JPH0441434A - Lactobacillus tablet provided with enteric coating - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to lactic acid bacteria tablets containing live bacteria that have high storage stability and are resistant to gastric acid.

(Prior Art) In general, lactic acid bacteria such as bifidobacteria are closely related to human health and are known to have beneficial effects on the human body, such as intestinal regulation. Therefore, by introducing these lactic acid bacteria from outside the body, it is expected that various health effects such as alleviation of symptoms of constipation and diarrhea can be obtained.

Conventionally, methods for producing live bacteria include adding stabilizers and bulking agents if desired to live bacteria obtained by culturing, and then drying under reduced pressure to powder, or adding further powder to this powder. A method of preparing a formulation by adding a stabilizer and a filler is known. However, in this case, the living bacteria may suffer from freezing damage, drying damage,
Heat damage occurs, and the number of sexually transmitted bacteria decreases during storage.

Furthermore, when taking the drug, the viable bacteria are significantly reduced by stomach acid, and the number of lactic acid bacteria that reach the intestines is extremely small, making it difficult to expect the original effects of taking the drug. Tokukai Showa 6
No. 0-23321 and JP-A No. 63-88133 also state that lactic acid bacteria, especially bifidobacteria, are easily inactivated by oxygen, water, light, acids, etc., and that deactivation can also be accelerated by pressure during tablet production. It is shown.

In recent years, various measures to improve this problem have been studied.

In other words, in improving the storage stability of live bacteria,
No. 2908 discloses a method of suspending a dry powder containing live bacteria in an oil or fat to obtain a stable live bacteria preparation. JP-A-57-33543 discloses a method of protecting bifidobacteria from environmental conditions such as oxygen by coating them with oils and fats that melt at body temperature. Also, JP-A-60-23321 and JP-A-61-26
No. 5085 discloses a method for stabilizing Bifidobacterium powder or lyophilized powder using specific compounds as stabilizers.

Furthermore, in JP-A No. 60-141281, a mixture of viable bifidobacterium cells and a protective film-forming solution thereof is injected into a coagulating salt solution to coagulate, and the coagulated product is dried, and if necessary, A method for obtaining enteric-coated bacterial cell granules suitable for long-term storage by coating with an oil or fat having a melting point above is disclosed.

On the other hand, for improvement regarding gastric acid resistance, JP-A-60=188
No. 060, by culturing bifidobacteria in a medium with specific components, the bifidobacteria have high resistance to gastric acid, and
A method for obtaining live Bifidobacterium powder that has a high shelf life is disclosed. Furthermore, JP-A-62230714 discloses a gastric acid-resistant enteric-coated capsule consisting of a core made of bifidobacteria dissolved or dispersed in a liquid substance and a wall made of hydrogenated oil having a melting point above body temperature. has been done.

JP-A-62-11053 discloses a method for enhancing the acid resistance of bifidobacteria by adding a hot water extract of mammalian liver as an active ingredient to acidic foods containing live bifidobacteria. There is.

Furthermore, as a stable method for manufacturing tablets containing bifidobacteria, a method for manufacturing tablets by coating live bacteria with a sugar fatty acid ester, which was disclosed in Japanese Patent Publication No. 53-37430, was disclosed in Japanese Patent Application Laid-Open No. 63-88133. There is.

(Problems to be Solved by the Invention) Although these conventional methods use specific compounds to obtain stable viable bacterial powder preparations and tablets, stability against gastric acid, which is a problem during oral administration, is not guaranteed. Not yet. Also in JP-A-60-188060 and JP-A-62-11053, which disclose gastric acid resistance, acid resistance is barely maintained at pH 3 or higher, and the objective is to obtain a preparation with sufficient gastric acid resistance. cannot be achieved.

Furthermore, the method disclosed in JP-A-60-141281 requires a complicated process of solidifying the bacterial fluid and then drying it, and the bacteria may die due to freezing damage during freeze-drying. Furthermore, the bacterial cells are coated on the protective film with an oil or fat that has a melting point above body temperature, such as hydrogenated oil, but at that time, the protective film of the bacterial cell granules obtained by coagulation and drying is thin, There is a possibility that the bacteria may come into contact with the hot hydrogenated oil that melts during coating and die.

In addition, the bacterial granules obtained by the above method, as described above,
Since a hydrogenated oil film is further applied on top of the protective film, there is a problem that it cannot be used effectively in the intestines unless the hydrogenated oil film disintegrates and the protective film also disintegrates.

On the other hand, enteric-coated microcapsules include those in which an enteric substance is contained as a core material in a wall made of ethyl cellulose (Japanese Patent Application Laid-open No. 58-67616), and furthermore, enteric-coated microcapsules contain polystyrene, polybutadiene, styrene-methacrylate in the wall material. It is composed of a membrane made of a polymer material such as a methyl acrylate copolymer, and a complex coacervate membrane made of gelatin and an enteric polymer electrolyte (e.g. methyl acrylate-methacrylic acid copolymer) thereon. (Japanese Unexamined Patent Publication No. 105615/1983) has been proposed.

Furthermore, the enteric-coated capsules disclosed in JP-A No. 62-230714 are manufactured using a special machine shown in JP-A-62-201635, and enteric-coated substances belonging to fats such as palm oil are There are large variations, and there are no awards at present.
. In addition, capsules are available from Pharmaceutical Sciences (Hitoshi Ilzaki et al., Kouyo Shoten 1).
98 pages, 1989), it is not common as a pharmaceutical preparation and has low productivity, so tablets with high productivity because they are cheap and easy to manufacture are used unless there is a special purpose. has been awarded. However, to date, there has been no preparation in the form of a tablet that has storage stability with viable bacteria and is resistant to gastric acid.

Therefore, the present invention aims to solve these problems and provide a lactic acid bacteria tablet that allows useful bacteria to reach the intestines without being reduced by gastric acid when the bacteria are orally ingested. Furthermore, it was an object of the present invention to provide a lactic acid bacteria tablet that can be stably and efficiently ingested with lactic acid bacteria, and can be inexpensively and easily manufactured using a general method.

(Means for Solving the Problems) As a result of studying the above-mentioned problems, the present inventors have found that - by using a unique combination of tablet additives and by keeping the compression pressure low during tablet compression, the In addition to minimizing the inactivation of bacteria, we applied the enteric coating method, which is currently used in by-product manufacturing, to increase the storage stability of tablets, and created an enteric coating that has sufficient gastric acid resistance. The objective of the present invention was achieved by efficiently producing lactic acid bacteria tablets.

That is, the present invention provides viable powder of lactic acid bacteria, starches, type Ii, celluloses, inorganic silicic acid compounds, tartar,
A tablet manufactured by a dry direct compression method etc. by mixing with one or more additives selected from the group consisting of polyvinyl pyrrolidone, wax and magnesium stearate,
This lactic acid bacteria tablet is characterized by being coated with an enteric coating that is resistant to stomach acid.

The viable lactic acid bacteria powder used in the present invention is preferably prepared by freeze-drying in a conventional manner and has a good shelf life.

The lactic acid bacteria used may be of human origin, such as Lactobacillus faecalis (Lactobacillus faecalis).
obacillus faecalis), Lactobacillus acidophilus (Lactobacillus acidophilus)
llusacido hilus), or Bifidobacterium longum (Bifidobacterium longum).
There are obacterium (obacterium), etc.

Additives that can be used in the present invention include corn, wheat,
Starches such as potatoes, sugars such as lactose, glucose, and sorbitol, inorganic silicate compounds such as aluminum silicate and silicic anhydride, crystalline cellulose, methyl cellulose,
Examples include celluloses such as carboxymethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose, polyvinylpyrrolidone, talc, wax, and magnesium stearate.

These additives can be used by mixing them in appropriate proportions, and from the viewpoint of the physical properties of the tablet, it is desirable to use the additives in an amount of 80 to 95% of the total ingredients.

Among these additives, a combination of all of lactose, potato starch, microcrystalline cellulose, hydroxypropyl cellulose, and magnesium stearate with either magnesium aluminate metasilicate or light silicic anhydride improves the physical properties of the tablet and It is particularly desirable in terms of the storage stability of lactic acid bacteria.

Tablets are made by mixing the components and directly compressing the tablets, but they may also be granulated in advance and then compressed. In that case, the dry granulation method is more preferable in terms of the storage stability of lactic acid bacteria.

It is desirable for tablets to have high hardness and low friability, physical properties suitable for coating, and to have small loss of lactic acid bacteria during tablet manufacturing. When manufacturing tablets, a tableting pressure of 500 to 1500 kg is used.

As enteric materials for coating the tablets, common gastric acid resistant materials such as hydroxymethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, styrene maleic acid copolymers, methacrylic acid copolymers, etc. can be used. These substances are dissolved in volatile solvents such as methylene dichloride and ethanol, and coated using conventional methods such as pan coating and fluidized bed coating.
Tablets can be coated. At this time, Mybaseft (edited by the Japan Federation of Industrial Science and Technology, Latest Formulation Technology Series LKL, Pharmaceutical Coatings 373-3) was used as a plasticizer.
It is also possible to lower the moisture permeability by adding an appropriate amount of materials such as (p. 74), or to add a general light blocking material such as titanium oxide.

The coating amount must be sufficient to prevent gastric juice penetration and increase long-term storage stability, and is preferably 10 to 15% of the total weight of the tablet.

The tablet of the present invention thus produced contains at least 10' viable bacteria, and the objective can be achieved by administering one tablet once a day.

(Example) Examples and test examples are shown below, but the present invention is not limited thereto.

Example 1 A mixed powder containing 1202.300.100.9.9 parts by weight of lactose, crystalline cellulose, hydroxypropyl cellulose, light anhydrous silicic acid, and magnesium stearate, respectively, was prepared as an additive.

1,620 parts by weight of this additive was mixed with Streptococcus faecalis (Streptococcus faecalis) using potato starch purchased from Japan Freeze Drying Research Institute Co., Ltd. as a protective agent.
cus faecalis), Lactobacillus.

Lactobacillus aci
do hilus), and Bifidobacterium longum (Bifid.

60 parts by weight of each freeze-dried powder of bacterium ion (u+w) was added. After mixing, tablets having a diameter of 8 fi, a tablet thickness of about 4 mm, and a weight of about 180 square centimeters per tablet were manufactured by dry direct compression at a compression pressure of 1000 kg. The hardness of the obtained tablets was 4.9 kg on average, and the average friability was 0.2.
7%, and the average disintegration time in purified water was 56 seconds.

The manufactured tablets contained 6.0% hydroxymethyl cellulose phthalate, 0.6% Mybacesotho, and 48% ethanol.
A coating solution consisting of 8% and 45.0% methylene dichloride was prepared, and the tablets were coated with a coverage of about 10% (W/W) by a pan coating method. Intake temperature is 60-65℃, exhaust temperature is 33℃
-35°C, pan rotation speed was 25 rpm.

Each coated tablet obtained was subjected to a disintegration test based on the disintegration test method of the Japanese Pharmacopoeia. When the first liquid was used as the test liquid, no abnormality was observed in appearance, and the penetration rate of the first liquid was 2.8% on average, indicating good one-liquid resistance. When the second liquid was subsequently tested, the average time was 8 minutes 55 minutes.
It disintegrated in seconds, and good second liquid disintegration properties were observed.

Test Example Changes in the number of lactic acid bacteria during compression of the manufactured tablets, gastric acid resistance of the tablets, and changes in the number of viable bacteria during storage of the tablets were tested.

(Change in the number of lactic acid bacteria during tablet compression of 17 tablets Changes in the number of viable bacteria in one tablet when tablets were compressed under the conditions in Example were investigated.

The results are shown in Table 1.

Table 1 Changes in the number of viable bacteria (X 10') in tablets during tableting (2) Gastric acid-resistant artificial gastric juice (0, IN HCI, 0.3% NaCl 1,1)
%pepsin.

p)I about 1.2) was prepared, and the coated tablets of the present invention prepared in the examples and the commercially available non-coated tablets as a control were immersed in this artificial gastric juice. After being held at 37°C for 60 minutes, the temperature was immediately reduced to 0. Neutralized with IN NaOH. Since the control tablet was dissolved, the number of viable bacteria in the suspension was directly measured.

On the other hand, the number of viable bacteria was measured after the coated tablets were removed from the artificial gastric fluid. The number of viable bacteria was measured basically according to the optical method.

The results are shown in Table 2.

As is clear from Table 2, the enteric-coated lactic acid bacteria-containing tablets produced in this example had an extremely high survival rate of lactic acid bacteria compared to tablets that were not enteric-coated.

Table 2: Gastric acid resistance of coated and uncoated tablets and storage.

Table 3 shows the storage results at 40° C. and 75% humidity, and Table 4 shows the storage results at room temperature.

There is a clear difference in storage stability between coated and uncoated products, and it has been shown that coating significantly improves storage stability.

Book 1: Coated tablets, *2: Commercially available non-coated tablets (
3) Changes in the number of viable bacteria during storage of tablets Changes in the number of viable bacteria during storage of tablets at 40°C and 75% humidity and at room temperature (no humidity adjustment)
Tested on day. As samples, the enteric-coated lactic acid bacteria-containing tablets produced in Examples and the lactic acid bacteria-containing tablet side of the plain tablets produced in Examples before enteric coating were used. The tablets are placed in a glass sample bottle and covered with a plastic cap. (Effects of the Invention) According to the present invention, tablets containing lactic acid bacteria are coated with a gastric acid-resistant enteric coating to prevent gastric juices from penetrating into the tablets. It is possible to protect lactic acid bacteria from gastric acid and prevent a decrease in viable bacteria.

Further, when the tablet passes through the stomach and reaches the intestine, the coating agent is rapidly dissolved by the action of intestinal fluids, and a high number of lactic acid bacteria is expected to be transferred into the intestine.

Furthermore, the lactic acid bacteria tablet of the present invention also has the advantage that viable bacteria decrease less during storage.

From the above, the present invention fully exhibits the effects of oral ingestion of lactic acid bacteria tablets, and is also useful from an economical point of view since it does not require complicated steps.

Claims (4)

[Claims] (1) Mix lactic acid bacteria powder with one or more additives selected from the group consisting of starches, sugars, cellulose, inorganic silicic acid compounds, talc, polyvinyl pyrrolidone, wax, and magnesium stearate. A lactic acid bacteria tablet characterized in that the manufactured tablet is coated with an enteric substance. (2) The lactic acid bacteria tablet according to claim 1, wherein the enteric substance is hydroxymethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, or methacrylic acid copolymer. (3) The lactic acid bacteria tablet according to claim 1, wherein the additives include all of potato starch, lactose, crystalline cellulose, hydroxypropyl cellulose, and magnesium stearate, and magnesium aluminate metasilicate or light anhydrous silicic acid. (4) The lactic acid bacteria tablet according to claim 1, which contains bifidobacteria as the lactic acid bacteria.