JP4466012B2 - Enteric preparation and production method thereof - Google Patents

Description

  The present invention relates to an enteric preparation. More specifically, the present invention relates to an enteric preparation that is enteric-coated on a physiologically active substance and does not dissolve in the stomach when taken orally, but dissolves in the intestinal tract and exhibits its effect, and a method for producing the same. Moreover, it is related with the use containing this enteric preparation.

  Useful living bacteria such as bifidobacteria and lactic acid bacteria have a beneficial effect on the host by suppressing the growth of bad bacteria in the intestine and improving the intestinal flora. In addition, the useful live bacteria have an intestinal action such as improvement of constipation and diarrhea. These useful live bacteria are food materials that are known as probiotics in recent years and are used for foods for specified health use. However, these useful live bacteria cannot fully exert their effects unless they ingest gastric acid, bile acids, etc. and reach the intestinal tract after ingestion. Therefore, in the past, inventions for acid-resistant and enteric coatings have been made to deliver bifidobacteria and lactic acid bacteria to the intestine alive and exert their effects.

  For example, Japanese Patent Application Laid-Open No. 5-186335 (Patent Document 1) proposes a method for producing an enteric granulated product of lactic acid bacteria using lactic acid bacteria and an excipient. In this method, dry lactic acid bacterial powder, excipients and zein are mixed, oil and fat melted at 40 ° C. are added to this mixture, stirred, extruded and granulated, then sprayed with zein solution to obtain an enteric preparation It is. However, in this method, although acid resistance and enteric properties can be imparted, the death of bacteria during the process of adding and extruding granulated oil and extruding granulation tends to be low, and the number of remaining bacteria after production tends to be low. . In addition, since the number of bacteria in the preparation is low, the value as an enteric preparation may be halved. Further, the extrusion granulation method has a large particle size and is not suitable as a molding powder for pellets and tablets.

  In addition, useful live bacteria such as lactic acid bacteria and bifidobacteria are often used as tablets or chewable health foods and confectionery. However, these useful live bacteria are weak against impact at the time of tableting, and there is a tendency that the survival rate of live bacteria becomes low when tableted.

Japanese Patent Laid-Open No. 5-186335 (page 3)

The present invention has been made under the above background.
The first object of the present invention is to provide an enteric preparation which is enteric-coated on a physiologically active substance and does not dissolve in the stomach when ingested orally but dissolves in the intestinal tract and exhibits physiological effects. is there.
Furthermore, the second object of the present invention is to provide a molded product in which the activity and the like remain particularly when the molded product is produced under pressure when used for a tablet or the like using the enteric preparation.

As a result of intensive studies on the above problems, the present inventors have found that an enteric preparation obtained by a specific method can solve the above problems, and have completed the present invention. The present invention includes the following [1] to [9].
[1] An enteric preparation produced by performing the following steps I, II and III.
Step I: The core (A) is coated with an oil (B) layer having a melting point of 40 ° C. or higher.
Step II: The oil-and-fat coating material and an excipient (C) containing carbonate and cellulose are blended, and a hydrous alcohol solution containing zein (D) is brought into contact and granulated.
Step III: Further, the granulated product is coated with an oil (E) layer having a melting point of 40 ° C. or higher.

  [2] The enteric preparation according to [1] above, wherein the core material of (A) is a useful bacterial powder, protein, peptide, amino acid, sugar, or glycolipid.

  [3] The coating method of the fat (B) layer in Step I is a method of forming a film by bringing the fine powder of fat (B) prepared to an average particle size of 20 μm or less into contact with and colliding with the core material (A). Enteric preparation according to [1] above.

[4] In the coating layer treated in Step II, the weight ratio of the zein (D) to the excipient (C) containing carbonate and cellulose is (1/4) to (1/1). Enteric preparation according to 1].

  [5] In step III, the method for coating the fat (D) layer is a method in which fine particles of fat and oil prepared to an average particle size of 20 μm or less are brought into contact with and collided with the coated particles to form a film, or in a molten state The enteric preparation according to [1] above, wherein the oil or fat is sprayed or dripped onto the coated particles and cooled to form a film.

[6] The weight ratio (core material weight / fat fat weight) of the core material (A) and the fat (B) is (30/70) to (70/30), and the primary coated particles, carbonate and cellulose are The weight ratio of the zein (D) layer containing the excipient (C) to be contained is (30/70) to (70/30), and the secondary coated particles obtained in Step II and the fats and oils of (E) The enteric preparation according to the above [1], wherein the weight ratio is (40/60) to (90/10).

  [7] The enteric preparation according to [1], wherein the preparation has an average particle size of 0.5 mm or less.

[8] A method for producing an enteric preparation comprising the following steps I, II and III.
Step I: The core (A) is coated with an oil (B) layer having a melting point of 40 ° C. or higher.
Step II: The oil-and-fat coating material and an excipient (C) containing carbonate and cellulose are blended, and a hydrous alcohol solution containing zein (D) is brought into contact and granulated.
Step III: Further, the granulated product is coated with an oil (E) layer having a melting point of 40 ° C. or higher.

[9] A compression-molded product obtained by compression-molding the enteric preparation according to any one of [1] to [ 7 ].

Since the enteric preparation of the present invention is coated with oils, fats, excipients, alcohol-soluble proteins, etc., it does not soak and dissolve under acidity and has enteric properties.
Moreover, since the enteric preparation of the present invention is coated with the above-described components, it is possible to suppress a decrease in the activity of the core material even during compression when it is molded into a tablet or the like. Therefore, the enteric preparation of the present invention can be used for molded articles such as pellets and tablets and is useful.

Hereinafter, the present invention will be described in detail.
The enteric preparation of the present invention is produced by performing the following steps I, II and III.
Step I: The core (A) is coated with an oil (B) layer having a melting point of 40 ° C. or higher.
Step II: The oil-and-fat coating substance and the excipient (C) are blended and a hydrous alcohol solution containing a hydrous alcohol-soluble protein (D) is brought into contact and granulated.
Step III; Further, the granulated product is coated with an oil (E) layer having a melting point of 40 ° C. or higher. Here, the core material of (A) includes useful live bacteria powder, protein, peptide, sugar, glycolipid and the like. .
Examples of the useful bacterial powder include useful bacterial powders such as bifidobacteria, lactic acid bacteria, yeast, natto bacteria, and acetic acid bacteria.
As said protein, the protein which has physiological activity is preferable, For example, enzymes, such as nattokinase and actinidine, immunoglobulin, an antibody, lactoferrin, collagen etc. are mentioned.
Examples of the peptide include blood pressure lowering peptide, casein phosphopeptide, opioid peptide, immunostimulatory peptide, cell growth promoting peptide, lactoferricin and the like.
Examples of the amino acid include essential amino acids such as tryptophan, methionine, lysine, phenylalanine, leucine, isoleucine, valine, threonine, and histidine.
Examples of the sugar include, for example, xylooligosaccharide, soybean oligosaccharide, galactooligosaccharide, fructooligosaccharide, dairy oligosaccharide, chitosan oligosaccharide, isomaltoligosaccharide, agarooligosaccharide, lactulose and other oligosaccharides; glucosamine, sialic acid and other amino acids Sugar: Polysaccharides such as glycogen, chitin, chitosan, fucoidan, chondroitin sulfate and the like.
Examples of the glycolipid include ceramide, ganglioside, sphingomyelin, sphingosine, cerebroside sulfate, cerebroside ester, sphingoplasmagen, ceramide dioxide, and the like.
Among these, useful live bacterial powders such as bifidobacteria, lactic acid bacteria, and yeast are preferable, and bifidobacteria are more preferable. Bifidobacteria produce lactic acid and acetic acid in the intestinal tract and lower the pH, thereby suppressing the growth of bad bacteria and exerting beneficial effects on the host. However, since these microorganisms have low resistance to gastric acid, bile acids and the like, they will die or become less active unless enteric coating is applied. Therefore, the utility value of enteric preparations is high against these microorganisms. These microorganisms are preferably lyophilized cell powder or vacuum spray-dried cell powder. These physiologically active substances may be used alone or in combination of two or more.

Examples of the fats and oils having a melting point of 40 ° C. or higher in (B) include naturally obtained animal and vegetable oils as raw materials. Specifically, for example, animal fats and oils such as beef tallow, pork tallow and fish oil, soybean oil, rapeseed oil, cottonseed oil, palm Examples include vegetable oils such as oil. Furthermore, these mixed oils, refined oils, fractionated oils, hydrogenated oils, transesterified oils, etc. include fats and oils having a melting point of 40 ° C. or higher. Preferably, extremely hardened vegetable oil, for example, soybean hardened oil, rapeseed hardened oil, palm hardened oil, is mentioned.
Here, the blending ratio of the core material (A) and the fat (B) is (30/70) to (70/30), preferably the weight ratio of the core material (A) / (B). Is (40/60) to (60/40). When the amount of oil / fat is greater than (30/70) in the weight ratio of the core / fat of (A) / (B), the amount of free oil / fat unrelated to the coating increases and the core material concentration is lowered. It is not preferable. Moreover, when the amount of fats and oils is smaller than (70/30), the coating of the core substance is insufficient, which is not preferable.
In the coating step using these fats and oils in Step I, the melted fats and oils are sprayed or dripped onto the core material and cooled to form a film, or fine powder of the ground fat and fat and the core material are mixed at high speed. There is a method of stirring and mixing, coordinating the fine oil and fat powder on the surface of the core material, and further stirring and mixing to form a film. In the coating step using the molten fats and oils, the coating method using fine powders of fats and oils is more preferable because there is a high possibility of killing useful live bacteria and denaturation of proteins due to heat during production. Moreover, it is preferable to use an oil and fat fine powder having an average particle diameter of 20 μm or less because an excellent coating is possible.
Here, the particle | grains which coat | covered the core substance with fats and oils may be called primary covering particle | grains. The above fats and oils may be used alone or in combination of two or more.

In Step II, the excipient (C) used includes dietary fiber, inorganic salts and the like.
Examples of the dietary fiber include poorly water-soluble dietary fibers such as cellulose, hemicellulose, lignin, agar, chitin, and collagen, and water-soluble dietary fibers such as pectin, guar gum, glucomannan, sodium alginate, and dextrin. In view of using hydrous alcohol in the process, poorly water-soluble dietary fiber is preferable. In addition, dietary fiber has a function of improving the enteric coating ability by forming a dense matrix by intricately intertwining with hydrous alcohol-soluble protein. Among these, cellulose is preferable from the viewpoint of easy handling such as fluidity. Here, examples of the cellulose include microfibrous cellulose, seaweed cellulose, crystalline cellulose, powdered cellulose, and linter cellulose. Among them, crystalline cellulose is known to have an intestinal action such as improvement of constipation and is more preferable for use in an enteric preparation. The amount of dietary fiber is usually 10 to 30% by weight. When the amount of dietary fiber is less than 10% by weight, the enteric coating ability decreases, and when the amount of dietary fiber is more than 30% by weight, other substances such as inorganic salts and oils are necessary and sufficient. Since it becomes impossible to mix | blend and enteric-coating ability will fall, it is unpreferable.
The dietary fiber may be used alone or in combination of two or more.

Examples of the inorganic salt include carbonate, sodium hydroxide salt, ammonium salt and the like. The carbonate has a function of neutralizing the stomach acid immersed in the preparation when the preparation is ingested, and a carbonate that generates carbon dioxide gas by reacting with the stomach acid can be used. Gastric acid that has been soaked in the preparation is neutralized with carbonate, the bioactive substance is further affected by the acid, and the generated carbon dioxide gas penetrates into the preparation by blocking the micropores present in the preparation. It will be impossible. Specific examples of the carbonate include calcium carbonate, magnesium carbonate, potassium carbonate, and sodium bicarbonate. In particular, calcium carbonate is more preferable because it is approved as a food additive and can be derived from natural products such as eggshell, coral, and shellfish. The compounding amount of the inorganic salt is usually 10 to 30% by weight. When the amount of the inorganic salt is less than 10% by weight, gastric acid is not sufficiently neutralized, which is not preferable. Moreover, when there are more compounding quantities of inorganic salt than 30 weight%, since other things, such as dietary fiber and fats and oils, cannot mix | blend necessary and sufficient amount, enteric film ability will fall, and it is unpreferable.
The inorganic salts may be used alone or in combination of two or more.
A combination of shell calcium calcium carbonate and crystalline cellulose is preferable.

  Examples of the hydrous alcohol-soluble protein (D) include proteins derived from cereals such as corn, wheat, rice and soybean, shellac derived from lacquer. Of these, corn-derived zein is more preferable from the viewpoint of the highest acid resistance. The hydrous alcohol to be solubilized here is a mixed solvent of water-ethanol, and the compounding ratio is a ratio of water / ethanol, and the protein is usually in the range of (40/60) to (10/90). Solubilize. Here, the blending ratio of the primary coated particles ((A) core material and (B) oil and fat) ((C) excipient and hydrous alcohol-soluble protein is {primary coated particles / ( The weight ratio of excipient + hydrous alcohol-soluble protein} is (30/70) to (70/30), preferably (40/60) to (60/40). When the amount of (excipient + hydrous alcohol-soluble protein) is larger than (30/70) in the weight ratio of particles / (excipient + hydrous alcohol-soluble protein)}, the particle size of the preparation is in the coating process. In addition, the weight ratio of {primary coated particles / (excipient + hydrous alcohol-soluble protein)} is more than (70/30) (excipient + hydrous alcohol-soluble protein). If the amount is small, cover the core It is insufficient undesirable.

In Step II, the fat-and-oil coating substance and the excipient (C) are blended, and a hydrous alcohol solution containing a hydrous alcohol-soluble protein (D) derived from grains is brought into contact and granulated. In this case, for example, an excipient may be added mechanically continuously to a granulator or the like that has produced an oil-and-fat coating material, and the alcohol-soluble protein dissolved in the hydrous alcohol may be sprayed. An excipient may be added and blended in advance in a granulator or the like that has produced the substance, and then the alcohol-soluble protein dissolved in the hydrous alcohol may be sprayed.
The particles obtained by the treatment in Step II may be referred to as secondary coated particles.

Here, the oil and fat (E) having a melting point of 40 ° C. or higher used in the step III can be the same as described in the above (B). In addition, the method for coating the fats and oils is to coat and granulate the core material coated with fats and oils with an excipient and a hydrous alcohol-soluble protein, and spray or drop the molten fats and oils on the treated particles to cool them. Or a method in which fine powder of fat and oil and the above-mentioned treated particles are stirred and mixed at high speed, the fine powder of fat and oil is coordinated on the particle surface, and stirring and mixing are continued to form a film. . In the coating step using the molten fat and oil, there is a high possibility that the bacteria will be killed or the protein is denatured by heat at the time of production. Therefore, a coating method using a fine powder of fat and oil is more preferable. Moreover, it is preferable to use an oil and fat fine powder having an average particle diameter of 20 μm or less because an excellent coating is possible. In this production, other components may be blended as necessary.
Here, in the enteric preparation of the present invention, the weight ratio between the secondary coated particles and the fat (E) is (40/60) to (90/10), preferably (50/50) to (80 / 20). When the amount of oil / fat is greater than (40/60) in the weight ratio of the core / fat of (A) / (B), the amount of free oil / fat unrelated to the coating increases and the core material concentration is lowered. It is not preferable. Moreover, when the amount of fats and oils is smaller than (90/10), the coating of the core substance is insufficient, which is not preferable.

  The enteric preparations produced by the processes and methods described above have particles that are coated with oils, fats, excipients, and proteins, and are approximately 200-500 μm in granular form. .

The enteric preparations of the above [1] to [8] can be compressed and molded into a compression-molded product by containing it as it is. Moreover, in that case, you may mix | blend another component as needed in the range which does not impair the effect of this invention. Furthermore, as what is mix | blended when shape | molding, a coloring agent, a flavoring agent, vitamins, a trace metal component, a fragrance | flavor, etc. are mentioned, for example. In the case of producing a compression-molded body using the present preparation, an appropriate amount of the present preparation, excipient, lubricant and the like can be selected and compression-molded using an ordinary compression-molding machine.
As the excipient, for example, starch derived from lactose, dextrin, crystalline cellulose, potato, corn, rice, etc .; reducing sugars such as starch, maltitol, lactitol, xylitol, erythritol; sugars such as fructose, sucrose, and glucose; Gum quality such as gum arabic, xanthan gum, guar gum, gellan gum, locust bean gum; proteins such as sodium caseinate, skim milk powder, milk protein, whey protein; xylooligosaccharide, soybean oligosaccharide, galactooligosaccharide, fructooligosaccharide, dairy oligosaccharide Examples thereof include oligosaccharides such as sugar, chitosan oligosaccharide, isomaltoligosaccharide, agarooligosaccharide, and lactulose.
Among them, lactose, dextrin, crystalline cellulose and the like are preferable.
The above excipients can be used alone or in combination of two or more.
Further, as the lubricant, those which can be usually used can be used, for example, polyglycerin fatty acid ester, sorbitan fatty acid ester, sucrose fatty acid ester, lecithin, enzymatically decomposed lecithin, fatty acid glyceride, polyoxyethylene sorbitan fatty acid ester, fatty acid calcium. Salt, fatty acid magnesium salt, hydrogenated oil, wax and the like can be mentioned.
Among them, sucrose fatty acid ester is preferable.
The above lubricants can be used alone or in combination of two or more.

The enteric preparation of the present invention is prepared by mixing the above excipients, lubricants and the like in powder form, using a model; rotary tablet press collect 12HU (manufactured by Kikusui Seisakusho Co., Ltd.), etc. Tablets can be molded under tableting conditions of 5 t / cm ³ , tablet weight; about 0.1 to 1 g.

Hereinafter, the present invention will be described in more detail using specific examples.
Moreover, the measuring method used and the evaluation method used are shown below.
1. <Measuring method of particle size>;
The particle size of the preparation was measured using a laser diffraction particle size distribution analyzer SALD-2100 (Shimadzu Corporation).
2. <Bifidobacterium viable count method>
Bifidobacteria were extracted by adding 100 mg of the preparation to 100 ml of the sample diluent and homogenizing. 1 ml of this solution was added to 9 ml of the diluted solution and homogenized (diluted 10 times). This operation was repeated an appropriate number of times according to the number of viable bacteria in the sample, and 10-fold serial dilution was performed. 1 ml of this diluted solution was mixed with 20 ml of BL agar medium (Nissui Pharmaceutical Co., Ltd.), and anaerobic culture (37 ° C., 48 to 72 hours) was performed. After completion of the culture, the viable count of bifidobacteria per gram of the preparation was calculated from the number of colonies of bifidobacteria grown on the medium. For example, when 100 mg of the preparation was tested and 120 Bifidobacteria colonies appeared at a dilution of 10 ⁻⁷ , the number of Bifidobacteria per 1 g of the sample was
120 × 10 (converted to 1 g) × 10 ⁷ (reciprocal of dilution rate) = 1.2 × 10 ¹⁰
It becomes. In addition, a table with a residual rate of 90% or more is shown as ◎, a sample with 80 to 90% is shown as ○, a sample with 50 to 80% is shown as Δ, and a sample with 50% or less is shown as ×.
3. <Acid resistance evaluation test method>;
100 mg of the preparation was added to 100 ml of an aqueous hydrochloric acid solution having a pH of 3.0, and the mixture was stirred in an incubator at 37 ° C., 300 rpm for 1 hour. Next, the viable count of bifidobacteria was measured by the method of 2. Further, the acid resistance of bifidobacteria was evaluated by the survival rate calculated by the following formula.
Survival rate (%) = (Bifidobacterium count after acid resistance test) / (Bifidobacterium count before test) × 100
The results of the acid resistance test are shown in the table as ◎ for those with a survival rate of 20% or more, ◯ for 15-20%, Δ for 10-15%, and x for 10% or less.
4). <Tabletability evaluation test method>;
Tablets containing 100 mg of the preparation were mixed with the following composition and tableted.
(Composition composition) Weight part Enteric preparation of the present invention 10 parts Lactose granulated product 68 parts Starch 10 parts Crystalline cellulose 10 parts
Sucrose fatty acid ester 2 parts
100 parts in total (tabletting conditions)
Model: Rotary tablet press collect 12HU (manufactured by Kikusui Seisakusho)
Tableting pressure: 3t / cm ³
The size of the bowl; diameter 15mmφ
Tablet weight; 1g
100 tablets were molded under the above tableting conditions, and their continuous tableting properties and tableting failures (capping, laminating, binding, sticking) for 10 tablets were evaluated.
Capping; Phenomenon in which the convex part of the tablet is peeled off in a cap shape Lamination; Phenomenon in which the tablet breaks into a layer; Binding; Phenomenon in which clouding occurs on the surface of a tablet that adheres, the continuous tableting property is good, and there are no tableting obstacles.
5). <Pressure resistance evaluation test method>;
The pressure resistance of bifidobacteria was evaluated by the following formula.
Survival rate (%) = {(number of bifidobacteria after tableting) / (number of bifidobacteria before tableting)} × 100
The results of the pressure resistance test are shown in the table as ◎ for those with a residual ratio of 90% or more, ◯ for 80 to 90%, Δ for 50 to 80%, and x for 50% or less.

(Invention Example 1)
500g of freeze-dried powder of bifidobacteria as a core material and 500g of soybean hardened oil (average particle size 10µm, melting point 67.8 ° C, manufactured by Nippon Oils & Fats Co., Ltd.) as fats and oils The mixture was mixed for 40 minutes at a stirring blade rotation speed of 1000 rpm and a granulation blade rotation speed of 3000 rpm, and contacted and collided to obtain primary coated particles. Next, 20 parts of Zein (manufactured by Showa Sangyo Co., Ltd.) was dissolved in 80 parts of hydrous ethanol (70 parts of ethanol, 30 parts of water) to prepare a spray solution. 200 g of primary coated particles, 100 g of shell calcium (manufactured by Kawai Co., Ltd.), 100 g of crystalline cellulose (manufactured by Asahi Kasei Co., Ltd.), and a rolling fluidized bed granulator (manufactured by Paulek Co., Ltd.) are sprayed with 500 g of the above zein solution. Subsequent coated particles were obtained. Next, 500 g of the secondary coated particles and 500 g of hydrogenated soybean oil (average particle size: 10 μm, melting point: 67.8 ° C., manufactured by Nippon Oil & Fats Co., Ltd.) as a fat / oil are mixed and dispersed granulator (manufactured by Nara Machinery Co., Ltd.). The mixture was mixed for 40 minutes at a stirring blade rotation speed of 1000 rpm and a granulation blade rotation speed of 3000 rpm, and contacted and collided to obtain an enteric preparation.
The residual ratio with respect to the blended value of bifidobacteria after the production of the preparation was calculated by the following formula.
Bifidobacteria survival rate after production (%)
= {(Number of bifidobacteria after production) / (number of mixed bifidobacteria)} × 100
The results are shown in Table 1. In Table 1, the composition is shown in wt%.

(Invention Examples 2-6, Comparative Examples 1-8)
A preparation was obtained in the same manner as in Example 1 except that the formulation was changed as shown in Tables 1 and 2.
Tables 1 and 2 show the results of the residual ratio with respect to the blended value of bifidobacteria after the preparation production.

(Invention Examples 7-12, Comparative Examples 9-11)
As shown in Tables 3 and 4, compression moldings were obtained using the enteric preparations of the inventive examples and the preparations of the comparative examples, excipients and lubricants. According to the above test methods, the tableting property evaluation test method and the pressure resistance evaluation test method were evaluated. The results are shown in Table 3 and Table 4.

From the above results, it can be seen that Invention Examples 1 to 6 have higher acid resistance than Comparative Examples 1 to 8, and high pressure resistance during tableting. Furthermore, it turns out that invention examples 7-12 are excellent in tableting property and the pressure | voltage resistance at the time of tableting compared with comparative examples 9-11.
In addition, when tablets of 100 mg of the preparation obtained in Invention Example 1 were orally ingested by 10 test subjects at 1 tablet / day for 1 month, they could be ingested without any problems.

Claims (9)

An enteric preparation produced by performing the following steps I, II and III.
Step I: The core (A) is coated with an oil (B) layer having a melting point of 40 ° C. or higher.
Step II: The oil-and-fat coating material and an excipient (C) containing carbonate and cellulose are blended, and a hydrous alcohol solution containing zein (D) is brought into contact and granulated.
Step III: Further, the granulated product is coated with an oil (E) layer having a melting point of 40 ° C. or higher. 2. The enteric preparation according to claim 1, wherein the core material of (A) is useful live bacterial powder, physiologically active protein, peptide, amino acid, sugar, glycolipid. 2. The method for coating the oil (B) layer in Step I is a method for forming a film by contacting and colliding fine powder of oil (B) prepared to an average particle size of 20 μm or less with the core (A). Enteric preparations according to 1. The intestine according to claim 1, wherein the coating layer treated in Step II has a weight ratio of (1/4) to (1/1) of the excipient (C) containing zein (D) , carbonate and cellulose. Soluble preparation. In step III, the method for coating the fat (E) layer is a method of coating the coated particles with fine powder of fats and oils prepared with an average particle size of 20 μm or less to make a coating, or coating the fats and oils in a molten state with coated particles The enteric preparation according to claim 1, which is a method of forming a film by spraying or dripping on a gel and cooling. The weight ratio of the core material (A) to the fat (B) (core weight / fat weight) is (30/70) to (70/30), and includes primary coating particles, carbonate and cellulose. The weight ratio of the zein (D) layer containing the agent (C) is (30/70) to (70/30), and the weight ratio of the secondary coated particles obtained in Step II to the fats and oils of (E) The enteric preparation according to claim 1, wherein is (40/60) to (90/10). The enteric preparation according to claim 1, wherein the preparation has an average particle size of 0.5 mm or less. The manufacturing method of the enteric preparation which performs the following process I, II, and III.
Step I: The core (A) is coated with an oil (B) layer having a melting point of 40 ° C. or higher.
Step II: The oil-and-fat coating material and an excipient (C) containing carbonate and cellulose are blended, and a hydrous alcohol solution containing zein (D) is brought into contact and granulated.
Step III: Further, the granulated product is coated with an oil (E) layer having a melting point of 40 ° C. or higher. Compression-molded body formed by compression molding by containing an enteric preparation according In any one of claims 1-7.