JPH0140008B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to a method for producing particles containing physiologically active substances. More specifically, the present invention relates to a method for producing particles in which the physiologically active substance contained therein is stably contained under neutral conditions, but has the property of being eluted under acidic conditions. Neutral conditions generally refer to a pH of 5 to 8, which is the primary condition for ruminants.
conditions within the stomach and, in monogastric animals, within the oral cavity and esophagus. Particles in which the physiologically active substance contained therein is stable under neutral conditions but elutes under acidic conditions are highly useful to living organisms. For example, the usefulness of ruminants has been attracting attention in recent years. Ruminants have a neutral primary
They have a stomach, and the microorganisms living in this rumen digest and utilize components such as cellulose that cannot be digested by monogastric animals. In recent years, through physiological and nutritional research on ruminants, the existence of the rumen has been pointed out as one of the factors restricting the productivity of ruminants. In other words, the idea is to use physiologically active substances more efficiently by allowing physiologically active substances that do not want to be broken down in the neutral rumen to pass through the rumen, and having them broken down and absorbed in the abomasum and beyond. It is something. In this way, technology to produce particles in which physiologically active substances are stable under neutral conditions (rumen) and elute under acidic conditions (abomasum) is a long-awaited technology for efficiently raising ruminants. ing. Furthermore, for monogastric animals, this technique is useful for biologically active substances expected to be gastrically soluble. (Prior Art) Several methods have already been proposed for passing through the rumen of ruminants, but none of them can be said to be sufficiently effective. For example, in Japanese Patent Publication No. 49-45224, amino acids or polypeptides are dispersed in a mixed melt of fats and oils with a melting point of 40℃ or higher and fats and oils with a melting point of 40℃ or lower, and this is dispersed at a temperature of 40℃ from 20℃.
We have proposed a method for producing amino acid-containing fat and oil capsules, which is characterized by injecting the capsules into water maintained at between 10°C and 30°C. Japanese Patent Publication No. 56-1057 also describes biologically active substances as saturated linear or branched substituted or unsubstituted aliphatic monocarboxylic acids having at least 14 carbon atoms or salts thereof; Covered with a matrix consisting of a mixture of a saturated acid or its salt and an unsaturated linear or branched substituted or unsubstituted aliphatic monocarboxylic acid having at least 14 carbon atoms or its salt. It shows. JP-A-56-154956 also discloses that a biologically effective substance is provided with a coating containing a salt of an aliphatic monocarboxylic acid having 14 to 22 carbon atoms or a mixture of several of said acids. It shows something in the form of particles. Furthermore, JP-A-58-175449 describes biologically active substances as linear or branched saturated or unsaturated monocarboxylic acids having 14 to 22 carbon atoms, hydrogenated vegetable fats and hydrogenated animal fats. This shows a product wrapped in a protective coating containing one or more substances selected from fats and chitosan. (Problems to be solved by the invention) However, Special Publication Nos. 49-45224 and 1973-
In No. 1057, it is expected that the disintegration of the coating material will take place after the small intestine, but there are restrictions on the time available for digestion and absorption, so there is a drawback that the target substance is not fully digested and absorbed. have. Also, JP-A-56-154956, JP-A-58-175449
In order to overcome the above-mentioned drawbacks, the method uses a coating material that disintegrates in the abomasum and elutes substances that are effective for living organisms.
Disintegration in the stomach is not sufficient, and its effects cannot be said to be stable. As described above, the reality is that there is still no satisfactory method for making the contained physiologically active substances stable in the rumen (under neutral conditions) and eluted from the abomasum (under acidic conditions). (Means for Solving the Problems) The present inventors have studied various prior art techniques as described above, and have determined that at least substances represented by A, B, and C, respectively, as shown in the claims. In the particles containing at least A and C prepared in advance, the surface of the particles is heat-treated in the presence of B at a temperature equal to or higher than the melting point of at least one substance selected from C, as described above. The present inventors have discovered that this is an excellent method without any drawbacks, and have completed the present invention. The present invention will be explained in more detail below. The physiologically active substance (A) referred to in the present invention may be, for example, nutrients in ruminants, feed containing the same, or even drugs, and can be used in the abomasum without being consumed by microorganisms in the rumen. These are the nutrients and drugs that we want to effectively absorb into the bodies of ruminants themselves, and in monogastric animals, they are required to be stomach-soluble. Next, examples of substances classified as Group B in the present invention that are stable under neutral conditions but have the property of disintegrating or eluting under conditions with a pH of 3 or less include cellulose derivatives such as benzylaminomethylcellulose and dimethylaminomethylcellulose. methylcellulose,
piperidylethylhydroxyethylcellulose,
Cellulose acetate diethylamino acetate, cellulose acetate dibutylamino hydroxypropyl ether, etc., polyvinyl derivatives such as vinyl diethylamine-vinyl acetate copolymer, vinylbenzylamine-vinyl acetate copolymer, polyvinyl diethylamino acetoacetal, vinyl piperidyl acetoacetal-vinyl acetate copolymer, polyvinyl acetal diethylamino acetate , polydimethylaminoethyl methacrylate, polydiethylaminomethylstyrene, polyvinylethylpyridine, vinylethylpyridine styrene copolymer, vinylethylpyridine acrylonitrile copolymer, methylvinylpyridine acrylonitrile copolymer, methylvinylpyridine styrene copolymer, etc. Nitrogen-containing polysaccharides such as chitosan, chitin, etc. , metal salts of polysaccharides, such as calcium alginate, and water-insoluble salts of acids that are weaker than hydrochloric acid and acceptable to the living body, such as calcium carbonate, tribasic calcium phosphate, dibasic calcium phosphate, tribasic magnesium phosphate, and zinc phosphate. , aluminum phosphate, calcium silicate, calcium pyrophosphate,
Examples include magnesium carbonate, lead carbonate, and cobalt carbonate. Next, the number of carbons shown as the group C in the present invention is
14 or more linear or branched saturated or unsaturated monocarboxylic acids or their salts, animal fats and oils with a melting point of 40°C or more, or vegetable oils and fats with a melting point of 40°C or more, or melting points of 40°C
At least one substance selected from the above waxes (C)
The amount used is usually 10% by weight or more based on the total amount of finished particles. At less than 10% by weight, problems tend to arise even in the stability of the physiologically active substance in neutral conditions, and sufficient effects cannot be obtained. Furthermore, if an extremely large amount is used, there are problems such as a decrease in the amount of the active ingredient and difficulty in elution even under conditions of pH 3 or lower, making it impossible to obtain sufficient effects. Furthermore, in addition to the above-mentioned A, B, and C, one or more fourth components may be appropriately added and used for various purposes in the present invention. Examples include binders, specific gravity adjusters, fillers, palatability enhancers, lubricants, and the like. In the present invention, it is first necessary to produce particles containing at least A and C. A,C
Alternatively, any method or shape known in the art may be employed as the method for producing the particles containing the fourth component or the shape of the particles. For example, methods for producing particles include conventional rolling granulation, extrusion granulation, compression granulation, sulfur granulation, crushing granulation, stirring granulation, and the like. The shapes of the particles include pellets, spheres, long spheres, tablets, and the like. The present invention is completed by heat-treating the surface of particles containing at least A and C in the coexistence of B at a temperature equal to or higher than the melting point of C. Heat treatment in the present invention refers to exposing the particles to a predetermined temperature, and is not limited to the heat treatment method. The heat treatment time is determined by the melting point of component C and the heat treatment temperature, and cannot be absolutely specified, but if the time is too short, the film may not be sufficiently formed, so 1 minute or more is usually appropriate. . Also, even if you do it for a long time, the effect will hardly change. Although a certain degree of effect can be observed even if the particles are heat-treated while standing still, in order to further enhance the effect, it is better to heat-treat the particles while fluidizing or vibrating them. Sulfur motion or vibration is performed to more uniformly code at least B around particles containing at least AC, and there are no limitations on the method, strength, etc. of flow or vibration. As the flow or vibration method, any method in the field is adopted,
Furthermore, the strength is set to at least a level that does not break the particles containing AC. The amount of B present is usually 5 parts by weight to 80 parts by weight, preferably 8 parts by weight to 70 parts by weight, based on 100 parts by weight of particles containing at least AC. If the amount of B coexisting is less than the above-mentioned lower limit, the coating will not be sufficient and stability of the physiologically active substance under neutral conditions will suffer, making it impossible to obtain sufficient effects. In addition, if the above upper limit is exceeded,
A sufficient effect cannot be obtained due to a decrease in the amount of active ingredients and problems with the elution of physiologically active substances under acidic conditions. (Effects of the Invention) As described above, the method for producing particles containing a physiologically active substance of the present invention allows the contained physiologically active substance to be more stable under neutral conditions than in conventional methods, and has a pH of 3 or less. It is an excellent method that can obtain particles that are easier to elute under certain conditions, and B and C can be used as appropriate.
It is also possible to increase economic efficiency by selecting . Moreover, since the process is simple, it is extremely useful industrially. The method of the present invention will be explained in more detail below using Examples and Comparative Examples. In the examples, parts are parts by weight, and % is % by weight. Examples 1 to 10, Comparative Examples 1 and 2 DL-methionine, stearic acid, and sodium polyacrylate (Example 4 only) were mixed uniformly in advance using a ribbon mixer in the ratio shown in Table 1, and then using a pelletizer, the diameter Pellets with a length of 2 mm and a length of 3 mm were produced. obtained pellets
After putting 100 parts of tribasic calcium phosphate in the amounts shown in Table 1 into a rotary evaporator, heat treatment was performed under the conditions shown in Table 1 while rotating.
The pellets prepared as described above were subjected to elution tests in a neutral solution (0.1M sodium phosphate buffer PH7.0) and an acidic solution (0.1N hydrochloric acid). For the elution test, 5 g of the pellets prepared above were immersed in an Erlenmeyer flask containing 100 ml of a neutral or acidic solution, kept at 37°C using a shaking device, and after shaking for a specified period of time, the pellets were eluted into each solution. did
DL-methionine was measured by iodometry. The shaking time was 10 hours for the neutral solution and 3 hours for the acidic solution. The blending ratio of the present example and comparative example,
The heat treatment conditions and elution test results are shown in Table 1. Example 11 In the same manner as Examples 1 to 10, L-lysine hydrochloride,
Pellets containing hydrogenated oil at 54°C were prepared, and 100 parts of the pellets and 30 parts of calcium carbonate were placed in a rotary evaporator and heat-treated while rotating. The eluted L-lysine hydrochloride was measured by ninhydrin colorimetry. Table 2 shows the blending ratio, heat treatment conditions, and elution test results. Example 12 Nicotinic acid amide and 54°C hydrogenated oil were uniformly mixed in advance using a ribbon mixer at the ratio shown in Table 3, and then spherical particles with a diameter of 2 mm were produced using a spherical granulator. After putting 100 parts of spherical particles and 30 parts of diaminocellulose into a rotary evaporator, heat treatment was performed while rotating. The N content of the eluted nicotinic acid amide was measured by the Kjeldahl method. Table 3 shows the blending ratio, heat treatment conditions, and elution test results.

【table】

【table】

【table】

Claims (1)

[Claims] 1 At least A: a physiologically active substance, B: a substance that is stable under neutral conditions but disintegrates or elutes under acidic conditions with hydrochloric acid, C: a linear or branched saturated substance having 14 or more carbon atoms. or particles containing at least one substance selected from unsaturated monocarboxylic acids or salts thereof, animal fats and oils with a melting point of 40°C or higher, vegetable oils and fats with a melting point of 40°C or higher, or waxes with a melting point of 40°C or higher, prepared in advance. did at least A
A method for producing particles containing a physiologically active substance, characterized in that the surface of the particles containing and C is heat-treated at a temperature equal to or higher than the melting point of C in the presence of B.