JP3024496B2 - Tablets containing useful intestinal bacteria - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a tablet containing useful enteric bacteria.

[0002]

2. Description of the Related Art In general, useful intestinal bacteria such as bifidobacteria have been widely used in medicines, quasi-drugs, and foods in recent years. However, useful intestinal bacteria are temperature, humidity,
There are various known problems in formulation, such as easy deactivation due to various factors such as light, pH, and compression pressure during tableting.

For example, since useful enteric bacteria (especially bifidobacteria) are extremely unstable with respect to humidity, it is difficult to form tablets using wet granulated tableting granules. However, it is known that, even in this case, the viability of viable bacteria decreases due to the tableting pressure during tableting. In addition, from the viewpoint of ingestibility, it is desirable to increase the content of useful enteric bacteria into small tablets, but if the content of useful enteric bacteria is increased, the moldability will be deteriorated. There is a problem that is difficult.
Furthermore, there is a problem that useful enteric bacteria in the tablet are easily deactivated during long-term storage, and after taking, the useful enteric bacteria in the formulation are partially killed by stomach acid and delivered to the small intestine. It has also been reported that the viable cell count is reduced to 1/100 to 1/1000.

[0004] In view of these problems, as a method for improving the stability of useful enteric bacteria during preparation or storage, tableting using a sucrose fatty acid ester as a binder (JP-A-63-88133) ) Or a method of coating useful intestinal bacteria with powdered lipid having a melting point of 40 ° C. or higher (Japanese Patent Publication No. 6-4).
No. 9654) and the like, as a method of suppressing inactivation of useful enteric bacteria by stomach acid, a method of coating a cell-containing core substance with an enteric polymer such as Eudragit (Japanese Unexamined Patent Publication No.
Nos. 7233, 4-41434, 4-364123
No. etc.) have been proposed. However, at present, a satisfactory intestinal useful bacteria-containing preparation has not yet been obtained with the above-mentioned conventional techniques.

[0005]

SUMMARY OF THE INVENTION The object of the present invention is to provide a tablet containing useful enteric bacteria which has a high content of active enteric useful bacteria and is excellent in stability.

[0006]

Means for Solving the Problems As a result of intensive studies, the present inventors have found that magnesium metasilicate aluminate and calcium citrate are combined, or magnesium metasilicate aluminate and anhydrous calcium hydrogen phosphate are combined. By using as a tableting excipient in combination, it is possible to suppress the inactivation of useful enteric bacteria during tableting, to increase the content of useful enteric bacteria, to reduce the size of tablets, and The inventors have found that stabilization of useful intestinal bacteria during long-term storage can be achieved at the same time, and have completed the present invention.

That is, the present invention provides a tablet containing useful enteric bacteria, which comprises (a) magnesium aluminate metasilicate and (b) calcium citrate or anhydrous calcium hydrogen phosphate together with the enteric useful bacteria. It is.

The intestinal useful bacteria used in the present invention include, for example, Bifidobacterium longum (Bifido).
Bacterium longum), Bifidobacterium bleb (Bifidobacterium b)
rev.), and other microorganisms belonging to the genus Bifidobacterium (Bifidobacteria).

The useful enteric bacteria used in the present invention may be in the form of, for example, live bacterial powder, lyophilized product and the like. The compounding amount is 0.1 to
The content can be set in the range of 40% by weight.
It is preferable that the content be 35 to 35% by weight, especially 20 to 30% by weight.

The magnesium aluminate metasilicate used in the present invention is not particularly limited, but is preferably a neutral type having a low moisture content. Specific examples of the magnesium aluminate metasilicate include NS2N and NF2LN of Neusilin (trade name, manufactured by Fuji Chemical Industry).

The calcium citrate or anhydrous calcium hydrogen phosphate used in the present invention is not particularly limited as long as it can be used as a pharmaceutical additive. Also,
Both can be mixed and used.

The total of (a) the amount of magnesium aluminate metasilicate and (b) the amount of calcium citrate or anhydrous calcium hydrogen phosphate is 60 to 95% by weight, based on all components in one tablet. Particularly, it is preferable to use 65 to 75% by weight. The ratio of (a) the amount of magnesium metasilicate aluminate to (b) the amount of calcium citrate or anhydrous calcium hydrogen phosphate is 1: 9.
Although it can be set and used in the range of 9: 1 to 9: 1, it is preferable to set the mixing ratio of 5: 5 to 8: 2, particularly 7: 3 to 8: 2.

[0013] In addition to the above, the preparation of the present invention may optionally contain
Various additives such as excipients, binders, disintegrants, lubricants, and anti-agglomeration agents commonly used in the field of pharmaceutical technology may be blended.

The amounts of the above-mentioned excipients and the like can be used without any problems within the range based on the knowledge commonly used in the field of pharmaceutical technology. It can be used without any problems as far as it is based on certain findings.

Examples of such excipients include sugars such as sucrose, lactose, mannitol and glucose, starches such as corn starch, potato starch and partially pregelatinized starch, crystalline cellulose, calcium hydrogen phosphate, and the like.
In addition to calcium sulfate, various antacids that can be used as excipients are exemplified.

Examples of the binder include sugars or sugar alcohols such as sucrose, glucose, lactose, maltose, sorbitol and mannitol, dextrin, starch, sodium alginate, polysaccharides such as carrageenan, guar gum, gum arabic and agar, tragacanth, Gelatin, natural polymers such as gluten, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, cellulose derivatives such as polyvinylpyrrolidone,
Examples thereof include synthetic polymers such as polyvinyl alcohol, polyvinyl acetate, polyethylene glycol, polyacrylic acid, polymethacrylic acid, and vinyl acetate resin.

Examples of the disintegrant include carboxymethylcellulose, carboxymethylcellulose calcium, sodium carboxymethylstarch, corn starch, hydroxypropyl starch, partially pregelatinized starch, low-substituted hydroxypropylcellulose, polyvinylpyrrolidone, croscarmellose calcium and the like.

Examples of the lubricant and the anti-agglomeration agent include talc, magnesium stearate, calcium stearate, colloidal silica, stearic acid, hydrated silicon dioxide, waxes, hardened oil, polyethylene glycol, sodium benzoate and the like.

The preparation of the present invention may be a tablet, and its shape and size are not particularly limited.
mm, especially 5 to 7 mm tablets.

The tablet of the present invention may be in the form of a coating comprising an enteric polymer around the tablet, thereby preventing the inactivation of useful intestinal bacteria due to the effect of stomach acid after taking the tablet. ,preferable.

The enteric polymer used in the case of applying a film made of an enteric polymer is generally used in the art.
There is no particular limitation as long as it is a film-forming polymer substance that dissolves in 5 or more water but does not dissolve in an acidic region.

Examples of the enteric polymer include a cellulose derivative, a polyvinyl derivative, a maleic-vinyl copolymer, and an acrylic acid copolymer. Specific examples of such a cellulose derivative include carboxymethylethylcellulose, cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, hydroxymethylethylcellulose phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, and the like. Specific examples include polyvinyl alcohol phthalate, polyvinyl butyrate phthalate, polyvinyl acetoacetal phthalate and the like. Specific examples of the maleic acid-vinyl copolymer include vinyl acetate maleic anhydride copolymer, vinyl butyl ether maleic anhydride copolymer, styrene maleic acid monoester copolymer, and acrylic acid. Specific examples of the copolymer include methyl acrylate methacrylic acid copolymer, styrene acrylic acid copolymer, methyl acrylate octyl acrylate acrylate copolymer, methacrylic acid methyl methacrylate copolymer (for example, Eudragit) L (trade name, manufactured by Lahm Pharma Co., Ltd.)).

Of these, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate and the like are preferred, and hydroxypropylmethylcellulose acetate succinate is particularly preferred. These enteric polymers may be used alone or in combination of two or more.

The preparation of the present invention may further contain another pharmaceutically active ingredient or the like, if desired, or may have a compression coating layer or film containing the pharmaceutically active ingredient or the like around it. Good.

The method for producing the tablet of the present invention can be carried out by a usual direct hitting method. For example, calcium citrate or anhydrous calcium hydrogen phosphate is added to live bacterial powder of intestinal useful bacteria and magnesium aluminate metasilicate, and if necessary, other suitable excipients, binders, lubricants, fluidizers , A foaming agent, a coloring agent, a flavoring agent, a sweetening agent and the like may be mixed and tableted as it is. Alternatively, a granulated product may be prepared in advance by mixing additives other than useful enteric bacteria, and then mixed with live bacterial powder of useful enteric bacteria for tableting.

Tableting can be carried out using a conventional tableting machine, for example, a rotary tableting machine. The tableting speed can be suitably performed under ordinary conditions, for example, 20 to 60 rpm. The tableting pressure may be a normal tableting pressure, but is preferably set slightly lower than usual because the decrease in bacterial activity can be further reduced, and is, for example, in the range of 200 to 1000 kg / punch, particularly 300 to 500 kg / punch. It is preferable to set at.

In the case where granules are prepared in advance by mixing additives other than useful intestinal bacteria, the granules can be prepared by ordinary dry and wet granulation methods. For example, after mixing the additives, a granulation using a net granulator, a cylindrical granulator, a tornado mill, a screw granulator, an extrusion granulator such as an Alexander machine, or each component, The powder may be used as a granule using a mixing granulator such as a blender granulator or a pin granulator.
Alternatively, granules may be produced by so-called tumbling granulation, in which a binder solution is sprayed on a powder of each component in a rotating drum or pan to granulate, and each component is fluidized in a fluidized bed dryer. It may be produced by a fluidized granulation method in which a binder solution is sprayed while the mixture is being stirred.

In the case of applying a film made of an enteric polymer to the obtained tablet, the coating method is as follows. The enteric polymer is dissolved in a solvent, and for example, a fluid coating device, a pan coating device, a tumbling fluid coating granulator The method can be performed by a method usually used in this field, such as a fluid coating method, a pan coating method, and a tumbling fluid coating method. The coating can be applied by any of aqueous and non-aqueous methods usually used in this field.

At this time, by adding a plasticizer such as triethyl citrate, gastric acid resistance can be further increased and moisture permeability can be further reduced, and a good enteric coated tablet can be obtained. In addition, an adhesion inhibitor such as talc which can be generally used in this field can be added to prevent adhesion between tablets during coating and to facilitate the coating operation.

Hereinafter, the present invention will be described specifically with reference to Examples and Test Examples.

[0031]

【Example】

Example 1 Viable Bacterial Powder of Bifidobacterium (Bifidobacterium longum) (trade name: Biodiasmin B, manufactured by Amano Pharmaceutical) 90
g, 66 g of calcium citrate, 166.2 g of magnesium metasilicate aluminate (trade name: Neusilin NS2N, manufactured by Fuji Chemical Industry Co., Ltd.), 2.4 g of talc, and 2.4 g of magnesium stearate were mixed with a rotary tableting machine ( (A Collect 12HUK, manufactured by Kikusui Seisakusho)) at a tableting pressure of 400 kg / punch and a rotation speed of 40 rpm to obtain a bifidobacterium-containing plain tablet having a diameter of 6 mm and a weight of 55 mg per tablet. The hardness of the obtained tablet was about 4 kg, and the disintegration time was about 50 seconds in warm water (37 ° C.).

Example 2 Coating solution consisting of 7.4% by weight of hydroxypropylmethylcellulose acetate succinate, 7.4% by weight of talc, 0.7% by weight of triethyl citrate, 68% by weight of ethanol and 16.5% by weight of purified water Was prepared. Using the coating liquid, a high coater (HCT-4)
8, manufactured by Freund), the tablet temperature is 40 to 45 ° C.
The bifidobacterium-containing uncoated tablet manufactured in Example 1 was spray-coated by adjusting the supply air temperature and the spray liquid amount so as to fall within the range of (1).

A disintegration test was performed on the obtained enteric-coated tablet containing Bifidobacterium in accordance with the disintegration test method of the 12th revision of the Japanese Pharmacopoeia. When the first liquid was used as the test liquid, no abnormality was observed in the appearance of the tablets, and the acid permeability of the first liquid was about 2%, indicating good acid resistance. 37 ° C in the first liquid
After immersion for 120 minutes, the tablets were taken out and the number of viable bacteria was examined. As shown in Table 1, even after the immersion, bifidobacteria hardly deactivated, and the enteric coating containing bifidobacteria of this example was used. The tablets were found to exhibit extremely high gastric acid resistance.

[0034]

[Table 1]

Subsequently, a test was carried out using the second liquid. As a result, it was confirmed that all the tablets disintegrated at 37 ° C. and 7 to 8 minutes, and had good disintegration properties.

Example 3 Bacterial powder of Bifidobacterium (Bifidobacterium longum) (trade name: Biodiasmin B, manufactured by Amano Pharmaceutical) 90
g, anhydrous calcium hydrogen phosphate 66 g, magnesium metasilicate aluminate (trade name: Neusilin NS2N, manufactured by Fuji Chemical Industry Co., Ltd.) 166.2 g, talc 2.4 g, and magnesium stearate 2.4 g, were mixed by rotary tableting. Tableting was performed using a press (Correct 12 HUK, manufactured by Kikusui Seisakusho) at a tableting pressure of 400 kg / punch and a rotation speed of 40 rpm to obtain uncoated Bifidobacterium-containing tablets having a diameter of 6 mm and a weight of 55 mg per tablet. The hardness of the obtained tablet was about 4 kg, and the disintegration time was about 50 seconds in warm water (37 ° C.).

EXPERIMENTAL EXAMPLE 1 Change in Viable Bacteria Number by Tableting Pressure at Tableting The tableting pressure at tableting was 400, 700, 1000 kg / punch, and the other conditions were the same as in Example 1, except that the present invention was used. (Bifidobacterium-containing uncoated tablet) was produced. Using a mixed powder of 90 g of viable Bifidobacterium powder (trade name: Biodiasmin B, manufactured by Amano Pharmaceutical Co., Ltd.), 232.2 g of calcium citrate, 2.4 g of talc, and 2.4 g of magnesium stearate, tableting was performed at the time of tableting. 400, 700, 1
A tablet for comparison was produced in the same manner as in Example 1 except that the weight was set to 000 kg / punch.

With respect to the preparation of the present invention and the control preparation obtained as described above, the change in the viable cell count (in one tablet) due to the tableting pressure was examined. The results are shown in Table 2. From Table 2, it can be seen that at all tableting pressures, the formulation of the present invention has a significantly higher viable cell count in the tablet than the control formulation, and less inactivation of bifidobacteria during tableting. Was.

[0039]

[Table 2]

EXPERIMENTAL EXAMPLE 2 Time-dependent change in the number of viable bacteria in tablets The preparation of the present invention (uncoated tablet containing bifidobacteria) produced in Example 1 and a comparative control produced in Experimental Example 1 with a tableting pressure of 400 kg / punch Of the tablets after storage for 0, 1, 3, and 6 months, the viable cell count was measured. The tablets were placed in a glass bottle, sealed, and stored under the conditions of (1) 40 ° C., 75% relative humidity (RH), or (2) 25 ° C. Table 3 shows the results. From Table 3, it was confirmed that the formulation of the present invention was a stable formulation in which the viable cell count in the tablet was significantly higher than that of the control formulation and that of the control formulation.

[0041]

[Table 3]

[0042]

EFFECTS OF THE INVENTION The tablet of the present invention has a small inactivation of useful enteric bacteria at the time of tableting and exhibits good moldability even when a high content of useful enteric bacteria is contained. small tablets are obtained that contain the viable cells useful bacteria ¹⁰⁷ or more per tablet. Furthermore, the tablet of the present invention can be stored for a long time,
The useful enteric bacteria in the preparation are kept in a stable state. Also,
In the case of a preparation coated with a film consisting of an enteric polymer,
It shows extremely high gastric acid resistance.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI A61K 47/38 A61K 47/38 (56) References JP-A-4-41434 (JP, A) JP-A-3-7233 (JP) , A) Edited by the Japan Pharmaceutical Excipients Association, “Encyclopedia of Pharmaceutical Additives”, Yakuji Nippo Co., Ltd. 172, 107-108 (58) Fields investigated (Int.Cl. ⁷ , DB name) A61K 35/74 A61K 9/20 A61K 9/36 A61K 47/02 A61K 47/12 A61K 47/38 C12N 1/20 CA (STN)

Claims (7)

(57) [Claims] 1. A tablet containing useful enteric bacteria, comprising (a) magnesium aluminate metasilicate, and (b) calcium citrate or anhydrous calcium hydrogen phosphate, together with the useful enteric bacteria. 2. The sum of (a) the amount of magnesium metasilicate aluminate and (b) the amount of calcium citrate or anhydrous calcium hydrogen phosphate is 60 to 95% by weight based on all components in one tablet. % Of the useful enteric bacteria-containing tablet according to claim 1. 3. The composition according to claim 1, wherein the ratio of (a) the amount of magnesium aluminate metasilicate to (b) the amount of calcium citrate or anhydrous calcium hydrogen phosphate is 9: 1 to 1: 9. Tablets containing useful intestinal bacteria. 4. The tablet according to claim 1, wherein the useful enterobacterium is a microorganism belonging to the genus Bifidobacterium. 5. The tablet containing useful enteric bacteria according to claim 1, wherein the amount of the useful enteric bacteria is 0.1 to 40% by weight based on all components in one tablet. 6. The tablet containing useful enteric bacteria according to claim 1, wherein the periphery of the tablet is coated with a film made of an enteric polymer. 7. The enteric polymer according to claim 6, wherein the enteric polymer is hydroxypropylmethylcellulose acetate succinate.
The tablet containing useful intestinal bacteria according to the above.