JP2859217B2 - Method for producing granules containing useful intestinal bacteria - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing useful enteric bacteria-containing granules capable of maintaining a high activity stably during production and storage and further maintaining a high activity even when administered orally.

[0002]

2. Description of the Related Art Useful intestinal bacteria such as bifidobacteria and lactobacilli promote intestinal peristalsis, produce certain vitamins, and suppress the growth of harmful bacteria such as Escherichia coli, Welsh and Bacteroides. It is known that
In humans, the useful bacteria in the intestinal flora decrease as adults grow up. Therefore, in order to grow useful bacteria in the intestine, it has been attempted to orally administer a solid preparation of useful intestinal bacteria.However, according to the usual administration method, more useful intestinal bacteria are killed by gastric juice and reach the intestine. Do not reach. It is also known that useful intestinal bacteria are killed if water is present during the production of a solid preparation of useful enteric bacteria. In order to solve these problems, for example, a preparation obtained by granulating the powder of useful intestinal bacteria with shellac as a binder (Japanese Patent Application Laid-Open No.
No. 66124), and a preparation coated with an enteric substrate such as carboxymethylcellulose or shellac according to the present applicant's application and coated with the powder surface of useful enteric bacteria (Japanese Unexamined Patent Publication No.
No. 273823) has been proposed.

[0003]

However, when shellac is simply used as a binder for the powder of useful enteric bacteria as described in Japanese Patent Application Laid-Open No. 66124/1988, the shellac will form a surface of the useful enteric bacteria. The problem that many intestinal useful bacteria are killed in the stomach during oral administration due to lack of coating has not been solved. Further, it has been found that when a solid preparation of useful enteric bacteria is produced or stored under conditions of high humidity of 45% or more, the activity of useful enteric bacteria is significantly reduced. Japanese Unexamined Patent Publication No. Hei 4-273823) is effective in that useful intestinal bacteria are not killed during the long-term storage of a solid preparation of intestinal useful bacteria without causing a portion of the intestinal useful bacteria to reach the intestine. However, even under adverse conditions such as high humidity of 45% or more, it has been required to obtain a preparation having higher stability during production and storage.

[0004]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to solve the above-mentioned problems. As a result, when producing granules containing useful enteric bacteria, an ethanol solution containing shellac at a concentration of 50% or more ( Hereinafter, a mixed solution of 50% or more shellac-ethanol solution and propylene glycol and / or macrogol, or a mixed solution of 50% or more shellac-ethanol solution and liquid paraffin is mixed with a binder and / or Alternatively, by using it as a coating agent after granulation, the activity of useful enteric bacteria is stably maintained during production and storage, and further, useful enteric bacterial granules that maintain high activity even when administered orally are obtained. It was found that the present invention was completed.

[0005] The useful enteric bacteria which can be used in the present invention include Bifidobacterium longum ( Bifidobacterium longum).
longum ), Bifidobacterium infantes ( Bif
idobacterium infantis ), Bifidobacterium breve , Bifidobacterium thermophilum , Bifidobacterium pseudolongum ( Bifidobacteri
um pseudolongum), Bifidobacterium Adoressentesu (Bifidobacterium adolescentis) bifidobacteria like; Lactobacillus acidophilus (Lactobacillu
s acidophilus ), Lactobacillus lactis ( Lacto)
bacillus lactis), Lactobacillus casei (Lactoba
cillus casei ), Lactobacillus salivarius ( Lacto
Lactobacillus such as Bacillus bacillus salivarius ) and Lactobacillus bulgaricus ; or Enterococcus faecali
s ), Enterococcus fae
cium ) and the like. These useful enteric bacteria may be used alone or in combination of two or more.

[0006] These useful enteric bacteria may be used in the form of viable bacteria, but are preferably used in the form of dried bacterial powder.
The dried bacterial powder may be prepared by any method as long as the method does not reduce the activity of the bacteria, and the powder is prepared by supporting the bacteria on skim milk powder, starch, etc. Bacterial powder is used. A freeze-dried bacterial powder is preferably used.

[0007] In the method of the present invention, when producing granules containing useful enteric bacteria, a mixture of 50% or more shellac-ethanol solution and propylene glycol and / or macrogol, or 50% or more shellac-ethanol solution is used. A liquid mixture of liquid paraffin is used as a binder during granulation and / or as a coating after granulation.

More specifically, the present invention relates to a method for producing granules containing useful enteric bacteria, which is characterized by using propylene glycol and / or macrogol 30 to 1 to 70 to 99 parts by volume of a shellac-ethanol solution of 50% or more. A mixed solution of 55 parts by volume of a 50% or more shellac-ethanol solution and 45 to 35 parts by volume of liquid paraffin is used as a binder during granulation and / or a coating agent after granulation. .

In the present invention, the shellac concentration of an ethanol solution containing shellac (hereinafter referred to as "shellac-ethanol solution") must be 50% or more from the beginning, and a binder and / or a coating agent are required. And has no relation to the relative concentration of shellac in the mixture. This means that, for example, a shellac concentration of 45%
Shellac-ethanol solution and a mixture of 85 parts by volume of propylene glycol and 15 parts by volume of propylene glycol (the concentration of shellac in the mixture is 38.25%) as compared with that using a coating agent. Is 50%
Using a mixture consisting of 75 parts by volume of shellac-ethanol solution and 25 parts by volume of propylene glycol or the like (the concentration of shellac in the mixture is 37.5%) is better than that in the granules containing useful enteric bacteria. The number of bacteria is large,
It is clear from the result that the stability of the preparation at the time of production is significantly improved (see Example 2 and Comparative Example 4).

As a solvent for dissolving shellac, anhydrous ethanol is preferable.
~ 60% is preferred. Propylene glycol and / or macrogol mixed in a 50% or more shellac-ethanol solution or liquid paraffin mixed in a 50% or more shellac-ethanol solution is not replaced with another alcohol or the like. 50%
Only the combination of the above-mentioned shellac-ethanol solution with propylene glycol and / or macrogol and the combination of 50% or more of the shellac-ethanol solution with liquid paraffin have an effect. The propylene glycol and / or macrogol or liquid paraffin mixed here also has a function of reducing the viscosity of the high-concentration shellac-ethanol solution and preventing clogging of the nozzle.

The macrogol is preferably a liquid at room temperature or a semisolid that becomes liquid when heated to 50 to 70 ° C., for example, macrogol 200, macrogol 300, macrogol 400, macrogol 10
00, Macrogol 1500, Macrogol 1540 and the like are preferably used.

Liquid paraffin is a mixture of liquid hydrocarbons obtained from petroleum, having a specific gravity of 0.860 to 0.890,
In addition to those listed as liquid paraffin in the Japanese Pharmacopoeia with a viscosity of 37 centistokes or more (37.8 ° C), it is a mixture of liquid hydrocarbons obtained from petroleum and has a specific gravity of 0.83.
0-0.870, viscosity less than 37 centistokes (37.
8 ° C) as those listed as light liquid paraffin in the Japanese Pharmacopoeia.

In the method of the present invention, a 50% or more shellac-ethanol solution and propylene glycol and / or
Or, as a quantitative ratio with macrogol, for 70 to 99 parts by volume of a 50% or more shellac-ethanol solution,
Propylene glycol and / or Macrogol 30
~ 1 volume part is preferred. Thus, for 80 to 90 parts by volume of a 50% or more shellac-ethanol solution, 20 to 10 parts by volume of propylene glycol and / or macrogol are more preferable.

In the method of the present invention, the amount ratio of a 50% or more shellac-ethanol solution to liquid paraffin is 50% or more of a shellac-ethanol solution 55.
Liquid paraffin of 45 to 35 parts by volume is preferable for -65 parts by volume. Thus, for 58 to 60 parts by volume of a 50% or more shellac-ethanol solution, liquid paraffin 4
2 to 40 parts by volume are more preferred.

Further, lanolin and / or glycerin monofatty acid ester can be further added to the above-mentioned mixed solution, and the amount of the lanolin and / or glycerin mono-fatty acid ester can be added in a mixed solution of 50% or more of a shellac-ethanol solution and propylene glycol and / or macrogol. Alternatively, 1 to 20 lanolin and / or glycerin monofatty acid ester is contained in a mixture of 50% or more shellac-ethanol solution and liquid paraffin.
It is preferable that the amount is contained by volume%, but the amount is more preferably 5 to 15%.

A 50% or more shellac-ethanol solution and a mixture of propylene glycol and / or macrogol or a 50% or more shellac-ethanol solution and a liquid paraffin mixture serve as a binder or a coating agent. The material to be used may be used in the granule production process, or may be used in the granule production process as a material that plays both roles of a binder and a coating agent, but is more preferably used as a material that plays both roles.

In producing the granules containing useful enteric bacteria, a granulation method using the mixture as a binder and / or
Alternatively, the method of coating the granules with the mixture may be any conventionally known method as long as it does not reduce the activity of useful enteric bacteria.

As the granulation method, it is necessary to select a method in which pressure and heat are not excessively applied to useful intestinal bacteria. Fluid bed granulation using a fluid bed granulator; screw extrusion granulator; Extrusion granulation using a basket type granulator or the like;
A rolling granulation method using a centrifugal rolling granulator or the like is preferable,
A mixture of 50% or more shellac-ethanol solution and propylene glycol and / or macrogol as a binder between useful enteric bacteria and a core substance or excipient when granulating by these methods, or 50% % Of shellac-ethanol solution and liquid paraffin. If necessary, other conventionally known additives such as a disintegrant, a lubricant, a coloring agent, a flavoring agent, and the like can be added to the granules.

Examples of the apparatus used in the coating method include a coating pan, a fluidized bed coating apparatus, a centrifugal fluidized coating apparatus, and a stirring granulator (high-speed mixer). The coating agent is 50% or more shellac.
A mixed solution of an ethanol solution and propylene glycol and / or macrogol, or a mixed solution of 50% or more shellac-ethanol solution and liquid paraffin is used.

Further, the granulation and the coating may be performed simultaneously if necessary. As a method to perform simultaneously, for example,
Lactose or the like is introduced as a core substance into a centrifugal fluidized coating apparatus, and a mixture of a 50% or more shellac-ethanol solution and propylene glycol and / or macrogol, or a 50% or more shellac-ethanol solution and liquid paraffin is added thereto. While spraying the mixture, granulate while adding useful intestinal bacterial powder and other additives such as sodium bicarbonate and cornstarch as necessary, and granulate 50%
A mixture of the above shellac-ethanol solution and propylene glycol and / or macrogol, or 50
% Of a mixture of shellac-ethanol solution and liquid paraffin. If the granules are dried with a fluid bed dryer or the like, the desired granules containing useful enteric bacteria can be obtained.

The amount of a mixture of at least 50% shellac-ethanol solution and propylene glycol and / or macrogol or a mixture of 50% or more shellac-ethanol solution and liquid paraffin used as a binder and / or coating agent is as follows: It is necessary that the amount be sufficient to produce granules as a binder and sufficient to coat the surface of useful intestinal bacteria, and the total amount of the mixture used is intestinal Useful bacterial weight (when dry)
It is preferably 50 to 500%, more preferably 100 to 500%.
More preferably, it is about 350%.

The granules obtained according to the present invention may further comprise tablets,
It can be a capsule or the like.

[0023]

According to the method for producing granules containing useful enteric bacteria of the present invention, the viable cell count of useful enteric bacteria is maintained at a high level, and granules having good shape retention can be obtained. Furthermore, useful enteric bacteria-containing granules having a high viable cell count maintained during storage and oral administration can be obtained. In particular, it is possible to obtain useful enteric bacteria-containing granules having a high viable cell count even under adverse conditions such as high humidity of 45% or more, which is considered to significantly reduce the activity of useful enteric bacteria. .

[0024]

EXAMPLES The present invention will be described below with reference to examples, but the examples do not limit the present invention.

Example 1 1000 g of lactose was put into a centrifugal fluidized coating machine CF-360 (manufactured by Freund Corporation) under the condition of a humidity of 68%, then 10 parts by volume of propylene glycol, 5 parts by volume of lanolin and shellac. Is sprayed with 250 g of a mixture obtained by mixing 85 parts by volume of a shellac-ethanol solution having a concentration of 50%, and 3 g of sodium bicarbonate, freeze-dried Bifidobacterium thermophilum powder (viable cell count 8.0 × 10 ¹⁰ pcs / g) 100 g, corn starch (purified, dried and sterilized corn starch; manufactured by Matsutani Chemical Industry Co., Ltd.) 300
g and 2 g of silicon dioxide were charged and granulated, and coated with the mixed solution. The granules were dried with a fluidized bed dryer FLO-2 (manufactured by Freund Corporation) to obtain Sample 1.

[Embodiment 2] In the embodiment 1, the humidity 58
% Of a shellac-ethanol solution having a shellac concentration of 50%, 15 parts by volume of propylene glycol, 2.5 parts by volume of lanolin and 7.5 parts by volume of glycerin monofatty acid ester. Except for using 316 g of the mixture, granulation, coating, and drying were performed in the same manner as in Example 1 to obtain Sample 2.

[Embodiment 3] In the embodiment 1, the humidity of 65
% Of shellac-ethanol solution having a shellac concentration of 50%, 10 parts by volume of propylene glycol, 2.5 parts by volume of lanolin, and 7.5 parts by volume of glycerin monofatty acid ester. Sample 3 was obtained by granulating, coating, and drying in the same manner as in Example 1 except that 132 g of the mixed solution was used.

[Embodiment 4] In the embodiment 1, the humidity 62
Example 1 except that 250 g of a mixed solution obtained by mixing 82 parts by volume of a shellac-ethanol solution having a shellac concentration of 50%, 8 parts by volume of propylene glycol and 10 parts by volume of lanolin under 50% conditions was used. In the same manner as in the above, the sample was granulated, coated and dried to obtain Sample 4.

[Embodiment 5] In Embodiment 1, the humidity of 56
% Granulated in the same manner as in Example 1 except that 244 g of a mixed solution obtained by mixing 90 parts by volume of a shellac-ethanol solution having a shellac concentration of 50% and 10 parts by volume of propylene glycol was used. , Coated and dried to obtain Sample 5.

[Embodiment 6] In the embodiment 1, the humidity 55
% Of shellac-ethanol solution with a concentration of 50% shellac and macrogol 40
A sample 6 was obtained by granulating, coating and drying in the same manner as in Example 1 except that 265 g of a mixed solution obtained by mixing 30 parts by volume was used and the amount of sodium bicarbonate charged was 4 g.

[Embodiment 7] In the embodiment 1, the humidity was set to 66.
% Of Lactobacillus salivarius bacteria powder as freeze-dried bacteria powder, and 80 parts by volume of a shellac-ethanol solution having a shellac concentration of 50% and 20 parts by volume of propylene glycol as a mixture. Except for using 237 g of the mixed liquid, granulation, coating, and drying were performed in the same manner as in Example 1 to obtain Sample 7.

[Embodiment 8] In the embodiment 1, the humidity 51
% Of Lactobacillus salivarius bacteria powder as freeze-dried bacteria powder, and 85 parts by volume of a shellac-ethanol solution having a shellac concentration of 50%, 10 parts by volume of propylene glycol and 5 parts by volume of lanolin as a mixture. Granulation, coating and drying were performed in the same manner as in Example 1 except that 250 g of the mixed solution obtained by mixing was used.
Sample 8 was obtained.

Example 9 1000 g of lactose was put into a centrifugal fluidized coating machine CF-360 (manufactured by Freund Corporation) under the condition of a humidity of 54%, and then 50 parts by volume of liquid paraffin and a shellac concentration of 50%. Is sprayed with 250 g of a mixed solution obtained by mixing 50 parts by volume of a shellac-ethanol solution which is a lyophilized bacterial powder of Bifidobacterium thermophilum (viable bacteria count 8.0 × 10 ¹⁰ cells / g) 100
g, corn starch (purified, dried and sterilized corn starch; 300 g, manufactured by Matsutani Chemical Industry Co., Ltd.) and 2 g of silicon dioxide were added, granulated, and coated with the mixture. The granules were dried using a fluidized bed dryer FLO-2 (manufactured by Freund Corporation) to obtain Sample 9.

[Embodiment 10] In Embodiment 9, the humidity 5
The procedure was performed in the same manner as in Example 9 except that 250 g of a liquid mixture obtained by mixing 40 parts by volume of liquid paraffin and 60 parts by volume of a shellac-ethanol solution having a shellac concentration of 50% under the conditions of 8% was used. Granules, coated, dried, sample 1
0 was set.

[Embodiment 11] In Embodiment 9, the humidity of 6
The procedure of Example 9 was repeated except that 250 g of a mixture obtained by mixing 30 parts by volume of liquid paraffin and 70 parts by volume of a shellac-ethanol solution having a shellac concentration of 50% was used under the condition of 0%. Granules, coated, dried, sample 1
It was set to 1.

[Embodiment 12] In Example 9, the humidity 5
Under 4% conditions, 100 g of Lactobacillus salivarius bacteria powder is used as the freeze-dried bacteria powder, and 50 parts by volume of a shellac-ethanol solution having a shellac concentration of 50% and 50 parts by volume of liquid paraffin are mixed as a mixed solution. Example 9 except that 250 g of the obtained mixed liquid was used.
In the same manner as in the above, granulation, coating, and drying were performed to obtain Sample 12.

Example 13 A liquid mixture obtained by mixing 40 parts by volume of liquid paraffin and 60 parts by volume of a shellac-ethanol solution having a shellac concentration of 50% under the conditions of 58% humidity in Example 12. Sample 13 was obtained by granulating, coating and drying in the same manner as in Example 12 except that 250 g was used.

Example 14 A liquid mixture obtained by mixing 30 parts by volume of liquid paraffin and 70 parts by volume of a shellac-ethanol solution having a shellac concentration of 50% under the conditions of 60% humidity in Example 12. Sample 14 was obtained by granulating, coating and drying in the same manner as in Example 12, except that 250 g was used.

[Comparative Example 1]
In the same manner as in Example 1 except that a shellac-ethanol solution having a shellac concentration of 15% was used under the conditions of%, granulation, coating, and drying were performed to prepare Sample 15.

[Comparative Example 2]
The sample was granulated, coated and dried in the same manner as in Example 1 except that a shellac-ethanol solution having a shellac concentration of 15% was used.

[Comparative Example 3]
In the same manner as in Example 1 except that a shellac-ethanol solution having a shellac concentration of 30% was used under the conditions of%, granulation, coating, and drying were performed to prepare Sample 17.

[Comparative Example 4]
Example 1 except that a mixture obtained by mixing 85 parts by volume of a shellac-ethanol solution having a shellac concentration of 45%, 10 parts by volume of propylene glycol, and 5 parts by volume of lanolin under the conditions of% was used. Similarly, granulation, coating,
It dried and was set as the sample 18.

[Comparative Example 5]
In the same manner as in Example 1, except that only a shellac-ethanol solution having a shellac concentration of 50% was used under the conditions of%, granulation, coating, and drying were performed to obtain a sample 19. The granules obtained by this method vary greatly in the size and the like of the granules, and many lumps and the like are generated in the apparatus, which is unsuitable as a method for producing granules.

Test Example 1 The number of viable bacteria immediately after production of the samples obtained in Examples 1 to 14 and Comparative Examples 1 to 5 was measured.
The results are as shown in Table 1. In the table, SE indicates a shellac-ethanol solution, PG indicates propylene glycol, LN indicates lanolin, GE indicates glycerin monofatty acid ester, MG indicates Macrogol 400, and LP indicates liquid paraffin.

[0045]

[Table 1]

Considering the above results, as in Comparative Examples 1 to 4, a shellac-ethanol solution having a shellac concentration of 15% to 45% was used as a binder during granulation and a coating agent after granulation. When used, the recovery of the viable cell count in the intestinal useful bacteria-containing granules is extremely poor at less than 5%. Further, when only a shellac-ethanol solution having a shellac concentration of 50% as in Comparative Example 5 was used as a binder at the time of granulation and a coating agent after the granulation, there was a large variation in the size of the granules, Further, many lumps and the like are generated in the apparatus, which is not suitable as a method for producing granules. In contrast, Example 1
A mixed solution consisting of 75 to 99 parts by volume of a shellac-ethanol solution having a shellac concentration of 50% and 25 to 1 part by volume of propylene glycol shown in Nos. To 8 was used as a binder during granulation and a coating agent after granulation. Case and Example 1
When a mixture of 60 parts by volume of a shellac-ethanol solution having a shellac concentration of 50% and 40 parts by volume of liquid paraffin shown in 0 and 13 was used as a binder during granulation and a coating agent after granulation, 43 The recovery was very high, 〜100%, and the state of the granules was also very good. Further, a mixed solution comprising 50 parts by volume of a shellac-ethanol solution having a shellac concentration of 50% and 50 parts by volume of liquid paraffin shown in Examples 9 and 12 was used as a binder during granulation and a coating agent after granulation. When used, the recovery rate of viable bacteria is as high as 67 and 72%, which is good. However, during granulation, separation of the intestinal useful bacteria-containing granules and the mixture is likely to occur, and the granules are likely to be in an uneven state. , Not very good. Further, a mixed solution comprising 70 parts by volume of a shellac-ethanol solution having a shellac concentration of 50% and 30 parts by volume of liquid paraffin shown in Examples 11 and 14 was used as a binder during granulation and a coating agent after granulation. In this case, the recovery rate of viable cells is as high as 63 and 64%, which is good. However, since the viscosity of the mixture is high, uniform spraying is difficult, and the obtained granules form lumps. In the method of the present invention, similarly, a high recovery rate can be obtained even under a high humidity condition of 45% or more.

Test Example 2 Examples 1, 5, 6, 8, and 10
Samples 1, 5, 6, 8, 10 and 13 obtained in and 13 were obtained at 37 ° C. for 30 minutes, 1 hour and 2 hours, respectively.
An artificial gastric juice treatment at pH 3.0 was performed. The composition of the artificial gastric juice used in the test is shown below. (Artificial gastric juice composition) Yeast extract 1.25 g Peptone 2.5 g Lactose 0.5 g Tween 80 0.5 g L-cysteine 0.05 g NaCl 1.0 g Distilled water 500 g 1N hydrochloric acid Appropriate amount (pH 3.0 Prepare) The results are as shown in Table 2.

[0048]

[Table 2]

As can be seen from the above results, the granules obtained according to the present invention exhibited a high viable cell recovery rate in the treatment with artificial gastric juice for 2 hours, indicating that they were very acid-resistant.

Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 47/32 A61K 47/32 D 47/46 47/46 D (72) Inventor Shigeo Hatanaka 5-3 Tsurugaoka, Oimachi, Iruma-gun, Saitama No. 1 Nisshin Flour Milling Co., Ltd. Drug Discovery Research Laboratory (72) Inventor Kiyoko Ohara 5-3-1 Tsurugaoka, Oi-machi, Iruma-gun, Saitama Prefecture Nisshin Flour Milling Co., Ltd. Drug Discovery Research Laboratory (72) Inventor Akiko Makai 5-3-1 Tsurugaoka, Oi-machi, Irima-gun, Saitama Prefecture Nisshin Flour Milling Co., Ltd. Discovery Research Laboratory (72) Inventor Kiyoshi Mogi 3--17-4 Uchikanda, Chiyoda-ku, Tokyo Horiuchi Food Industry Co., Ltd. 56) References JP-A-3-95122 (JP, A) JP-A-50-121485 (JP, A) JP-A-2-174727 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , (DB name) A61K 35/74 A61K 9/16 A61K 47/10 A61K 47/32 A61K 47/46

Claims (5)

(57) [Claims] When producing useful enteric bacteria-containing granules, a mixed solution of an ethanol solution containing shellac at a concentration of 50% or more and propylene glycol and / or macrogol, or shellac at a concentration of 50% or more is contained. A method for producing useful enteric bacteria-containing granules, comprising using a mixed solution of ethanol solution and liquid paraffin to be used as a binder during granulation and / or a coating agent after granulation. 2. The intestinal useful bacteria-containing composition according to claim 1, wherein a mixture of 70 to 99 parts by volume of an ethanol solution containing shellac at a concentration of 50% or more and propylene glycol and / or 30 to 1 part by volume of macrogol is used. A method for producing granules. 3. An ethanol solution containing shellac at a concentration of 50% or more by 55 to 65 parts by volume and liquid paraffin 4.
The method for producing useful enteric bacteria-containing granules according to claim 1, wherein the mixed solution is used in an amount of 5 to 35 parts by volume. 4. The process for producing granules containing useful enteric bacteria according to claim 1, wherein a mixed solution further containing a glycerin monofatty acid ester and / or lanolin is used as the mixed solution. 5. The method for producing granules containing useful enteric bacteria according to claim 1, wherein the total amount of the mixed solution used is 50 to 500% based on the weight of useful enteric bacteria.