JPS60258112A - Preparation of particle containing physiologically active substance - Google Patents

Abstract

PURPOSE:In preparing particles comprising a physiologically active substance, a substance that collapses under acidic conditions with hydrochloric acid, and a substance selected from a monocarboxylic acid, a specific animal or vegetable oil, and wax, to form a protecting film by heat-treating the particles at >= a specified temperature. CONSTITUTION:In preparing particles comprising (A) a physiologically active substance (e.g., nutrient, feed, or drug), (B) a substance (e.g., benzylaminomethyl cellulose, vinyldiethylamine vinyl acetate copolymer), and (C) a substance selected from a >=14C straight-chain or branched (un)saturated monocarboxylic acid, its salt, an animal and vegetable oil and wax having >=40 deg.C melting point, the surfaces of the particles containing at least components A and C are heat-treated in the presence of the component B at a temperature >= the melting point of the component C, to form a protecting film. These particles are not consumed in the first stomach of a ruminant, but decomposed and absorbed in the fourth or latter stomach.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) 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 condition in the rumen of ruminants, and the condition in the oral cavity and esophagus of monogastric animals.

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, for ruminants,
In particular, its usefulness has attracted attention in recent years. Ruminants have a neutral rumen, 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, physiologically active substances that we do not want to be degraded in the neutral rumen are allowed to pass through the rumen as they are.
The idea is to use physiologically active substances more efficiently by decomposing and absorbing them in the abomasum and beyond. The technology for producing particles in which physiologically active substances are stable under neutral conditions (rumen) and elute under acidic conditions (abomasum) is as follows:
This is a much-awaited technology for efficiently raising ruminants.

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 transporting the rumen of ruminants, but none of them can be said to be sufficiently effective. For example, Tokuko Sho 49-452
24 is characterized by dispersing amino acids or polypeptides in a mixed melt of fats and oils with a melting point of 40°C or higher and fats and oils with a melting point of 40°C or lower, and pouring this into water maintained between 20°C and 400°C. A method for manufacturing amino acid-containing fat and oil capsules has been submitted.

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, or Coated with a matrix consisting of a mixture of a saturated acid or a salt thereof and an unsaturated linear or branched substituted or unsubstituted aliphatic monocarboxylic acid having at least 14 carbon atoms or a salt thereof. It shows.

Furthermore, JP-A-56-154956 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. Further, in JP-A-58-175449, biologically active substances are classified as linear or branched saturated or unsaturated monocarboxylic acids having 14 to 22 carbon atoms, hydrogenated vegetable fats and hydrogenated animal fats. It shows how many months it has been covered with a protective substance coating containing one or more substances selected from fats and chitosan.

(Problems to be solved by the invention) However, Japanese Patent Publication No. 45224 of 1983,
In No. 1057, it is expected that the disintegration of the coating substance will occur after the small intestine, but because there are restrictions on the time allotted for digestion and absorption ``1'', sufficient digestion and absorption of the target material may not occur. It has no drawbacks.
No. 6-154956 and Japanese Patent Application Laid-open No. 175449/1987, in order to overcome the above-mentioned drawbacks, the method of disintegrating in the abomasum,
Although a coating material is used that elutes substances that are effective for living organisms, the disintegration of the coating material in the abomasum is insufficient (and its effect cannot be said to be stable).

The reality is that there is still no satisfactory method for making the physiologically active substances contained in this way stable in the rumen (under neutral conditions) and eluted in the abomasum (V-section) and beyond.

(Means for solving the problem) The present inventors have studied the prior art as described above, and have
As shown in the claims, at least each of A,
In particles containing substances represented by B and C, particles containing at least A and C prepared in advance are heated to the surface of the particles at a temperature higher than the melting point of one of the substances in the presence of B. The present inventors have discovered that a heat treatment method is an excellent method without the above-mentioned drawbacks, and have completed the present invention.

The present invention will be explained in more detail below.

The physiologically active substance (Al) referred to in the present invention may be, for example, in ruminants, nutrients, feed containing it, or even drugs, and is not consumed by microorganisms in the rumen (Al).
These are nutrients and drugs that should be effectively absorbed into the ruminant's body after the stomach, and in monogastric animals, they are required to be stomach-soluble.

Next, examples of substances belonging to Group B in the present invention that are stable under neutral conditions but have the property of disintegrating or eluting under conditions where the pH is 6 or less include cellulose derivatives such as benzylaminomethyl □cellulose, dimethylaminomethylcellulose, piperidylethylhydroxyethylcellulose, cellulose acetate diethylaminoacetate, cellulose acetate dibutylaminohydroxypropyl ether, etc., folyhinyl derivatives such as vinyljetylamine-vinyl acetate copolymer, vinylbenzylamine-vinyl acetate copolymer, polyvinyldiethylaminoacetoacetal, vinyl Piberidyl acetoacetal-vinyl acetate copolymer, polyvinyl acetal diethylaminoacetate, polydimethylaminoethyl methacrylate, polydiethylaminomethylstyrene, polyvinylethylpyridine, vinylethylpyridine styrene copolymer, vinylethylpyridine acrylonitrile copolymer, methylvinylpyridine acrylonitrile copolymer, methylvinyl Pyridine styrene copolymers, nitrogen-containing polysaccharides such as chitosan and chitin, 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 and hexacalcium phosphate. , dibasic calcium phosphate, tertiary magnesium phosphate, zinc phosphate, aluminum phosphate, calcium silicate, calcium pyrophosphate, magnesium carbonate, lead carbonate, cobalt carbonate, and the like.

Next, in the present invention, a linear or branched saturated or unsaturated monocarboxylic acid having 14 or more carbon atoms or a salt thereof, or an animal fat or oil with a melting point of 40°C or more, or an animal fat or oil with a melting point of 40°C
At least one substance selected from vegetable oils and fats with a melting point of 40°C or higher (the amount of q used is usually 10% by weight or more based on the total amount of finished particles. 10% by weight)
If the amount is less than that, problems tend to occur even in the stability of the physiologically active substance in neutral conditions, and sufficient effects cannot be obtained. Also, if used in an extremely large amount, the amount of active ingredients may be small (and the PH,
Even under conditions of 3 or less, there are problems with elution ((), and sufficient effects cannot be obtained.

Furthermore, in addition to the above-mentioned A, B, and C, one or more fourth components may be 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. As for the method for producing particles containing A, C or the fourth component, or the shape of the particles, any method or shape known in the art may be employed.

For example, methods for producing particles include the usual rolling granulation method, extrusion granulation method, compression granulation method, subtraction granulation method, crushing granulation method,
Examples include stirring granulation method.

Further, the shape of the particles includes a pellet shape, a spherical shape, a long spheroid shape, a tablet shape, and the like.

The present invention is completed by heat-treating the surface of particles containing A and C at a temperature higher than the melting point of C in the coexistence of B. Heat treatment in the present invention refers to , refers to exposing the particles, and is not limited to the heat treatment method.The heat treatment time is determined by the melting point of the C component and the heat treatment temperature, and although it cannot be generally specified, if the time is too short, the film may deteriorate. Since there is a risk that it will not be formed sufficiently, it is usually appropriate to wait for more than 1 minute. Also, the effect will hardly change even if it is left standing for a long time. Although some effect can be seen even if it is left standing and heat treated, it will be even more effective. In order to increase this, it is best to heat-treat the particles without causing them to flow or vibrate.

The particle method containing AC is
Any method in the art may be employed, and the strength is at least such that the particles containing AC are not broken.

The main component of B that is allowed to coexist is the shaft element 1 containing at least AC.
The amount is usually 5 parts by weight to 80 parts by weight, preferably 8 parts by weight to 70 parts by weight. If the amount of coexisting B is less than the above-mentioned lower limit, the coating will not be sufficient and the stability of the physiologically active substance under neutral conditions will suffer, making it impossible to obtain sufficient effects. Furthermore, if the amount exceeds the above upper limit, the amount of the active ingredient will decrease and problems will occur with the elution of the physiologically active substance under acidic conditions, making it impossible to obtain sufficient effects.

(Effects of the Invention) As described above, the method for producing particles containing a physiologically active substance of the present invention has the advantage that the physiologically active substance contained therein is more stable under neutral conditions than in the conventional method. It is an excellent method that can obtain particles that are more easily eluted under the following conditions, and it is also possible to increase economic efficiency by selecting B and C appropriately.Moreover, it is extremely useful industrially because the process is simple. It is.

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 1-10. Comparative Examples 1 and 2 DL-methionine, stearic acid, and polyacrylic acid) IJium (Example 4 only) were added to the ratio shown in Table 1,
After uniformly mixing in advance using a ribbon mixer, pellets with a diameter of 2 mm and a length of 3 U were produced using a pelletizer. After putting 100 parts of the obtained pellets and the amounts of tertiary calcium phosphate shown in Table 1 into a rotary evaporator, the rotary evaporator was heated under the conditions shown in Table 1 while rotating. The pellets prepared as described above were mixed with a neutral solution (0,1
M phosphoric acid solution) IJum buffer pH 7.0), acidic solution (
An elution test was conducted under (0,1,N hydrochloric acid). For the elution test, the pellets prepared above were immersed for 5f in an Erlenmeyer flask filled with a neutral or acidic solution for 50 minutes, kept at 37°C using a shaker, and shaken for a predetermined period of time, then immersed in each solution. DL-methionine eluted from the pellet was measured by iodometry. 5 hours with shaking, 10 hours with neutral solution,
The acidic solution was used for 3 hours. Table 1 shows the blending ratios, heat treatment conditions, and elution test results of this example and comparative examples.

Example 11 L-IJ resin acid salt, 54, in the same manner as Examples 1 to 10
℃Prepared pellets containing hydrogenated oil, pellets 100
and 30 parts of calcium carbonate were placed in a rotary evaporator and heated 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 Monocotinamide, 54°C hardened oil Ratio shown in Table 6
After uniformly mixing the mixture in advance using a ribbon mixer at a ratio of 0.05 to 1.00 m, spherical particles with a diameter of 2 rns 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 Kjerguhl method. Table 3 shows the blending ratio, heat treatment conditions, and elution test results.

Claims (1)

[Claims] A: Physiologically active substances, B: Substances that are stable under neutral conditions but disintegrate or elute under acidic conditions with hydrochloric acid, C: Straight-chain or branched substances with 14 or more carbon atoms Saturated or unsaturated monocarboxylic acid or salt thereof or melting point 40°C
In particles containing at least one substance selected from the above animal fats and oils, vegetable oils and fats with a melting point of 40°C or more, or waxes with a melting point of 40°C or more, the surface of the particles containing at least A and C prepared in advance is 1. A method for producing particles containing a physiologically active substance, which comprises heat-treating in the presence of B at a temperature equal to or higher than the melting point of C.