered to a ruminant. For example, amino acids such as methionine and lysine hydrochloride; amino acid analogs such as 2-hydroxy-4-methylmercaptobutyric acid and salts thereof; vitamins such as nicotinic acid, nicotinamide, choline, vitamin A and vitamin E; glucose; Saccharides such as fructose; various veterinary medicines such as antibiotics and anthelmintics; These biologically active substances can be used alone or in combination of two or more. Among these, in the present invention, amino acids or amino acid analogs are preferable, amino acids are more preferable, methionine and lysine hydrochloride are further preferable, and methionine is particularly preferable. Methionine is an essential amino acid for ruminants, but is orally degraded by the rumen and is difficult to be effectively digested and absorbed. Therefore, a methionine-containing ruminal bypass preparation is particularly useful.
[0015]
The content of the biologically active substance (a) in the nuclear preparation (A) is usually 50 to 90% by weight (dry at 80 to 120 ° C. to remove adsorbed water) with respect to the nuclear preparation (A). % By dry weight based on the weight; the same applies hereinafter), preferably 60 to 85% by weight. When the content of the biologically active substance (a) is less than 50% by weight, it is economically disadvantageous. When the content is more than 90% by weight, the lumen bypass property of the lumen bypass preparation decreases, and the nuclear preparation (A) The moldability of the resin decreases.
[0016]
Fatty acid salt (b)
The fatty acid salt (b) has a property of being digested in the abomasum and beyond without being decomposed by the rumen. The fatty acid salt (b) used in the core preparation (A) is preferably a linear or branched, saturated or unsaturated aliphatic monocarboxylic acid salt. The number of carbon atoms of the aliphatic monocarboxylic acid is not particularly limited, but is preferably 12 to 24. If the number of carbon atoms is less than 12, the lumen bypass property of the rumen bypass preparation is reduced, and if the number of carbon atoms is more than 24, digestibility in the abomasum and thereafter is undesirably reduced.
[0017]
Specific examples of the aliphatic monocarboxylic acid include lauric acid, palmitic acid, myristic acid, stearic acid, oleic acid, linoleic acid, linoleic acid and the like. As the fatty acid, one kind or two or more kinds of these fatty acids may be used. Among them, the use of animal and plant-derived fatty acids such as palm fatty acid and beef tallow fatty acid is preferred because of easy availability.
[0018]
Examples of the fatty acid salt (b) include salts of the above-mentioned aliphatic monocarboxylic acids with alkaline earth metals such as calcium and magnesium, aluminum salts, and zinc salts. Of these, the calcium salt is preferable.
[0019]
Further, the fatty acid salt (b) is preferably of high purity. In particular, the purity of the fatty acid salt in the solid content (hereinafter referred to as “purity”) is preferably 90% or more. This is because impurities reduce the lumen bypass property and the hardness of the lumen bypass preparation. The term “purity” as used herein means an insoluble residue obtained by extracting a fatty acid salt with a solvent such as ethers and ketones, which is a common method of fat and oil analysis, and is calculated by excluding absorbed water. % By weight. However, the solvent used in this extraction treatment is selected to dissolve the fats and oils mixed therein without dissolving the fatty acid salt.
[0020]
Binder (c)
The binder (c) used in the nuclear preparation (A) is a substance having a melting point lower than the melting points of other substances contained in the nuclear preparation. The binder (c) reduces the crystallinity of the fatty acid salt (b) and improves the affinity between the biologically active substance (a) and the fatty acid salt (b). (A) has the role of smoothing the coating of the coating agent.
[0021]
In the present invention, the binder (c) is composed of at least one selected from aliphatic monocarboxylic acids, aliphatic alcohols, aliphatic dicarboxylic acids and aliphatic tricarboxylic acids.
[0022]
Examples of the aliphatic monocarboxylic acid include a linear or branched, saturated or unsaturated aliphatic monocarboxylic acid. The carbon number of the aliphatic monocarboxylic acid is not particularly limited, but is preferably 8 to 24, more preferably 12 to 18. If the number of carbon atoms is less than 8, the rumen bypass preparation is softened and the rumen bypass property is reduced, and if the number of carbon atoms is more than 24, digestibility in the abomasum and beyond is undesirably reduced.
[0023]
Specific examples of the aliphatic monocarboxylic acid include caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, behenic acid, hydrogenated castor oil fatty acid, etc. Aliphatic monocarboxylic acids, and mixtures thereof.
[0024]
Examples of the aliphatic alcohol include a linear or branched, saturated or unsaturated, monovalent aliphatic alcohol. The carbon number of the aliphatic alcohol is not particularly limited, but is preferably 8 to 24, and more preferably 12 to 18. If the number of carbon atoms is less than 8, the rumen bypass preparation is softened and the rumen bypass property is reduced, and if the number of carbon atoms is more than 24, digestibility in the abomasum and beyond is undesirably reduced.
[0025]
Specific examples of the aliphatic alcohol include octanol, nonanol, decanol, undecanol, lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, eicosanol, docosanol, dodecenol, fiseteryl alcohol, zomalyl alcohol, oleyl alcohol, and gadolyl alcohol. And their isomers.
[0026]
Examples of the aliphatic dicarboxylic acid or aliphatic tricarboxylic acid include linear or branched, saturated or unsaturated aliphatic dicarboxylic acids or aliphatic tricarboxylic acids. The carbon number of the aliphatic monocarboxylic acid or the aliphatic tricarboxylic acid is not particularly limited, but is preferably 2 to 8, and more preferably 2 to 6, respectively. When the number of carbon atoms is less than 2, or when the number of carbon atoms is more than 8, the lumen bypass property of the ruminal bypass preparation is undesirably reduced.
[0027]
Specific examples of aliphatic dicarboxylic acids include oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, malic acid, and the like. Specific examples of aliphatic tricarboxylic acids include citric acid and the like. Is mentioned.
[0028]
The content of the binder (c) in the core preparation (A) is not particularly limited as long as the binder (c) is compatible with the fatty acid salt (b). The weight ratio of the agent (c) is preferably in the range of 70:30 to 90:10. By using the core preparation (A) containing the binder (c) at such a weight ratio, a rumen bypass preparation exhibiting good rumen bypass properties can be obtained. The total content of the fatty acid salt (b) and the binder (c) is preferably 10 to 50% by weight based on the core preparation (A).
[0029]
Moisture content
The water content of the core preparation (A) used in the present invention is 1% by weight or less, preferably 0.5% by weight or less. When the water content of the core preparation (A) is not within this range, water is evaporated with an increase in the product temperature (temperature of the mixture in the stirring device) when producing a lumen bypass preparation, and the surface is not glossy. It is not preferable because a rumen bypass preparation having rough and inferior rumen bypass properties can be obtained.
[0030]
As a method for obtaining a core preparation (A) having a water content of 1% by weight or less, for example, (a) a raw material having a water content of 1% by weight or less (a biologically active substance (a), a fatty acid salt (b) And (b) a method of producing a core preparation having a water content of 1% by weight or less by drying the core preparation before coating with a coating agent. And a method for obtaining the same. When the core preparation is dried, in order to avoid melting of the binder (c) having a low melting point, it is preferable to dry the core preparation in a vacuum at a temperature equal to or lower than the melting point of the binder (c) or to cool quickly after drying.
[0031]
The water content of the core preparation (A) can be measured by a known water content measuring method. For example, a part of the manufactured nuclear preparation (A) is taken out, crushed in a dry box to obtain a uniform powder, and the water content of the nuclear preparation (A) can be measured by Karl Fischer moisture measurement.
[0032]
The method for producing the core preparation (A) is not particularly limited, and various known granulation methods can be employed. Above all, extrusion granulation under dry conditions is preferable, and in order to obtain a preparation having a low porosity and a small water content, kneading is performed while performing vacuum degassing, and immediately after extrusion granulation, the granulated product is subjected to A method of quenching with dry cold air or the like is more preferable.
[0033]
The shape of the nuclear preparation (A) is not particularly limited, but is preferably a shape having no corners such as a sphere, a spheroid, a shell, and a cylinder. The size of the preparation may be any suitable size as a feed ingredient. Preferred particle sizes are in the range of 0.5 mm to 10 mm.
[0034]
In addition, a modifier may be added to the core preparation (A) for improving moldability, mechanical strength, and other properties. Examples of the modifier used include waxes such as rice wax; waxes such as carnauba wax and beeswax; various polymers such as ethyl cellulose, propyl cellulose, polyethylene, chitosan and derivatives thereof, pH-sensitive polymers; Inorganic powders; various additives such as stabilizers and fragrances; and the like. It is preferable to use those modifiers having a water content of 1% by weight or less.
[0035]
2) Coating agent (B)
The coating agent (B) used in the present invention is a substance that coats the surface of the core preparation (A). The coating agent (B) plays a role in improving the lumen bypass property during long-time ruminal immersion.
[0036]
Examples of the coating agent to be used include salts of aliphatic monocarboxylic acids; polymers and zeins which do not dissolve in a neutral region but dissolve in an acidic region.
Examples of the salt of the aliphatic monocarboxylic acid include the same salts as those listed as specific examples of the fatty acid salt (b).
[0037]
Examples of polymers and zeins that do not dissolve in the neutral region but dissolve in the acidic region include cellulose derivatives such as benzylaminomethylcellulose, piperidylethylhydroxyethylcellulose, cellulose acetate diethylaminoacetate, and dibutylaminohydroxypropyl ether; vinyl diethylamine-vinyl acetate copolymer , Polyvinyldiethylaminoacetoacetal, vinylpiperidylacetoacetal-vinylacetate copolymer, polyvinylacetal diethylaminoacetate, polydimethylaminoethylmethacrylate, polydiethylaminomethylstyrene, polyvinylethylpyridine, vinylethylpyridine-styrene copolymer, vinylethylpyridine-acrylonitrile copolymer, methyl Vinylpyridine- Polyvinyl derivatives such as Tylene copolymers; chitosan; metal salts of polysaccharides such as calcium alginate; calcium carbonate, dibasic calcium phosphate, tribasic magnesium phosphate, zinc phosphate, aluminum phosphate, calcium silicate, calcium pyrophosphate, magnesium carbonate, A water-insoluble metal salt of an acid which is weaker than hydrochloric acid such as lead carbonate and is acceptable to a living body. In the present invention, these coating agents can be used alone or in combination of two or more. In the present invention, as the coating agent (B), in addition to the aliphatic monocarboxylate; a polymer or zein which does not dissolve in the neutral region but dissolves in the acidic region, the core agent (A) A modifier to which the same ones as those listed can be added.
[0038]
Among them, the use of an aliphatic monocarboxylate is particularly preferred from the viewpoint of availability and a lumen bypass preparation having excellent lumen bypass properties. The aliphatic monocarboxylate used is preferably the same as the above-mentioned fatty acid salt (b), but need not be the same.
[0039]
The coating agent (B) is usually used as a powder. The particle size of the powder to be used is preferably 100 mesh passes or less, and more preferably 10 to 30 μm or less in average particle size, in order to coat the core preparation (A) efficiently.
[0040]
The amount of the coating agent (B) to be used is generally 2 to 20 parts by weight, preferably 3 to 15 parts by weight, based on 100 parts by weight of the core preparation (A). The coating agent (B) does not adhere to the core preparation (A) in an amount exceeding a certain amount, but there is no particular problem even if the coating agent that does not adhere remains.
[0041]
3) Manufacturing method of lumen bypass preparation
The lumen bypass preparation of the present invention (hereinafter sometimes simply referred to as “preparation”) stirs a mixture of the core preparation (A) and the coating agent (B) while heating the mixture to a predetermined temperature using a stirrer. Thereby, a component having a low melting point (usually a binder (c)) is eluted from the core preparation (A), and the powder of the coating agent (B) is added to the low melting point component that has oozed on the surface of the core preparation (A) And the surface of the nuclear preparation (A) is coated.
[0042]
The production method of the present invention can be carried out using a known heating and stirring device having a stirring means and a heating means.
Examples of the stirring means of the stirring device used in the present invention include (i) a stirring device using a stirring blade attached to the stirring device, and (ii) a stirring device in which a stirring vessel is rotated (rotary drum type).
[0043]
In the case of using the stirring device (i) equipped with a stirring blade, the clearance (the distance between the stirring blade and the inner wall of the stirring vessel) is preferably 5 times or less the diameter of the preparation. If the clearance is more than 5 times, the stirring efficiency becomes poor, and a good preparation cannot be obtained.
[0044]
When the rotary drum type stirring device (ii) is used, a scraper (a scraping plate or a scraping blade) is preferably provided inside the device. When a rotating drum type stirring device is used, the mixture may adhere to the inner wall of the stirring device in a layered manner during the stirring operation. This layered material remarkably hinders the heat transfer, slows the heating temperature, and lowers the heating efficiency. The scraper functions to prevent the formation of the layered material and to remove the adhered layered material.
[0045]
The heating means of the stirring device used in the present invention is not particularly limited as long as it can heat the inside of the stirring vessel to a predetermined temperature. Examples of the heating means include a heater in which a heater is arranged around a stirring vessel, and a heater in which a jacket for circulating hot water and heating is arranged around (or at the bottom of) the stirring vessel. In the present invention, since the melting point of the binder (c), which is a raw material, is low (less than 100 ° C.), it is preferable to use a jacket-type heating device that is easy to heat, has high thermal efficiency, and is inexpensive. This jacket type heating and stirring device is a device in which a jacket is attached to a main body casing and warm water is passed through the jacket to heat the inside of the device to a predetermined temperature.
[0046]
The heating temperature of the mixture is a temperature higher than the melting point of the binder (c) and lower than the melting point of the coating agent (B). When the difference between the melting point of the binder and the melting point of the coating agent is larger than 30 ° C., the temperature is preferably about 35 ° C., more preferably about 25 ° C. higher than the melting point of the binder (c). By setting the temperature in this manner, only the binder (c) in the core preparation (A) is melted and exudes on the surface of the core preparation (A). Then, the powder of the coating agent is appropriately adhered to the surface of the core preparation, and the core preparation (A) can be efficiently coated with the coating agent (B).
[0047]
When the heating temperature of the mixture is low, the binder (c) does not melt sufficiently and does not exude on the surface of the core preparation (A), so that the powder of the coating agent is efficiently applied to the surface of the core preparation (A). Cannot be attached. When the heating temperature of the mixture is too high, the melting of the binder (c) proceeds excessively, soaks out on the surface of the coating agent (B) coated on the surface of each of the preparations (A), and the preparations are not separated from each other. The attached spheres increase. Further, if the heating / mixing treatment is further continued, the manufactured preparation and the container adhere to each other, and the whole becomes millet-like, so that the preparation of the preparation becomes impossible. In any case, a good preparation cannot be obtained. Therefore, after the coating agent (B) is coated, it is desirable that the obtained preparation is immediately circulated through a jacket or quenched by cold air or the like to stabilize the shape and quality of the preparation.
[0048]
The time during which the mixture of the core preparation (A) and the coating agent (B) is retained in the stirring vessel of the stirrer is set so that the manufactured preparation is further heated and the coating agent does not excessively adhere. Is preferred. When the powder of the coating agent uniformly adheres to the surface of the core preparation (A), the gloss of the surface increases. This state is confirmed by visual observation, thereby completing the coating. It is preferred to remove the formulation at this point. When the mixture is kept in the stirring container for too long, the binder (c) further exudes from the inside of the coating agent (B) adhered to the core preparation (A), and the powder of the coating agent (B) becomes core. It is not preferable because it excessively adheres to the preparation (A) and the content ratio of the biologically active substance as an active ingredient decreases.
[0049]
In the present invention, a batch stirrer can be used as the stirrer, but a stirrer having an inlet and an outlet can also be used. By using the latter type of agitator, the mixture is continuously supplied from the input port, and the prepared product is continuously taken out from the outlet, thereby continuously and efficiently producing the product. Becomes possible.
[0050]
An example of a continuous production jacket-added heat stirrer comprising a stirring blade, a stirring vessel, a heating means, an inlet and an outlet, and mixing and stirring the mixture in the stirring vessel by rotating the stirring blade. As shown in FIG. FIG. 1A is a cross-sectional view of the jacket-added thermal stirring device for continuous production as viewed from the side, and FIG. 1B is a cross-sectional view as viewed from the front.
[0051]
The stirrer shown in FIG. 1 is attached to a central stirring shaft 1 for accommodating a mixture of the core preparation (A) and the coating agent (B) and stirring the mixture, and for stirring the mixture. And a jacket 4 for storing hot water and heating the mixture. Two shafts 5 are mounted horizontally at the center of the stirring vessel 1 of the stirring device, and at the tip of the shaft 5, a predetermined distance from the left to the right in FIG. A plurality of stirring blades 2 are attached. The number, shape, and the like of the stirring blades are not particularly limited, and can be appropriately set and selected according to the size of the stirring device. As shown in FIG. 1B, when the two shafts 5 rotate in the direction of the arrow in the figure, the stirring blade 2 rotates, and the mixture in the stirring vessel is stirred. Further, a projection 12 is attached to the inside of the stirring vessel 1, whereby the mixture is sufficiently stirred by the two stirring blades 2.
[0052]
Further, hot water of a predetermined temperature flows in the jacket 4, and the inside of the stirring vessel 1 can be heated to a predetermined temperature by the hot water. In the stirring device shown in FIG. 1, a pipe (not shown) connected to the jacket 4 is further arranged. By circulating hot water between the jacket 4, the piping and the hot water heater, hot water of a constant temperature always flows in the jacket 4.
[0053]
The present invention can be carried out as follows using the stirring device shown in FIG. First, in FIG. 1A, a mixture of the core preparation (A) and the coating agent (B) is charged into the stirring vessel 1 from a charging port (not shown) provided on the left side of the stirring vessel 1. . While the mixture is stirred in the stirring vessel 1 by the stirring blade 2, the mixture is sent out from the left side to the right side by the slight inclination of the stirring vessel 1 in FIG. As means for sending the mixture from the left to the right, a propulsion blade 7 having a predetermined angle is attached to the shaft 5, and when the shaft 5 rotates, the mixture is sent from the left to the right in FIG. 1A while being stirred. It is also possible to adopt a method of forming a structure.
[0054]
In FIG. 1 (a), while being sent from the left side to the right side, the mixture is heated to a predetermined temperature while being stirred, and the low melting point binder (c) is melted and exudes to the surface of the core preparation (A). . Therein, the coating agent (B) uniformly adheres to the surface of the core preparation (A) to obtain a lumen bypass preparation. The obtained preparation can be sequentially taken out from an outlet (not shown) attached to the right side in FIG. 1 (a).
[0055]
In addition, in the stirring device shown in FIG. 1, the clearance 3 is preferably set to 5 times or less the particle diameter of the preparation 6. If the clearance 3 is larger than 5 times the diameter of the obtained lumen bypass preparation, the stirring efficiency becomes poor and a good preparation cannot be obtained. However, even with an appropriate clearance, a layer of the formulation may be formed between the machine wall and the stirring blade, which may significantly hinder heat transfer. As a solution, a scraping plate 6 may be attached.
[0056]
FIG. 2 is a structural sectional view of a rotary drum type stirring device provided with a stirring container having a scraper mounted therein and a jacket 4 'as heating means. FIG. 2A is a cross-sectional view of the stirring device as viewed from the side, and FIG. 2B is a cross-sectional view of the stirring device as viewed from the front. This stirring device accommodates a mixture of the core preparation (A) and the coating agent (B), and is attached to a cylindrical stirring container 1 ′ for stirring the mixture, and a central portion in the stirring container 1 ′. A fixed shaft 5 ', a scraper 6' attached to the fixed shaft 5 ', and a jacket 4' for storing hot water and heating the inside of the stirring vessel 1 'are provided.
[0057]
In the stirring device shown in FIG. 2, the rotating drum-type stirring container 1 'is rotated by a rotor 8' to stir the mixture contained in the stirring container 1 '.
The scraper 6 'plays a role of scraping the mixture stuck on the inner wall surface of the stirring vessel 1' when the stirring vessel 1 'rotates and stirs the mixture. By attaching the scraper 6 ', it is possible to prevent a problem that a layer of the mixture is formed on the inner wall surface of the stirring vessel 1', heating is insufficient, and a desired lumen bypass preparation cannot be obtained. The number of scrapers to be attached may be appropriately selected according to the scale of the apparatus.
[0058]
The stirrer shown in FIG. 2 has a jacket 4 'for containing circulating hot water similarly to the stirrer shown in FIG. 1, and the inside of the stir vessel 1' is heated by the hot water stored in this jacket 4 '. be able to.
[0059]
The present invention can be implemented as follows using the stirring device shown in FIG. First, in FIG. 2 (a), a mixture of the core preparation (A) and the coating agent (B) is charged into the stirring vessel 1 'from the charging port 9 provided on the left side of the stirring vessel 1'. The charged mixture is sent from the left to the right while being stirred in the stirring vessel 1 'by the rotation of the stirring vessel 1'. In the stirring device shown in FIG. 2, the cylindrical stirring vessel 1 'is provided with a slight gradient so that the mixture can be sent from left to right.
[0060]
In FIG. 2A, while the mixture is sent from left to right, the mixture is heated to a predetermined temperature while being stirred, and the low-melting binder (c) is melted and exudes to the surface of the nuclear preparation (A). . Therein, the coating agent (B) uniformly adheres to the surface of the core preparation (A) to obtain a lumen bypass preparation. The obtained preparation can be continuously taken out from the outlet 10 attached to the right side in FIG. 2 (a).
[0061]
By using the stirrer shown in FIG. 1 and FIG. 2, a good lumen bypass preparation can be manufactured even in a long-time continuous operation. When performing continuous production for a long time, it is particularly preferable to use the stirrer shown in FIG.
[0062]
【Example】
Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples, but the present invention is not limited to the following Examples and Comparative Examples. The parts in these examples are on a weight basis unless otherwise specified.
(1) Hardness
A weight was applied to the nuclear preparation, and the weight at which destruction started was measured using a tablet hardness meter, and the hardness was defined as the hardness.
(2) Water content
The core preparation was ground in a dry air atmosphere to obtain a uniform powder, and the water content of the powder was measured by Karl Fischer moisture content measurement.
[0063]
Example 1
Methionine (melting point 280 ° C.) as biologically active substance (a), palm oil fatty acid calcium salt (purity 94.0%) as fatty acid salt (b), and lauric acid (melting point 45 ° C.) as binder (c) Was used to produce a nuclear preparation according to the method described in JP-A-10-215789. This core preparation was subjected to centrifugal dehydration and then vacuum degassed and dried at room temperature until the water content became 0.9% by weight. The nuclear preparation thus obtained is referred to as (A1). The hardness of the core preparation (A1) was 350. The composition ratio (weight ratio) of the core preparation (A1) was palm oil fatty acid calcium salt: lauric acid: methionine = 21: 6: 73.
[0064]
45 kg of the core preparation (A1) and 4.5 kg of fatty acid calcium powder as a coating agent (B) were put into a 100-liter jacketed multi-fin processor (manufactured by Nara Machinery Co., Ltd.), and mixed at 70 ° C. in an outer jacket while mixing. Heated through water. The heating was stopped when the fatty acid calcium powder was completely attached to the surface of the core preparation (product temperature: about 60 ° C.). Cooling was carried out by passing cold water through the jacket while stirring until the product temperature reached 30 ° C., to obtain a lumen bypass preparation (C1).
[0065]
Example 2
The nuclear preparation prepared in the same manner as in Example 1 was subjected to centrifugal dehydration treatment and then vacuum-degassed and dried at room temperature until the water content became 0.3% by weight. Let the obtained nuclear preparation be a nuclear preparation (A2). The hardness of the core preparation (A2) was 360. A lumen bypass preparation (C2) was produced in the same manner as in Example 1 except that the core preparation (A2) was used.
[0066]
Example 3
30 kg of the nuclear preparation (A2) having a water content of 0.3% by weight used in Example 2 was placed in a 70-liter paddle mixer equipped with a jacket (manufactured by Nara Machinery Co., Ltd.) provided with an inlet and an outlet, and an outer jacket was provided. And heated through 70 ° C. hot water. When the product temperature reached 40 ° C., a mixture prepared by mixing 100 parts of the core preparation (A2) and 10 parts of fatty acid calcium at a rate of 0.5 kg at an interval of 1 minute was supplied from the inlet, and the mixture was taken out of the other end. The coated formulation was continuously removed by overflow. The removed formulation was immediately cooled with cold air. The obtained lumen bypass preparation (C3) was glossy and non-sticky as in Examples 1 and 2.
[0067]
Example 4
A hot water heating and stirring device (manufactured by Umeda Kogyo Co., Ltd.) for continuous production, having a charging drum and a rotary drum having a diameter of 400 mm and a length of 500 mm, and having a scraper attached to the upper part of the inner wall was prepared. Hot water at 80 ° C. was passed through the outside of the apparatus, and the drum was rotated at 12 rpm. There, 8 kg of the core preparation (A2) and 0.8 kg of fatty acid calcium were mixed in advance, and this raw material mixture was continuously supplied from the inlet. The preparation overflowed from the outlet and was discharged, and when the product temperature reached 55 ° C., the gloss of the preparation improved, and the preparation with the coating completed was continuously taken out. The removed formulation was immediately cooled with cold air. The obtained preparation (C4) was glossy and non-sticky as in Examples 1 and 2.
[0068]
In addition, 0.5 kg of the mixture was injected from the inlet every minute, and the operation of continuously taking out the lumen bypass preparation from the outlet was performed. Even after one hour, the product temperature was kept constant without increasing the external temperature, and the resulting preparation was as glossy and non-sticky as the initially obtained preparation.
[0069]
Comparative Example 1
Methionine (melting point 280 ° C.) as biologically active substance (a), palm oil fatty acid calcium salt (purity 94.0%) as fatty acid salt (b), and lauric acid (melting point 45 ° C.) as binder (c) Was used to produce a nuclear preparation (A3) according to the method described in JP-A-10-215789. The composition ratio (weight ratio) of the core preparation (A3) was palm oil fatty acid calcium salt: lauric acid: methionine = 25: 5: 70, and the water content was 1.6% by weight. The hardness of the core preparation (A3) was 280.
Next, a rumen bypass preparation (C5) was obtained in the same manner as in Example 1.
[0070]
The preparations (C1 and C2) obtained in Examples 1 and 2 were compared with the preparation (C5) obtained in Comparative Example 1. As a result of visual observation, the preparations (C1, C2) obtained in Examples 1 and 2 were clearly glossy compared to the preparation (C5) of Comparative Example 1. In addition, the feel was smooth without stickiness as compared with the preparation of Comparative Example 1.
[0071]
For each of the preparations (C1 to C4) obtained in Examples 1 to 4 and the preparation (C5) obtained in Comparative Example 1, the amount of the coating layer (weight (%) of the coating agent attached to the weight of the preparation), methionine The concentration (weight (%) of methionine contained in the nuclear preparation with respect to the weight of the preparation) was calculated. The results are shown in Table 1.
[0072]
[Table 1]

[0073]
From Table 1, it was found that a preparation having a higher concentration of methionine, which is a biologically active substance, was obtained in Examples than in Comparative Examples.
[0074]
Nylon back test
The preparations (the preparations obtained in Comparative Example 1 and Examples 1 to 4) packed in a 200-mesh nylon bag were immersed in the lumen of two milking cows equipped with a rumen fistula with a milk amount of 40 kg / day, The methionine residual rate (the weight (%) of methionine after immersion in the preparation relative to methionine before immersion) when the methionine was taken out after a certain period of time (8 hours, 16 hours, 24 hours) was calculated. Table 2 shows the results (average of tests performed on two animals).
[0075]
[Table 2]

[0076]
From Table 2, it was found that each of the preparations (C1 to C4) obtained in the examples had a higher methionine residual ratio in the rumen than the preparation (C5) obtained in the comparative example. In particular, the residual ratio after 24 hours is high, and the long-term lumen bypass property is more excellent. Moreover, when Comparative Example 1, Example 1 and Example 2 were compared, it was found that the lower the water content, the better the lumen bypass property.
In addition, it was found that the preparations obtained in the examples were excellent in not only appearance such as gloss and stickiness but also lumen bypass property.
[0077]
【The invention's effect】
ADVANTAGE OF THE INVENTION According to this invention, the surface is glossy, there is no stickiness, and the lumen bypass preparation excellent in the lumen bypass property can be manufactured efficiently.
[Brief description of the drawings]
FIG. 1 is a diagram showing an example of a heating and stirring device for continuous production used in the production method of the present invention. (A) is a sectional view seen from the side, and (b) is a sectional view seen from the front.
FIG. 2 is a diagram showing another example of a heating and stirring apparatus for continuous production used in the production method of the present invention. (A) is a sectional view seen from the side, and (b) is a sectional view seen from the front.
[Explanation of symbols]
DESCRIPTION OF SYMBOLS 1 ... Stirring container, 1 '... Rotary drum, 2 ... Stirring blade, 3 ... Clearance, 4, 4' ... Jacket, 5 ... Shaft, 5 '... Fixed shaft, 6 ... Scrape plate, 6' ... Scraper, 7 ... Propulsion impeller, 8 ... rotor, 9 ... inlet, 10 ... outlet, 11 ... protrusion

Claims (5)

Contains a biologically active substance (a), a fatty acid salt (b), and a binder (c) comprising at least one selected from aliphatic monocarboxylic acids, aliphatic alcohols, aliphatic dicarboxylic acids and aliphatic tricarboxylic acids. The mixture of the core preparation (A) having a water content of 1% by weight or less and the coating agent (B) is mixed at a temperature higher than the melting point of the binder (c) using a stirrer. A method for producing a lumen bypass preparation, wherein the surface of the core preparation (A) is coated with a coating agent (B) by heating and stirring at a temperature lower than the melting point of (B). The method for producing a lumen bypass preparation according to claim 1, wherein a core preparation (A) having a water content of 0.5% by weight or less is used as the core preparation (A). The stirring device includes a stirring blade, a stirring vessel, and a heating unit, and uses a stirring-type stirring device that mixes and stirs the mixture in the stirring container by rotating the stirring blade. The method for producing a lumen bypass preparation according to claim 1 or 2, wherein the mixture is heated and stirred under a condition that a clearance of a wall surface of a container is 5 times or less of a particle diameter of a manufactured lumen bypass preparation. 2. The mixture is heated and stirred by using a rotating drum type stirring device in which a stirring container having a scraper mounted therein and a heating unit are used as the stirring device, and the stirring container rotates. 3. Or the method for producing a lumen bypass preparation according to 2. As the stirring device, a stirring device having an inlet and an outlet is used, the mixture is continuously supplied from the inlet, and the lumen bypass preparation manufactured from the outlet is continuously removed. The method for producing a rumen bypass preparation according to any one of claims 1 to 4.

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