JPH05186335A - Enteric particle - Google Patents

Abstract

PURPOSE:To provide the subject enteric particle insoluble in the stomach after oral administration, not dissolved till it reaches the intestine, capable of allowing a large amount of a bioactive substance such as Lactobacillus viable cell to be dissolved in the intestine with out suffering the effect of the low pH gastric juice and stable even after long-term storage. CONSTITUTION:A bioactive substance such as Lactobacillus or Lactobacillus bifidus, exhibiting a high utilization in the living body (especially the intestine) and readily affected by the gastric juice is used for granulation. The above- mentioned substance is coated with two layers of (A) a layer containing fats and oils (preferably 30 to 45 deg.C melting point), a vehicle and a hydrous alcohol soluble protein (preferably zein) and (B) a layer containing a hydrous alcohol soluble protein to obtain the objective enteric particle having the above- mentioned effects. In addition, it doesn't matter which is applied first, the (A) layer or the (B) layer. When the (A) layer is applied first, a particle excellent in acid resistance is produced with an excellent work efficiency. When the (B) layer is applied first, a particle having a small particle size can be obtained. The (A) and (B) layers may be alternately applied many times to obtain a multilayer particle.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a granulated product which is poorly soluble in gastric juice but excellent in intestinal juice. More specifically, it is dissolved in the stomach after ingestion through the mouth. However, the present invention relates to an enteric-coated granulated product which can be dissolved in the intestinal tract for the first time and a large amount of physiologically active substances such as live lactic acid bacteria can be eluted in the intestinal tract.

[0002]

2. Description of the Related Art In recent years, bifidobacteria, which are considered to be beneficial bacteria of the intestinal flora, and general lactic acid bacteria, have been increased in the body, and the growth of harmful bacteria such as Escherichia coli and Bacteroides has been suppressed, and they have been resident. Attempts have been made to prevent and treat various diseases of the digestive system by improving the sex flora. Examples of the method of increasing the beneficial bacteria include a method of ingesting foods and drinks or tablets containing them.

However, bifidobacteria and lactic acid bacteria are
It is cultivated under conditions of pH 4.5 or higher, anaerobic, and 36 to 42 ° C., and especially, it is rapidly killed at pH 4.2 or lower, presence of dissolved oxygen, and high temperature of 45 ° C. or higher. Therefore, if bifidobacteria or lactic acid bacteria are simply ingested directly from the mouth, gastric juice (pH 1.0 to 1.5, HCl 0.2
~ 0.5 wt% (hereinafter referred to as%)),
The utilization efficiency in the intestinal tract is significantly impaired.

Conventionally, for example, JP-A-60-255731.
A method for producing bifidobacteria granules as described in Japanese Patent Publication No. 2004-242242 has been proposed. This method is a method in which the pressure damage during granulation is alleviated by granulating bifidobacteria with an excipient such as saccharides and organic acids and hydrogenated oil, and the survival rate of bifidobacteria is increased.

However, in this method, although the survival rate of the bifidobacteria in the granules is increased, the bifidobacteria are killed when the granules are treated with artificial gastric juice (pH 1.2). Therefore, when the above-mentioned granules are taken from the mouth, a considerable number of cells are killed by the gastric juice, and the proportion of the cells remaining as viable cells in the intestine decreases. Further, since the bacterial cells thus granulated have a large contact area with the air, a special preservation method for maintaining the activity of the bacterial cells is required.

As a method for solving the above-mentioned drawbacks, Japanese Patent Laid-Open No.
The method disclosed in Japanese Unexamined Patent Publication No. 0-141281 can be mentioned. In this method, a protective film-forming solution such as sodium alginate and starch is mixed with viable cells, and the mixture is dropped into a coagulating liquid using a fine pore nozzle having an inner diameter of 1 mm or less, coagulated, dried, and then coated with oil and fat. To do.

However, in this method, a viable cell-containing solution tank, a fine nozzle for dropping it, a coagulation tank for coagulating the viable cell-containing solution, a coagulation step, and a washing, recovery and drying step are performed. A special device such as a device for Further, since the amount of dropping per nozzle is small, it takes a long time for production and it is difficult to mass-produce.

[0008]

SUMMARY OF THE INVENTION The present invention has been made in view of the above circumstances, and its purpose is to not be dissolved in the low pH stomach after ingestion, and the first time in the intestine. It dissolves and is affected by the pH of gastric juice, and bioactive substances such as viable lactic acid bacteria can be eluted in large amounts in the intestinal tract without being killed, and the activity of bioactive substances decreases even after long-term storage. The purpose of the present invention is to provide an enteric-coated granulated product which is stable and can be stored.

[0009]

The above-mentioned object is achieved by an enteric-coated granulated product characterized in that the granulated product is coated with two layers shown in (A) and (B) below. It (A) Oil-and-fat, excipient, and hydrous alcohol-soluble protein-containing layer. (B) Hydrous alcohol-soluble protein-containing layer.

That is, the present inventors have found that after ingestion, the enteric-coated granules are not dissolved in the gastric juice, but are dissolved by the intestinal digestive juice and the activity of the physiologically active substance is not lowered during long-term storage. The thing was examined. As a result, (A) a layer containing fats and oils, an excipient and a hydrous alcohol-soluble protein (a long-term storage stability stabilizing layer and a low pH range stabilizing layer), and The inventors have found that a granulated product having two layers of an alcohol-soluble protein-containing layer (stabilized layer in a low pH range) can be an enteric-coated granulated product that achieves the above-mentioned object, and has reached the present invention.

Next, the present invention will be described in detail. The granules used in the present invention include lactic acid bacteria (preferably viable bacteria number of 10 ⁶ / g or more), bifidobacteria, yeasts and the like, which are highly available in vivo (especially in the intestinal tract) after ingestion, and these And various physiologically active substances that are easily affected by gastric juice, such as microbial growth factors such as peptides and peptides. As the above-mentioned microorganism, it is preferable to use freeze-dried and vacuum spray-dried bacterial cell powder.

Next, of the two layers that coat the granules, the (A) layer for stabilizing the granules for a long period of time and for stabilizing the granules in a low pH range contains oil and fat. A shaping agent and a hydrous alcohol-soluble protein are used.

First, as fats and oils, palm oil, palm oil,
Examples include vegetable oils and fats such as soybean oil, rapeseed oil and cocoa butter, solid oils such as hardened oils obtained by hardening them, and edible waxes such as rice wax, candelilla wax and honey wax. 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 survival property of the granulated product.
5 ° C is preferred.

Similarly, as the excipients used in the layer (A), proteins, glucose, lactose, etc., made from potatoes, corn, rice, wheat, etc., as raw materials, starch and eggs, milk, cereals, beans, etc. as raw materials, Examples include sugars such as sucrose and maltose, and these may be used alone or in combination of several kinds.

Similarly, examples of the hydrous alcohol-soluble protein used in the layer (A) include zein contained in corn, and vegetable or animal proteins derived from wheat, soybean, rice, collagen, gelatin and the like. These may be used alone or in combination of two or more. Further, for example, a fraction such as a zein peptide having a molecular weight of 5,000 to 40,000 obtained by subjecting zein to alkali treatment and then acetone extraction may be used, or the untreated zein and zein peptide may be used in combination. Good. Among these, the use of zein is more preferable because it has excellent gastric juice resistance. Further, a dried product obtained by mixing about 10% by weight (hereinafter referred to as%) of a water-soluble protein with the hydrous alcohol-soluble protein and drying the mixture may be used.

[0016] In the present invention, the term "coating" includes the case where the granules are mixed in the coating layer. Also,
The layer (A) is usually in a state in which a hydrous alcohol-soluble protein is mixed in a mixture or a melt mixture of fats and oils and an excipient. However, the above three components may be dispersed and mixed separately.

Next, of the two layers that coat the agglomerate, a hydrous alcohol-soluble protein is used in the layer (B) for stabilizing the agglomerate at a low pH. As the hydrous alcohol-soluble protein, the same hydrous alcohol-soluble protein used in the layer (A) can be used. The hydrous alcohol-soluble protein to be used may be used alone or in combination of two or more kinds, and the same hydrous alcohol-soluble protein as in the layer (A) may be used, or another hydrous alcohol-soluble protein may be used. Among them, the use of zein is more preferable because it is more resistant to gastric juice.

In addition, a plasticizer may be used in the layer (B), if necessary, in order to improve the uniform dissolution and dispersibility of the hydrous alcohol-soluble protein. Examples of the plasticizer include emulsifiers such as glycerin fatty acid ester, sucrose fatty acid ester, polyglycerin fatty acid ester, and sorbitan fatty acid ester, and glycerin and sugar alcohol. Among these, glycerin fatty acid ester is particularly preferable in terms of uniform dissolution and dispersibility of the hydrous alcohol-soluble protein and uniform coverage when the granules are coated. The amount of the plasticizer added varies depending on the amount of the hydrous alcohol-soluble protein, but is preferably about 0.8% of the total weight of the layer (B) solution.

The granules to be coated with the layers (A) and (B) may be coated with either the layer (A) or the layer (B) first. When the layer (A) is first coated and then the layer (B) is coated, the gastric juice resistance is more excellent, and the work efficiency in producing the granulated product is good. On the contrary, when the layer (B) is first coated and then the layer (A) is coated, a granulated product having a smaller particle size can be obtained. Further, the enteric-coated granule of the present invention may be formed as a multi-layer granule by coating and forming several layers (A) and (B) alternately.

Next, the enteric-coated granulated product of the present invention can be produced, for example, as follows using the above-mentioned granulated product, (A) layer and (B) layer. That is, when the layer (A) is first coated, first, the granules, the excipient, and the hydrous alcohol-soluble protein are mixed, and the oil and fat previously melted in a liquid state are added to the mixture while keeping it warm. Mix and stir. The heat retention temperature is preferably 45 ° C. or lower, more preferably 30 to 45, from the viewpoint of uniform dispersibility of fats and oils and prevention of thermal denaturation of the granulated material.
To ℃.

The amount of the oil / fat used is preferably 10 to 30% of the total weight of the layer (A). 10% fat
If it is less than the above range, the surface of the granulated product cannot be sufficiently covered with oils and fats, and the long-term storage stability and gastric juice resistance tend to deteriorate. On the other hand, if it exceeds 30%, a slip phenomenon occurs during granulation, and granulation tends to be difficult. The amounts of the excipient and the hydrous alcohol-soluble protein used may be set appropriately, but from the viewpoints of uniform dispersibility of fats and oils, suitability for coating fats and oils on granules, and suitability for granulation, the total weight of layer (A) Medium is 20 to 5
It is desirable that the protein content is 0% and the hydrous alcohol-soluble protein content is 10 to 50%.

Next, the above mixture is supplied to a granulating apparatus while being stirred, and granulated. Examples of the granulating device include a granulator with a screen and an extruder.
The one provided with a cooling means is preferable because the granulated product can be solidified quickly.

The (A) layer coating thus obtained is coated with the (B) layer by spraying, dipping or the like. That is, first, the hydrous alcohol-soluble protein is dispersed and dissolved in hydrous alcohol. The hydrous alcohol used here preferably has an alcohol concentration of about 85 to 95%. That is, outside this range, the uniform dispersion and solubility of the hydrous alcohol-soluble protein in the hydrous alcohol tend to deteriorate.

At this time, the ratio of hydrous alcohol-soluble protein to hydrous alcohol is preferably 6 to 14 hydrous alcohol to hydrous alcohol-soluble protein 1 from the viewpoint of uniform solubility and dispersibility. At this time, a plasticizer is added as needed.

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

The total weight of the thus obtained enteric-coated granules preferably contains 5 to 50%, more preferably 15 to 30% of hydrous alcohol-soluble protein. If the content of hydrous alcohol-soluble protein is less than 5%, gastric juice resistance tends to deteriorate, and conversely 50%.
When it exceeds, the texture in the mouth tends to deteriorate.

The enteric-coated granules thus obtained are
It may be taken orally as it is, or may be used as a center for powdered juice, chewing gum, and candy. Further, it may be a health food that is tableted by adding flavors, dairy products and the like.

[0028]

INDUSTRIAL APPLICABILITY As described above, the enteric-coated granulated product of the present invention is a layer (A) containing oils and fats, an excipient and a hydrous alcohol-soluble protein (a long-term storage stability stabilizing layer and a low pH range stabilizing layer). ) And a hydrous alcohol-soluble protein (B)
Since the granules such as intestinal physiologically active substances are covered with the two layers (layer for stabilizing low pH range), the granules are not dissolved in the gastric juice and It is not affected by gastric juice after ingestion, and can exert its physiological activity in the intestinal tract. In addition, long-term storage stability is stable.

In order to form the layer (B), since the application of the hydrous alcohol-soluble protein and the drying are repeated, it takes a long time. However, the hydrous alcohol-soluble protein should be mixed in the layer (A). With this, since the formation layer of the layer (B) can be reduced, the time can be shortened and the enteric effect is high. Further, since it can be continuously manufactured by using a conventional granulating device 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
Tobacillus acidophilus) dry lactic acid bacterial cell powder (viable cell count 10 ¹⁰ cells / g) 27 parts by weight (hereinafter referred to as “part”), skim milk powder 170 parts and glucose 28
Part of the excipient and 40 parts of zein are mixed, 75 parts of palm oil and fat melted at 40 ° C. is added to this mixture, and the mixture is stirred, and then the mixture is squeezed with an extrusion granulator equipped with a screen having a pore diameter of 0.8 mm. A layer (A) coating having a thickness of 1.5 to 2 mm was obtained.

Next, 20 parts of zein was added and dispersed little by little to 130 parts of an aqueous ethanol solution (100 parts of ethanol, 30 parts of water), and then 1 part of glycerin fatty acid ester was added to obtain a coating solution. Then, using a centrifugal granulation drier, the above coating solution was sprayed onto 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, and finally a zein of 19%, An enteric-coated granule containing 23% oil and 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 was replaced with water.

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

[0035]

[Table 1]

From the above results, the enteric-coated granules of Examples were granules excellent in 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 oil / fat used (% by weight in 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. The amount of skim milk powder was adjusted as the amount of fat and oil increased. The above results are shown in Table 2.
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 oil and fat, the slipping phenomenon did not occur during granulation, and the granulation suitability was good.

[Examples 6 to 8] Granules were prepared in the same manner as in Example 1 except that the zein of Example 1 was replaced with each hydrous alcohol-soluble protein fractionated to be soluble in hydrous alcohol as shown in Table 3. After preparation, the viable cell count was measured. The results are shown in Table 3.

[0041]

[Table 3]

From the above results, the enteric-coated granules using the hydrous alcohol-soluble protein were granules excellent in gastric juice resistance.

[Examples 9 to 13] Granules were prepared in the same manner as in Example 1 except that the zein content (% by weight in the total weight of the granules) of Example 1 was changed as shown in Table 4. And prepare
The viable cell count was measured. The above results are also shown in Table 4.

[0044]

[Table 4]

From the results shown in Table 4, the zein content is 15%.
Above all, the granules exhibited good resistance to gastric juice, and were particularly good.

[Example 14] Lactobacillus casei and Streptococcus thermophilus (Streptococcus) containing the dried lactic acid bacterial cell powder of Example 1 in a viable cell count of 10 ⁹ cells / g.
cus thermophilus) was used in combination with the dried lactic acid bacterial cell powder, and the procedure was performed in the same manner as in Example 1.
As a result, the residual viable cell count was good at 10 ⁷ cells / g.

[Example 15] Bifidobacterium containing 10 ⁹ viable cells / g of the dry lactic acid bacterial cell powder of Example 1
Longum (Bifidobacterium long
um) to replace with dried bifidobacteria powder.
I went the same way. In accordance with a conventional method, culture 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 of Example 15 was changed to the oligosaccharide used as a growth factor of Bifidobacterium and the following procedure was used. That is, a mixture of 150 parts of skim milk powder, 18 parts of glucose and 30 parts of oligosaccharide was used as an excipient. The number of remaining viable bacteria of the obtained enteric coated granule was about 10 ⁷ cells / g, which was good.

Example 17 The procedure of Example 1 was repeated, except that the coating solution of Example 1 was combined with zein and gelatin as follows. 3 parts of gelatin was dissolved in 30 parts of water, and 17 parts of zein was added and dispersed little by little in a solvent solution containing 100 parts of ethanol, and then sugar alcohol 2 was added.
What added the part was made into the coating solution. The number of remaining viable bacteria in the obtained enteric coated granule was as good as 10 ⁸ cells / g, which was good.

[Example 18] Lactobacillus acidophilus
(Ilus) dried lactic acid bacterial powder (10 ¹⁰ viable cells / g) to be granulated, 20 parts of zein are dispersed and dissolved in 130 parts of ethanol aqueous solution (100 parts of ethanol, 30 parts of water), and centrifugally dried. The granules were coated and dried. Next, a mixture of 60 parts of skimmed milk powder, 50 parts of powdered sugar, 40 parts of zein and 150 parts of melted hardened palm oil and fat was coated on the coated dried product using a rotary pot to obtain an enteric-coated granulated product. The obtained enteric-coated granules had an initial viable cell count of 10 ⁸ cells / g and a residual viable cell count of 10 ⁸
The number was per piece / g, which satisfied the constitutional requirements of the present invention.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display area A61K 35/74 A 7431-4C C12N 1/04 7236-4B 1/20 C 7236-4B

Claims (1)

[Claims] 1. An enteric-coated granulated product, wherein the granulated product is coated with two layers shown in the following (A) and (B). (A) Oil-and-fat, excipient, and hydrous alcohol-soluble protein-containing layer. (B) Hydrous alcohol-soluble protein-containing layer.