JPWO2014097664A1 - Large intestine delivery capsule and method for producing the same - Google Patents

Abstract

Provided is a large intestine delivery system which can reach the large intestine without losing the active ingredient in the stomach or small intestine and can rapidly release the active ingredient in the large intestine. A capsule encapsulating useful colon, alginic acid and calcium salt, a chitosan-containing layer covering the capsule, and an enteric substrate-containing layer covering the chitosan-containing layer, wherein the chitosan mass in the chitosan-containing layer is The composition for large intestine delivery which is 0.5 mass%-8.0 mass% with respect to the mass of a capsule.

Description

  The present invention relates to a composition for delivering large intestine containing useful colons and a method for producing the same.

  2. Description of the Related Art Conventionally, attempts have been made to achieve health functions by taking pharmaceutical preparations, health foods, health supplements, and the like that contain useful microorganisms. Good enteric bacteria such as bifidobacteria and lactic acid bacteria suppress the growth of bad bacteria such as Escherichia coli in the intestine, improve the intestinal bacterial flora and intestinal environment, and have various health effects such as intestinal regulation It has been known. Various foods such as oral pharmaceutical preparations and yogurt containing live bacteria of these bacteria are commercially available. However, when live bacteria are ingested orally, most of the live bacteria are inactivated by digestive fluids such as stomach acid and bile acid when passing through the stomach and small intestine. Therefore, in order to reach an effective amount of viable bacteria to the large intestine, which is the site of action, a large amount of viable bacteria must be taken orally.

  For the purpose of preventing inactivation of viable bacteria by digestive juice, oral preparations containing viable physically protected bacteria have been developed. However, if the protection is too strong, the viable bacteria taken will pass through the large intestine and be excreted, so that a sufficient effect cannot be obtained. Therefore, it is possible to allow live bacteria useful in the large intestine to reach the large intestine that is the active site without being inactivated in the stomach or small intestine, and to deliver live bacteria that have reached the large intestine appropriately on the spot. A system is needed.

  Patent Documents 1 and 2 propose a colon delivery system preparation containing an active ingredient coated with a chitosan coating. Since chitosan is a substance that is assimilated by microorganisms in the large intestine, when the preparation reaches the large intestine, the chitosan coating covering the active ingredient is decomposed there and the encapsulated active ingredient is released. However, since chitosan is soluble in acid, the chitosan coating is also degraded by stomach acid. Therefore, in the above-mentioned large intestine delivery system preparation, an acid-resistant coating is further coated on the chitosan coating to prevent the chitosan coating from being decomposed by stomach acid. As materials for acid-resistant coatings, Patent Documents 1 and 2 include anionic types such as prolamin proteins such as wheat gliadin and zein, fats and oils, methacrylic acid-methyl methacrylate copolymer, and methacrylic acid-ethyl acrylate copolymer. Cellulose derivatives such as acrylic resin, hydroxypropylmethylcellulose acetate succinate, and hydroxypropylmethylcellulose phthalate are described.

  However, even in a preparation having an acid-resistant film as described above, when passing through the stomach and reaching the small intestine, the acid-resistant film collapses and the chitosan film is exposed. Since a chitosan coating usually has many pores, water such as intestinal fluid enters the formulation from the pores while the formulation with the chitosan coating exposed passes through the small intestine. Department is inactivated or leaked. This problem can be solved to some extent by increasing the thickness of the chitosan coating. However, a thick chitosan coating is not preferable because it takes time and labor to produce and is easily damaged during handling. Furthermore, since chitosan has a strong water absorption property and easily retains moisture, the thicker the chitosan coating, the more the chitosan coating absorbs water and swells in a watery environment such as the intestine, resulting in a structure of the formulation. It becomes brittle and easily collapses.

  Alginates and alginates such as potassium alginate, ammonium alginate, calcium alginate and sodium alginate are used in the manufacture of pharmaceuticals and foods as tablet excipients and disintegrants, as well as thickeners, gelling agents and dispersing agents. ing. Patent Documents 3 and 4 propose enteric capsules made of a film containing gelatin, polysaccharides such as agar, pectin, gums, and alginic acid. However, these are capsules that are not intended to disintegrate in the stomach but are intended to disintegrate in the small intestine and are not manufactured for substance delivery to the large intestine.

Japanese Patent Publication No. 08-013748 JP-A-10-324642 JP 2009-185022 A JP 2009-196961 A

  Therefore, the large intestine can prevent the invasion of water in the stomach and small intestine, the active ingredient can reach the large intestine without being inactivated or outflowed in the stomach or small intestine, and can rapidly release the active ingredient in the large intestine. A delivery system is awaited.

  As a result of intensive studies, the present inventors have encapsulated the active ingredient together with alginic acid and calcium salt, and coated the surface of the capsule encapsulating the active ingredient with a layer containing chitosan having a predetermined thickness. From the above, it has been found that by coating with an enteric base material-containing layer, a composition that has a thin chitosan-containing coating that is difficult to disintegrate in the stomach and intestine and can be delivered to the large intestine without losing the active ingredient can be obtained. The present inventors have also found that the composition makes it possible to deliver and release useful bacteria in the large intestine to the large intestine while maintaining the number of bacteria.

That is, the present invention comprises a capsule encapsulating useful colons, alginic acid and calcium salt, a chitosan-containing layer covering the capsule, and an enteric substrate-containing layer covering the chitosan-containing layer, There is provided a composition for large intestine delivery, wherein the chitosan mass in the layer is 0.5 mass% to 8.0 mass% with respect to the mass of the capsule.
Moreover, this invention provides the manufacturing method of the said composition for large intestine delivery.

  In the composition for large intestine delivery of the present invention, since the capsule containing the useful bacteria is coated with the chitosan-containing layer and the enteric substrate-containing layer, the capsule further contains alginic acid and a calcium salt together with the useful bacteria. Thus, it is a large intestine delivery system capable of delivering useful bacteria contained in a capsule to the large intestine without deactivation or outflow without disintegrating in the stomach or small intestine. Furthermore, the composition for large intestine delivery of the present invention is rapidly degraded in the large intestine to release useful bacteria in the capsule. Therefore, the composition for large intestine delivery of the present invention is useful for improving intestinal flora and intestinal environment.

  The composition for large intestine delivery of the present invention comprises a capsule containing useful colons, alginic acid and calcium salt, a chitosan-containing layer covering the capsule, and an enteric substrate-containing layer covering the chitosan-containing layer. .

  When the composition for large intestine delivery of the present invention is orally ingested, it is protected from gastric acid by the enteric base material-containing layer, so that useful bacteria in the large intestine inside the capsule are prevented from being inactivated by gastric acid. When the composition for large intestine delivery of the present invention moves from the stomach to the small intestine, the enteric base material-containing layer is dissolved by the small intestine digestive fluid, and the chitosan-containing layer is exposed. However, in the composition of the present invention, by having the chitosan-containing layer and the alginic acid and calcium salt inside the capsule, the capsule is prevented from swelling or collapsing due to digestive juice of the small intestine or other moisture, In addition, it protects useful colon bacteria inside the capsule from inactivation and outflow in the small intestine. Eventually, in the large intestine, the chitosan-containing layer and the capsule are assimilated and broken down by microorganisms living in the large intestine, and the useful colon in the capsule is released into the large intestine. The useful bacteria in the large intestine inside the capsule are released from the large intestine and biological activity while being protected from inactivation and outflow in the stomach and intestine. Even if the useful colon in the capsule is viable, it is delivered to the large intestine while maintaining a high viable count. Therefore, the composition for large intestine delivery of the present invention is useful for improving the intestinal microflora, improving the intestinal environment, or adjusting the intestine.

  The composition for delivery of the large intestine of the present invention contains a capsule encapsulating useful colons. The useful bacteria in the large intestine contained in the capsule may be any microorganism that exhibits a function that is favorable for the living body in the large intestine. Examples of the useful colon bacteria include good enteric bacteria such as bifidobacteria, lactic acid bacteria, and natto bacteria.

  The bifidobacteria are not particularly limited as long as they provide useful effects on humans, and can be appropriately selected according to the purpose. Examples of Bifidobacteria include Bifidobacterium thermophilum, Bifidobacterium longum, Bifidobacterium bifidobium, Bifidobacterium bifidum, Bifidobacteria Bifidobacterium adolescentis, Bifidobacterium infantis, Bifidobacterium animalis, Bifidobacterium pseudoro It includes bacteria belonging to the genus Bifidobacterium, such as gums (Bifidobacterium pseudolongum). Among these, Bifidobacterium longum (B. longum), Bifidobacterium (B. bifidum), and Bifidobacterium breve (B. breve), which are bacteria that can be used as food, are preferable. Any one of these bifidobacteria may be used alone, or any two or more thereof may be used in combination.

  There is no restriction | limiting in particular as said lactic acid bacteria as long as it brings a useful effect | action with respect to a person, According to the objective, it can select suitably. Preferable examples of lactic acid bacteria include bacteria of the genus Lactobacillus and Streptococcus, such as Lactobacillus gasseri, Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus casei and Lactobacillus casei. ), And plant lactic acid bacteria such as lactic acid bacteria RIE strains. Any one of the lactic acid bacteria may be used alone, or two or more of them may be used in combination.

  The Bacillus natto is not particularly limited as long as it has a useful effect on humans, and can be appropriately selected according to the purpose. Suitable examples of Bacillus natto include Bacillus natto derived from commercially available natto, as well as commercially available Bacillus natto, such as Takahashi bacteria (manufactured by Yuzo Takahashi Laboratory, Yamagata), Naruse bacteria (manufactured by Naruse Fermentation Chemistry Laboratory, Inc., Tokyo ), Miyagino fungus (manufactured by Miyagino Natto Factory, Sendai), Asahi fungus (Asahi Kogyo Co., Ltd., Tokyo), Nitto fungus (manufactured by Nitto Pharmaceutical Co., Ltd., Kyoto), Meguro fungus (Meguro Research Institute , Osaka). Any one of these Bacillus natto may be used alone, or any two or more thereof may be used in combination.

  Preferably, the large intestine useful bacteria contained in the composition for large intestine delivery of the present invention includes at least one selected from the above-mentioned bifidobacteria, lactic acid bacteria and natto bacteria, and more preferably the above mentioned bifidobacteria. And more preferably at least one selected from the bifidobacteria listed above. The useful colon bacteria contained in the composition of the present invention may be live bacteria, dead bacteria, disrupted bacteria thereof, and mixtures thereof, but preferably contain live bacteria. More preferably, the large intestine useful bacteria maintain a high viable count even when filled in the composition of the present invention in the state of viable bacteria and delivered to the large intestine.

  The capsule contained in the composition for delivery of the large intestine of the present invention contains alginic acid and a calcium salt together with the useful bacteria for the large intestine. The alginic acid reacts with moisture and calcium inside the capsule to form a gel, and forms a wall on the inner wall side of the capsule and around the useful colon. Therefore, if there are alginic acid and calcium salt in the capsule, even if external liquids such as gastric juice and intestinal fluid pass through the chitosan-containing layer and enter the capsule, the capsule swells and collapses, and kills or flows out useful colon bacteria Can be minimized, and the bacteria can be protected from the digestive fluid to prevent the inactivation of the bacteria.

  As the alginic acid, at least one selected from the group consisting of alginic acid, alginates and esters of alginic acid can be selected. Examples of the alginate include monovalent salts such as sodium alginate and potassium alginate; divalent salts such as magnesium alginate; and basic salts such as ammonium alginate. Examples of the alginic acid ester include alginic acid propylene glycol ester. Among these, from the viewpoint of gelation performance and gel properties, alginate is preferable, and sodium alginate is more preferable.

  The calcium salt may be any calcium salt that is allowed to be added to food or medicine, and is selected from the group consisting of calcium citrate, calcium sulfate, calcium lactate, calcium carbonate, calcium chloride, and calcium phosphate, for example. At least one of them. Of these, calcium carbonate is preferred.

  The amount of alginic acid filled in the capsule is preferably 0.1% by mass to 20% by mass in the capsule filling, and more preferably 1% by mass to 6% by mass. Alternatively, the content of alginic acid in the capsule is preferably 0.1% by mass to 20% by mass, preferably 1% by mass to the total mass of the colon useful bacteria in the capsule, or the liquid or solid containing the same. 6 mass% is more preferable. The amount of the calcium salt in the capsule is preferably 0.02% by mass to 8% by mass and more preferably 0.05% by mass to 3% by mass in the capsule filling. Alternatively, the amount of the calcium salt in the capsule is preferably 2% by mass to 40% by mass and more preferably 5% by mass to 35% by mass with respect to 100% by mass of alginic acid. Each of alginic acid and calcium salt may be separately filled in the capsule, but a mixed powder in which alginic acid and calcium salt are previously mixed in the above ratio may be filled in the capsule.

  In the composition for large intestine delivery of the present invention, examples of capsules that encapsulate useful colons include capsules that are usually used in the production of pharmaceuticals and foods, and can be, for example, hard capsules, soft capsules, seamless capsules, and the like.

  The capsule is preferably manufactured from a base material made of gelatin, which has been widely used in the past, or a cellulose derivative obtained by modifying cellulose derived from animals or plants. Examples of the cellulose derivative include alkyl cellulose (for example, methyl cellulose), hydroxyalkyl cellulose (for example, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, etc.), and hydroxyalkyl alkyl cellulose (for example, hydroxypropyl methyl cellulose (HPMC)). , Hydroxyethylmethylcellulose, hydroxyethylethylcellulose, etc.). Among these, hydroxyalkylalkylcellulose is preferable, and HPMC is more preferable in terms of excellent strength as a capsule and quick dissolution in the large intestine. The said base material may be used individually by 1 type, and may use 2 or more types together.

  What is necessary is just to make the said capsule into a desired shape and size according to the quantity of the content. As the size of the capsule, for example, generally used sizes such as 00, 0, 1, 2, 3, 3, 4, 5 and the like can be mentioned. , And the like, but are not limited thereto.

  Preferably, the capsule is filled with live bacteria of the large intestine useful bacteria. Also preferably, the above-mentioned viable bacteria of the large intestine are filled in the capsule, and then the bacteria are further grown in the capsule. The form of useful colon in the above capsule is not particularly limited as long as it is a form that can be filled in the capsule, and is appropriately selected according to the type of bacteria and the purpose of use of the composition for large intestine delivery of the present invention. Can do. For example, the useful colon can be filled in the capsule in the form of a liquid suspended in an appropriate medium, a dry powder, a solid obtained by mixing the dry powder and hardened oil or the like, and the like. As for the procedure for filling the capsule with useful colon bacteria, a person skilled in the art may select an appropriate method according to the form of the colon bacteria and the type of capsule.

  Useful hard capsules when useful colonic bacteria to be encapsulated are bacteria that are sensitive to high temperatures or are easily inactivated, because capsules can be produced under relatively mild conditions such as temperature conditions. . The hard capsule is manufactured by fitting a body part and a cap part manufactured from the above-described base material. What is necessary is just to manufacture the said body part and a cap part according to the manufacturing method of a general hard capsule. For example, the body part and the cap part are soaked in a metal pin molded in the shape of the body part and the cap part in the aqueous solution of the cellulose derivative to attach the cellulose derivative aqueous solution to the surface, and then the pin is pulled up from the liquid. It can be manufactured by drying.

  When filling the hard capsules with useful colon bacteria, the capsule body may be filled with useful colon bacteria. Examples of the filling method include a method of injecting or dripping a liquid substance containing useful colon bacteria into the body portion of the capsule, a method of dropping powdery useful colon bacteria into the capsule body portion while vibrating the feeder, and the like. However, it is not limited to these. Filling the colons with useful colon can be performed by known capsule filling machines, for example, fully automatic capsule filling machines (for example, LIQFIL super 40 type manufactured by Qualicaps Co., Ltd.), fully automatic capsule sealing machines (for example, Qualicaps Corporation). Manufactured by HICAPSEAL 40 type). By fitting the cap part into the body part filled with useful colon bacteria, a hard capsule enclosing the colon useful bacteria can be obtained.

  A band seal may be further applied to the fitting portion of the capsule. The material for the band seal can be appropriately selected from known materials without particular limitation, and examples thereof include gelatin, cellulose derivatives, polyethylene glycol (PEG), and polyvinyl alcohol (PVA). Examples of the cellulose derivative include the capsule base materials listed above. Preferably, the band seal is made from the same material as the hard capsule material to be sealed. The procedure for applying a band seal to the capsule may follow a general method. For example, the band seal can be formed by applying an aqueous solution of the above band seal material to the fitting portion of the body portion and the cap portion of the hard capsule and drying. The band seal prevents the coating agent from entering the inside of the capsule from the fitting portion when the capsule is coated with the chitosan-containing layer, and smoothes the capsule fitting portion to make a thin and uniform thickness of the chitosan-containing coating. Facilitates the formation of However, band sealing may be performed as necessary, and is not necessarily required as long as fitting and film formation are effective.

What is necessary is just to change suitably the quantity of the colon large bacterium filled with the said capsule according to the form of the microbe at the time of filling the said capsule, the size of a capsule, etc. Preferably, the amount of useful colon bacteria filled in the capsule is preferably 3% by mass to 90% by mass, and more preferably 10% by mass to 60% by mass in the capsule filling. If the filling amount of useful colon bacteria is too small, the intestinal environment improving effect and intestinal regulating effect of the colon delivery composition of the present invention are reduced. On the other hand, if the filling amount of useful colon bacteria is too large, the balance of the intestinal flora may be lost, causing side effects such as diarrhea. Alternatively, when the large intestine useful bacteria are in the form of a dry powder, the concentration of useful colon in the colon when filled into the capsule is preferably 1 × 10 ⁶ cfu / g or more, and more preferably 1 × 10 ¹⁰ cfu / g or more. Cfu represents a colony forming unit. When the large intestine useful bacteria are in the form of a liquid such as a medium suspension, if the bacteria concentration is too high, the viscosity of the liquid will increase and it will be difficult to fill the capsule. After filling, it is preferable to grow the fungus to a desired concentration in the capsule. The concentration of useful colon bacteria in the liquid is preferably 1 × 10 ⁶ cfu / g or more, more preferably 1 × 10 ⁹ cfu / g to 1 × 10 ¹² cfu / g.

  If necessary, the capsule may further contain other components. Other ingredients include: Suspension culture medium used when useful colonic bacteria are converted into liquid; Hardened oil used when useful colon colonies are used as solids; Lactose, starch, dried potato starch and other powders used in some cases; carrageenan, agar, pectin, gum arabic, fine silicon oxide, microcrystalline cellulose, iron salt, hemirose, gelatin, xanthan gum, casein, sodium caseinate, calcium casein , Casein potassium, casein magnesium, milk protein, milk protein peptides, milk protein digest, pullulan, gellan gum, lactoferrin, vegetable oil, hardened oil, sugar, whey, maltodextrin, carmellose sodium, pregelatinized starch, modified starch A component having low water activity or reducing water activity, such as And oligosaccharides, water-soluble dietary fibers, other useful active ingredients for improving the intestinal environment such as water-insoluble dietary fiber. Any one of the other components listed above may be used alone, or any two or more of them may be used in combination.

  The composition for delivery of the large intestine of the present invention was prepared by coating a capsule containing encapsulated useful bacteria of the large intestine obtained by the procedure as described above, alginic acid and a calcium salt with a chitosan-containing layer, and then coating with the chitosan-containing layer. The capsule is further produced by coating with an enteric substrate-containing layer. In the composition for large intestine delivery of the present invention, a capsule containing an active ingredient is coated with a chitosan-containing layer.

  There are no particular restrictions on the properties of chitosan contained in the chitosan-containing layer, such as the degree of deacetylation and molecular weight, but if the degree of deacetylation is 60 mol% or more, it is dissolved in the acid solution during the preparation of the coating solution. Is preferable from the viewpoints of film property and film forming property. The chitosan content in the chitosan-containing layer (dried product) may be 25% by mass or more, preferably 25% by mass to 85% by mass, and more preferably 35% by mass to 80% by mass in the total mass.

  The chitosan-containing layer is preferably a layer containing chitosan and zein (hereinafter also referred to as chitosan-zein layer). When the chitosan-containing layer is a chitosan-zein layer, by containing both chitosan and zein, the same chitosan coating as that used in conventional preparations and the like exhibits good colonic disintegration, while the conventional chitosan The film-forming property is improved as compared with the coating, and it has higher water resistance, and prevents swelling and disintegration of the composition of the present invention due to water absorption in the intestine.

  Zein is a water-insoluble protein extracted from corn, and is also called corn protein. The purified zein is usually a white to light yellow powder. Zein is hardly soluble in water or ethanol, but is easily soluble in hydrous ethanol or acetone, and is dissolved by the action of a strongly alkaline region or a proteolytic enzyme. Zein is highly safe and is often used as an additive for foods and pharmaceuticals. Zein has been used in conventional chitosan coating preparations, but is generally separately coated on the upper layer of the chitosan coating as a gastric acid resistant coating (for example, Patent Document 1), and a chitosan-containing layer that is an enteric-soluble layer Was not added.

  The content of zein in the chitosan-zein layer may be 0.5 to 100 parts by mass, preferably 5 to 80 parts by mass with respect to 100 parts by mass of chitosan. When the zein content is less than the above-mentioned amount, the film-forming property is lowered, and the water resistance of the obtained coating film is lowered to be easily disintegrated. On the other hand, when the content of zein is larger than the above amount, the obtained chitosan film becomes too hard and the disintegration property is deteriorated.

  The chitosan-containing layer or chitosan-zein layer is prepared by dissolving the chitosan or chitosan and zein in a liquid by a known method to prepare a coating solution, and attaching the obtained coating solution to the surface of the capsule, and then drying it. Can be formed. Chitosan can be dissolved in an acidic aqueous solution. Examples of the acid to be coexisted in the acidic aqueous solution include inorganic acids and organic acids, and organic acids are preferable because inorganic acids have a strong interaction with chitosan. The organic acid is not particularly limited, but formic acid, acetic acid, lactic acid, sulfamic acid, propionic acid, and trichloroacetic acid are preferable examples because they have sufficient volatility at normal pressure. Among these, acetic acid is more preferable because it is inexpensive, easy to handle, and has little influence on the human body even if it remains in the chitosan-containing layer or chitosan-zein layer. The pH of the acidic aqueous solution may be in the range of 3.5 to 6.5. When the pH of the acidic aqueous solution is less than 3.5, an acid may remain in the chitosan-containing layer or the chitosan-zein layer, and the water resistance of the obtained coating film may be lowered. On the other hand, when the pH of the solution is higher than 6.5, the solubility of chitosan decreases.

  Since zein is difficult to dissolve in water, it is easy to handle when a solution containing an organic solvent is used. When preparing a coating solution for the chitosan-zein layer, it is preferable to add an organic solvent to the chitosan acidic aqueous solution prepared above and dissolve zein therein. Alternatively, zein may be dissolved in a water / ethanol solution and then mixed with a chitosan solution. In addition, when an organic solvent is added to an acidic solution containing chitosan, the volatility of the acid increases, so that the acid can be easily removed in the film formation process, and the drying temperature of the film can be lowered. Preferred for survival. Examples of the organic solvent include alcohols such as methanol and ethanol, ketones such as acetone, and ethers. Ethanol is preferable from the viewpoint of interaction with chitosan.

  In the coating solution containing chitosan or chitosan and zein prepared, the concentration of chitosan may be about 0.05% to 12% by mass, preferably 1% to 5% by mass, based on the total mass of the solution. Degree. The concentration of zein in the solution may be about 0.01% to 12% by mass of the total mass of the solution, preferably about 0.1% to 5% by mass, or 100 parts by mass of chitosan. 0.5 parts by mass to 100 parts by mass, preferably 5 parts by mass to 80 parts by mass. The concentration of ethanol in the solution may be 40% to 90% by weight, preferably 50% to 80% by weight of the total weight of the solution. The viscosity of the coating solution is preferably 5 to 500 mPa · s at room temperature. The viscosity in the present specification is a value measured by a C-type viscometer (available from TOKIMEC INC or the like).

  If necessary, the coating solution containing chitosan or chitosan and zein may further contain other components that can be contained in the chitosan-containing layer or chitosan-zein layer. Examples of the other components include, but are not limited to, a film-forming substrate, a filler, and a plasticizer. When a film-forming base material is added to the coating solution, it becomes easier to form a film on the chitosan-containing layer or the chitosan-zein layer. Preferably, the substrate has an emulsifying power in addition to the film forming property. Examples of the base material having a film-forming property and emulsifying power include water-soluble celluloses such as alkyl celluloses (for example, methyl cellulose and ethyl cellulose), hydroxyalkyl celluloses (for example, hydroxyethyl cellulose and hydroxypropyl cellulose), hydroxyalkyl alkyl celluloses (for example) For example, hydroxypropyl methylcellulose, hydroxyethylmethylcellulose, hydroxyethylethylcellulose, etc.); pullulan, gum arabic, carrageenan, fine silicon oxide, microcrystalline cellulose, hemirose, agar, gelatin, xanthan gum, casein, milk protein, oligosaccharide, maltodextrin, Carmellose sodium, starch, pregelatinized starch, modified starch, polyethylene glycol, polyvinylpyrrolidone (PVP) Corn fiber, gelling agents such as guar gum and pectin, thickeners or water-soluble polysaccharide, and the like. Content of the film-forming base material in the coating solution may be 0.1 to 100 parts by mass with respect to 100 parts by mass of chitosan in the solution.

  The filler is not particularly limited, and examples thereof include talc, precipitated calcium carbonate, silicon dioxide, microcrystalline cellulose, reduced maltose, bentonite, and a metal salt of an organic acid having 10 or more carbon atoms. The filler content in the coating solution may be 0.06 parts by mass to 60 parts by mass with respect to 100 parts by mass of chitosan in the solution.

  Plasticizers include glycerin, diglycerin, diethylene glycol, propylene glycol, triethylene glycol, polyethylene glycol, sorbitol, mannitol and other polyhydric alcohols, glycerin fatty acid esters, polyglycerin fatty acid esters, sorbitan fatty acid esters, lecithin derivatives, organic acid monoglycerides , Medium chain fatty acid triglycerides, sucrose esters and the like. The content of the plasticizer in the coating solution may be 0.05 to 100 parts by mass with respect to 100 parts by mass of chitosan in the solution.

  The chitosan-containing layer or chitosan-zein layer covering the capsule containing useful colon in the colon delivery composition of the present invention is a means for applying, spraying, immersing, etc. the above-mentioned chitosan or a coating solution containing chitosan and zein. Can be formed by attaching to the surface of the capsule and then drying. Alternatively, a chitosan-containing film or a chitosan- and zein-containing film can be produced by blending together a composition containing chitosan or chitosan and zein at the time of soft capsule film formation and drying.

  Capsule coating is usually performed using a coating apparatus, for example, a breathable coating apparatus (for example, POWREC Coater: manufactured by POWREC Co., Ltd.), a fluidized bed granulation coating apparatus (for example, flow coater, manufactured by Freund Sangyo Co., Ltd.) , Centrifugal rolling granulation coating apparatus (for example, CF granulator, Granurex, manufactured by Freund Sangyo Co., Ltd.), composite granulation coating apparatus (for example, Spiraflow, manufactured by Freund Sangyo Co., Ltd.), sugar coating film coating apparatus (for example, , High coater, aqua coater: manufactured by Freund Sangyo Co., Ltd.) and the like. Specifically, while the capsule containing useful colon bacteria is flowed in the apparatus, the coating solution containing chitosan or chitosan and zein is applied to the surface of the capsule using a spray or the like while supplying and exhausting dry air. The chitosan-containing layer or chitosan-zein layer can be formed on the surface of the capsule by spraying and then drying to remove the acid.

  Although there is no restriction | limiting in particular as supply air temperature in the formation (coating) process of a chitosan containing layer or chitosan-zein layer using the said apparatus, 40-90 degreeC is preferable. When the supply air temperature is less than 40 ° C., the acid is not sufficiently removed, and thus water resistance is not sufficiently imparted to the coating of the chitosan-containing layer or the chitosan-zein layer. On the other hand, when the supply air temperature exceeds 90 ° C., the chitosan-containing layer or the chitosan-zein layer has problems in appearance such as coloring and deformation, and it is preferable because an excessive heat load is applied to the useful colon in the capsule. Absent. The exhaust temperature in the chitosan-containing layer or chitosan-zein layer forming step using the above apparatus may be 30 ° C. to 85 ° C., and can be appropriately selected according to the composition of the coating solution.

  The thickness of the chitosan-containing layer or chitosan-zein layer in the composition for large intestine delivery according to the present invention is converted to the chitosan mass in the chitosan-containing layer or chitosan-zein layer, and the mass of the capsule containing the contents, 0.5% by mass or more, preferably 0.5% by mass to 8.0% by mass, more preferably 0.8% by mass to 6.0% by mass, and still more preferably 0.8% by mass to 4.0% by mass. It is. When the chitosan mass is less than 0.5% by mass of the capsule mass, the chitosan-containing layer or chitosan-zein layer is thin, so that the enteric base material-containing layer soon collapses in the small intestine. The layer may also collapse, and capsules containing useful colon can not be delivered to the large intestine. On the other hand, when the chitosan mass exceeds 8.0% by mass of the capsule mass, it takes time to form the chitosan-containing layer or the chitosan-zein layer, and useful colonic bacteria in the capsule are heated for a long time. Therefore, it is not preferable.

  In the composition for large intestine delivery of the present invention, an enteric substrate-containing layer coating is further formed on the chitosan-containing layer or chitosan-zein layer. The material of the enteric base material-containing layer is not particularly limited as long as it is acid-resistant and difficult to dissolve in the stomach but dissolves in the small intestine, so-called enteric base material. Examples of the enteric substrate include carboxymethyl ethyl cellulose (CMEC), methacrylic acid copolymer, hypromellose phthalate (HPMCP), zein, alcohol shellac, aqueous shellac and the like. Among these, methacrylic acid copolymers, zein, HPMCP, and alcohol shellac are preferable because they are highly effective in preventing water from entering the capsule.

  If necessary, the enteric substrate-containing layer may further contain other components other than the enteric substrate. The other components are not particularly limited as long as the acid resistance of the enteric substrate-containing layer is not impaired, but water-insoluble additives are preferable. Examples of the water-insoluble additive include talc, bentonite, and metal salts of organic acids having 10 or more carbon atoms.

  The coating of the enteric base material-containing layer can be formed by the same procedure as the above-described chitosan-containing layer or chitosan-zein layer. That is, the coating solution containing the enteric base material is attached to the surface of the capsule coated with the chitosan-containing layer or chitosan-zein layer by means of application, spraying, dipping, etc., and then dried to contain the enteric base material. A layer can be formed. The concentration of the enteric substrate in the coating solution containing the enteric substrate is preferably 0.1% by mass to 12% by mass of the total mass of the solution. The viscosity of the enteric base solution is preferably about 10 mPa · s to 500 mPa · s at room temperature. For the formation of the layer, the aforementioned commonly used coating apparatus can be used. The supply temperature of the coating apparatus in the layer forming step is preferably 30 ° C. to 80 ° C., and the exhaust temperature is preferably 30 ° C. to 80 ° C. If the supply air temperature is less than 30 ° C., the drying efficiency is low and the coating time is long, which is not preferable. On the other hand, if the supply air temperature is too high, an excessive heat load is applied to the useful colon in the capsule, which is not preferable.

  The thickness of the enteric substrate-containing layer in the large intestine delivery composition of the present invention can be appropriately selected according to the shape, size, mass, etc. of the capsule to be coated. For example, the thickness of the enteric substrate-containing layer is preferably 0.5% by mass to 10.0% with respect to the mass of the capsule containing the content, in terms of the mass of the enteric substrate in the layer. It is 0.5 mass%, More preferably, it is 0.5 mass%-7.0 mass%, More preferably, it is 0.8 mass%-5 mass%. When the thickness of the enteric base material-containing layer is less than 0.5% by mass of the enteric base material, the thin enteric base material-containing layer rapidly disintegrates in the small intestine, so that the chitosan-containing layer or chitosan-zein The layer may also collapse in the small intestine and capsules containing useful colon bacteria may not be delivered to the large intestine. On the other hand, when the thickness of the enteric substrate-containing layer exceeds 10.0% by mass, it takes time to form the enteric substrate-containing layer, and the large intestine useful bacteria in the capsule are heated for a long time. This is not preferable.

  The composition for large intestine delivery of the present invention comprises, in addition to the above-mentioned capsule containing useful colon, alginic acid and calcium salt, chitosan-containing layer or chitosan-zein layer, enteric base material-containing layer, and further the enteric group. On the material containing layer, you may have the coating layer which uses beeswax, carnauba wax, etc. as a base material.

  The composition for large intestine delivery of the present invention can protect the components inside the capsule from inactivation and outflow in the small intestine and release them to the large intestine. Therefore, the composition for large intestine delivery of the present invention can be applied to large intestine delivery of active ingredients that are easily inactivated in the small intestine and active ingredients that are easily absorbed in the small intestine and difficult to reach the large intestine, in addition to the above-mentioned useful bacteria for the large intestine. I can do it. Such active ingredients include, for example, vitamin C, vitamins B1, B2, B6, B12, water-soluble vitamins such as niacin (nicotinic acid) and folic acid, pharmacological ingredients intended to be released in the large intestine, and the like Can be mentioned. The active ingredients can be applied to the composition for delivery of the large intestine of the present invention alone or together with the above useful colonic bacterium. Therefore, the composition for large intestine delivery of the present invention may contain the above-mentioned active ingredient in a capsule instead of or in addition to the above-mentioned useful colon.

  The composition for large intestine delivery of the present invention is a composition for oral administration. Preferably, the composition for large intestine delivery of the present invention is an orally administered composition for improving the intestinal environment of an animal or for adjusting the intestine of an animal. The composition for large intestine delivery of the present invention may be provided by being added to food or feed, or may be provided as a pharmaceutical or a supplement. For example, the composition for large intestine delivery of the present invention can be a pharmaceutical or supplement for improving intestinal environment or intestinal regulation. The composition, medicament or supplement for improving the intestinal environment or the intestine is coated with a chitosan-containing layer or a chitosan-zein layer in a capsule containing encapsulated useful bacteria of the large intestine, alginic acid and calcium salt in the procedure described above. It is manufactured by coating with an enteric substrate-containing layer from above. Alternatively, the composition for large intestine delivery of the present invention can be used for the improvement of the intestinal environment or the manufacture of a pharmaceutical or supplement for intestinal regulation.

  The composition, medicine or supplement for large intestine delivery of the present invention is given orally to an animal to improve the intestinal microflora or intestinal environment of the animal or to provide an intestinal regulating action to the animal. Examples of animals that can be provided with the composition for large intestine delivery of the present invention include humans and non-human animals, and examples of non-human animals include non-human primates, cows, pigs, sheep, goats, dogs, cats, rodents. Etc.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated further in detail, this invention is not limited only to these Examples.

<Reference Example 1> Capsule containing useful colon (Capsule No. 1)
Bifidobacteria live powder (Morinaga Milk Industry Co., Ltd., Morinaga Bifidobacterium powder) 520 g, dried potato starch (Matsuya Chemical Co., Ltd.) 550 g, milk protein (Nippon Shinyaku Co., Ltd.) 390 g, sodium alginate (Co., Ltd.) 30 g of Kimika) and 10 g of calcium carbonate (Shiraishi Kogyo Co., Ltd.) were uniformly triturated and mixed to obtain a powder for capsule filling.
As hard capsules filled with the bacteria-containing powder, hydroxypropylmethylcellulose (HPMC) capsules (Qualicaps Co., Ltd., Quali-V (R) -N, No. 3, capsule mass: 46 mg) were used.
The bifidobacteria-containing powder and hard capsules were set in a capsule filling machine (LIQFIL super 40 type, manufactured by Qualicaps Co., Ltd.), and 230 mg of the bifidobacteria-containing powder was filled into the hard capsules. The concentration of bifidobacteria per capsule was 1.1 × 10 ¹⁰ cfu / g.

(Capsule No. 2)
Bifidobacteria live bacteria powder (Morinaga Milk Industry Co., Ltd., Morinaga Bifidobacterium powder) 520 g, dried potato starch (Matsuya Chemical Co., Ltd.) 940 g, sodium alginate (Kimika Co., Ltd.) 30 g, calcium carbonate (Shiraishi Kogyo Co., Ltd.) (Product made) 10 g of powder was uniformly dispersed and mixed to obtain a powder for capsule filling.
As hard capsules filled with the bacteria-containing powder, hydroxypropylmethylcellulose (HPMC) capsules (Qualicaps Co., Ltd., Quali-V (R) -N, No. 3, capsule mass: 46 mg) were used.
The bifidobacteria-containing powder and hard capsules were set in a capsule filling machine (LIQFIL super 40 type, manufactured by Qualicaps Co., Ltd.), and 230 mg of the bifidobacteria-containing powder was filled into the hard capsules. The concentration of bifidobacteria per capsule was 1.0 × 10 ¹⁰ cfu / g.

(Capsule No. 3)
Bifidobacteria live powder (Morinaga Milk Industry Co., Ltd., Morinaga Bifidobacterium powder) 520 g was uniformly triturated with 980 g of dried potato starch (Matsuya Chemical Co., Ltd.) and mixed to obtain a powder for capsule filling.
As hard capsules filled with the bacteria-containing powder, hydroxypropylmethylcellulose (HPMC) capsules (Qualicaps Co., Ltd., Quali-V (R) -N, No. 3, capsule mass: 46 mg) were used.
The bifidobacteria-containing powder and hard capsules were set in a capsule filling machine (LIQFIL super 40 type, manufactured by Qualicaps Co., Ltd.), and 230 mg of the bifidobacteria-containing powder was filled into the hard capsules. The concentration of bifidobacteria per capsule was 1.0 × 10 ¹⁰ cfu / g.

<Reference Example 2> Coating solution (Solution No. 1: Chitosan-Zein-containing coating solution)
Acetic acid was added to purified water to prepare acidic water having a pH of about 4. In this acidic water, chitosan having a degree of deacetylation of 80 mol% or more (Flownack C: manufactured by Nihon Suisan Co., Ltd.) was dissolved. To the obtained chitosan solution, glycerin (manufactured by Kao Corporation) was added, ethanol was added, and zein (Kobayashi Twein DP (manufactured by Kobayashi Fragrance Co., Ltd.)) was further added. The coating solution containing chitosan and zein was prepared by adjusting with purified water so that the final concentration of chitosan was 2.5% by mass and the final concentration of zein was 0.5% by mass.

(Solution No. 2: Chitosan-containing coating solution)
As in Reference Example 2, but without adding ethanol and zein, glycerin fatty acid ester (Sakamoto Yakuhin Kogyo Co., Ltd .: decaglycerin monoester) was added to 50 parts by mass with respect to 100 parts by mass of chitosan. A chitosan-containing coating solution was prepared.

(Solution No. 3: Chitosan-containing coating solution)
A chitosan-containing coating solution was prepared in the same manner as in Reference Example 2 except that ethanol and zein were not added.

(Solution No. 4: Coating solution containing chitosan and sodium alginate)
In the same manner as in Reference Example 2, but without adding ethanol and zein, sodium alginate (Kimika Co., Ltd.) was added to 0.5 parts by mass with respect to 100 parts by mass of chitosan, containing chitosan and sodium alginate. The coating solution was adjusted.
<Production Examples 1-3>
Useful colon-containing capsule No. 1 produced in Reference Example 1 1 to 3 were prepared using solution Nos. 1 prepared with the compositions shown in Table 1. 1 (chitosan-zein containing coating solution) was used to coat with a chitosan-zein layer. The coating was performed using a film coater high coater mini-type pan (Freund Sangyo Co., Ltd.) at a constant drying temperature (65 ° C.). The chitosan-zein layer was formed so that the chitosan mass with respect to the capsule mass was about 1.4% by mass. A part of the produced capsule was extracted, and the composition of the chitosan-zein layer was examined.
Next, the capsule coated with the chitosan-zein layer was further coated with shellac, which is an enteric base material (about 1.2% by mass with respect to the capsule mass). A small amount of Carnauba wax was applied to the surface of the obtained capsule to produce a multi-coated capsule.

<Production Examples 4 to 6>
Useful colon-containing capsule No. 1 produced in Reference Example 1 1 to 3 were prepared using solution Nos. 1 prepared with the compositions shown in Table 1. 2 (chitosan-containing coating solution) was used to coat the chitosan-containing layer. The coating was performed using a film coating apparatus high coater mini-type pan (Freund Sangyo Co., Ltd.) with the drying temperature of the coating apparatus kept constant (80 ° C.). The chitosan layer was formed so that the chitosan mass with respect to the capsule mass was about 1.7 mass%. A part of the produced capsule was extracted, and the composition of the chitosan layer was examined.
Next, the capsule coated with the chitosan layer was further coated with shellac as an enteric base material (about 1.2% by mass with respect to the capsule mass). A small amount of Carnauba wax was applied to the surface of the obtained capsule to produce a multi-coated capsule.

<Production Examples 7-9>
Useful colon-containing capsule No. 1 produced in Reference Example 1 1 to 3 were prepared using solution Nos. 1 prepared with the compositions shown in Table 1. 3 (chitosan-containing coating solution) was used to coat the chitosan-containing layer. The coating was performed using a film coating apparatus high coater mini-type pan (Freund Sangyo Co., Ltd.) with the drying temperature of the coating apparatus kept constant (80 ° C.). The chitosan-containing layer was formed so that the chitosan mass relative to the capsule mass was about 1.7% by mass. A part of the produced capsule was extracted, and the composition of the chitosan layer was examined.
Next, the capsule coated with the chitosan layer was further coated with shellac as an enteric base material (about 1.2% by mass with respect to the capsule mass). A small amount of Carnauba wax was applied to the surface of the obtained capsule to produce a multi-coated capsule.

<Production Example 10>
Capsule No. containing capsules useful in large intestine produced in Reference Example 3 3 were prepared using the solution No. 3 prepared with the composition shown in Table 1. 4 (alginate and chitosan-containing coating solution) was used to coat the chitosan-containing layer. The coating was performed using a film coating apparatus high coater mini-type pan (Freund Sangyo Co., Ltd.) with the drying temperature of the coating apparatus kept constant (80 ° C.). The chitosan-containing layer was formed so that the chitosan mass relative to the capsule mass was about 1.7% by mass. A part of the produced capsule was extracted, and the composition of the chitosan layer was examined.
Next, the capsule coated with the chitosan layer was further coated with shellac as an enteric base material (about 1.2% by mass with respect to the capsule mass). A small amount of Carnauba wax was applied to the surface of the obtained capsule to produce a multi-coated capsule.

<Production Example 11>
Capsule containing useful colons No. 1 in the same procedure as in Production Example 7 except that the mass of chitosan was about 0.5% by mass relative to the mass of the capsule. 1 was coated with a chitosan-containing layer and shellac to produce multi-coated capsules.

<Production Example 12>
Except that the chitosan mass was about 0.4 mass%, the same procedure as in Production Example 7, 1 was coated with a chitosan-containing layer. A zein coating (about 0.3% by mass with respect to the capsule mass) was applied to the surface of the obtained capsule. The zein solution used for the zein coating was prepared by dissolving zein (Kobayashi Twein DP (manufactured by Kobayashi Fragrance Co., Ltd.)) in a 60% ethanol solution to a concentration of 6% by mass, and using glycerin (manufactured by Kao Corporation) as a plasticizer. It was prepared by adding 30% by mass to zein. Next, the capsule coated with the chitosan layer and zein was further coated with shellac as an enteric base material (about 1.2% by mass with respect to the capsule mass). A small amount of Carnauba wax was applied to the surface of the obtained capsule to produce a multi-coated capsule.

<Test Example 1>
(Residual acetic acid amount / membrane strength test) A part of each capsule obtained was dissolved, and the remaining acetic acid amount was measured by HPLC using an Inertsil ODS-4 column, and the peak area ratio with respect to a standard solution of acetic acid prepared separately. As sought. The membrane strength of the capsules was measured as a pressure at which the capsules were broken with a pressurization type measuring device (load measuring device manufactured by Minebea Co., Ltd.)

(Disintegration test)
The disintegration property of the multi-coated capsules of Production Examples 1 to 12 in the stomach, small intestine and large intestine was examined. The disintegration test was performed using 6 capsules each and using a disintegration test apparatus of Japanese Pharmacopoeia.
The capsule is moved up and down in a pH 1.2 solution (stomach solution) for 60 minutes without an auxiliary board, the disintegrated capsule is removed, and then in a pH 6.8 solution (small intestine solution) for 120 minutes. The capsule which collapsed was moved up and down, the disintegrated capsule was removed, and then moved up and down for 120 minutes in a pH 3.5 solution (large intestine assumed liquid) under the condition using an auxiliary board. The disintegration properties of the capsules in each solution were determined in three stages according to the following evaluation criteria.
-Evaluation criteria-(disintegration in assumed stomach and small intestine fluids)
A: All six maintained their shape, and no deformation such as swelling or collapse was observed (conformity)
B: There is swelling or deformation in 6 pieces, but the total number of collapses is 2 or less (conformity)
C: Collapse is observed in 3 or more out of 6 (unsuitable)
-Evaluation criteria-(disintegration in the assumed large intestine fluid)
A: All 6 were tested and all collapsed in the assumed colon fluid (adapted)
B: 5 or more of 6 were tested, and all collapsed in the assumed large intestine fluid (adapted)
C: 5 or more of 6 were tested, and some capsules did not collapse (unsuitable)
Not implemented: When only 4 or less of 6 can be tested (unsuitable)

The evaluation results are shown in Table 2. Capsules containing alginic acid and calcium salt and coated with a chitosan-containing layer in the capsules of Production Examples 1-2, 4-5, and 7-8 have high membrane strength, and disintegration in the assumed solution of the stomach and small intestine While it was highly resistant, it disintegrated well in the assumed large intestine. Furthermore, the capsules of Production Examples 1 and 2 coated with a layer containing chitosan and zein further improved the disintegration resistance in the assumed liquid of the stomach and small intestine, and the residual amount of acid in the chitosan-containing layer decreased. . In Production Examples 3, 6, and 9 in which the capsule did not contain alginic acid and calcium salt, the disintegration resistance in the stomach and small intestine assumed liquid decreased, and many capsules disintegrated before the large intestine assumed liquid test. In the capsule of Production Example 3, in Test Example 2 to be described later, it was suggested that the liquid entered the capsule in the assumed small intestine solution.
The capsule of Production Example 10 coated with a chitosan layer containing alginic acid was found to be unable to deliver the substance in the capsule to the large intestine because the capsule collapsed in the assumed small intestine solution.
When the thickness of the chitosan layer was reduced, the capsule disintegration resistance in the assumed solution of the stomach and small intestine decreased. Furthermore, when the thickness of the chitosan layer was less than 0.5% by mass with respect to the capsule, the capsule collapsed before the test for the assumed large intestine solution (Production Examples 11 to 12).

<Test Example 2>
Using the multi-coated capsules of Production Examples 1, 3, 4, 6, 7, and 9, the remaining viable count of bifidobacteria in the capsule after immersion in the assumed gastric fluid was examined. A disintegration test was carried out for 60 minutes in the assumed gastric fluid at pH 1.2 in the same manner as in Test Example 1, and the number of remaining bifidobacteria in the capsule was measured for the capsules that remained undisintegrated. The number of remaining bacteria is determined by suspending the powder extracted from the capsule in a dilute solution, aseptically diluting it to a predetermined concentration by a dilution method, and then inoculating this bacterial solution on the surface of the anaerobic BL agar medium. After culturing, the number of bacteria was counted.
Furthermore, about the capsule of manufacture example 1 and 3, after performing the disintegration test for 60 minutes in the gastric liquid of pH1.2, the disintegration test is performed for 120 minutes in the small intestine of pH6.8, and the number of bacteria is similarly measured. Measured.
The results are shown in Table 3. The capsules of Production Examples 1, 4, and 7 containing alginic acid and a calcium salt in the capsule and coated with a chitosan-containing layer had water resistance and acid resistance, and the bifidobacteria remained high. In Production Example 1 in which the capsule was filled with alginic acid and calcium salt and coated with a chitosan-zein layer, there was almost no decrease in the number of viable bacteria. The capsule of Production Example 3 having a chitosan-zein layer coating but containing no alginic acid and calcium salt in the capsule maintained a high viable count after the test with the assumed gastric solution, but the test with the assumed small intestine solution Later, the number of viable bacteria decreased significantly.

<Test Example 3>
Using the capsule of useful colon-containing bacteria (capsule No. 1) of Reference Example 1, the amount of zein added was confirmed. A chitosan-zein-containing coating solution prepared with the composition described in Table 4 was used to coat the chitosan-zein layer. The coating was performed using a film coater high coater mini-type pan (Freund Sangyo Co., Ltd.) at a constant drying temperature (65 ° C.). The chitosan-zein layer was formed so that the chitosan mass with respect to the capsule mass was about 1.4% by mass. Next, the capsule coated with the chitosan-zein layer was further coated with shellac, which is an acid-resistant substrate (about 1.2% by mass with respect to the capsule mass). A small amount of Carnauba wax was applied to the surface of the obtained capsule to produce a multi-coated capsule. Each manufactured capsule was evaluated in the same procedure as in Test Example 1. The results are shown in Table 5. In Production Example 18, a test was not performed because a precipitate was generated in the coating solution.

<Test Example 4>
Using the capsule of useful colon-containing bacteria (capsule No. 1) of Reference Example 1, the effect of the thickness of the chitosan-containing layer on the capsule disintegration property was confirmed. Capsule containing useful colons No. 1 in the same procedure as in Production Example 7 except that the chitosan mass in the chitosan-containing layer was adjusted to the value described in Table 6 with respect to the capsule mass. 1 was coated with a chitosan-containing layer and shellac to produce multi-coated capsules. Each manufactured capsule was evaluated in the same procedure as in Test Example 1. The results are shown in Table 7. Tables 6 and 7 show examples of Production Example 7 and Production Example 11 again.
When the chitosan-containing layer was thickened, the resistance to disintegration in the stomach and small intestine assumed liquid was improved. On the other hand, as the thickness of the chitosan-containing layer increased, the drying time during layer formation increased. In particular, in Production Example 19, since it took time to dry, there was a fear that the residual rate of bifidobacteria in the capsule was reduced by heating.

Claims (12)

  A capsule containing a colonic fungus, alginic acid and calcium salt; a chitosan-containing layer covering the capsule; and an enteric substrate-containing layer covering the chitosan-containing layer, wherein the chitosan mass in the chitosan-containing layer is The composition for large intestine delivery which is 0.5 mass%-8.0 mass% with respect to the mass of a capsule.   The composition according to claim 1, wherein the chitosan-containing layer is a layer containing chitosan and zein.   The composition of Claim 2 whose content of this zein is 0.5 mass part-100 mass parts with respect to 100 mass parts of said chitosan in the layer containing the said chitosan and zein.   The composition according to any one of claims 1 to 3, wherein the alginic acid is at least one selected from the group consisting of alginic acid, alginates and esters of alginic acid.   The amount of the alginic acid contained in the capsule is 0.1% by mass to 20% by mass in the filling in the capsule, and the amount of the calcium salt contained in the capsule is 100 parts by mass of the alginic acid. The composition of any one of Claims 1-4 which is 2 mass parts-40 mass parts with respect to this.   The amount of the enteric base material-containing layer is 0.5% by mass to 10.0% by mass with respect to the mass of the capsule in terms of mass of the enteric base material in the layer. The composition of any one of these. Preparing capsules containing useful colonic bacteria, alginic acid and calcium salt;
Coating the capsule with a chitosan-containing layer; and further coating the capsule coated with the chitosan-containing layer with an enteric substrate-containing layer;
A method for producing a composition for large intestine delivery comprising:
The method whose chitosan mass in this chitosan content layer is 0.5 mass%-8.0 mass% with respect to the mass of this capsule.   The method according to claim 7, wherein the chitosan-containing layer is a layer containing chitosan and zein.   The method according to claim 8, wherein in the layer containing chitosan and zein, the content of zein is 0.5 to 100 parts by mass with respect to 100 parts by mass of chitosan.   The method according to any one of claims 7 to 9, wherein the alginic acid is at least one selected from the group consisting of alginic acid, alginates and esters of alginic acid.   The amount of the alginic acid contained in the capsule is 0.1% by mass to 20% by mass in the filling in the capsule, and the amount of the calcium salt contained in the capsule is 100 parts by mass of the alginic acid. The method of any one of Claims 7-10 which is 2 mass parts-40 mass parts with respect to.   The amount of the enteric base material-containing layer is 0.5% by mass to 10.0% by mass with respect to the mass of the capsule in terms of mass of the enteric base material in the layer. The method of any one of these.