JP2017149681A - Large intestine delivery capsule formulation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a large intestine delivery capsule preparation which is excellent in storage stability of an encapsulated bacterium useful for the large intestine and is capable of delivering the active bacterium useful for the large intestine in an amount sufficient for exhibiting excellent health effects to the large intestine.SOLUTION: The large intestine delivery capsule preparation of the present invention has a capsule encapsulating the bacterium useful for the large intestine, and the capsule has a chitosan-containing layer and an enteric base material-containing layer in order from the inside. The capsule encapsulates a sucrose fatty acid ester, and the encapsulated amount of the sucrose fatty acid ester is 0.5 to 25 mass% based on the total amount encapsulated in the capsule.SELECTED DRAWING: None

Description

  The present invention relates to a composition for delivering large intestine containing useful colons.

  Good enteric bacteria such as bifidobacteria and lactic acid bacteria have an intestinal regulating action such as suppressing the growth of bad bacteria such as E. coli in the intestine and improving the intestinal bacterial flora and intestinal environment. Conventionally, attempts have been made to obtain various health effects such as intestinal regulation by orally ingesting such useful colon bacteria as viable bacteria. However, it is necessary to pass through the stomach and small intestine to reach the lower part of the digestive tract, where the intestinal useful bacteria that are taken orally are active, especially the large intestine, digestion of gastric acid and bile acids in the stomach and small intestine Due to the influence of the liquid, many useful bacteria of the large intestine were inactivated before reaching the large intestine, and there was a problem that sufficient health effects could not be obtained.

  Conventionally, use of a so-called drug delivery system (DDS) formulation has been proposed as a solution to this problem. A DDS preparation is a preparation in which an active ingredient is physically protected, and the active ingredient can be delivered to a desired site of a human body by ingestion. Regarding a large intestine delivery system for useful colons using a DDS preparation, for example, Patent Documents 1 to 4 enclose useful colons such as bifidobacteria in hard capsules made of a cellulose derivative and the like. An oral capsule preparation that is sequentially coated with an acid resistant coating is disclosed. In the capsule preparation having such a structure, the acid-resistant film of the outermost layer plays a role of preventing the decomposition of the chitosan film by gastric acid, and the chitosan film passes the stomach and reaches the small intestine from the intestinal juice. Play a protective role. As for the chitosan coating, Patent Document 3 describes a chitosan-containing composition suitable for the chitosan coating, in which chitosan, polyhydric alcohol, and zein are blended in specific amounts.

JP 2011-105654 A JP 2012-149032 A JP 2014-122184 A JP 2014-139200 A

  The conventional large intestine delivery capsule preparations described in Patent Documents 1 to 4 are all useful to deliver to the large intestine without inactivating useful bacteria, but the number of active useful bacteria that can be released in the large intestine. There is still room for improvement or increase. As a method of increasing the number of active and useful bacteria that can be released in the large intestine of capsule preparations, it is effective to increase the thickness of the chitosan coating that protects useful bacteria, but the thick chitosan coating takes time and labor to produce. It is disadvantageous in terms of production cost, and above all, if it takes time to produce capsule preparations including processes such as heating and pressurization, it will have adverse effects due to heat and pressure during production, humidity (moisture) in the production environment, etc. However, there is a possibility that useful bacteria may be inactivated during the production thereof, and a situation may occur in which a considerable number of useful bacteria already encapsulated in the capsule preparation have been inactivated before the ingestion in the body. In addition, increasing the thickness of protective members for useful bacteria such as acid-resistant coatings and chitosan coatings will result in remaining protective members that should have disappeared when the capsule preparation reaches the large intestine. As a result, the capsule preparation is useful in the large intestine. There is a possibility that an inconvenient situation that the bacteria are discharged outside the body without releasing the bacteria frequently occurs. A large intestine delivery capsule preparation that can be delivered to the large intestine without inactivating a large number of useful bacteria has not yet been provided.

  An object of the present invention is to provide a large intestine delivery capsule preparation that is excellent in the storage stability of the encapsulated large intestine useful bacteria and is capable of delivering a sufficient amount of active large intestine useful bacteria to the large intestine to have an excellent health effect. It is in.

  The present invention is a colon delivery capsule preparation having a capsule encapsulating useful colons, wherein the capsule has a chitosan-containing layer and an enteric base material-containing layer in this order from the inside, and the capsule contains a sucrose fatty acid ester Is a large intestine delivery capsule preparation in which the amount of the sucrose fatty acid ester is 0.5 to 25% by mass based on the total amount of the capsule inclusions.

  ADVANTAGE OF THE INVENTION According to this invention, the colon delivery capsule formulation which is excellent in the preservation stability of the encapsulated large intestine useful bacteria, and can deliver the active large intestine useful microbe to the large intestine enough to have the outstanding health effect is provided. . Therefore, the large intestine delivery capsule preparation of the present invention has an excellent intestinal regulating action, and can greatly improve the intestinal environment.

  The large intestine delivery capsule preparation of the present invention comprises a useful colon microbe and a capsule containing the same. Useful bacteria for the large intestine are not particularly limited as long as they are capable of exhibiting a preferable function in the large intestine of a human or animal body, and examples thereof include bifidobacteria, lactic acid bacteria, natto bacteria, and butyric acid bacteria. These can be used alone or in combination of two or more.

  Examples of Bifidobacterium that can be used in the present invention include Bifidobacterium Thermophilum, Bifidobacterium longum, Bifidobacterium bifidum, Bifidobacterium Bifidobium breve), Bifidobacterium adolescentis, Bifidobacterium infantis, Bifidobacterium animaris, Bifidobacterium Bifidobacterium Bifidobacterium Bifidobacterium Bifidobacterium Bifidobacterium Bifidobacterium Bifidobacterium Bifidobacterium Bifidobacterium Bifidobacterium Bifidobacterium spp. such as ifidobacterium pseudolongum). Among these, Bifidobacterium longum (B. longum), Bifidobacterium bifidum (B. bifidum), and Bifidobacterium breve (B. breve) are preferably used.

  Examples of lactic acid bacteria that can be used in the present invention include bacteria of the genus Lactobacillus and Streptococcus, such as Lactobacillus gasseri, Lactobacillus acidophilus, Lactobacillus casei and Lactobacillus casei. (Lactobacillus rhamnosus), as well as plant lactic acid bacteria, such as lactic acid bacteria RIE strains.

  Examples of Bacillus natto that can be used in the present invention include Bacillus natto derived from commercially available natto, as well as commercially available Bacillus natto, such as Takahashi (Yuzo Takahashi, Yamagata), Naruse (Naruse Fermentation and Chemical Research, Inc.) , Tokyo), Miyagino fungus (Miyagino Natto Factory, Sendai), Asahi fungus (Asahi Kogyo Co., Ltd., Tokyo), Nitto fungus (Nitto Pharmaceutical Co., Ltd., Kyoto), Meguro fungus (Meguro Co., Ltd.) Research Institute, Osaka).

  Examples of butyric acid bacteria that can be used in the present invention include commercially available butyric acid bacteria, such as Miyairito (Miyarisan Pharmaceutical Co., Ltd., Tokyo), Toa (Toa Pharmaceutical Co., Ltd., Tokyo), Nitto Bacteria (Nippon Pharmaceutical Co., Ltd.). Manufactured by Kyoto).

  In the present invention, the form of useful colon in the capsule is not particularly limited, and can be appropriately selected from dry powder, solid, liquid, and the like according to the purpose. The solid useful colonic bacteria are, for example, a solid mixture of useful colon and hardened fats and oils, and the liquid useful colon is, for example, a suspension obtained by suspending useful colons in an appropriate medium. is there. A particularly preferable form of useful colon bacteria is a dry powder. The useful bacteria of the large intestine in a dry powder have a lower water content than liquids and are easy to handle. Useful dry colon bacteria that are easy to handle reduce the production time of capsule preparations and suppress the inactivation of useful colon bacteria due to the use of dry powder that is easy to handle. In combination with the action and effect of the combined use of sucrose fatty acid ester, which is the main characteristic part of the present invention, the preservation stability of useful colon can be improved. In addition, the useful powder of large intestine in dry powder can encapsulate a large amount of useful bacteria in large intestine in a capsule as compared with a liquid or the like, and an amount capable of sufficiently obtaining a health effect can be easily blended.

In the present invention, useful colon bacteria are usually encapsulated in a live state. After encapsulating useful bacteria in the large intestine in a capsule, it may be grown in the capsule. The amount of useful large intestine bacteria encapsulated in the capsule is not particularly limited as long as it is appropriately changed according to the form of the bacteria encapsulated in the capsule, the size of the capsule, and the like. For example, when the form of the useful colon in the capsule is a dry powder, the amount of the useful colon in the capsule is preferably 5.0 to 99.5 mass relative to the total amount of the capsule. %, More preferably 20.0 to 75.0 mass%. If the amount of useful colon bacteria is too small, the health benefits of useful colon bacteria will not be sufficient, and if the amount of useful colon bacteria is too large, the balance of the intestinal flora will be lost, causing side effects such as diarrhea. There is a fear. In addition, if the amount of useful colons in the colon is too large, it may be difficult to use excipients with low water activity, resulting in a significant decrease in useful colons during manufacture and storage of capsule preparations. Therefore, there is a risk that a sufficient amount of active useful bacteria cannot be secured before ingestion, that is, the shelf life of the capsule preparation may be shortened. From the same viewpoint, when the colon useful bacteria are in a dry powder form, the concentration of the colon useful bacteria in the capsule is preferably 1 × 10 ⁶ cfu / g or more, and more preferably 1 × 10 ⁹ cfu / g or more. “Cfu” represents a colony forming unit.

  One of the main features of the large intestine delivery capsule preparation of the present invention is that the capsule contains a sucrose fatty acid ester together with useful colon bacteria. As a result, the storage stability of the useful colons of the large intestine is improved, and it becomes possible to significantly increase the number of active useful colons of the large intestine that can be released from the capsule preparation in the large intestine as compared with the prior art. Sucrose fatty acid esters can strongly protect useful colon bacteria from gastric acid and intestinal juice until the capsule preparation taken orally reaches the large intestine. Therefore, according to the present invention, there is no need to physically reinforce the capsule itself, such as increasing the thickness of the chitosan coating for the purpose of protecting useful colon bacteria, and it is possible to increase the thickness of the chitosan coating without encapsulating sucrose fatty acid esters. Compared with conventional capsule preparations, the storage stability of useful colon bacteria is comparable to that of the present invention, so that the time for producing capsule preparations can be shortened. Inactivation can be effectively prevented. That is, the combined use of useful colon bacteria and sucrose fatty acid ester makes it possible to efficiently produce a high-quality colon delivery capsule preparation that exhibits excellent health effects such as intestinal regulation.

  As sucrose fatty acid ester used by this invention, what is normally used as a food additive can be especially used without a restriction | limiting. The main use of sucrose fatty acid ester as a conventional food additive is an emulsifier, and the protection of useful colon in the large intestine by sucrose fatty acid ester proposed by the present invention is different in technical idea from such conventional technology. It can be said that there is. According to the knowledge of the present inventor, the lower the HLB (hydrophilic-lipophilic balance) value of the sucrose fatty acid ester, that is, the higher the lipophilicity, the better the protective effect of useful colon bacteria. From such a viewpoint, the sucrose fatty acid ester preferably has an HLB value of 0 to 10, and more preferably has an HLB value of 0 to 6.

  The encapsulated amount of sucrose fatty acid ester in the capsule is 0.5 to 25% by mass, preferably 0.5 to 15% by mass, more preferably 0.5 to 10% by mass with respect to the total amount of the encapsulated product. %. When the encapsulated amount of sucrose fatty acid ester is less than 0.5% by mass with respect to the total amount of capsule inclusion, it is not meaningful to use sucrose fatty acid ester. When the encapsulated amount exceeds 25% by mass, the working efficiency of encapsulating the powder in the capsule is remarkably lowered, and for example, the control of the encapsulated amount may be difficult, and the capsule preparation is efficiently produced. Can not be. Moreover, when the amount of inclusion exceeds 25% by mass, the amount of inclusion of useful colon bacteria is relatively reduced, and various health effects due to useful colon bacteria may not be sufficiently achieved.

  In the present invention, if necessary, other components other than useful colon bacteria and sucrose fatty acid esters can be used as capsule inclusions. Other components include: a medium for suspending bacteria used when the large intestine useful bacteria are converted into a liquid; a hardened oil used when the large intestine useful bacteria are converted into a solid; Lactose, starch, dried potato starch, etc. used in the case of thickening polysaccharides such as carrageenan, agar, pectin, gum arabic, xanthan gum, pullulan, gellan gum, alginate; fine silicon oxide, microcrystalline cellulose, Iron salt, hemirose, gelatin, casein, sodium caseinate, calcium caseinate, potassium casein, magnesium casein, milk protein, milk protein peptides, milk protein digest, lactoferrin, vegetable oil, hardened oil, sugar, whey, maltodextrin, Low water activity such as carmellose sodium, pregelatinized starch, and modified starch Ingredients that reduce water activity; ingredients useful for improving the intestinal environment, such as oligosaccharides, water-soluble dietary fiber, and water-insoluble dietary fiber, can be used alone or in combination of two or more Can do. In particular, when a thickening polysaccharide such as xanthan gum is encapsulated in a capsule preparation, after the capsule preparation is ingested, the thickening polysaccharide forms a gel on the surface of useful colon bacteria in the capsule, thereby entering the inside of the capsule. It is expected that the penetration of gastric juice and intestinal fluid will be suppressed. That is, the thickening polysaccharide is expected to have an effect of protecting useful colon in the digestive tract, and therefore, as in Example 3 described later, the combined use of sucrose fatty acid ester and thickening polysaccharide is preferable.

  The capsule according to the present invention has a chitosan-containing layer and an enteric base material-containing layer in order from the inside. In the present invention, both layers need only be arranged in this order from the inside, and the capsule layer structure can take various forms without departing from the spirit of the present invention. In the present invention, as the layer structure of the capsule, 1) a form in which the chitosan-containing layer is the innermost layer of the capsule, 2) layers other than the chitosan-containing layer and the enteric substrate-containing layer inside the chitosan-containing layer (for example, , A layer mainly composed of gelatin or cellulose derivatives), 3) a form in which a chitosan-containing layer and an enteric base material-containing layer are laminated without interposing another layer, 4) a chitosan-containing layer Form in which one or more other layers are interposed between the enteric base material containing layer and 5) Enteric base material containing layer is the outermost layer of the capsule, 6) Outside the enteric base material containing layer A form in which one or more layers other than the chitosan-containing layer and the enteric base material-containing layer (for example, a layer made of beeswax, carnauba wax, etc.) are present is included, and the above 1) to 6) are appropriately combined with each other Can do.

  In addition, the form of the capsule according to the present invention is not particularly limited as long as it has an accommodating part for colonic useful bacteria therein, and may be, for example, a hard capsule, a soft capsule, or a seamless capsule. Among them, hard capsules that have a body part and a cap part are fitted with bifidobacteria that are sensitive to high temperatures and moisture due to relatively mild temperature conditions in the manufacturing process and low moisture contained in the preparation. It is preferably used in the present invention because it can suppress the inactivation of useful colon bacteria. In particular, the combination of dry colon useful bacteria (bifidobacteria) and hard capsules effectively removes the colon useful bacteria from gastric acid or intestinal juice without the need for physical reinforcement of the capsule itself with the sucrose fatty acid ester. Since it can be said that the effect that can be protected is easily extracted to the maximum, it is preferably used in the present invention. A typical form of the hard capsule includes a cylindrical body portion in which stored items such as useful bacteria of the large intestine and sucrose fatty acid ester are accommodated, and a cylindrical cap portion. By fitting inside the cap part, a capsule form is obtained. Hard capsules can be produced by a known method.

  A preferred embodiment of the capsule according to the present invention includes a hard capsule in which a body part and a cap part are fitted, wherein the hard capsule contains a useful powder of large intestine and a sucrose fatty acid ester in a dry powder, and the outside of the hard capsule. Is coated with a chitosan-containing layer, and the chitosan-containing layer is further coated with an enteric substrate-containing layer. Hard capsules in such a form are usually substantially free of chitosan and enteric base.

  A band seal may be applied to the fitting portion between the body portion and the cap portion in the hard capsule from the viewpoint of enhancing the protection of the capsule inclusion. That is, the hard capsule according to the present invention may have its fitting portion sealed with a band seal. Capsule band sealing can be performed according to a conventional method using a known band sealing material. However, as described above, in the present invention, the use of sucrose fatty acid ester in the capsule inclusions can strongly protect the useful bacteria of the large intestine from gastric acid and intestinal fluid, and therefore there is no need for band sealing. If the band seal is omitted, the production time can be further shortened, which contributes to the suppression of inactivation of useful colon bacteria.

  As the material of the capsule, those conventionally used for this type of capsule preparation can be used without particular limitation, and examples thereof include cellulose and cellulose derivatives obtained by modifying cellulose derived from animals or plants. Examples of cellulose derivatives include alkyl cellulose (eg, methyl cellulose), hydroxyalkyl cellulose (eg, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, etc.), hydroxyalkyl alkyl cellulose (eg, hydroxypropyl methyl cellulose (HPMC), Hydroxyethyl methylcellulose, hydroxyethylethylcellulose, etc.), and the like can be used alone or in combination of two or more. Among these, hydroxyalkylalkyl cellulose is preferable, and HPMC is more preferable from the viewpoint of the strength of the capsule and the ease of dissolution in the large intestine.

  As the chitosan contained in the chitosan-containing layer according to the present invention, those used in this type of capsule preparation can be used without particular limitation, but when the degree of deacetylation of chitosan is 60 mol% or more, chitosan It is preferable in terms of ease of formation of the containing layer (solubility in an acid solution when preparing a coating liquid for forming a chitosan-containing layer) and film forming properties. The chitosan content in the chitosan-containing layer is preferably 25% by mass or more, more preferably 25 to 85% by mass, and more preferably 35 to 80% by mass in the total mass of the chitosan-containing layer in the dry state.

  The chitosan-containing layer according to the present invention preferably further contains zein in addition to chitosan. Zein is a water-insoluble protein extracted from corn and is also called corn protein. When the chitosan-containing layer according to the present invention contains both chitosan and zein, it exhibits good colonic disintegration similar to a chitosan-containing layer not containing zein, but compared to a chitosan-containing layer not containing zein. As a result, the film-forming property and water resistance are improved, and the swelling and disintegration of the capsule before reaching the large intestine can be more effectively prevented. The content of zein in the chitosan-containing layer according to the present invention is preferably 0.5 to 100% by mass, more preferably 5 to 80% by mass with respect to the chitosan mass in the chitosan-containing layer. If the zein content is too low, it is not meaningful to use zein. If the zein content is too high, the chitosan mass is reduced and the protective effect from the intestinal juice is impaired, and the capsule may collapse before reaching the large intestine. There is.

  On the other hand, the enteric substrate contained in the enteric substrate-containing layer according to the present invention may be any material that has acid resistance and is difficult to dissolve in the stomach but dissolves in the small intestine. For example, carboxymethyl ethyl cellulose (CMEC) ), Methacrylic acid copolymer, hypromellose phthalate (HPMCP), zein, shellac, and one of these can be used alone or two or more can be used in combination. Shellac is a resinous substance obtained by purifying a larval body cover secreted by Laccifer lacca and several closely related scale insects, and is also called shellac.

  The content of the enteric substrate in the enteric substrate-containing layer according to the present invention is preferably 80.0% by mass or more, more preferably 80.0 to the total mass of the enteric substrate-containing layer in the dry state. It is 99.5 mass%, More preferably, it is 90.0-99.5 mass%. The enteric substrate-containing layer can contain other components other than the enteric substrate, for example, a water-insoluble additive, if necessary. Examples of the water-insoluble additive include glycerin fatty acid ester, talc, an organic acid having 10 or more carbon atoms, or a metal salt thereof.

  Each of the chitosan-containing layer and the enteric base material-containing layer according to the present invention can be formed according to a conventional method. For example, in the case where the outside of the hard capsule is coated with a chitosan-containing layer as described above, the chitosan-containing liquid prepared by dissolving various components such as chitosan and zein in a solvent is applied to the hard capsule by means such as coating, spraying, and impregnation. The chitosan-containing layer can be formed by attaching to the outer surface and then drying. The enteric substrate-containing layer can also be formed by a known method similar to this.

  Regarding the thickness of the chitosan-containing layer according to the present invention, the thickness of the chitosan-containing layer is preferably as thick as possible from the viewpoint of protecting the inclusions after the capsule preparation is orally ingested until reaching the large intestine. The chitosan-containing layer may increase the production time of the capsule preparation, which may lead to the inactivation of useful colon bacteria during the manufacture of the capsule preparation, and the number of active colon useful bacteria that can be delivered to the large intestine May be insufficient. In that respect, in the present invention, the use of a sucrose fatty acid ester in the capsule inclusions can strongly protect the colonic bacteria from gastric acid, intestinal fluid, etc., so that the chitosan-containing layer is particularly thick for the purpose of protecting the colonic bacteria. There is no need to do. In addition, if the thickness of the chitosan-containing layer is too thick, the capsule preparation still remains in a form that can sufficiently protect the inclusions in the capsule preparation that has reached the large intestine. As a result, the capsule preparation releases useful bacteria in the large intestine in the large intestine. There is a risk that it will be discharged outside the body.

  From such a viewpoint, the thickness of the chitosan-containing layer according to the present invention is preferably 0.5 to 2.0 with respect to the mass of the portion in which the mass of the chitosan-containing layer is inward of the chitosan-containing layer. The thickness is 0.5% by mass, more preferably 0.5-1.3% by mass, and most preferably 0.8-1.2% by mass. As used herein, “part existing inward from the chitosan-containing layer” means all parts existing inward rather than including the chitosan-containing layer. For example, the hard capsule is the innermost layer. In this case, they are hard capsules (gelatin or cellulose derivative-containing layer) and capsule inclusions (such as useful colons and sucrose fatty acid esters).

  From the same point of view, the thickness of the enteric base material-containing layer according to the present invention is such that the mass of the enteric base material-containing layer is inward of the part of the enteric base material-containing layer. , Preferably 0.5 to 2.0% by mass, more preferably 0.5 to 1.2% by mass, and most preferably 0.8 to 1.1% by mass. As used herein, the “part existing inward from the enteric base material-containing layer” means all parts existing inward from the enteric base material-containing layer without including the enteric base material-containing layer. In the case of the innermost layer, a chitosan-containing layer, a hard capsule (gelatin or cellulose derivative-containing layer), and a capsule inclusion (useful colon, sucrose fatty acid ester, etc.).

  The size and shape of the large intestine delivery capsule preparation of the present invention are not particularly limited as long as it is appropriately adjusted according to the amount of inclusions. Examples of the capsule size include commonly used sizes such as No. 0, No. 1, No. 2, No. 2, No. 3, No. 4, No. 5, etc. Examples include spherical shapes. In the production of the large intestine delivery capsule preparation of the present invention, for each step such as the production of a capsule including the formation of a chitosan-containing layer and an enteric base material-containing layer, and filling into a capsule of useful colons, etc., Patent Documents 1 to The description of 4 can be referred to as appropriate.

  The large intestine delivery capsule preparation of the present invention is usually used by oral ingestion, improves the intestinal microflora and intestinal environment of a human or animal, and brings about an intestinal regulating effect on the human or animal. Examples of non-human animals to which the large intestine delivery capsule preparation of the present invention can be applied include primates, cows, pigs, sheep, goats, dogs, cats, rodents and the like.

  The large intestine delivery capsule preparation of the present invention may be provided by being added to food or feed, or may be provided as a medicine or a supplement. The colon delivery capsule preparation of the present invention that can be used as a composition, pharmaceutical or supplement for improving the intestinal environment or adjusting the intestine, as described above, is produced by producing a capsule containing a useful colon and sucrose fatty acid ester. The capsule has a chitosan-containing layer and an enteric base material-containing layer in this order from the inside. The large intestine delivery capsule preparation of the present invention is produced, for example, by coating a hard capsule encapsulating useful colon and sucrose fatty acid ester with a chitosan-containing layer, and then coating the chitosan-containing layer with an enteric base material-containing layer. The

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated further in detail, this invention is not restrict | limited by an Example.

[Examples 1-3 and Comparative Examples 1-5]
Using a dry powder of viable bifidobacteria (manufactured by Morinaga Milk Industry Co., Ltd., Morinaga bifidobacterial powder) as useful colon bacteria, a composition containing useful colon colonies is obtained by appropriately mixing other ingredients, and the colon useful composition is obtained. After filling the fungus-containing composition into a commercially available hard capsule, a chitosan-containing layer and an enteric base material-containing layer having a predetermined thickness are sequentially formed on the outside of the hard capsule, and the surface of the bifidobacteria-containing hard capsule is formed on the surface of the chitosan-containing layer, intestine A large intestine delivery capsule preparation was produced by sequentially coating with a soluble substrate-containing layer. The details of such production are as described in [1] and [2] below. The composition of the large intestine delivery capsule formulation of each Example and Comparative Example is shown in Table 1 below.

[1] Filling hard capsules with useful colon-containing fungus composition In an environment at a temperature of 25 ° C. and a humidity of 60% or less, a predetermined amount of a plurality of capsule-encapsulated components containing useful colon bacteria is mixed and stirred to dry powder Obtained a composition containing useful bacteria of the large intestine. The useful colon-containing bacteria-containing composition and the hard capsule were set in a capsule filling machine (LIQFIL super JCF40, manufactured by Qualicaps Co., Ltd.), and 240 mg of the useful colon-containing bacteria-containing composition was filled into the hard capsule according to a conventional method. The hard capsules used here were HPMC capsules (Qualicaps Co., Ltd., Quali-V (R) -N, No. 3, capsule mass: 51 mg). Moreover, the band seal was not given to the fitting part of the body part and cap part in a hard capsule. The components used in addition to the useful colon (bifidobacteria) as the capsule encapsulated components are as follows.
・ Sucrose fatty acid ester (Mitsubishi Chemical Foods, HLB value 3.0)
・ Xanthan gum (Mitsubishi Corporation Foodtech)
・ Hydroxypropyl methylcellulose (HPMC) (manufactured by Shin-Etsu Chemical)
・ Sodium alginate and calcium carbonate (Morinaga Milk Industry)
・ Potato starch (powder, made by Matsutani Chemical)

[2] Hard Capsule Coating A chitosan-containing layer is prepared by applying and drying a chitosan-containing layer-forming coating solution prepared by the following method on the outer surface of the hard capsule containing the useful colon-containing bacteria-containing composition obtained in [1]. Formed (chitosan-containing layer forming step). Such a process was carried out at a constant drying temperature (48 ° C.) using a film coating apparatus high coater mini-type pan (manufactured by Freund Corporation). In the chitosan-containing layer, the chitosan content was 57% by mass and the zein content was 28% by mass.
Furthermore, an enteric substrate-containing layer forming coating solution prepared by the following method was applied to the surface of the chitosan-containing layer and dried to form an enteric substrate-containing layer (enteric substrate-containing layer forming step). Such a process was performed using a film coating apparatus high coater mini-type pan (Freund Sangyo Co., Ltd.). In such an enteric substrate-containing layer, the content of the enteric substrate (shellac) was 95% by mass.
Furthermore, 1% by mass of anhydrous ethanol in which a saturated dissolution amount of carnauba wax was dissolved was applied to the surface of the enteric substrate-containing layer and dried.

(Preparation of coating liquid for forming chitosan-containing layer)
Chitosan (Flornack C: made by Nihon Suisan Co., Ltd.) having a degree of deacetylation of 80 mol% or more is dissolved in acidic water adjusted to pH 4 by adding acetic acid to purified water, and glycerin (made by EmeryOlechemicals) is added. To obtain a chitosan-dissolved solution. After adding a solution obtained by dissolving zein (Kobayashi Twein DP: manufactured by Kobayashi Fragrance Co., Ltd.) with an ethanol solution to the chitosan-dissolved solution, the final concentration of chitosan becomes 2.0% by mass. Thus, a chitosan-containing layer forming coating solution was prepared by adjusting with purified water and ethanol. The composition of the resulting coating liquid for forming a chitosan-containing layer was composed of 100% by mass of all components, and 2.0% by mass of chitosan, 0.5% by mass of zein, 1.0% by mass of glycerin, 52% by mass of ethanol, and the remainder Was water.

(Preparation of coating solution for enteric substrate-containing layer formation)
Dissolve shellac as an enteric base material (decolored shellac, manufactured by Gifu Serac Manufacturing Co., Ltd.) in ethanol, add a predetermined amount of ethanol and water, and then add glycerin fatty acid ester to enteric base material A layer-forming coating solution was prepared. The composition of the coating solution for forming an enteric base material-containing layer obtained was 10% by mass of shellac, 0.5% by mass of glycerin fatty acid ester, 72% by mass of ethanol, and the balance water. It was.

<Evaluation test 1>
About the large intestine delivery capsule formulation of each Example and Comparative Example, the thickness of each of the chitosan-containing layer and the enteric base material-containing layer constituting the coating layer on the outer side of the hard capsule is the same with respect to the mass of the portion existing inside the layer. Measured as a percentage of the mass of the layer. In addition, for both of these layers, the formation time of the layer, that is, “the time required to process 150,000 grains in the chitosan-containing layer forming step or enteric substrate-containing layer forming step” was measured, Bacterial survival rate at the time of formation, that is, “ratio of the number of active bifidobacteria at the time of formation of the layer to the number of bifidobacteria that are active large intestine useful bacteria before capsule preparation production” was measured. The number of bifidobacteria was measured by a colony counting method using a BL agar plate, and the number of colonies per gram was defined as the number of bifidobacteria. The above results are shown in Table 1 below.

<Evaluation Test 2>
About the large intestine delivery capsule formulation of each Example and a comparative example, the disintegration test was done using the disintegration test apparatus and shaker of a Japanese pharmacopoeia. As an outline of the test procedure, the capsule preparation to be evaluated is placed so that the entire capsule preparation is immersed in the test solution using an auxiliary cylinder, immersed in the disintegration test first liquid (gastric fluid) for 1 hour, and then Similarly, it was immersed in the second disintegration test solution (small intestinal fluid) for 2 hours, and after each immersion treatment, the number of Bifidobacteria which are useful colon in the capsule preparation was measured by the above method. The above results are shown in Table 1 below.

  The cell viability in the bottom two rows of the column “After small intestinal fluid treatment” in Table 1 is an index of the number of active bifidobacteria that each large intestine delivery capsule preparation can release in the large intestine. In particular, the “bacterial survival rate before the start of the test” in the second line from the bottom can be an indicator of the storage stability of the bifidobacteria after ingestion of the large intestine delivery capsule preparation. In addition to the in-vivo storage stability, the “bacterial survival rate based on the pre-start” can be an index that further considers the storage stability of bifidobacteria during the production of a colon delivery capsule preparation. As shown in Table 1, since the numerical values of these both bacteria survival rates are larger in each example than in each comparative example, each example can have an excellent intestinal regulation effect as compared with each comparative example. I understand. In Comparative Examples 1 to 4, the thicknesses of the chitosan-containing layer and the enteric base material-containing layer are the same as those in each example, but each is different in that 0.5% by mass or more of sucrose fatty acid ester is not included in the capsule. Different from the embodiment. Since it can be considered that the difference between each Example and Comparative Examples 1 to 4 appears as a difference in the survival rate of the bacteria, the sucrose fatty acid ester is useful for protecting bifidobacteria in the body. I can say that. Further, regarding the amount of sucrose fatty acid ester contained, it is clear from the comparison between each Example and Comparative Example 2 that the amount of inclusion in the capsule exceeds 0.4% by mass. In addition, as mentioned above, the upper limit of the amount of sucrose fatty acid ester should be 25% by mass from the viewpoint of securing the amount of useful colon bacteria and improving the production efficiency of the capsule preparation.

  Further, Comparative Example 5 was obtained by increasing the thickness of the chitosan-containing layer and the enteric base material-containing layer as compared with Comparative Example 1, and compared with Comparative Example 1 in the disintegration test, Since the “survival rate” is high, it can be said that increasing the thickness of these layers is effective in improving the protective effect of the encapsulated bifidobacteria in the body. However, in Comparative Example 5, the thickness of each layer is relatively large, so that it takes longer to manufacture than other examples, and as a result, the bacteria survival rate at the time of forming each layer is another example. Low compared to In other words, even if the capsule coating thickness is increased to increase the protective effect of bifidobacteria in the body, a considerable amount of bifidobacteria is due to the longer production time before the capsule preparation is taken into the body. There is a concern that the fungus will be inactivated and the desired intestinal regulation effect will not be obtained. On the other hand, in each example, since the capsule coating is thinner than Comparative Example 5, the production time is shortened compared with Comparative Example 5, and as a result, the bacteria survival rate at the time of forming each layer is reduced. In addition, the protective effect of bifidobacteria in the body is equivalent to or higher than that of Comparative Example 5.

Claims (3)

A capsule containing a colon-containing fungus, wherein the capsule has a chitosan-containing layer and an enteric base material-containing layer in order from the inside,
A large intestine delivery capsule preparation in which a sucrose fatty acid ester is encapsulated in the capsule, and an encapsulated amount of the sucrose fatty acid ester is 0.5 to 25% by mass with respect to a total amount of the encapsulated product.   The capsule includes a hard capsule in which a body part and a cap part are fitted, and the hard capsule contains the useful bacteria of the large intestine and the sucrose fatty acid ester in a dry powder, and the outside of the hard capsule is the chitosan-containing layer. The large intestine delivery capsule preparation according to claim 1, which is coated and further the chitosan-containing layer is covered with the enteric base material-containing layer.   The thickness of the chitosan-containing layer is such that the mass of the chitosan-containing layer is 0.8 to 1.2 mass% with respect to the mass of the portion existing inward of the chitosan-containing layer. Or the large intestine delivery capsule formulation of 2.