JP3187502B2 - Enteric granules - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to granules which are sparingly soluble in gastric juice but have high solubility in intestinal fluid. The present invention relates to an enteric granulated substance which dissolves in the intestinal tract for the first time and can elute a large amount of a physiologically active substance such as live lactic acid bacteria in the intestinal tract.

[0002]

2. Description of the Related Art In recent years, bifidobacteria and general lactic acid bacteria, which are beneficial bacteria of the intestinal flora, have been increased in the body, and the growth of harmful bacteria such as Escherichia coli and Bacteroides has been suppressed. It has been attempted to prevent and treat various diseases of the digestive system by improving the sexual flora. As a method of increasing the beneficial bacteria, there is a method of ingesting food or drink or a tablet containing them.

[0003] However, bifidobacteria and lactic acid bacteria are
It is cultivated under conditions of pH 4.5 or more, anaerobic, 36 to 42 ° C., and rapidly dies when the pH is 4.2 or less, in the presence of dissolved oxygen, and at a high temperature of 45 ° C. or more. Therefore, when bifidobacteria and lactic acid bacteria are simply ingested directly from the mouth, gastric juice (pH 1.0-1.5, HCl 0.2
~ 0.5% by weight (hereinafter referred to as%))
The efficiency of use in the intestinal tract is significantly impaired.

Conventionally, for example, Japanese Unexamined Patent Publication No.
A method for producing bifidobacterium granules as described in Japanese Patent Application Laid-Open Publication No. H11-209,837 has been proposed. This method is a method of granulating bifidobacteria with excipients such as saccharides and organic acids and hardened oil, thereby reducing pressure damage during granulation and increasing the survival rate of bifidobacteria.

[0005] In this method, however, the survival rate of the bifidobacterium in the granules is increased, but when the granules are treated with artificial gastric juice (pH 1.2), the bifidobacteria are killed. Therefore, when the above granules are ingested from the mouth, a considerable number of cells are killed by gastric juice, and the ratio of living cells remaining in the intestine is reduced. In addition, since the cells thus granulated have a large contact area with air, a special preservation method for maintaining the activity of the cells is required.

As a method for solving the above-mentioned disadvantage, Japanese Patent Application Laid-Open No.
A method disclosed in Japanese Patent Application Publication No. 0-141281 is exemplified. In this method, a protective film-forming solution such as sodium alginate and starch is mixed with a viable cell, dropped into a coagulating liquid using a pore nozzle having an inner diameter of 1 mm or less, coagulated, dried, and then coated with an oil or fat. Is what you do.

However, in this method, a viable cell-containing solution tank, a pore nozzle for dropping the cell, a coagulation tank for coagulating the viable cell-containing solution, a coagulation, washing, recovery and drying. A special device such as a device for the above is required. In addition, since the amount of dripping per nozzle is small, there is a disadvantage that a long time is required for production and mass production is difficult.

[0008]

DISCLOSURE OF THE INVENTION The present invention has been made in view of such circumstances, and it is an object of the present invention to dissolve in a low-pH stomach after oral ingestion and to dissolve in the intestinal tract for the first time. Dissolves and is affected by the pH of gastric juice, so that a large amount of physiologically active substances such as living lactic acid bacteria can be eluted in the intestinal tract without dying, etc., and the activity of the physiologically active substances decreases even after long-term storage An object of the present invention is to provide a stable enteric granulated product which does not need to be stored.

[0009]

The purpose of the Means for Solving the Problems] is an enteric granules coated with two layers composed as shown in the granules is below (A) and (B), 該被granulation Things are biologically active substances
There, and wheat contained in the (B) layer, soybean, rice, co
Hydrous alcohol soluble protein from lagen and gelatin
This is achieved by an enteric granulate characterized in that at least one of the substance and the zein is contained in an amount of 3% by weight or more based on the total weight of the enteric granulate. (A) Derived from wheat, soy, rice, collagen and gelatin
Low in hydroalcohol soluble protein or zein
Both one fat and excipients containing organic layer. (B) from wheat, soy, rice, collagen and gelatin
Low in hydroalcohol soluble protein or zein
A layer containing both of them .

That is, the present inventors have found that after oral ingestion, enteric-coated granules which are not dissolved in gastric juice but dissolved in intestinal digestive juice and do not cause a decrease in the activity of physiologically active substances during long-term storage. The thing was examined. As a result, the granulated material such as cells was (A) wheat, soybeans, rice, collagen and
Hydrous alcohol-soluble protein derived from gelatin and gelatin or
Layer containing at least one and the oil and excipient zein and (long-term storage stabilization and low pH range stabilizing layer),
(B) from wheat, soy, rice, collagen and gelatin
Low in hydroalcohol soluble protein or zein
The present inventors have found that a granulated product composed of two layers, one of which is a low pH region stabilizing layer, is an enteric granulated product that achieves the above object, and the present invention has been achieved.

Next, the present invention will be described in detail. Granules to be used in the present invention include lactic acid bacteria (preferably having a viable cell count of 10 ⁶ / g or more), bifidobacteria, yeast, and other microorganisms having high availability in vivo (particularly in the intestinal tract) after oral ingestion, and the like. extract, or microbial growth factors such as peptides, Ru susceptible various physiologically active substance Shitsudea the influence of gastric juices. As the microorganism, freeze-dried and reduced pressure spray-dried cell powder may be used.

Next, among the two layers covering the granulated material, the layer (A) for stabilizing the granulated material for a long period of time and stabilizing in a low pH range includes a small layer.
Hydrous alcohol derived from wheat, soy, rice, collagen and gelatin
At least one of col soluble proteins or zein, fats and oils and excipients are used.

First, as fats and oils, coconut oil, palm oil,
Vegetable oils and fats such as soybean oil, rapeseed oil and cocoa butter, solid fats such as hardened oils obtained by hardening them, and edible waxes such as rice wax, candelilla wax and honey wax are included. The melting point of these fats and oils is 30 to 4 in terms of uniform dispersibility and spreadability in a low temperature range that does not impair the viability of the granulated material.
5 ° C. is preferred.

Similarly, excipients used in the layer (A) include starch, eggs, milk, cereals, beans and other proteins as raw materials such as potato, corn, rice and wheat, and glucose, lactose and the like. Saccharides such as sucrose and maltose may be mentioned, and these may be used alone or in combination of several kinds.

Similarly, the layer (A) includes wheat, soybean,
Soluble with aqueous alcohol derived from rice, collagen and gelatin
Contains at least one of the sex protein or zein
You. These may be used alone or in combination of two or more. Also,
For example, a fraction such as a zein peptide having a molecular weight of 5,000 to 40,000 obtained by subjecting zein to an alkali treatment and then extracting with acetone may be used, or the untreated zein and the zein peptide may be used in combination. . Among them, the use of zein is more excellent in gastric juice resistance and is preferred. In addition, the above wheat, soybeans, rice, collagen and zeo
Hydrous alcohol-soluble protein or t
A dried product obtained by mixing about 10% by weight (hereinafter referred to as "%") of a water-soluble protein with at least one of the inks may be used.

In the present invention, covering the granulated material includes the case where the granulated material is mixed in the coating layer adjacent to the granulated material. Further, the layer (A) usually contains wheat, soybean,
Soluble with aqueous alcohol derived from rice, collagen and gelatin
At least one of the sex protein or zein . However, the three components may be dispersed and mixed separately.

Next, of the two layers covering the granulated material, the (B) layer for stabilizing the granulated material at a low pH includes a water-containing material derived from wheat, soybeans, rice, collagen and gelatin.
Alcohol soluble protein or zein
Contains one . Wheat, soybeans, rice, collagen and ze
Hydrous alcohol soluble protein or ts
Inn is the wheat, soybean, rice, cocoa used in the above (A) layer.
Hydrous alcohol soluble protein from lagen and gelatin
Similar to quality or zein can be used. Water content derived from wheat, soybeans, rice, collagen and gelatin used
The alcohol-soluble protein or zein may be used alone or in combination of two or more .
Hydrous alcohol derived from soybeans, rice, collagen and gelatin
It is used Le soluble protein or zein, another small
Hydrous alcohol derived from wheat, soy, rice, collagen and gelatin
Chole soluble protein or zein may be used. Among them, the use of zein is more excellent in gastric juice resistance and is preferred.

The layer (B) includes wheat, soybeans, rice, and cocoa.
Hydrous alcohol soluble protein from lagen and gelatin
In order to enhance the uniform dissolution and decomposition of
If necessary, a plasticizer may be used. As the plasticizer, glycerin fatty acid ester, sucrose fatty acid ester,
Examples include emulsifiers such as polyglycerin fatty acid esters and sorbitan fatty acid esters, glycerin, sugar alcohols and the like. Among them, particularly, glycerin fatty acid esters are derived from wheat, soybeans, rice, collagen and gelatin.
It is suitable in terms of uniform dissolution and dispersibility of the alcohol-soluble protein or zein , and uniform coverage when coated on granules. The amount of plasticizer added is wheat, soy, rice,
Hydrous alcohol soluble protein derived from gen and gelatin
Alternatively, although it depends on the amount of zein , it is preferably about 0.8% of the total weight of the layer (B) solution.

Regarding the coating of the granulated material with the layer (A) and the layer (B), either the layer (A) or the layer (B) may be coated first. When the (A) layer is coated first and then the (B) layer is coated, the gastric juice resistance is more excellent, and the working efficiency at the time of producing a granulated product is good. Conversely, when the layer (B) is coated first and then the layer (A) is coated, a granulated product having a smaller particle size can be obtained. The enteric granulated product of the present invention may be formed into a multilayer granulated product by alternately coating and forming several layers of the (A) layer and the (B) layer.

Next, the enteric granulated product of the present invention can be produced, for example, as follows using the above-mentioned granulated product, layer (A) and layer (B). That is, when coating the layer (A) first, first, the granulated material, excipient, wheat,
Hydrous alcohol derived from beans, rice, collagen and gelatin
Soluble protein or mixture of at least one bets zein, and mixed stirred while kept by addition of fat was melted beforehand liquid thereto. Insulation temperature is uniform dispersibility of fats and oils,
From the viewpoint of preventing thermal denaturation of the granulated material, preferably 45 ° C or less,
More preferably, the temperature is 30 to 45 ° C.

The amount of the fat or oil is desirably 10 to 30% based on the total weight of the layer (A). 10% fat
By weight, can not be sufficiently coated with oil to be granulated surface, long term storage stability tends to gastric juice is deteriorated. On the other hand, if it exceeds 30%, a slip phenomenon occurs during granulation, and the granulation tends to be difficult. In addition, excipients, and small
Hydrous alcohol derived from wheat, soy, rice, collagen and gelatin
The amount of the coal-soluble protein or zein may be appropriately set, but from the viewpoint of uniform dispersibility of fats and oils, suitability for covering fats and oils on granules, and suitability for granulation, (A) the total weight of the layer, Is 20-50%, wheat, soy, rice, collagen and
Gelatin-derived hydroalcoholic soluble protein or tutu
The gain is desirably 10% to 50%.

Next, the mixture is supplied to a granulator while stirring, and granulated. Examples of the granulator include a granulator with a screen, an extruder, and the like,
The one provided with a cooling means is preferable because the granulated material can be solidified quickly.

The (A) layer thus obtained is coated with the (B) layer by spraying or dipping. First, wheat, soy, rice, collagen and gelatin
The hydrous alcohol soluble protein or zein is dispersed and dissolved in the hydroalcohol. The hydrous alcohol used here preferably has an alcohol concentration of about 85 to 95%. In other words, if it deviates from this range, wheat, soybeans, rice,
Hydrous alcohol soluble protein from lagen and gelatin
Quality or zein uniformly dispersed in aqueous alcohol,
The solubility tends to be poor.

At this time, wheat, soybeans, rice,
Hydrous alcohol soluble protein derived from gen and gelatin
Or the ratio of zein to hydrous alcohol is wheat, large
Hydrous alcohol derived from beans, rice, collagen and gelatin
It is desirable to use 6 to 14 hydroalcohols with respect to the soluble protein or zein 1 from the viewpoint of uniform solubility and dispersibility. At this time, a plasticizer is added as needed.

Next, the step of applying the solution dispersed and dissolved in the water-containing alcohol to the surface of the coating of the layer (A) and drying is repeated to form the layer (B). Examples of the method of application include spraying and dipping. For example, when spraying,
A rolling machine such as a revolving pan, a fluidized dryer, a centrifugal fluidized-bed granulator, or the like may be used.

In the total weight of the enteric granules thus obtained, wheat, soybeans, rice, collagen and gelatin
Low amount of native hydrous alcohol soluble protein or zein
At least one of them is preferably contained in an amount of preferably 5 to 50%, more preferably 15 to 30%. Wheat, large
Hydrous alcohol derived from beans, rice, collagen and gelatin
5% at least one of soluble protein or zein
If it is less than 50, the gastric juice resistance tends to be poor.
%, The texture in the mouth tends to deteriorate. Among them, wheat, soybean, rice, and kora contained in layer (B)
Hydrous alcohol soluble protein derived from gen and gelatin
Alternatively, at least one of the zeins is contained in an amount of 3% by weight or more based on the total weight of the enteric granules. That is, 3%
If it is less than this, gastric juice resistance becomes poor.

The enteric granules thus obtained are
It may be taken orally as it is, or it may be used in powdered juice, chewing gum or candy centers. Also, it may be a health food that is compressed with a flavor, dairy product or the like.

As described above, the enteric granulated product of the present invention comprises:
Hydrous water derived from wheat, soy, rice, collagen and gelatin
At least one of a soluble protein or zein
One, containing fats and excipients (A) layer and the (long-term storage stabilization and low pH range stabilizing layer), wheat, soybean, rice, Kola
Hydrous alcohol soluble protein derived from gen and gelatin
Or containing at least one of the zein layer (B) intestinal bioactive substances by two layers of the (low pH range stabilizing layer)
Because the granulated material is coated, the granulated material does not dissolve in gastric juice, and the physiologically active substance exerts its biological activity in the intestinal tract without being affected by gastric juice after ingestion from the mouth be able to. In addition, long-term storage stability is stable.

In order to form the layer (B), wheat, large
Hydrous alcohol derived from beans, rice, collagen and gelatin
It takes a long time to repeatedly apply and dry at least one soluble protein or zein ,
Wheat, soybeans, rice, collagen and gelatin in layer (A)
Of hydrous alcohol soluble protein or zein
By mixing at least one , the formation layer of the layer (B) can be reduced, so that the time can be reduced and the enteric effect is high. In addition, since it can be manufactured continuously using a conventional granulating apparatus or the like, it can be mass-produced.

Next, the present invention will be specifically described with reference to examples. Example 1 Lactobacillus acidophilus (Lac
27 parts by weight (hereinafter referred to as "parts") of dried lactic acid bacterial cell powder (viable cell count of 10 ¹⁰ cells / g) of tobacillus acidophilus, 170 parts of skim milk powder and glucose 28
Parts of the excipient and 40 parts of zein, 75 parts of palm oil and fat melted at 40 ° C. were added to the mixture and stirred, and then the mixture was extruded with an extrusion granulator equipped with a screen having a pore diameter of 0.8 mm. A (A) layer coating having a thickness of 1.5 to 2 mm was obtained.

Next, 20 parts of zein were dispersed and dissolved in 130 parts of an aqueous ethanol solution (100 parts of ethanol and 30 parts of water) little by little, and then 1 part of glycerin fatty acid ester was added to obtain a coating solution. Then, using a centrifugal granulation dryer, the above coating solution was sprayed on the above (A) layer coating under the conditions of a rotor rotation speed of 120 rpm, a product temperature of 25 ° C., and a blower of 150 L / min. An enteric granulated product of 23% fat was obtained.

Comparative Example 1 A granulated product was obtained in the same manner as in Example 1 except that the coating solution was not used.

Comparative Example 2 A granulated product was obtained in the same manner as in Example 1 except that palm oil and fat were replaced with water.

1.00 g of the granules obtained in Example 1 and Comparative Examples 1 and 2 were weighed accurately, and were placed in an artificial gastric juice (0.12 M-HC).
1, NaCl 2%, pepsin 0.32%, pH 1.2)
It was immersed in 50 g for 2 hours, and then filtered, and the obtained residue was washed with sterile water and immediately thereafter, artificial intestinal fluid (0.1 M-
_{KH 2 PO 4, 0.1M-Na} 2 HPO 4 · 2H 2 O,
1: 6, pH 6.8) at 37 ° C. for 1 hour. The number of remaining viable cells of the lactic acid bacteria after the immersion was examined by a conventional method of plate culture. The initial viable cell count was determined by examining the viable cell count after immersion of only artificial intestinal juice (without immersion of artificial gastric juice). Furthermore, the viable cell count after each granulated product was stored at 20 ° C. for 4 months was examined. Table 1 shows the results.

[0035]

[Table 1]

From the above results, the enteric granules of Examples were granules having excellent gastric juice resistance. The storage stability was also stable.

[Examples 2 to 5] Granules were obtained in the same manner as in Example 1 except that the amount of fats and oils used (% by weight based on the total weight of the (A) layer coating) was changed to the ratio shown in Table 2. . The gastric juice resistance of the obtained granules was examined in the same manner as in Example 1. In addition, the amount of skim milk powder was adjusted according to the increase and decrease of the fats and oils. Table 2 shows the above results.
Shown in

[0038]

[Table 2]

From the results shown in Table 2, the viable cell count was high even with the addition of 30% of fats and oils, no slip phenomenon occurred during granulation, and the granulation suitability was good.

[Examples 6 to 8] Granules in the same manner as in Example 1 except that zein of Example 1 was replaced with soybean protein, wheat protein and gelatin which were fractionated so as to be soluble in hydroalcohol as shown in Table 3. Was prepared, and the number of viable bacteria was measured. Table 3 shows the results.

[0041]

[Table 3]

From the above results, soy protein, wheat protein and
The enteric granules using gelatin were granules having excellent gastric juice resistance.

[Examples 9 to 13] Except that the content of zein (% by weight based on the total weight of the granulated product) of Example 1 was changed as shown in Table 4, the granulated product was prepared in the same manner as in Example 1. Is prepared,
The number of viable bacteria was measured. The above results are also shown in Table 4.

[0044]

[Table 4]

From the results shown in Table 4, the zein content was 15%.
Above, the granulated material exhibited gastric juice resistance and was particularly good.

Example 14 Lactobacillus casei and Streptococcus thermophilus containing 10 ⁹ viable cells / g of the dried lactic acid bacterial cell powder of Example 1
Cus thermophilus) in the same manner as in Example 1 except that the dried lactic acid bacteria powder was used in combination.
As a result, the residual viable cell count was favorable at 10 ⁷ cells / g.

[Example 15] Bifidobacterium containing 10 ⁹ viable cells / g of the dried lactic acid bacteria powder of Example 1
Longum (Bifidobacterium long)
Example 1 except that the dried bifidobacterium powder of um) was replaced with the powder.
The same was done. According to a conventional method, cultivation was performed under anaerobic conditions using an anaerobic jar to confirm the viable cell count. As a result, a good result was obtained with a residual viable cell count of 10 ⁷ cells / g.

Example 16 The procedure of Example 15 was repeated, except that the excipient used in Example 15 was an oligosaccharide used as a growth factor for Bifidobacterium, and the following was carried out. That is, a mixture comprising excipients of 150 parts of skim milk powder, 18 parts of glucose, and 30 parts of oligosaccharide was used. The number of viable cells remaining in the obtained enteric granules was about 10 ⁷ / g, which was good.

[Example 17] The coating solution of Example 1 was used in the same manner as in Example 1 except that zein and gelatin were used in combination, and the following was carried out. Dissolve 3 parts of gelatin in 30 parts of water, disperse and dissolve while adding 17 parts of zein little by little to a solvent solution to which 100 parts of ethanol is added.
A part of the solution was added. The number of viable cells remaining in the obtained enteric granules was as good as 10 ⁸ cells / g.

Example 18 Lactobacillus acidophilus
A coating solution in which 20 parts of zein were dispersed and dissolved in 130 parts of an aqueous ethanol solution (100 parts of ethanol and 30 parts of water) was added to a granulated product of dried lactic acid bacteria powder (viable cell count: 10 ¹⁰ cells / g) of Ilus) The coating was dried with a granulator. Next, a mixture of 60 parts of skim milk powder, 50 parts of powdered sugar, 40 parts of zein and 150 parts of melted palm oil and fat was coated on the coated dried product using a rotary kiln to obtain enteric granules. The resulting enteric granulated product had an initial viable cell count of 10 ⁸ / g and a residual viable cell count of 10 ^8.
Pcs / g, which satisfied the constituent requirements of the present invention.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61K 35/74 A61K 35/74 A C12N 1/04 C12N 1/04 1/20 1/20 C (58) Fields surveyed (Int. .Cl. ⁷ , DB name) A61K 9/38 A23L 1/00 A23L 1/28 A61K 9/14 A61K 9/20 A61K 35/74 C12N 1/04 C12N 1/20

Claims (1)

(57) [Claims] 1. A subjected to granulation is below (A) and enteric granules coated with two layers composed as shown (B), the 該被granulation
The granules are physiologically active substances, and the water contained in layer (B) is derived from wheat, soybeans, rice, collagen and gelatin
Alcohol soluble protein or zein
An enteric granulated product comprising one or more of 3% by weight or more based on the total weight of the enteric granulated product. (A) Derived from wheat, soy, rice, collagen and gelatin
Low in hydroalcohol soluble protein or zein
Both one fat and excipients containing organic layer. (B) from wheat, soy, rice, collagen and gelatin
Low in hydroalcohol soluble protein or zein
A layer containing both of them .