Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4891—Coated capsules; Multilayered drug free capsule shells
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
  • A61K35/66—Microorganisms or materials therefrom
  • A61K35/74—Bacteria
  • A61K35/741—Probiotics
  • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
  • A61K35/745—Bifidobacteria
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/12—Antidiarrhoeals

Definitions

• the present invention relates to a composition for delivering large intestine containing useful colons and a method for producing the same.
• Oral preparations containing physically protected live bacteria have been developed for the purpose of preventing the inactivation of live bacteria by digestive fluid.
• 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.
• Patent Documents 1 and 2 disclose 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.
• 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.
• 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.
• 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.
• 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.
• 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,
• a composition for large intestine delivery wherein the mass of chitosan in the layer is 0.5% by mass to 8.0% by mass with respect to the mass of the capsule.
• this invention provides the manufacturing method of the said composition for large intestine delivery.
• 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.
• the capsule 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.
• 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.
• 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. .
• composition for large intestine delivery of the present invention When the composition for large intestine delivery of the present invention is taken orally, it is protected from gastric acid by the enteric base material-containing layer, so that the useful colon in the capsule is prevented from being inactivated by gastric acid.
• the enteric base material-containing layer 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.
• the capsule 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.
• 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.
• 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 that encapsulates 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 have a useful effect on humans, and can be appropriately selected according to the purpose.
• Examples of Bifidobacteria include Bifidobacterium thermophilum, Bifidobacterium longum, Bifidobacterium bifidum Bifidobium bifidum Um Adrecentis (Bifidobacterium adolescentis), Bifidobacterium infantis (Bifidobacterium infantitis), Bifidobacterium animaris (Bifidobacterium animaris), Bifidobacterium Yudorongamu (Bifidobacterium pseudolongum) bacteria belonging to the Bifidobacterium genus, and the like.
• Bifidobacterium longum B. longum
• Bifidobacterium bifidum B. bifidum
• B. breve Bifidobacterium breve
• Any one of these bifidobacteria may be used alone, or any two or more thereof may be used in combination.
• the lactic acid bacterium is not particularly limited as long as it has a useful effect on humans, and can be appropriately selected according to the purpose.
• lactic acid bacteria include bacteria of the genus Lactobacillus and Streptococcus, such as Lactobacillus gasseri, Lactobacillus acidophilus, Lactobacillus Lactobacillus Lactobacillus Lactobacillus Lactobacillus Lactobacillus Lactobacillus Lactobacillus Lactobacillus Lactobacillus Lactobacillus Lactobacillus Lactobacillus Lactobacillus Lactobacillus Lactobacillus Lactobacillus Lactobacillus Lactobacillus Lactobacillus Lactobacillus Lactobacillus Lactobacillus Lactobacillus Lactobacillus Lactobacillus Lactobacillus ), 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
• the natto bacterium 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 Laboratories, Inc., Tokyo, Japan) ), Miyagino fungus (manufactured by Miyagino Natto Factory, Sendai), Asahi fungus (Asahi Kogyo Co., Ltd., Tokyo), Nitto fungus (manufactured by Nitto Yakuhin Kogyo Co., Ltd., Kyoto), Meguro fungus (manufactured by Meguro Research Co., Ltd.) , Osaka). Any one of these Bac
• 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 above-mentioned capsules contained in the composition for large intestine delivery of the present invention contain alginic acid and a calcium salt together with the above-mentioned useful colon.
• 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.
• alginic acid at least one selected from the group consisting of alginic acid, alginates and esters of alginic acid can be selected.
• alginate include monovalent salts such as sodium alginate and potassium alginate; divalent salts such as magnesium alginate; and basic salts such as ammonium alginate.
• 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, more preferably 1% by mass to 6% by mass in the capsule filling.
• the content of alginic acid in the capsule is preferably 0.1% by mass to 20% by mass, and preferably 1% by mass to 20% by mass with respect to the total mass of useful colon bacteria, or a liquid or solid substance containing the same. 6 mass% is more preferable.
• the amount of the calcium salt in the capsule is preferably 0.02 to 8% by mass, more preferably 0.05 to 3% by mass in the capsule filling.
• the amount of calcium salt in the capsule is preferably 2% by mass to 40% by mass, 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.
• capsules that contain useful colon bacteria 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 produced 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.
• the cellulose derivative include alkyl cellulose (eg, methyl cellulose), hydroxyalkyl cellulose (eg, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, etc.), hydroxyalkyl alkyl cellulose (eg, hydroxypropyl methyl cellulose (HPMC)) , Hydroxyethylmethylcellulose, hydroxyethylethylcellulose, etc.).
• 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.
• the above capsules may have a desired shape and size depending on the amount of contents.
• 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.
• the capsule is filled with the live bacteria of the useful colon.
• 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.
• 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.
• 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.
• the body part of the capsules may be filled with useful colon bacteria.
• 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.
• Filling the colons with useful colon can be performed by known capsule filling machines, for example, fully automatic capsule filling machines (for example, Qualicaps Co., Ltd., LIQFIL super 40 type), fully automatic capsule sealing machines (for example, Qualicaps Co., Ltd.). Manufactured by HICAPSEAL 40 type).
• 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.
• 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.
• 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.
• band sealing may be performed as necessary, and is not necessarily required as long as fitting and film formation are effective.
• 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.
• 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.
• 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.
• 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
• 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.
• a capsule containing an active ingredient is coated with a chitosan-containing layer.
• chitosan contained in the 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, 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).
• chitosan-zein layer a layer containing chitosan and zein layer
• 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 pale yellow powder.
• Zein is hardly soluble in water and ethanol, but is easily soluble in hydrous ethanol and 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.
• a gastric acid resistant coating for example, Patent Document 1
• the zein content 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.
• 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.
• 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.
• Chitosan can be dissolved in an acidic aqueous solution.
• 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.
• 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.
• 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 resulting coating may be lowered.
• the pH of the solution is higher than 6.5, the solubility of chitosan decreases.
• Zein is difficult to dissolve in water, so handling with an organic solvent makes it easy to handle.
• an organic solvent to the acidic aqueous chitosan solution prepared above and dissolve zein therein.
• zein may be dissolved in a water / ethanol solution and then mixed with a chitosan solution.
• 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.
• 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 based on the mass.
• the concentration of ethanol in the solution can 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).
• 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.
• the other components include, but are not limited to, a film-forming substrate, a filler, and a plasticizer.
• a film-forming base material is added to the coating solution, it becomes easier to form a film of the chitosan-containing layer or the chitosan-zein layer.
• 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 poly
• 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 plasticizer content 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 for coating the capsule containing useful colon in the large intestine 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.
• 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.
• 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.).
• 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.
• a chitosan-containing layer or chitosan-zein layer can be formed on the surface of the capsules by spraying and then drying to remove the acid.
• the air supply temperature in the step of forming (coating) the chitosan-containing layer or chitosan-zein layer using the above apparatus is not particularly limited, but is preferably 40 to 90 ° C. If 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 an excessive heat load is applied to useful colonic bacteria in the capsule. Absent.
• the exhaust temperature in the step of forming a chitosan-containing layer or chitosan-zein layer 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 of the present invention is converted to the chitosan mass in the chitosan-containing layer or chitosan-zein layer, with respect to 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.
• 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.
• 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 colon bacteria in the capsule are heated for a long time. Therefore, it is not preferable.
• a coating of an enteric base material-containing layer 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.
• the enteric substrate include carboxymethyl ethyl cellulose (CMEC), methacrylic acid copolymer, hypromellose phthalate (HPMCP), zein, alcohol shellac, aqueous shellac and the like.
• CMEC carboxymethyl ethyl cellulose
• HPPMCP hypromellose phthalate
• zein zein
• alcohol shellac aqueous shellac and the like.
• methacrylic acid copolymers, zein, HPMCP, and alcohol shellac are preferable because they are highly effective in preventing water from entering the capsule.
• 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.
• water-insoluble additives include talc, bentonite, and metal salts of organic acids having 10 or more carbon atoms.
• the coating of the enteric substrate-containing layer can be formed by the same procedure as that for the chitosan-containing layer or chitosan-zein layer described above. 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 with respect to 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.
• the air 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 composition for delivering large intestine of the present invention can be appropriately selected according to the shape, size, mass, etc. of the capsule to be coated.
• 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. % By mass, more preferably 0.5% by mass to 7.0% by mass, and still more preferably 0.8% by mass to 5% by mass.
• the thickness of the enteric substrate-containing layer is less than 0.5% by mass of the enteric substrate, the thin enteric substrate-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.
• 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.
• composition for large intestine delivery of the present invention comprises, in addition to the above-mentioned capsule containing useful colon bacteria, alginic acid and calcium salt, a chitosan-containing layer or chitosan-zein layer, an enteric base material-containing layer, and further the enteric group.
• a chitosan-containing layer or chitosan-zein layer an enteric base material-containing layer, and further the enteric group.
• 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 can be released into 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.
• 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.
• the composition for large intestine delivery of the present invention can be a pharmaceutical or supplement for improving intestinal environment or intestinal regulation.
• composition, medicament or supplement for improving the intestinal environment or adjusting the intestine is coated with a chitosan-containing layer or chitosan-zein layer on a capsule containing useful colonic bacteria, alginic acid and calcium salt in the procedure described above. It is manufactured by coating with an enteric substrate-containing layer from above.
• 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.
• composition, medicine or supplement for large intestine delivery of the present invention is given orally to an animal to improve the intestinal bacterial flora and intestinal environment of the animal or bring about an intestinal regulating effect on the animal.
• 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.
• 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.
• hydroxypropylmethylcellulose (HPMC) capsules 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.
• HPMC hydroxypropylmethylcellulose
• 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 mass 46 mg
• 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.
• 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.
• hydroxypropylmethylcellulose (HPMC) capsules 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.
• 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 relative 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.
• the capsule coated with the chitosan-zein 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.
• 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).
• 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.
• 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).
• 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.
• 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.
• 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).
• 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.
• 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.
• 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).
• 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. 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.).
• the disintegration properties of the multi-coated capsules of Production Examples 1 to 12 in the stomach, small intestine and large intestine were 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.
• Capsules containing alginic acid and calcium salt in the capsules of Production Examples 1 to 2, 4 to 5 and 7 to 8 and coated with a chitosan-containing layer 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.
• the capsules of Production Examples 1 and 2 coated with a layer containing chitosan and zein further improved the resistance to disintegration in the assumed liquid of the stomach and small intestine, and the amount of acid remaining in the chitosan-containing layer decreased. .
• ⁇ 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.
• 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.
• 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 relative to the capsule mass was about 1.4% by mass.
• 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).
• shellac is an acid-resistant substrate (about 1.2% by mass with respect to the capsule mass).
• 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.
• 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.

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