WO2006082824A1 - Matrix-type enteric coated sustained release composition - Google Patents

Matrix-type enteric coated sustained release composition Download PDF

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Publication number
WO2006082824A1
WO2006082824A1 PCT/JP2006/301619 JP2006301619W WO2006082824A1 WO 2006082824 A1 WO2006082824 A1 WO 2006082824A1 JP 2006301619 W JP2006301619 W JP 2006301619W WO 2006082824 A1 WO2006082824 A1 WO 2006082824A1
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Prior art keywords
release composition
sustained release
matrix
lipid
substance
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PCT/JP2006/301619
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French (fr)
Japanese (ja)
Inventor
Genji Kawano
Isamu Seto
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Nrl Pharma, Inc.
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Priority to JP2007501580A priority Critical patent/JP4050784B2/en
Publication of WO2006082824A1 publication Critical patent/WO2006082824A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • 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
    • 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
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention relates to a matrix-type enteric 'sustained-release composition for allowing physiologically active substances such as proteins and polypeptides to be orally administered, a method for producing the same, and the like. More specifically, the present invention relates to a matrix-type enteric 'sustained-release composition that can be effectively dissolved in the intestinal tract after the oral ingestion, and the physiologically active substance hardly dissolves in the stomach and efficiently exhibits its physiological activity, and a method for producing the same. .
  • Physiologically active substances such as proteins and polypeptides are degraded and inactivated in the stomach by the action of gastric acid and pepsin, and almost lose their biological activity.
  • the physiologically active substance is absorbed in the intestinal tract and exerts its function, or acts in the intestinal tract, so it is preferable to reach the intestinal tract with little elution in the stomach.
  • enteric-coated oral preparations such as enteric-coated tablets and enteric-coated capsules with enteric coatings have been developed!
  • enteric coating agents are often used in these enteric oral preparations.
  • Enteric coating agents for pharmaceutical use include acrylic acid polymers (EUDRAGIT Z Eudragit (registered trademark)), hydroxypropyl methylcellulose phthalate (HPM CP), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose succinate (HPMCAS). ), Enteric polymers such as carboxymethylethyl cellulose (CMEC) are used.
  • acrylic acid polymers EUDRAGIT Z Eudragit (registered trademark)
  • HPM CP hydroxypropyl methylcellulose phthalate
  • CAP cellulose acetate phthalate
  • HPMCAS hydroxypropyl methylcellulose succinate
  • CMEC carboxymethylethyl cellulose
  • shellac twein derived from natural products is used as an enteric coating agent.
  • the enteric coating agent is used after being dissolved in an organic solvent, it is often not applicable to physiologically active substances such as proteins and polypeptides that are inactivated by a small amount of organic solvent.
  • the enteric coating agent for food and feed is an enteric coating for pharmaceutical use. Compared with soluble polymer, it is inferior in enteric function.
  • DDS Drug Delivery System
  • a typical example of the basic design of DDS is a matrix-type sustained-release preparation.
  • the matrix-type sustained-release preparation is a sustained-release preparation for the purpose of controlling the diffusion of a surface-force drug by uniformly dispersing the drug in a polymer matrix.
  • the matrix preparation is produced by dissolving a fish growth hormone and an enteric polymer solution in ammonia water and then freeze-drying, there remain problems in terms of operability and cost.
  • sustained release tablets containing seamless capsules and a matrix composed of acrylic polymers such as Eudragit, celluloses such as hydroxypropylcellulose and methylcellulose, and fats and oils such as hardened oil have been reported.
  • Japanese Patent Laid-Open No. 9-52847; Patent Document 2 Japanese Patent Laid-Open No. 9-52847; Patent Document 2.
  • acrylic polymers such as Eudragit
  • celluloses such as hydroxypropyl cellulose and methylcellulose
  • composition comprising an alginate gel matrix, a protein entangled in the gel matrix, an agent capable of binding to the entangled protein, and any pharmaceutically usable excipient, A controlled-release pharmaceutical that causes the protein to be degraded and the drug to be released when the composition reacts under conditions containing a proteolytic enzyme.
  • Patent No. 3264948; Patent Document 3 A composition has been reported (Patent No. 3264948; Patent Document 3).
  • drugs that can be used here are that they can bind to forceful proteins and are not degraded by proteolytic enzymes, so applicable drugs are limited to inorganic compounds and relatively small organic compounds. There is a problem that cannot be applied to physiologically active substances such as proteins and polypeptides.
  • a drug and a weakly swellable polymer for example, gelatin
  • a strong swellable polymer for example, HPMC, HPMCZ pectin mixture
  • a matrix-type sustained-release preparation produced as a tablet has been reported (US Pat. No. 6,337,091; Patent Document 5).
  • This preparation is a sustained-release preparation of an organic synthetic compound drug with high water solubility, and is a preparation intended for sustained release of a drug for a long time (16 to 20 hours) by combining polymers having different swelling properties. is there.
  • this preparation is a sustained-release preparation having a two-layer structure, and the production process is complicated.
  • a method of granulating using ethanol is used, it cannot be applied to physiologically active substances such as proteins unstable to organic solvents.
  • Patent Document 1 JP-A-5-85941
  • Patent Document 2 JP-A-9 52847
  • Patent Document 3 Patent No. 3264948
  • Patent Document 4 JP 2004-231566
  • Patent Document 5 U.S. Pat.No. 6,337,091
  • the present invention is excellent in stability in gastric juice and has physiological activities such as proteins and polypeptides.
  • the substance can reach the intestinal tract without being decomposed by gastric acid or pepsin in the gastric juice, and can be efficiently absorbed into the living body to fully exert its physiological activity.
  • the present inventor has dispersed gastric juice by uniformly dispersing physiologically active substances such as proteins and polypeptides in a matrix containing specific components. It was found that the stability in the medium and the stability to the heat sterilization treatment were remarkably increased, and the present invention was completed.
  • Matrix type enteric 'sustained release composition containing a physiologically active substance, a gelling substance, a basic organic compound and an excipient, wherein the physiologically active substance is a protein, polypeptide, peptide Or a microorganism, a physiologically active substance and a gelling substance are powder particles coated with a lipid coating, and these components or other additional components are alkali metal, alkaline earth metal, manganese,
  • a matrix-type enteric * sustained-release composition characterized by containing one or more elements selected from the group consisting of copper, iron, zinc and cobalt;
  • the lipid content of the lipid-coated powder particles of the physiologically active substance and the gelling substance is 1% to 90% by weight based on the total weight of the lipid-coated powder particles of the physiologically active substance and the gelling substance.
  • the matrix-type enteric 'sustained-release composition as described above;
  • the lipid content of the lipid-coated powder particles of the physiologically active substance and the gelling substance is 5% to 20% by weight based on the total weight of the lipid-coated powder particles of the physiologically active substance and the gely substance.
  • the matrix-type enteric 'sustained-release composition as described above;
  • the gelling substance is carrageenan, alginic acid, fucoidan, galactan sulfate, xanthan gum, carboxymethylcellulose, pectin, gum arabic, dielan gum, natto fungus gum, soybean water-soluble polysaccharide, agar, starch, farcellulan, tracant gum
  • the matrix according to any one of (1) to (5) above, wherein the group power is selected from the group consisting of, gelatin, tamarind seed gum, locust bean gum, guar gum, chitin, and chitosan.
  • Type enteric / sustained release composition
  • Excipient power One or more selected from the group consisting of cellulose, crystalline cellulose, dextrin, buttermilk powder, casein, soymilk powder, soybean powder, skim milk, vegetable powder, and fruit juice powder
  • Organic acidity One or more selected from the group consisting of acetic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, ethylene diammine tetraacetic acid, chondroitin sulfate, and salts thereof.
  • the matrix type enteric-sustained release composition according to any one of the above [2] to [8];
  • the inorganic acid salt is an alkali metal salt, an alkaline earth metal salt, or an ammonium salt salt.
  • the group power is also selected.
  • One or more kinds are selected. Any one of the above [2] to [9] Matrix type enteric / sustained release composition according to item;
  • Matrix enteric -sustained release composition As described in any one of [1] to [10] above, which is in the form of a powder, a capsule, a tablet, a granule, a pill, an emulsion, a suspension, or a gel.
  • Matrix enteric -sustained release composition As described in any one of [1] to [10] above, which is in the form of a powder, a capsule, a tablet, a granule, a pill, an emulsion, a suspension, or a gel.
  • Matrix enteric -sustained release composition As described in any one of [1] to [10] above, which is in the form of a powder, a capsule, a tablet, a granule, a pill, an emulsion, a suspension, or a gel.
  • Matrix enteric -sustained release composition As described in any one of [1] to [10] above, which is in the form of a
  • a feed containing the matrix type enteric / sustained release composition according to any one of [1] to [12];
  • the matrix-type enteric 'sustained-release composition of the present invention is stable in gastric juice, and a physiologically active substance such as protein polypeptide is eluted, so that these physiologically active substances are It can reach the intestinal tract while maintaining its physiological activity without being degraded by gastric acid or pepsin.
  • the physiologically active substance contained in the sustained release composition of the present invention has a high pH. In the intestinal tract in which the bile is secreted, the composition force can be eluted, so that it can be efficiently absorbed into the living body and exhibit physiological activity.
  • the powder particles of the physiologically active substance and the gelling substance absorb the water in the aqueous binder solution over the granulation process. Therefore, it is possible to produce a granular granulated product in which a physiologically active substance is uniformly dispersed by spraying with an aqueous binder solution.
  • a water-soluble base material when a large amount of a water-soluble base material is used in the granulation process, the base material absorbs and dissolves water in the binder solution, and the blocking progresses.
  • the matrix-type enteric and sustained-release composition of the present invention is advantageous in production.
  • the binder solution contains an organic solvent such as ethanol at a high concentration
  • a physiologically active substance such as protein is covered with a lipid film, so that the physiologically active substance is an organic solvent such as ethanol. It is possible to prevent denaturation by direct contact with.
  • the matrix type enteric 'sustained release composition of the present invention can be applied to a wide range of uses such as pharmaceuticals, foods and feeds. Furthermore, since the matrix-type enteric 'sustained release composition of the present invention is stable with respect to heat sterilization treatment in an aqueous system, it is a process involving heating such as heat sterilization treatment in the production of foods, feeds, pharmaceuticals and the like. As a result, it can be applied to a wide variety of products.
  • FIG. 1 is a graph showing changes in ratatopherin absorption over time in rats.
  • Panel (A) shows the total amount of ratatopherin absorbed per hour when ratatopherin powder (“Powder LF”) and the composition of the present invention (“Enteric LF”) are administered intragastrically to rats. is there.
  • Panels (B) and (C) are also graphs showing the amount of ratatoferrin absorbed per hour when administered intraduodenum.
  • FIG. 2 is a graph showing the total amount of ratatopherin absorbed up to 4 hours after ratatopherin administration in rats.
  • the “physiologically active substance” is not particularly limited as long as it can act in a living body.
  • the advantages of the present invention can be used particularly advantageously to include proteins, polypeptides, peptides, nucleic acids and the like derived from humans, animals and plants and microorganisms, and useful enteric bacteria such as bifidobacteria and lactic acid bacteria.
  • useful enteric bacteria such as bifidobacteria and lactic acid bacteria.
  • Proteins, polypeptides, etc. include natural ones as well as genetically modified forms. Specifically, for example,
  • 6Ckine amphiregulin, angiogenin, ⁇ -microglobulin, betacellulin,
  • Brain-derived neurotrophic factor C10, ciliary neurotrophic factor, ciliary neurotrophic factor receptor alpha, CPP32 (Cysteine Protease Protein 32), CRG-2, cytoforce-in-induced neutrophil chemotactic factor 1 , Cytoforce-in-induced neutrophil chemotaxis factor 2 alpha, cytoforce-in-induced neutrophil chemotactic factor 2 beta, cytotoxic T lymphocyte antigen 4, beta vascular endothelial growth factor, endothelin-1, Eotaxin, Eotaxin-2, epithelial neutrophil attractant 78, erythropoietin receptor, Fas, fibroblast growth factor 4, fibroblast growth factor 5, fibroblast growth factor 6, fibroblast growth factor 7ZKGF (keratinocyte growth factor): fibroblast growth factor 8, fibroblast growth factor 8b, fibroblast growth factor 8c, fibroblast growth factor 9, acidic fibroblast growth factor, basic fibroblasts Growth factor, Fit— 3 Gand, fractal
  • gely substance refers to a water-soluble polymer having gelling ability.
  • Polysaccharide power commonly used as a food additive is also preferred because of its availability, price, and aspects such as Z or safety.
  • carrageenan alginic acid, fucoidan, galactan sulfate, xanthan gum, carboxymethylcellulose (CMC), pectin, gum arabic, dielan gum, natto gum, soybean water-soluble polysaccharide, agar, starch , Farsellan, tracant gum, gelatin, tamarind seed gum, locust bean gum, guar gum, chitosan, o
  • CMC carboxymethylcellulose
  • pectin pectin
  • gum arabic dielan gum
  • natto gum soybean water-soluble polysaccharide
  • agar starch
  • Farsellan tracant gum
  • gelatin tamarind seed gum
  • locust bean gum locust bean gum
  • guar gum chitosan
  • an “excipient” is a component added to form a matrix structure together with a gelling substance. More specifically, for example, cellulose, crystalline cellulose, dextrin, buttermilk powder, casein, soymilk powder, soybean powder, skimmed milk, vegetable powder, and fruit juice power are selected. You can select and use it.
  • natural food materials such as soy milk powder, vegetable juice (or its powder), fruit juice (or its powder) contain sufficient elements such as sodium, iron, potassium, calcium, magnesium and zinc.
  • prepared soymilk powder is sodium: 300-800, iron: 1-20, potassium: 1,000-3,000, calcium: 100-300, magnesium: 300-600; / 100g) is Na !; um: 2-50, potassium: 100-200, calcium: 5-30, magnesium: 10-50, iron: 0.1-3.0, zinc: 0.01- 0.5, Copper: 0.01-0.3; Potato (raw) (ppm), Potassium: 1,350, Calcium: 15.2, Magnesium: 160, Iron: 1.6; Vegetable juice (MgZ200mL) is known to contain about 20 to 300 sodium and about 300 to 1,000 rhodium.
  • the “basic organic compound” means that the matrix is stabilized by maintaining the pH of the aqueous system at 3 to 6 when the matrix-type enteric 'sustained release composition is dispersed in the aqueous system. It is a component added to make it disappear.
  • soy milk powder chitosan, polylysine, polyarginine, polyglutamine, arginine, glutamine, histidine, lysine, orthine, or a group power that also has darcosamine power is selected.
  • Soymilk powder is preferred because it can be used not only as a basic organic compound but also as an excipient.
  • Chitosan is preferred because it can be used not only as a basic organic compound but also as a gelling substance.
  • the matrix type enteric 'sustained release composition of the present invention comprises an alkali metal, an alkaline earth metal, manganese, copper, iron, zinc, and the like derived from the above components or other additional components. It contains one or more elements selected from the group consisting of cobalt. When the composition contains any one or more of these, the matrix stability is improved, and sufficient acid resistance and pepsin resistance are obtained. On the other hand, in the intestinal environment, physiologically active substances present in the matrix are present. It will be released moderately. Sodium, power Elements such as lithium are necessary for increasing the ionic strength in an acidic water system to cause gelation (pH 2 or less, ion strength: 0.5 or more), and for the expression of gastric juice resistance and enteric function. In addition, divalent metals such as calcium are involved in gel crosslinking in aqueous systems and are necessary for the function of heat stability in aqueous systems.
  • the element preferably contains at least one alkali metal or alkaline earth metal, more preferably contains sodium, potassium, calcium, magnesium, etc., and particularly contains at least sodium, potassium or calcium. It is preferable.
  • the alkali metal or alkaline earth metal should be contained in an effective amount for the above-mentioned action, and this effective amount is generally 10 to 10, OOOmg / lOOg, preferably 100 to 5, OOOmgZlOOg. It is.
  • the “organic acid” may be a free form or a salt form. Specifically, for example, quenic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, ethylene diamine tetraacetic acid, chondroitin sulfate, and their salt strength are selected. Can be used.
  • the “inorganic acid salt” is generally a salt such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and carbonic acid, preferably an alkali metal salt, alkaline earth metal salt, ammonium. In the form of a salt.
  • the powder containing a physiologically active substance and the powder containing a gelling substance are preferably a coating material mainly comprising lipids. It is coated with.
  • the physiologically active substance and the gelling substance can be prepared as a raw material composition by previously coating with a coating material containing lipid.
  • a material composition includes a step of producing a mixture by combining a physiologically active substance, a gelling substance and a coating material containing lipid, a step of heating the mixture to melt the lipid, The method includes the steps of: attaching the coating material to the physiologically active substance and the gelling substance; and forming a coating comprising the coating material on the surface of the physiologically active substance and the gelling substance. it can.
  • Lipids used in the coating material may be acceptable among oils and fats, waxes, and complex lipids depending on uses such as edible and pharmaceutical use.
  • oils and fats For example, naturally obtained animal and vegetable oils or hardened oils made from these oils and fats (beef tallow oil, tallow hardened oil, fish oil hardened oil, rapeseed hardened oil, soybean hardened oil, palm hardened oil, olive hardened oil, lacquer SE hardened oil, hard oil hardened oil, etc.).
  • a lipid having a melting point in the range of 30 ° C to 80 ° C, more preferably a lipid having a melting point of 40 ° C to 70 ° C is used.
  • lipids having the same melting point more preferably lipids having the same composition are used as the lipid of the physiologically active substance powder and the lipid of the gelling substance powder.
  • the lipid content of the lipid film covering the physiologically active substance and the gelling substance is generally 1% by weight to 90% based on the total weight of the lipid-coated powder particles of the physiologically active substance and the gely substance. %, Preferably about 5% to 20% by weight. The same applies to the material composition described above, and the lipid content is generally about 1% to 90% by weight, preferably about 5% to 20% by weight, based on the weight of the material composition.
  • the matrix-type enteric 'sustained release composition is prepared by, for example, mixing a powder of a physiologically active substance and a gelling substance coated with a lipid film with a powder of an organic acid and an inorganic acid salt to form a binder solution. After granulating by spraying, it is formed by drying the granulated product.
  • the granulation method is classified into a wet method and a dry method, but the wet method is preferable.
  • the wet granulation methods include extrusion granulation, stirring granulation, rolling granulation, fluidized bed granulation, and spray granulation, and can be appropriately selected from these methods.
  • the appropriate temperature for drying is 40 ° C to 80 ° C. Preferably, it is in the range of 50 ° C to 65 ° C.
  • the binder can be appropriately selected from those used in ordinary wet granulation in the industry, and a water-soluble binder and an organic solvent-soluble binder such as ethanol can be used.
  • the amount of the binder to be sprayed is preferably 10% by weight or less, or 1% by weight or less based on the dry matter of the composition.
  • the formed matrix type enteric 'sustained release composition in solid form such as powders, granules, fine particles and the like may be further processed into another form such as a suspension.
  • this composition is added to an acidic solution of ⁇ 1-2 containing 0.5M to 2M inorganic acid salt or organic acid salt, for example, for 10 minutes to After immersing for 3 hours, preferably 30 minutes to 2 hours, the pH of this solution can be adjusted to 3-9, preferably 3-8, to produce a suspension.
  • the inorganic acid salt is preferably one or more selected from the group forces of alkali metal salts, alkaline earth metal salts and ammonium salt salts.
  • organic acid salt acetic acid, citrate, maleic acid, fumaric acid, tartaric acid, succinic acid, ethylenediamine tetraacetic acid and chondroitin sulfate are preferred.
  • acidic solution hydrochloric acid solution, lactic acid solution, acetic acid solution or citrate solution is preferred.
  • the sustained-release yarn and composition in the solid form is added to an acidic solution having a pH of 3 to 5 containing 0.01 to 2M metal ions, for example, 10 minutes to 3 hours, preferably 30 minutes to 2 hours.
  • the suspension can be prepared by adjusting the pH of the solution to, for example, 3 to 9, preferably 3 to 8.
  • the metal ions are preferably one or more selected from the group power consisting of alkali metals and alkaline earth metals.
  • As the acidic solution hydrochloric acid solution, lactic acid solution, acetic acid solution or citrate solution is preferred.
  • the liquid such as a suspension is heat-treated at 60 ° C to 100 ° C for 1 to 60 minutes for long-term storage. It is preferable to perform heat sterilization.
  • composition of the present invention in the form of a liquid such as a suspension or a solid such as a powder includes, for example, dairy products such as yogurt and cheese, vegetable juice products, fruit juice products, candy, etc.
  • dairy products such as yogurt and cheese
  • vegetable juice products such as yogurt and cheese
  • fruit juice products such as candy
  • confectionery it can be used with appropriate addition.
  • the matrix-type enteric 'sustained release composition of the present invention is specifically a microcapsule such as a powder, granule, tablet, pill, emulsion, suspension, gel or capsule encapsulated form. It can be used in any form such as a force capsule, soft capsule, or hard capsule.
  • the encapsulation of the composition of the present invention can be performed by a known microencapsulation technology, soft encapsulation technology, hard encapsulation technology, or the like.
  • the matrix-type enteric 'sustained-release composition of the present invention may be provided as it is as it is used as food, medicine, feed, etc. Also, food, medicine, feed, etc. Can be contained. Appropriate contents of physiologically active substances in the case of containing them for use in this way are known.
  • Example 1 Preparation of greasy-coated lactoferrin / pectin mixed powder
  • Ratatohuelin (Tatza 'Milk' Bioguchi Jix Co., Ltd.) 16kg, Pectin (Happo Shokai) 4kg, Rapeseed hardened oil (melting point 67 ° C; Yokoseki Oil & Fat Co., Ltd.) 2kg at Kneader (Kajiwara) Processed. These powders were thoroughly mixed with stirring at 10 to 50 rpm, and then dry steam was injected into the jacket to raise the product temperature to 75 ° C to melt the rapeseed oil. The stirring and mixing were continued, and the product temperature was maintained at 75 ° C. for about 10 minutes, and then gradually cooled to lower the product temperature. A coating of rapeseed oil was formed on the surface of ratatopherin and bectin particles, and about 21 kg of lipid-coated ratatopherin and pectin mixed powder was obtained.
  • Example 3 Production of greasy-coated core isolate / bectin mixed powder
  • Co-isolate (ratatoferrin, lactoperoxidase; Taza Milk Milk Bio-Jix) 16kg, Pectin (Happo Shokai) 4kg, Rapeseed oil (melting point 67 ° C; Yokoseki Oil & Fat Co., Ltd.) 2kg (Kajiwara Co., Ltd.).
  • dry steam was injected into the jacket to raise the product temperature to 75 ° C. to melt the rapeseed oil. Stirring and mixing were continued, and the product temperature was maintained at 75 ° C for about 10 minutes, and then gradually cooled to lower the product temperature.
  • a coating of rapeseed oil was formed on the surface of coisolate and pectin particles to obtain about 21.1 kg of lipid-coated core isolate and pectin mixed powder.
  • Example 4 Sustained release product containing core isolate.
  • Example 6 Production of a composition for sustained release containing ectoferrin / quenate / calcium lactate
  • lipid-coated ratatopherin Z pectin mixed powder obtained in the same manner as in Example 1, 10 g of citrate, calcium lactate, 60 g of crystalline cellulose, and 60 g of dextrin were processed with a stirring and mixing granulator (KOMASA MIC DV). . These powders are thoroughly mixed and stirred at the bottom stirring at 300rpm and the tipper 3, OOOrpm, then 0.2% force from the top of the container under mixing stirring. It was granulated by spraying a lupoxymethylcellulose 'sodium (CMC. Na) solution. The granulated granule was dried in a dryer at 60 ° C. for 8 hours to obtain about 200 g of a sustained release composition (ratatopherin content: about 22%) containing ratatopherin Z citrate Z lactic acid.
  • a sustained release composition ratatopherin content: about 22%) containing ratatopherin Z citrate Z lactic acid.
  • Example 7 Making a lactoferrin-containing sustained release composition
  • Lactoperoxidase (Tatsumi Milk Bio-Koji Jix Co., Ltd.) 600g, Pectin (Sanki Co., Ltd.) 300g, Rapeseed hardened oil (Yokoseki Oil & Fat Co., Ltd.) lOOg was processed with a kneader tester (homemade) . After sufficiently stirring and mixing these powders, the product temperature was raised to 75 ° C to melt the rapeseed oil. Stirring and mixing were continued, and the product temperature was maintained at 75 ° C for about 10 minutes, and then cooled gradually to lower the product temperature. A coating of rapeseed oil was formed on the surface of the powder particles of lactoperoxidase and bectin, and about 950 g of lipid-coated lactoperoxidase Z pectin mixed powder was obtained.
  • Example 9 Production of sustained release composition containing lactoperoxidase
  • Example 10 Preparation of greasy-coated lactoferrin / xanthan gum mixed powder
  • Ratatophelin (Tatsumi's Milk Biotech Company) 12 kg, xanthan gum (Taiyo Chemical Co., Ltd.) 6 kg, rapeseed hydrogenated oil (Yokoseki Oil & Fat Co., Ltd.) 2 kg were treated with a kneader (Kajiwara Co., Ltd.). These powders were thoroughly stirred and mixed at 10 to 50 rpm, and then dry steam was injected into the jacket to raise the product temperature to 75 ° C. to melt the rapeseed oil.
  • Lipid-coated ratatopherin / xanthan gum mixed powder 340 g, prepared soymilk powder 500 g, and chitosan lactate (Kyowa Technos Co., Ltd.) 160 g obtained in the same manner as in Example 10 were treated with a stirring and mixing granulator. These powders were thoroughly mixed and stirred at 300 rpm at the bottom and 3 rpm at the chopper, and then 450 g of a 17 wt% Zane Z83 wt% ethanol solution was added from the top of the container under mixing and granulation.
  • the granulated granule was dried with a dryer at 60 ° C for 8 hours to obtain about 995 g of a sustained release composition containing ratatopherin Z xanthan gum Z soymilk (ratatopherin content: about 21%).
  • Example 13 Making a greasy-coated lactoferrin / carrageenan mixed powder
  • Ratatohuelin (Tatza 'Milk' Bioguchi Jix Co., Ltd.) 12 kg, Carrageenan (Ina Food Industry Co., Ltd.) 6 kg, and rapeseed hydrogenated oil (Yokoseki Oil & Fat Co., Ltd.) 2 kg were treated with a kneader (Kajiwara Co., Ltd.). These powders are thoroughly stirred and mixed at 10 to 50 rpm and then dried in a jacket. Steam was injected to raise the product temperature to 75 ° C, and the rapeseed oil was melted. Stirring and mixing were continued, and the product temperature was maintained at 75 ° C for about 10 minutes, and then gradually cooled to lower the product temperature. A coating of rapeseed oil was formed on the surface of ratatopherine and carrageenan powder particles to obtain about 19.5 kg of lipid-coated ratatopherin / carrageenan mixed powder.
  • Example 14 Sustained release composition containing lactoferrin / carrageenan / soy milk
  • Lipid-coated ratatopherin / carrageenan mixed powder 34 Og, prepared soymilk powder 500 g, and chitosan lactate (Kyowa Technos Co., Ltd.) 160 g obtained in the same manner as in Example 13 were treated with a stirring and mixing granulator. These powders were sufficiently mixed and stirred with a lower stirring speed of 300 rpm and a chopper of 3, OOO rpm, and then 450 g of a 17 wt% Tween Z83 wt% ethanol solution was added from the upper portion of the container and granulated. The granulated granule was dried with a dryer at 60 ° C. for 8 hours to obtain about 990 g of a sustained release composition containing ratatopherin Z carrageenan Z soymilk (ratatopherin content: about 21%).
  • ovotransferrin (Canada Innovatech), 60 g of chitosan lactate (Kyowa Technos Co., Ltd.), and 20 g of rapeseed oil (Yokoseki Oil & Fat Co., Ltd.) were treated with a kneader tester (homemade). After sufficiently stirring and mixing these powders, the product temperature was raised to 75 ° C to melt the rapeseed oil. Stirring and mixing were continued, and the product temperature was maintained at 75 ° C for about 10 minutes, and then cooled gradually to lower the product temperature. A coating of rapeseed oil was formed on the surface of the powder particles of lactoperoxidase and bectin, and about 190 g of lipid-coated lactoperoxidase Z pectin mixed powder was obtained.
  • Example 16 Production of sustained release composition containing ovotransferrin Z chitosan Z soymilk
  • Example 15 70 g of the lipid-coated ovotransferrin / chitosan mixed powder 170 and 830 g of the prepared soymilk powder obtained in the same manner as in Example 15 were processed by a stirring and mixing granulator. These powders were thoroughly mixed and stirred with a lower stirring speed of 300 rpm and chopper 3, OOO rpm, and granulated by adding 500 g of 17 wt% Zane Z83 wt% ethanol solution from the upper part of the container under mixing and stirring. . The granulated granule was dried with a dryer at 60 ° C. for 8 hours to obtain about 990 g of a sustained release composition containing ovotransferrin Z chitosan Z soymilk (ratatopherin content: about 10%).
  • Test Example 1 Stable release of exoferrin / NaCl-containing sustained release composition in gastric fluid PH
  • Ratatopherin ZNaCl-containing sustained-release composition 250 mg produced in the same manner as in Example 2 was dispersed in model gastric juice (0.2% NaCl, 70 mM HCl, pH l. 2) lOmL, and gently rotated at 37 ° C for 1 hour. After mixing, the mixture was centrifuged and the supernatant was collected. Ratatopherin concentration in the supernatant was measured by high performance liquid chromatography.
  • Test Example 2 Dissolution of intestinal fluid fistula of exoferrin / NaCl-containing sustained release composition
  • ratatopherin ZNaCl-containing sustained release composition prepared in the same manner as in Example 2 in model intestinal fluid (50 mM potassium dihydrogen phosphate, 24 mM NaOH, pH 6.8) lOmL, and gently at 37 ° C for 1 hour After rotary mixing, centrifugation was performed and the supernatant was collected. The lactofrin concentration in the supernatant was measured by high performance liquid chromatography.
  • the ratatopherin concentration in the supernatant was 5 mgZmL. This means that about 91% of ratatopherin (about 55 mg) contained in 250 mg of the treated composition was eluted, and the ratatopherin / NaCl-containing sustained release composition of the present invention releases ratatopherin at intestinal pH. It was confirmed.
  • Test Example 3 Lactoferrin ⁇ 3 ⁇ 4, Contained sustained release ⁇ . Stabilization of adult gastric juice ⁇
  • sustained release composition containing ratatopherin / soy milk prepared in the same manner as in Example 5 was dispersed in 10 mL of modelole gastric juice (0.2% NaCl, 70 mM HC1, pHl. 2), and gently stirred at 37 ° C for 1 hour. Then, the mixture was centrifuged, and the supernatant was collected. The ratoferrin concentration in the supernatant was measured by high performance liquid chromatography.
  • Test Example 4 Dissolution of intestinal fluid phlegm with a sustained release composition containing exoferrin / soy milk
  • 500 mg of sustained release composition containing ratatopherin / soy milk prepared in the same manner as in Example 5 was dispersed in 10 mL of model intestinal fluid (50 mM potassium dihydrogen phosphate, 24 mM NaOH, pH 6.8) at 37 ° C, and 1 After gently rotating and mixing for a period of time, the mixture was centrifuged and the supernatant was collected. The lactofrin concentration in the supernatant was measured by high performance liquid chromatography. The ratatopherin concentration in the supernatant was 4.7 gZmL.
  • Test Example 5 Stable heat treatment of sustained release composition containing lactoferrin ZNaCl in vegetable juice
  • ratatopherin / NaCl-containing sustained-release composition produced in the same manner as in Example 2 was suspended in 1 mL of commercially available vegetable juice (Glico Dairy Co., Ltd. “Vegetable &Fruit”; vegetable juice 35% + fruit juice 65%, pH 4) It was made turbid and heat-treated in a heat block at 65 ° C, 75 ° C, 85 ° C and 95 ° C for 30 minutes each. After the heat treatment, centrifugation was performed and the supernatant was collected. The lactoferrin in the supernatant was measured by high performance liquid chromatography.
  • the ratio of elution after heat treatment to 5.5 mg of lactofrin in 25 mg of sample was expressed as the elution rate (%).
  • ratatopherin-containing sustained-release composition of the present invention is stable in heat treatment at 65 ° C. to 95 ° C. for 30 minutes in vegetable juice.
  • the sustained release composition containing ratatopherin / taenoic acid / calcium lactate is stable against heat treatment at 70 ° C for 30 minutes near neutral pH by treatment in the presence of 1M NaCl at ⁇ 1-2. I found that there was. Therefore, the composition sterilized by heating can be added to sterilized dairy products such as yogurt or vegetable juice.
  • Test Example 7 Rakutofuerin containing sustained-release Ken ⁇ Narubutsu stable matter in the gastric juice ⁇ ⁇ of
  • Ratatopherin-containing sustained-release composition produced in the same manner as in Example 7 (ratatopherin content: 22%) 250 mg was added to model gastric fluid (0.2% NaCl, 70 mM HC1, pHl. 2) at 0, 0.25, Disperse in 10 mL of a solution supplemented with 0.50, 0.75, 1.0 M NaCl 37. After gently rotating and mixing at C for 1 hour, the mixture was centrifuged and the supernatant was collected. The ratoferrin concentration in the supernatant was measured by high performance liquid chromatography.
  • Test Example 8 Dissolution of intestinal fluid phlegm with a composition containing sustained release of exogenous ferrin
  • Ratatopherin-containing sustained release composition produced in the same manner as in Example 7 (ratatopherin content: 22%) 250 mg of model intestinal fluid (50 mM potassium dihydrogen phosphate, 24 mM NaOH, pH 6. 8) [each 0, 0 25, 0.50, 0.75, 1.0 In a 10 mL solution supplemented with NaCl After dispersing and gently rotating and mixing at 37 ° C for 1 hour, the mixture was centrifuged and the supernatant was collected. The lactofrin concentration in the supernatant was measured by high performance liquid chromatography.
  • Test Example 9 Stability of a controlled release composition containing exoferrin / soymilk powder to pepsin treatment
  • Sustained release composition containing extra-feroferin Z soymilk powder produced in the same manner as in Example 5 1 g was suspended in 5 mL of water and adjusted with 0.4 mg ZmL pepsin solution ( ⁇ 2; 1 ⁇ hydrochloric acid solution) 5mL was added and treated at 37 ° C for 30 minutes.
  • a pH 2 solution containing no pepsin (adjusted with a 1N hydrochloric acid solution) was added and treated in the same manner.
  • Centrifugation was performed after the treatment, and the precipitate was dispersed in 10 mL of 3% bile Z50 mM sodium bicarbonate solution (model intestinal fluid) and treated at 37 ° C for 60 minutes. Subsequently, centrifugation was performed, the supernatant was collected, and ratatopherin in the supernatant that had been dissolved out was measured by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • the ratatopherin concentration in the supernatant after pepsin treatment was almost the same as the ratatopherin concentration in the control supernatant. Therefore, it was confirmed that the sustained release composition containing ratatopherin Z soymilk powder of the present invention is stable against pepsin present in gastric juice.
  • Test Example 10 Lactoferrin Z Xanthan gum Z Soymilk containing sustained release composition treated with pepsin
  • lactoperoxidase-containing sustained-release composition of the present invention is stable against pepsin present in gastric juice. It was also confirmed that ratatofurin was eluted in model intestinal fluid containing bile.
  • Test Example 11 Stability of a sustained release composition containing lactoperoxidase to pepsin treatment
  • Ratatophelin Z xanthan gum Z soymilk powder-containing sustained release composition (ratatopherin content: 21%) lg produced in the same manner as in Example 11 was used to examine the stability against pepsin treatment in the same manner as in Test Example 9.
  • the ratatopherin concentration in the supernatant after pepsin treatment was almost the same as the ratatopherin concentration in the control supernatant. Therefore, it can be confirmed that the sustained release composition containing ratatofolin Z xanthan gum Z soymilk powder of the present invention is stable against pepsin present in the gastric juice.
  • Naked lactofurin (“powder LF”) was dissolved in physiological saline (30 mgZkg, 300 mgZkg) and administered to the two groups of controls for intragastric administration and intraduodenal administration.
  • the sustained release composition containing ratatopherin and soy milk (“enteric LF”) prepared in 1 was suspended in physiological saline and administered (30 mgZkg as ratatopherin).
  • Chest lymphatic fluid was collected every hour from 1 hour before administration (“Pre”) to 4 hours after administration, and ratatopherin was quantified by ELISA. The results are shown in Figure 1.
  • the experimental group (30 mgZkg as lactoferrin) in the intragastric administration was about twice as large as the control ratatofurin 300 mgZkg administration ( Figure 2).
  • the ratatopherin content of the sustained release composition containing ratatopherin / soy milk is one-tenth that of the naked ratatopherin. It was revealed. In addition, it was revealed that the intestinal force was absorbed about 15 times more in the control ratatopherin 30mgZkg administration group.
  • ratatopherin in the sustained-release composition of the present invention is resistant to digestion in the stomach, It was found that there is an effect of improving the absorption efficiency of ratatopherin.

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Abstract

A matrix-type enteric coated sustained release composition comprising a physiologically active substance, a gelling agent, a basic organic compound and an excipient; a process for producing the composition; and a food, pharmaceutical product, feed or the like comprising the composition, characterized in that the physiologically active substance is a protein, a polypeptide, a peptide or a microorganism, the physiologically active substance and the gelling agent are both in the form of powder particles coated with a lipid coating, and each of the components described above and other auxiliary components has one or more elements selected from the group consisting of an alkaline metal, an alkaline earth metal, manganese, cupper, iron, zinc and cobalt.

Description

明 細 書  Specification
マトリックス型腸溶性 ·徐放性組成物  Matrix type enteric / sustained release composition
技術分野  Technical field
[0001] 本発明は、タンパク質やポリペプチドなどの生理活性物質を経口投与可能にする ためのマトリックス型腸溶性'徐放性組成物およびその製造方法等に関する。さらに 詳しくは、経口摂取した後、生理活性物質が胃では殆ど溶出せず、腸管において溶 出し、その生理活性を効率よく発揮し得るマトリックス型腸溶性'徐放性組成物および その製造方法等に関する。  [0001] The present invention relates to a matrix-type enteric 'sustained-release composition for allowing physiologically active substances such as proteins and polypeptides to be orally administered, a method for producing the same, and the like. More specifically, the present invention relates to a matrix-type enteric 'sustained-release composition that can be effectively dissolved in the intestinal tract after the oral ingestion, and the physiologically active substance hardly dissolves in the stomach and efficiently exhibits its physiological activity, and a method for producing the same. .
背景技術  Background art
[0002] タンパク質やポリペプチドなどの生理活性物質は、胃内において胃酸やペプシン の作用により分解され、失活し、殆どその生物活性を失う。生理活性物質は、腸管で 吸収されて機能を発揮するか、あるいは、腸管で作用するため、胃内では殆ど溶出 せずに腸管まで到達させることが好まし ヽ。  [0002] Physiologically active substances such as proteins and polypeptides are degraded and inactivated in the stomach by the action of gastric acid and pepsin, and almost lose their biological activity. The physiologically active substance is absorbed in the intestinal tract and exerts its function, or acts in the intestinal tract, so it is preferable to reach the intestinal tract with little elution in the stomach.
そのような観点から、腸溶性コーティングを施した腸溶錠や腸溶性カプセルなどの 腸溶性経口製剤が開発されて!ヽる。  From such a viewpoint, enteric-coated oral preparations such as enteric-coated tablets and enteric-coated capsules with enteric coatings have been developed!
[0003] 一般に、これらの腸溶性経口製剤には腸溶性コーティング剤が使用されることが多 い。  [0003] Generally, enteric coating agents are often used in these enteric oral preparations.
医薬用途での腸溶性コーティング剤としては、アクリル酸系ポリマー (EUDRAGIT Zオイドラギット（登録商標） )、ヒドロキシプロピルメチルセルロースフタレート（HPM CP)、酢酸フタル酸セルロース（CAP)、ヒドロキシプロピルメチルセルロースァセテ ートサクシネート (HPMCAS)、カルボキシメチルェチルセルロース（CMEC)などの 腸溶性高分子が使われて 、る。  Enteric coating agents for pharmaceutical use include acrylic acid polymers (EUDRAGIT Z Eudragit (registered trademark)), hydroxypropyl methylcellulose phthalate (HPM CP), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose succinate (HPMCAS). ), Enteric polymers such as carboxymethylethyl cellulose (CMEC) are used.
[0004] 一方、食品や飼料の用途では、腸溶性コーティング剤として天然物由来のシェラッ クゃツエインが使用されて 、る。  [0004] On the other hand, in food and feed applications, shellac twein derived from natural products is used as an enteric coating agent.
[0005] しかし、前記腸溶性コーティング剤は有機溶媒に溶解させて使用するため、微量の 有機溶媒で失活するタンパク質やポリペプチド等の生理活性物質には適用できない ことが多い。また、上記食品'飼料用の腸溶性コーティング剤は、上記医薬用途の腸 溶性高分子に比べると腸溶性の機能等の点で劣っている。 [0005] However, since the enteric coating agent is used after being dissolved in an organic solvent, it is often not applicable to physiologically active substances such as proteins and polypeptides that are inactivated by a small amount of organic solvent. In addition, the enteric coating agent for food and feed is an enteric coating for pharmaceutical use. Compared with soluble polymer, it is inferior in enteric function.
さらに、上記腸溶性コーティングを施した腸溶性経口製剤は、摂取時に水に分散さ せると、腸溶性コーティング被膜が溶解して、胃液耐性および腸溶性の機能が失わ れる問題がある。  Furthermore, when the enteric oral preparation with the enteric coating is dispersed in water at the time of ingestion, there is a problem that the enteric coating film dissolves and the gastric juice resistance and enteric function are lost.
[0006] 近年、医薬品分野において薬物伝達システム（Drug Delivery System: DDS )の研究開発が活発に行われている。この DDSの基本設計の代表的なものとして、 マトリックス型徐放性製剤がある。マトリックス型徐放性製剤は、高分子マトリックス中 に薬物を均一に分散させ、表面力 の薬物の拡散制御を目的とした徐放性製剤であ る。  In recent years, research and development of a drug delivery system (Drug Delivery System: DDS) has been actively conducted in the pharmaceutical field. A typical example of the basic design of DDS is a matrix-type sustained-release preparation. The matrix-type sustained-release preparation is a sustained-release preparation for the purpose of controlling the diffusion of a surface-force drug by uniformly dispersing the drug in a polymer matrix.
[0007] 例えば、有機溶媒を使用しないで製造することができる、魚類の成長ホルモン (分 子量約 2〜3万のポリペプチド)と前記腸溶性高分子とからなるマトリックス製剤が報 告されている（特開平 5— 85941；特許文献 1)。  [0007] For example, a matrix preparation comprising a fish growth hormone (polypeptide having a molecular weight of about 20,000 to 30,000) and the enteric polymer that can be produced without using an organic solvent has been reported. (JP-A-5-85941; Patent Document 1).
[0008] しかし、前記マトリックス製剤はアンモニア水中で魚類の成長ホルモンと腸溶性高 分子溶液とを溶解した後、凍結乾燥させて製造するため、操作性やコスト等の点で 課題が残っている。 However, since the matrix preparation is produced by dissolving a fish growth hormone and an enteric polymer solution in ammonia water and then freeze-drying, there remain problems in terms of operability and cost.
さらに、これらの腸溶性高分子は薬事法により医薬用途のみに使用が限定されて V、るため、一般の食品や飼料の用途には使用ができな!/、。  Furthermore, because these enteric polymers are limited to pharmaceutical use by the Pharmaceutical Affairs Law V, they cannot be used for general food and feed applications!
[0009] また、シームレスカプセルと、オイドラギット等のアクリル系ポリマー、ヒドロキシプロピ ルセルロース、メチルセルロース等のセルロース類、硬化油等の油脂類によって構成 されるマトリックスとを含む徐放性錠剤が報告されている（特開平 9— 52847；特許文 献 2)。 [0009] In addition, sustained release tablets containing seamless capsules and a matrix composed of acrylic polymers such as Eudragit, celluloses such as hydroxypropylcellulose and methylcellulose, and fats and oils such as hardened oil have been reported. (Japanese Patent Laid-Open No. 9-52847; Patent Document 2).
[0010] し力し、ここで使用しているオイドラギット等のアクリル系ポリマー、ヒドロキシプロピル セルロース、メチルセルロース等のセルロース類は、薬事法により医薬用途のみに限 定されて!/、るため、一般の食品や飼料の用途には使用ができな!/、。  [0010] However, since acrylic polymers such as Eudragit, and celluloses such as hydroxypropyl cellulose and methylcellulose, which are used here, are limited to medicinal use only by the Pharmaceutical Affairs Law! / Cannot be used for food and feed applications!
[0011] また、アルギン酸ゲルマトリックス、ゲルマトリックスにからみついたタンパク質、から みついたタンパク質に結合することができる薬剤、および任意の医薬的に使用し得る 賦形剤を包含する組成物であって、この組成物がタンパク質分解酵素を含む条件下 で反応するときにタンパク質が分解され、薬物が放出されるようにした放出制御医薬 組成物が報告されて 、る (特許第 3264948号；特許文献 3)。 [0011] Also, a composition comprising an alginate gel matrix, a protein entangled in the gel matrix, an agent capable of binding to the entangled protein, and any pharmaceutically usable excipient, A controlled-release pharmaceutical that causes the protein to be degraded and the drug to be released when the composition reacts under conditions containing a proteolytic enzyme. A composition has been reported (Patent No. 3264948; Patent Document 3).
[0012] しかし、ここで使用できる薬剤の要件は、力もみついたタンパク質に結合できること およびタンパク質分解酵素により分解されないことであるため、適用可能な薬剤は無 機化合物および比較的小さい有機化合物に限定され、タンパク質やポリペプチド等 の生理活性物質には適用できない問題がある。 [0012] However, the requirements for drugs that can be used here are that they can bind to forceful proteins and are not degraded by proteolytic enzymes, so applicable drugs are limited to inorganic compounds and relatively small organic compounds. There is a problem that cannot be applied to physiologically active substances such as proteins and polypeptides.
[0013] また、ぺクチンと金属イオン封鎖剤と二価金属イオンとを含有する医薬用の経口投 与用徐放性液剤が報告されて ヽる（特開 2004— 231566；特許文献 4)。この液剤 は、服用後に胃液中でゲルィ匕することにより薬剤がゲル中に取り込まれ、その後、そ のゲルカゝら徐々に薬剤が放出される。 [0013] In addition, a sustained-release solution for oral administration containing pectin, a sequestering agent, and a divalent metal ion has been reported (JP 2004-231566; Patent Document 4). This solution is gelled in the gastric juice after administration, and the drug is taken into the gel, and then the drug is gradually released from the gel.
[0014] しかし、この製剤は、溶液または懸濁液の状態で使用するために、胃液中で形成さ れるゲルの性能、大きさ、形状は一定でなぐそのため薬剤の徐放性も不均一になる と考えられる。 [0014] However, since this preparation is used in the form of a solution or suspension, the performance, size, and shape of the gel formed in the gastric juice are not constant, so that the sustained release of the drug is not uniform. It is considered to be.
[0015] また、最初に薬剤と弱膨潤性ポリマー (例えば、ゼラチン)とを混合して顆粒を作り、 次に強膨潤性ポリマー（例えば、 HPMC、 HPMCZぺクチン混合物）をカ卩えて、打 錠して錠剤として製造されるマトリックス型徐放性製剤が報告されて ヽる (米国特許第 6, 337, 091号;特許文献 5)。この製剤は、水溶性の高い有機合成化合物薬剤の 徐放化製剤であり、膨潤性の異なるポリマーを組み合わせることにより、長時間（16 〜20時間）の薬剤の徐放化を目的とした製剤である。  [0015] In addition, a drug and a weakly swellable polymer (for example, gelatin) are first mixed to form granules, and then a strong swellable polymer (for example, HPMC, HPMCZ pectin mixture) is collected and compressed into tablets. Thus, a matrix-type sustained-release preparation produced as a tablet has been reported (US Pat. No. 6,337,091; Patent Document 5). This preparation is a sustained-release preparation of an organic synthetic compound drug with high water solubility, and is a preparation intended for sustained release of a drug for a long time (16 to 20 hours) by combining polymers having different swelling properties. is there.
[0016] しかし、この製剤は、二層構造による徐放性製剤であり、製造工程が複雑である。ま た、エタノールを使用して造粒を行う方法を用いるため、有機溶媒に不安定なタンパ ク質ゃポリペプチド等の生理活性物質には適用できない。 [0016] However, this preparation is a sustained-release preparation having a two-layer structure, and the production process is complicated. In addition, since a method of granulating using ethanol is used, it cannot be applied to physiologically active substances such as proteins unstable to organic solvents.
特許文献 1 :特開平 5— 85941  Patent Document 1: JP-A-5-85941
特許文献 2：特開平 9 52847  Patent Document 2: JP-A-9 52847
特許文献 3：特許第 3264948号  Patent Document 3: Patent No. 3264948
特許文献 4：特開 2004— 231566  Patent Document 4: JP 2004-231566
特許文献 5 :米国特許第 6, 337, 091号  Patent Document 5: U.S. Pat.No. 6,337,091
発明の開示  Disclosure of the invention
[0017] 本発明は、胃液中での安定性が優れており、タンパク質やポリペプチド等の生理活 性物質が胃液中の胃酸やペプシンによる分解を受けることなく腸管に到達して効率 よく生体に吸収されて充分に生理活性を発揮することができ、それ自体を少な!、製 造工程で容易に製造することができ、さらに食品、飼料、医薬などの製造において水 系での加熱滅菌処理を行う上で好都合に利用し得、使用時に水に分散させて経口 摂取できる、という特徴を兼ね備えたマトリックス型腸溶性'徐放性組成物、その製造 方法、ならびにこの徐放性組成物を含む食品、医薬品および飼料等を提供すること を目的とする。 [0017] The present invention is excellent in stability in gastric juice and has physiological activities such as proteins and polypeptides. The substance can reach the intestinal tract without being decomposed by gastric acid or pepsin in the gastric juice, and can be efficiently absorbed into the living body to fully exert its physiological activity. A matrix that can be manufactured and can be conveniently used for heat sterilization in water in the production of food, feed, medicine, etc., and can be dispersed in water at the time of use and taken orally. It is an object of the present invention to provide a type enteric 'sustained-release composition, a production method thereof, and foods, pharmaceuticals, feeds and the like containing the sustained-release composition.
[0018] 本発明者は、上記の課題を解決するために、鋭意研究した結果、タンパク質やポリ ペプチドなどの生理活性物質を、特定の成分を含むマトリックス中に均一に分散させ ることにより、胃液中での安定性、および加熱滅菌処理に対する安定性が顕著に増 大することを見出し、本発明を完成した。  [0018] As a result of diligent research to solve the above problems, the present inventor has dispersed gastric juice by uniformly dispersing physiologically active substances such as proteins and polypeptides in a matrix containing specific components. It was found that the stability in the medium and the stability to the heat sterilization treatment were remarkably increased, and the present invention was completed.
[0019] 即ち、本発明は、  [0019] That is, the present invention provides
〔1〕生理活性物質、ゲル化物質、塩基性有機化合物および賦形剤を含有するマト リックス型腸溶性 '徐放性組成物であって、生理活性物質が、タンパク質、ポリべプチ ド、ペプチドまたは微生物であり、生理活性物質およびゲル化物質が、脂質被膜で 被覆された粉末粒子であり、かつ、これらの成分またはその他の付加的な成分が、ァ ルカリ金属、アルカリ土類金属、マンガン、銅、鉄、亜鉛およびコバルトからなる群から 選択される 1種または 2種以上の元素を含有することを特徴とするマトリックス型腸溶 性 *徐放性組成物；  [1] Matrix type enteric 'sustained release composition containing a physiologically active substance, a gelling substance, a basic organic compound and an excipient, wherein the physiologically active substance is a protein, polypeptide, peptide Or a microorganism, a physiologically active substance and a gelling substance are powder particles coated with a lipid coating, and these components or other additional components are alkali metal, alkaline earth metal, manganese, A matrix-type enteric * sustained-release composition characterized by containing one or more elements selected from the group consisting of copper, iron, zinc and cobalt;
〔2〕有機酸、無機酸塩および結合剤カゝらなる群カゝら選択される 1種または 2種以上 をさらに含む、前記〔1〕記載のマトリックス型腸溶性'徐放性組成物；  [2] A matrix-type enteric 'sustained-release composition according to [1], further comprising one or more selected from the group consisting of an organic acid, an inorganic acid salt, and a binder.
〔3〕生理活性物質およびゲル化物質の脂質被膜粉末粒子の脂質の含有量が、生 理活性物質およびゲル化物質の脂質被膜粉末粒子の全重量を基準として 1重量％ 〜90重量％である、前記〔1〕記載のマトリックス型腸溶性'徐放性組成物；  [3] The lipid content of the lipid-coated powder particles of the physiologically active substance and the gelling substance is 1% to 90% by weight based on the total weight of the lipid-coated powder particles of the physiologically active substance and the gelling substance. And [1] the matrix-type enteric 'sustained-release composition as described above;
〔4〕生理活性物質およびゲル化物質の脂質被膜粉末粒子の脂質の含有量が、生 理活性物質およびゲルィ匕物質の脂質被膜粉末粒子の全重量を基準として 5重量％ 〜20重量％である、前記〔1〕記載のマトリックス型腸溶性'徐放性組成物；  [4] The lipid content of the lipid-coated powder particles of the physiologically active substance and the gelling substance is 5% to 20% by weight based on the total weight of the lipid-coated powder particles of the physiologically active substance and the gely substance. And [1] the matrix-type enteric 'sustained-release composition as described above;
〔5〕前記元素が、ナトリウム、カリウム、カルシウム、マグネシウム力 なる群力 選択 される 1種または 2種以上を含む、前記〔1〕〜〔3〕の 、ずれか 1項記載のマトリックス 型腸溶性，徐放性組成物； [5] Select the group power that the element is sodium, potassium, calcium, magnesium power The matrix-type enteric and sustained-release composition according to any one of the above [1] to [3], comprising one or more of the above;
〔6〕ゲル化物質が、カラギーナン、アルギン酸、フコィダン、硫酸ガラクタン、キサン タンガム、カルボキシメチルセルロース、ぺクチン、アラビアガム、ジエランガム、納豆 菌ガム、大豆水溶性多糖類、寒天、デンプン、ファーセルラン、トラカントガム、ゼラチ ン、タマリンド種子ガム、ローカストビーンガム、グァーガム、キチン、キトサンからなる 群力も選択される 1種または 2種以上である、前記〔1〕〜〔5〕の 、ずれか 1項記載の マトリックス型腸溶性 ·徐放性組成物；  [6] The gelling substance is carrageenan, alginic acid, fucoidan, galactan sulfate, xanthan gum, carboxymethylcellulose, pectin, gum arabic, dielan gum, natto fungus gum, soybean water-soluble polysaccharide, agar, starch, farcellulan, tracant gum The matrix according to any one of (1) to (5) above, wherein the group power is selected from the group consisting of, gelatin, tamarind seed gum, locust bean gum, guar gum, chitin, and chitosan. Type enteric / sustained release composition;
〔7〕賦形剤力 セルロース、結晶セルロース、デキストリン、バターミルクパウダー、 カゼイン、豆乳粉末、大豆粉末、脱脂ミルク、野菜粉末、果汁粉末からなる群から選 択される 1種または 2種以上である、前記〔1〕〜〔6〕の 、ずれ力 1項記載のマトリックス 型腸溶性，徐放性組成物；  [7] Excipient power One or more selected from the group consisting of cellulose, crystalline cellulose, dextrin, buttermilk powder, casein, soymilk powder, soybean powder, skim milk, vegetable powder, and fruit juice powder The matrix-type enteric and sustained-release composition according to claim 1, wherein the above-mentioned [1] to [6] have a displacement force;
〔8〕塩基性有機化合物が、豆乳粉末、キトサン、ポリリジン、ポリアルギニン、ポリグ ノレタミン、ァノレギニン、グルタミン、ヒスチジン、リジン、オル二チン、ダルコサミンからな る群力も選択される 1種または 2種以上である、前記〔1〕〜〔7〕のいずれか 1項記載の マトリックス型腸溶性 ·徐放性組成物；  [8] One or more basic organic compounds selected from the group power consisting of soymilk powder, chitosan, polylysine, polyarginine, polygnoretamine, anoleginine, glutamine, histidine, lysine, ornitine, darcosamine The matrix type enteric / sustained release composition according to any one of the above [1] to [7];
〔9〕有機酸力 酢酸、クェン酸、マレイン酸、フマル酸、酒石酸、コハク酸、エチレン ジァミン四酢酸、コンドロイチン硫酸、およびそれらの塩からなる群から選択される 1 種または 2種以上である、前記〔2〕〜〔8〕の 、ずれか 1項記載のマトリックス型腸溶性 -徐放性組成物；  [9] Organic acidity One or more selected from the group consisting of acetic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, ethylene diammine tetraacetic acid, chondroitin sulfate, and salts thereof. The matrix type enteric-sustained release composition according to any one of the above [2] to [8];
〔10〕無機酸塩が、アルカリ金属塩、アルカリ土類金属塩、アンモニゥム塩カもなる 群力も選択される 1種または 2種以上である、前記〔2〕〜〔9〕の 、ずれか 1項記載の マトリックス型腸溶性 ·徐放性組成物；  [10] The inorganic acid salt is an alkali metal salt, an alkaline earth metal salt, or an ammonium salt salt. The group power is also selected. One or more kinds are selected. Any one of the above [2] to [9] Matrix type enteric / sustained release composition according to item;
〔11〕粉末、カプセルに封入されている形態、錠剤、顆粒、丸薬、乳化液、懸濁液ま たはゲルの形態である、前記〔1〕〜〔10〕の 、ずれか 1項記載のマトリックス型腸溶性 -徐放性組成物；  [11] As described in any one of [1] to [10] above, which is in the form of a powder, a capsule, a tablet, a granule, a pill, an emulsion, a suspension, or a gel. Matrix enteric -sustained release composition;
〔12〕マイクロカプセル、ソフトカプセルまたはハードカプセルに封入されている、前 記〔 11〕記載のマトリックス型腸溶性 ·徐放性組成物； 〔 13〕前記〔 1〕〜〔 12〕の ヽずれか 1項記載のマトリックス型腸溶性 ·徐放性組成物を 含有する食品； [12] The matrix-type enteric / sustained-release composition according to [11], which is encapsulated in microcapsules, soft capsules, or hard capsules; [13] A food containing the matrix type enteric / sustained release composition according to any one of [1] to [12];
〔14〕前記〔1〕〜〔12〕の ヽずれか 1項記載のマトリックス型腸溶性 '徐放性組成物を 含有する医薬；  [14] Any one of the above-mentioned [1] to [12] The pharmaceutical comprising the matrix-type enteric 'sustained release composition according to 1;
〔 15〕前記〔 1〕〜〔 12〕の ヽずれか 1項記載のマトリックス型腸溶性 ·徐放性組成物を 含有する飼料；  [15] A feed containing the matrix type enteric / sustained release composition according to any one of [1] to [12];
〔16〕前記〔1〕記載のマトリックス型腸溶性 '徐放性組成物用の素材組成物であって 、生理活性物質とゲル化物質とが脂質被膜で被覆されて ヽることを特徴とする素材 組成物；  [16] A material composition for a matrix-type enteric and sustained-release composition according to [1], wherein the physiologically active substance and the gelling substance are coated with a lipid film. Material composition;
〔17〕脂質被膜の脂質の含有量が、素材組成物の重量を基準として 1重量％〜90 重量％である、前記〔16〕記載の素材組成物；  [17] The material composition according to [16], wherein the lipid content of the lipid coating is 1% to 90% by weight based on the weight of the material composition;
〔18〕前記〔16〕または〔17〕記載の素材組成物の製造方法であって、生理活性物 質とゲル化物質と脂質を含む被膜材とを一緒にして混合物を生成する工程、前記混 合物を加熱して脂質を融解させる工程、前記混合物中で前記生理活性物質および ゲル化物質に前記被膜材を付着させる工程、および前記生理活性物質およびゲル 化物質の表面に前記被膜材カゝらなる被膜を形成させる工程を含むことを特徴とする 方法；  [18] The method for producing a raw material composition according to [16] or [17], wherein the bioactive substance, the gelling substance, and the coating material containing lipid are combined to form a mixture, Heating the compound to melt the lipid; attaching the coating material to the physiologically active substance and the gelling substance in the mixture; and coating the coating material cover on the surface of the physiologically active substance and the gelling substance. A method comprising the step of forming a film comprising:
〔19〕前記〔1〕記載のマトリックス型腸溶性'徐放性組成物の製造方法であって、生 理活性物質、ゲル化物質、塩基性有機化合物および賦形剤を含有し、かつ、これら の成分またはその他の付カ卩的な成分に由来するアルカリ金属またはアルカリ土類金 属を含有する、組成物の構成成分を一緒にして混合物を生成する工程、前記混合 物に結合剤を噴霧して造粒する工程、および前記造粒物を乾燥させる工程を含むこ とを特徴とする方法  [19] A method for producing a matrix-type enteric 'sustained release composition according to [1] above, comprising a physiologically active substance, a gelling substance, a basic organic compound and an excipient, and A step of combining components of the composition containing an alkali metal or an alkaline earth metal derived from the above components or other auxiliary components to form a mixture, and spraying the mixture with a binder And granulating, and drying the granulated product
を提供する。 I will provide a.
本発明のマトリックス型腸溶性 '徐放性組成物は、胃液中では、安定であり、タンパ ク質ゃポリペプチドなどの生理活性物質が溶出してこな 、ので、これらの生理活性物 質は、胃酸やペプシンによる分解を受けずに生理活性を維持したまま腸管に到達す ることができる。また、本発明の徐放性組成物に含有される生理活性物質は、高 pH の状態であり胆汁が分泌される腸管においては組成物力 溶出することができるため 、効率よく生体に吸収されて生理活性を発揮することができる。 The matrix-type enteric 'sustained-release composition of the present invention is stable in gastric juice, and a physiologically active substance such as protein polypeptide is eluted, so that these physiologically active substances are It can reach the intestinal tract while maintaining its physiological activity without being degraded by gastric acid or pepsin. In addition, the physiologically active substance contained in the sustained release composition of the present invention has a high pH. In the intestinal tract in which the bile is secreted, the composition force can be eluted, so that it can be efficiently absorbed into the living body and exhibit physiological activity.
[0021] さらに、生理活性物質およびゲルィ匕物質を脂質被膜で被覆しておくことにより、造 粒工程にぉ ヽて、生理活性物質およびゲル化物質の粉末粒子が結合剤水溶液中 の水を吸収して溶解することを防止できるため、結合剤水溶液を噴霧すること等によ り、生理活性物質が均一に分散した微粒子状の造粒物を製造することができる。一 般に、造粒工程において水溶性の基材を多量に使用する場合、基材が結合剤溶液 中の水を吸収して溶解し、ブロック化が進行するので均一な微粒子状の造粒物を形 成することは困難であるが、その点において、本発明のマトリックス型腸溶性 '徐放性 組成物は製造上も有利である。  [0021] Furthermore, by coating the physiologically active substance and the gelling substance with a lipid coating, the powder particles of the physiologically active substance and the gelling substance absorb the water in the aqueous binder solution over the granulation process. Therefore, it is possible to produce a granular granulated product in which a physiologically active substance is uniformly dispersed by spraying with an aqueous binder solution. In general, when a large amount of a water-soluble base material is used in the granulation process, the base material absorbs and dissolves water in the binder solution, and the blocking progresses. However, in that respect, the matrix-type enteric and sustained-release composition of the present invention is advantageous in production.
また、結合剤溶液中に高濃度のエタノール等の有機溶媒を含有する場合、タンパ ク質などの生理活性物質が脂質被膜で被覆されて ヽるので、生理活性物質がェタノ ール等の有機溶媒と直接接触して変性することを防止することができる。  In addition, when the binder solution contains an organic solvent such as ethanol at a high concentration, a physiologically active substance such as protein is covered with a lipid film, so that the physiologically active substance is an organic solvent such as ethanol. It is possible to prevent denaturation by direct contact with.
[0022] 本発明のマトリックス型腸溶性'徐放性組成物は、医薬、食品、飼料等の広い用途 に適用可能である。さらに、本発明のマトリックス型腸溶性 '徐放性組成物は、水系に おける加熱滅菌処理に対して安定であるので、食品、飼料、医薬などの製造におい て加熱滅菌処理などの加熱を伴う工程を行う上で好都合に利用することができ、製 造上の制限が緩和される結果、多種多様な製品に応用することができる。  [0022] The matrix type enteric 'sustained release composition of the present invention can be applied to a wide range of uses such as pharmaceuticals, foods and feeds. Furthermore, since the matrix-type enteric 'sustained release composition of the present invention is stable with respect to heat sterilization treatment in an aqueous system, it is a process involving heating such as heat sterilization treatment in the production of foods, feeds, pharmaceuticals and the like. As a result, it can be applied to a wide variety of products.
図面の簡単な説明  Brief Description of Drawings
[0023] [図 1]は、ラットにおけるラタトフエリン吸収量の経時変化を示す図である。 パネル (A )は、ラタトフエリン粉末（「粉末 LF」 )および本発明の組成物（「腸溶性 LF」 )をラットに 胃内投与したときの 1時間ごとの吸収された総ラタトフエリン量を示す図である。 パネ ル (B)および (C)は、同様に、十二指腸内投与したときの 1時間ごとの吸収されたラタ トフエリン量を示す図である。  [0023] FIG. 1 is a graph showing changes in ratatopherin absorption over time in rats. Panel (A) shows the total amount of ratatopherin absorbed per hour when ratatopherin powder (“Powder LF”) and the composition of the present invention (“Enteric LF”) are administered intragastrically to rats. is there. Panels (B) and (C) are also graphs showing the amount of ratatoferrin absorbed per hour when administered intraduodenum.
[図 2]は、ラットにおけるラタトフエリン投与後 4時間までの吸収されたラタトフエリンの総 量を示す図である。  FIG. 2 is a graph showing the total amount of ratatopherin absorbed up to 4 hours after ratatopherin administration in rats.
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0024] 本発明において、「生理活性物質」とは、生体において作用しうるものであれば特に 限定されないが、本発明の利点を特に有利に利用できるものとしては、ヒト、動植物 および微生物由来のタンパク質、ポリペプチド、ペプチド、核酸等、さらには、ビフィズ ス菌ゃ乳酸菌等の腸内有用細菌等の微生物が挙げられる。また、タンパク質、ポリべ プチド等は、天然のもののほか遺伝子組換え型をも包含する。具体的には、例えば、In the present invention, the “physiologically active substance” is not particularly limited as long as it can act in a living body. Although not limited, the advantages of the present invention can be used particularly advantageously to include proteins, polypeptides, peptides, nucleic acids and the like derived from humans, animals and plants and microorganisms, and useful enteric bacteria such as bifidobacteria and lactic acid bacteria. Of the microorganisms. Proteins, polypeptides, etc. include natural ones as well as genetically modified forms. Specifically, for example,
6Ckine、アンフィレグリン、アンジォジェニン、 β —ミクログロブリン、ベータセルリン、 6Ckine, amphiregulin, angiogenin, β-microglobulin, betacellulin,
2  2
脳由来神経栄養因子、 C10、毛様体神経栄養因子、毛様体神経栄養因子受容体ァ ルファ、 CPP32(Cysteine Protease Protein 32)、 CRG— 2、サイト力イン誘導性好中 球走化因子 1、サイト力イン誘導性好中球走ィ匕因子 2アルファ、サイト力イン誘導性好 中性走化因子 2ベータ、細胞障害性 T リンパ球抗原 4、ベータ血管内皮細胞増殖 因子、エンドセリン— 1、ェォタキシン、ェォタキシンー2、上皮由来好中球誘引物質 78、エリスロポエチン受容体、 Fas、線維芽細胞増殖因子 4、線維芽細胞増殖因子 5 、線維芽細胞増殖因子 6、線維芽細胞増殖因子 7ZKGF (keratinocyte growth facto r:角化細胞増殖因子）、線維芽細胞増殖因子 8、線維芽細胞増殖因子 8b、線維芽 細胞増殖因子 8c、線維芽細胞増殖因子 9、酸性線維芽細胞増殖因子、塩基性線維 芽細胞増殖因子、 Fit— 3リガンド、フラクタル力イン、グリア細胞株由来神経栄養因 子、顆粒球走ィ匕性タンパク質、顆粒球コロニー刺激因子受容体、顆粒球マクロファー ジコロニー刺激因子、成長関連タンパク質、成長関連タンパク質アルファ、成長関連 タンパク質ベータ、成長関連タンパク質ガンマ、血液ろ過 CCケモカイン 1、へパリン 結合性上皮成長因子、肝細胞増殖因子、ヘレダリンアルファ、ヘレダリンベータ 1、 I 309、インターロイキン 1アルファ、インターロイキン 1ベータ、インターロイキン 1レセ プターアンタゴ-スト（インターロイキン 1受容体拮抗タンパク）、 IP— 10、 JE/MCP 1、 KC、角化細胞増殖因子 ZFGF— 7、ラタトフヱリン、レブチン、白血病阻害因 子、ルシフェラーゼ、マクロファージコ口-一刺激因子、マクロファージコ口-一刺激 因子受容体、マクロファージ炎症タンパク質 1アルファ、マクロファージ炎症タンパク 質 1ベータ、マクロファージ炎症タンパク質 1ガンマ、マクロファージ炎症タンパク質 2 、マクロファージ炎症タンパク質 3アルファ、マクロファージ炎症タンパク質 3ベータ、 マクロファージ遊走阻止因子、マクロファージ由来ケモカイン、 MARCZMCP— 3、 マクロファージ刺激タンパク、ミツドカイン、単球走化性タンパク質 lZMCAF (monoc yte chemotactic and activating factor:単球走ィ匕活 '性因子）、単球走ィ匕'性タンパク質 2、単球走ィ匕性タンパク質 3、単球走ィ匕性タンパク質 4、単球走ィ匕性タンパク質 5、マト リックスメタ口プロテアーゼー 1、マトリックスメタ口プロテアーゼー 2、マトリックスメタロプ 口テアーゼー 3、マトリックスメタ口プロテアーゼー 7、マトリックスメタ口プロテアーゼー 9、マトリックスメタ口プロテアーゼ 12、ミエ口ペルォキシダーゼ、ベータ神経成長因 子、ニューロトロフィン (神経栄養因子） 3、ニューロトロフィン (神経栄養因子) 4、一酸 化窒素合成酵素、オンコスタチン M、胎盤成長因子、胎盤成長因子 2、血小板由来 血管内皮細胞増殖因子、プレイオト口フィン、プレ B細胞増殖刺激因子 (PBSF)ZS DF (stromal cell-derived factor :間質細胞由来因子） 1、 RANTES、分泌型白血 球プロテアーゼ阻害剤、間質細胞由来因子 l/PBSF (pre- B cell growth stimulatin g factor :プレ B細胞増殖刺激因子）、間質細胞由来因子 1アルファ ZPBSF、間質細 胞由来因子 1ベータ ZPBSF、胸腺活性化調節ケモカイン (TARC)、胸腺発現ケモ 力イン、形質転換成長因子 (TGF)アルファ、形質転換成長因子 (TGF)ベータ、形質 転換成長因子 (TGF)ベータ 1、形質転換成長因子 (TGF)ベータ 1. 2、形質転換成 長因子 (TGF)ベータ 2、形質転換成長因子 (TGF)ベータ 3、形質転換成長因子 (TG F)ベータ 5、潜在性関連ペプチド（latency- associated peptide)、潜在型形質転換成 長因子 (LTGF)ベータ 1、形質転換成長因子ベータ結合タンパク質、腫瘍壊死因子 アルファ、腫瘍壊死因子ベータ、および血管内皮細胞増殖因子、ラクトバーオキシダ ーゼ、トランスフェリン、オボトランスフェリン、インシュリン、成長ホルモン等が挙げられ る。これらの生理活性物質は、適宜 1種または 2種以上を選択して用いることができる Brain-derived neurotrophic factor, C10, ciliary neurotrophic factor, ciliary neurotrophic factor receptor alpha, CPP32 (Cysteine Protease Protein 32), CRG-2, cytoforce-in-induced neutrophil chemotactic factor 1 , Cytoforce-in-induced neutrophil chemotaxis factor 2 alpha, cytoforce-in-induced neutrophil chemotactic factor 2 beta, cytotoxic T lymphocyte antigen 4, beta vascular endothelial growth factor, endothelin-1, Eotaxin, Eotaxin-2, epithelial neutrophil attractant 78, erythropoietin receptor, Fas, fibroblast growth factor 4, fibroblast growth factor 5, fibroblast growth factor 6, fibroblast growth factor 7ZKGF (keratinocyte growth factor): fibroblast growth factor 8, fibroblast growth factor 8b, fibroblast growth factor 8c, fibroblast growth factor 9, acidic fibroblast growth factor, basic fibroblasts Growth factor, Fit— 3 Gand, fractal force-in, glial cell line-derived neurotrophic factor, granulocyte chemotactic protein, granulocyte colony stimulating factor receptor, granulocyte macrophage colony stimulating factor, growth-related protein, growth-related protein alpha, growth-related Protein beta, growth-related protein gamma, hemofiltration CC chemokine 1, heparin-binding epidermal growth factor, hepatocyte growth factor, heredarin alpha, heredarin beta 1, I 309, interleukin 1 alpha, interleukin 1 beta, inter Leukine 1 receptor antagonist (interleukin 1 receptor antagonist protein), IP-10, JE / MCP 1, KC, keratinocyte growth factor ZFGF-7, ratatofurin, lebutin, leukemia inhibitory factor, luciferase, macrophage core -One stimulating factor, macrophage mouth-One stimulating factor Macrophage inflammatory protein 1 alpha, macrophage inflammatory protein 1 beta, macrophage inflammatory protein 1 gamma, macrophage inflammatory protein 2, macrophage inflammatory protein 3 alpha, macrophage inflammatory protein 3 beta, macrophage migration inhibitory factor, macrophage-derived chemokine, MARCZMCP— 3 , Macrophage-stimulating protein, mitodocaine, monocyte chemotactic protein lZMCAF (monoc yte chemotactic and activating factor: monocyte running protein, monocyte running protein 2, monocyte running protein 3, monocyte running protein 4, monocyte running protein Protein 5, Matrix meta-oral protease 1, Matrix meta-oral protease 2, Matrix metallo-oral protease 3, Matrix meta-oral protease 7, Matrix meta-oral protease 9, Matrix meta-oral protease 12, Mye oral peroxidase, Beta nerve growth factor Child, neurotrophin (neurotrophic factor) 3, neurotrophin (neurotrophic factor) 4, nitric oxide synthase, oncostatin M, placental growth factor, placental growth factor 2, platelet-derived vascular endothelial growth factor, Pleitomouth fin, pre-B cell growth stimulating factor (PBSF) ZS DF (stromal cell-derived factor) 1, RANTES, secretory leukocyte protease inhibitor, stromal cell-derived factor l / PBSF (pre-B cell growth stimulating factor), stromal cell-derived factor 1 alpha ZPBSF, stromal cell Cell-derived factor 1 beta ZPBSF, thymus activation-regulated chemokine (TARC), thymic expression chemokine, transforming growth factor (TGF) alpha, transforming growth factor (TGF) beta, transforming growth factor (TGF) beta 1, Transforming growth factor (TGF) beta 1.2, transforming growth factor (TGF) beta 2, transforming growth factor (TGF) beta 3, transforming growth factor (TG F) beta 5, latency related peptide (latency -associated peptide), latent transforming growth factor (LTGF) beta 1, transforming growth factor beta binding protein, tumor necrosis factor alpha, tumor necrosis factor beta, and vascular endothelial growth factor, lactobacoxidase, transferrin Ovalbumin transferrin, insulin, Ru growth hormone and the like. One or more of these physiologically active substances can be appropriately selected and used.
[0025] 本発明にお ヽて、「ゲルイ匕物質」とはゲル化能を有する水溶性高分子を指す。一般 に食品添加物として使用されている多糖類力 入手の容易性、価格および Zまたは 安全性等の面力も好まし 、。 [0025] In the present invention, "gely substance" refers to a water-soluble polymer having gelling ability. Polysaccharide power commonly used as a food additive is also preferred because of its availability, price, and aspects such as Z or safety.
[0026] 具体的には、例えば、カラギーナン、アルギン酸、フコィダン、硫酸ガラクタン、キサ ンタンガム、カルボキシメチルセルロース（CMC)、ぺクチン、アラビアガム、ジエラン ガム、納豆菌ガム、大豆水溶性多糖類、寒天、デンプン、ファーセルラン、トラカント ガム、ゼラチン、タマリンド種子ガム、ローカストビーンガム、グァーガム、キトサン、お よびこれらの塩力 なる群から 1種または 2種以上を選択して用いることができる。 [0026] Specifically, for example, carrageenan, alginic acid, fucoidan, galactan sulfate, xanthan gum, carboxymethylcellulose (CMC), pectin, gum arabic, dielan gum, natto gum, soybean water-soluble polysaccharide, agar, starch , Farsellan, tracant gum, gelatin, tamarind seed gum, locust bean gum, guar gum, chitosan, o And one or more kinds selected from the group consisting of these salt strengths can be used.
[0027] 本発明にお ヽて、「賦形剤」とは、ゲル化物質と共にマトリツス構造を形成させるため に加えられる成分である。具体的には、例えば、セルロース、結晶セルロース、デキス トリン、バターミルクパウダー、カゼイン、豆乳粉末、大豆粉末、脱脂ミルク、野菜粉末 、および果汁粉末力 なる群力 選択される 1種または 2種以上を選択して用いること ができる。一般に、豆乳粉末、野菜ジュース (またはその粉末)、果汁 (またはその粉 末)などの天然食品素材は、ナトリウム、鉄、カリウム、カルシウム、マグネシウム、亜鉛 などの元素を充分含有している。例えば、調製豆乳粉末 (mgZlOOg)は、ナトリウム : 300〜800、鉄： 1〜20、カリウム： 1, 000〜3, 000、カルシウム： 100〜300、マグ ネシゥム： 300〜600；豆孚 L (mg/100g)は、ナ卜!;ゥム： 2〜50、カリウム： 100〜200 、カルシウム： 5〜30、マグネシウム： 10〜50、鉄： 0. 1〜3. 0、亜鉛： 0. 01〜0. 5、 銅： 0. 01〜0. 3 ;卜マ卜（生）（ppm)は、カリウム： 1, 350、カルシウム： 15. 2、マグネ シゥム：160、鉄： 1. 6 ;野菜ジュース（mgZ200mL)は、ナトリウム： 20〜300、力リウ ム： 300〜1, 000程度を含有することが知られている。 In the present invention, an “excipient” is a component added to form a matrix structure together with a gelling substance. More specifically, for example, cellulose, crystalline cellulose, dextrin, buttermilk powder, casein, soymilk powder, soybean powder, skimmed milk, vegetable powder, and fruit juice power are selected. You can select and use it. In general, natural food materials such as soy milk powder, vegetable juice (or its powder), fruit juice (or its powder) contain sufficient elements such as sodium, iron, potassium, calcium, magnesium and zinc. For example, prepared soymilk powder (mgZlOOg) is sodium: 300-800, iron: 1-20, potassium: 1,000-3,000, calcium: 100-300, magnesium: 300-600; / 100g) is Na !; um: 2-50, potassium: 100-200, calcium: 5-30, magnesium: 10-50, iron: 0.1-3.0, zinc: 0.01- 0.5, Copper: 0.01-0.3; Potato (raw) (ppm), Potassium: 1,350, Calcium: 15.2, Magnesium: 160, Iron: 1.6; Vegetable juice (MgZ200mL) is known to contain about 20 to 300 sodium and about 300 to 1,000 rhodium.
[0028] 本発明において、「塩基性有機化合物」とは、マトリックス型腸溶性 '徐放性組成物 を水系に分散させたとき、水系の pHを 3〜6に維持させることによってマトリックスを安 定ィ匕させるために加えられる成分である。具体的には、例えば、豆乳粉末、キトサン、 ポリリジン、ポリアルギニン、ポリグルタミン、アルギニン、グルタミン、ヒスチジン、リジン 、オル-チン、ダルコサミン力もなる群力も選択される 1種または 2種以上を選択して 用いることができる。なお、豆乳粉末は、塩基性有機化合物としてのみならず賦形剤 としても使用できるため好ましい。また、キトサンは、塩基性有機化合物としてのみな らずゲルイ匕物質として使用できるため好まし 、。 In the present invention, the “basic organic compound” means that the matrix is stabilized by maintaining the pH of the aqueous system at 3 to 6 when the matrix-type enteric 'sustained release composition is dispersed in the aqueous system. It is a component added to make it disappear. Specifically, for example, soy milk powder, chitosan, polylysine, polyarginine, polyglutamine, arginine, glutamine, histidine, lysine, orthine, or a group power that also has darcosamine power is selected. Can be used. Soymilk powder is preferred because it can be used not only as a basic organic compound but also as an excipient. Chitosan is preferred because it can be used not only as a basic organic compound but also as a gelling substance.
[0029] 本発明のマトリックス型腸溶性 '徐放性組成物は、上記の成分中またはその他の付 加的な成分に由来するアルカリ金属、アルカリ土類金属、マンガン、銅、鉄、亜鉛お よびコバルトからなる群から選択される 1種以上の元素を含有することを特徴とする。 組成物がこれらのいずれか 1種以上を含有することによってマトリックス安定性が向上 し、また、充分な耐酸性およびペプシン耐性が得られる一方、腸内環境においては マトリックス内に存在する生理活性物質が適度に放出されることになる。ナトリウム、力 リウムなどの元素は、酸性水系でイオン強度を上げ、ゲル化させるため（pH2以下、ィ オン強度: 0. 5以上）、また、胃液耐性および腸溶性の機能発現のために必要となる 。また、カルシウム等の 2価金属は、水系でのゲル架橋に関与し、水系での加熱安定 性の機能に必要となる。 [0029] The matrix type enteric 'sustained release composition of the present invention comprises an alkali metal, an alkaline earth metal, manganese, copper, iron, zinc, and the like derived from the above components or other additional components. It contains one or more elements selected from the group consisting of cobalt. When the composition contains any one or more of these, the matrix stability is improved, and sufficient acid resistance and pepsin resistance are obtained. On the other hand, in the intestinal environment, physiologically active substances present in the matrix are present. It will be released moderately. Sodium, power Elements such as lithium are necessary for increasing the ionic strength in an acidic water system to cause gelation (pH 2 or less, ion strength: 0.5 or more), and for the expression of gastric juice resistance and enteric function. In addition, divalent metals such as calcium are involved in gel crosslinking in aqueous systems and are necessary for the function of heat stability in aqueous systems.
[0030] 前記元素は、好ましくは少なくとも 1種のアルカリ金属またはアルカリ土類金属を含 み、さらに好ましくはナトリウム、カリウム、カルシウム、マグネシウム等を含み、特に少 なくともナトリウム、カリウムまたはカルシウムを含有することが好ましい。  [0030] The element preferably contains at least one alkali metal or alkaline earth metal, more preferably contains sodium, potassium, calcium, magnesium, etc., and particularly contains at least sodium, potassium or calcium. It is preferable.
[0031] アルカリ金属またはアルカリ土類金属は、上記の作用に関して有効量で含有される 必要があり、この有効量は、一般的には 10〜10, OOOmg/lOOg,好ましくは 100 〜5, OOOmgZlOOgである。  [0031] The alkali metal or alkaline earth metal should be contained in an effective amount for the above-mentioned action, and this effective amount is generally 10 to 10, OOOmg / lOOg, preferably 100 to 5, OOOmgZlOOg. It is.
[0032] 本発明において、「有機酸」とは、遊離のもののほか塩の形態であっても良い。具体 的には、例えば、クェン酸、マレイン酸、フマル酸、酒石酸、コハク酸、エチレンジアミ ン四酢酸、コンドロイチン硫酸、およびそれらの塩力 なる群力 選択される 1種また は 2種以上を選択して用いることができる。  In the present invention, the “organic acid” may be a free form or a salt form. Specifically, for example, quenic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, ethylene diamine tetraacetic acid, chondroitin sulfate, and their salt strength are selected. Can be used.
[0033] 本発明において、「無機酸塩」とは、一般的には塩酸、硫酸、硝酸、リン酸および炭 酸等の塩であって、好ましくはアルカリ金属塩、アルカリ土類金属塩、アンモニゥム塩 の形態のものが挙げられる。具体的には、例えば、塩ィ匕ナトリウム、塩ィ匕カリウム、塩 化アンモ-ゥム、塩ィ匕カルシウム、塩化マグネシウム、硫酸ナトリウム、硫酸カリウム、 硫酸マグネシウム、硝酸ナトリウム、硝酸カリウム、硝酸マグネシウム、硝酸アンモニゥ ム、リン酸一水素ニナトリウム、リン酸二水素ナトリウム、リン酸三ナトリウム、リン酸一水 素カリウム、リン酸二水素カリウム、リン酸三カリウム、炭酸水素ナトリウム、炭酸カルシ ゥムカもなる群力も選択される 1種または 2種以上を選択して用いることができる。  In the present invention, the “inorganic acid salt” is generally a salt such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and carbonic acid, preferably an alkali metal salt, alkaline earth metal salt, ammonium. In the form of a salt. Specifically, for example, sodium chloride, potassium salt, ammonium chloride, calcium chloride, magnesium chloride, sodium sulfate, potassium sulfate, magnesium sulfate, sodium nitrate, potassium nitrate, magnesium nitrate, nitric acid Ammonium, disodium monohydrogen phosphate, sodium dihydrogen phosphate, trisodium phosphate, potassium monohydrogen phosphate, potassium dihydrogen phosphate, tripotassium phosphate, sodium bicarbonate, calcium carbonate One or more selected can be selected and used.
[0034] 本発明のマトリックス型腸溶性 '徐放性組成物の製造に際しては、組成物全重量を 基準にして、生理活性物質が 5〜40重量％、ゲル化物質が 1〜20重量、賦形剤が 2 0〜70重量％程度であることが好ましい。塩基性有機化合物の含有量は、組成物全 重量を基準にして、 5〜50重量％程度であることができる。組成物は、これらの必須 成分のほかに、本明細書で説明するものをはじめとして、当業界で公知の一般的な 各種の成分を含有して!/ヽてもよ ヽ。 [0035] 本発明のマトリックス型腸溶性'徐放性組成物を製造する場合、好ましくは、生理活 性物質を含有する粉末とゲル化物質を含有する粉末は、脂質を主成分とする被膜材 でコーティングされている。したがって、生理活性物質とゲル化物質とを、予め脂質を 含む被膜材によって被覆することにより素材組成物としておくことができる。例えば、 このような素材組成物は、生理活性物質とゲル化物質と脂質を含む被膜材とを一緒 にして混合物を生成する工程、前記混合物を加熱して脂質を融解させる工程、前記 混合物中で前記生理活性物質およびゲル化物質に前記被膜材を付着させる工程、 および前記生理活性物質およびゲルィ匕物質の表面に前記被膜材カゝらなる被膜を形 成させる工程を含む方法によって製造することができる。 [0034] In the production of the matrix-type enteric 'sustained release composition of the present invention, 5-40% by weight of the physiologically active substance, 1-20% by weight of the gelling substance, based on the total weight of the composition. The form is preferably about 20 to 70% by weight. The content of the basic organic compound can be about 5 to 50% by weight based on the total weight of the composition. In addition to these essential components, the composition may contain various general components known in the art, including those described herein. [0035] When producing the matrix-type enteric 'sustained release composition of the present invention, the powder containing a physiologically active substance and the powder containing a gelling substance are preferably a coating material mainly comprising lipids. It is coated with. Therefore, the physiologically active substance and the gelling substance can be prepared as a raw material composition by previously coating with a coating material containing lipid. For example, such a material composition includes a step of producing a mixture by combining a physiologically active substance, a gelling substance and a coating material containing lipid, a step of heating the mixture to melt the lipid, The method includes the steps of: attaching the coating material to the physiologically active substance and the gelling substance; and forming a coating comprising the coating material on the surface of the physiologically active substance and the gelling substance. it can.
[0036] 被膜材において使用される脂質としては、油脂、ロウ、および複合脂質の中で食用 •医薬用などの用途に応じて許容されるものであればよい。例えば、天然に得られる 動植物性油脂またはこれらの油脂を原料にした硬化油 (牛脂硬化油、豚脂硬化油、 魚油硬化油、ナタネ硬化油、ダイズ硬化油、パーム硬化油、ォリーブ硬化油、ラッカ セィ硬化油、力ラシ硬化油など）が挙げられる。好ましくは、 30°C〜80°Cの範囲内の 融点を有する脂質、さらに好ましくは、 40°C〜70°Cの融点を有する脂質が用いられ る。また、生理活性物質粉末の脂質とゲル化物質粉末の脂質として、好ましくは同程 度の融点を有する脂質、さらに好ましくは同じ組成の脂質を使用する。  [0036] Lipids used in the coating material may be acceptable among oils and fats, waxes, and complex lipids depending on uses such as edible and pharmaceutical use. For example, naturally obtained animal and vegetable oils or hardened oils made from these oils and fats (beef tallow oil, tallow hardened oil, fish oil hardened oil, rapeseed hardened oil, soybean hardened oil, palm hardened oil, olive hardened oil, lacquer SE hardened oil, hard oil hardened oil, etc.). Preferably, a lipid having a melting point in the range of 30 ° C to 80 ° C, more preferably a lipid having a melting point of 40 ° C to 70 ° C is used. In addition, as the lipid of the physiologically active substance powder and the lipid of the gelling substance powder, lipids having the same melting point, more preferably lipids having the same composition are used.
[0037] 生理活性物質およびゲル化物質を被覆する脂質被膜の脂質の含有量は、生理活 性物質およびゲルィ匕物質の脂質被膜粉末粒子の全重量を基準として、一般に 1重 量％〜90重量％、好ましくは 5重量％〜20重量％程度である。上記の素材組成物 についても同様であり、脂質含有量は、素材組成物の重量を基準として、一般に 1重 量％〜90重量％、好ましくは 5重量％〜20重量％程度である。  [0037] The lipid content of the lipid film covering the physiologically active substance and the gelling substance is generally 1% by weight to 90% based on the total weight of the lipid-coated powder particles of the physiologically active substance and the gely substance. %, Preferably about 5% to 20% by weight. The same applies to the material composition described above, and the lipid content is generally about 1% to 90% by weight, preferably about 5% to 20% by weight, based on the weight of the material composition.
[0038] マトリックス型腸溶性 '徐放性組成物は、例えば、脂質被膜で被覆された生理活性 物質およびゲル化物質の粉末と有機酸および無機酸塩の粉末とを混合し、結合剤 溶液を噴霧して造粒を行った後、この造粒物を乾燥することによって形成される。造 粒法は、湿式法と乾式法に分類されるが、湿式法が好ましい。湿式造粒法には、押 出造粒、撹拌造粒、転動造粒、流動層造粒、噴霧造粒があり、これらの方法から適宜 選択することができる。ここで乾燥する場合の温度は、 40°C〜80°C程度が適当であ り、好ましくは 50°C〜65°Cの範囲である。 [0038] The matrix-type enteric 'sustained release composition is prepared by, for example, mixing a powder of a physiologically active substance and a gelling substance coated with a lipid film with a powder of an organic acid and an inorganic acid salt to form a binder solution. After granulating by spraying, it is formed by drying the granulated product. The granulation method is classified into a wet method and a dry method, but the wet method is preferable. The wet granulation methods include extrusion granulation, stirring granulation, rolling granulation, fluidized bed granulation, and spray granulation, and can be appropriately selected from these methods. The appropriate temperature for drying is 40 ° C to 80 ° C. Preferably, it is in the range of 50 ° C to 65 ° C.
結合剤は、本業界において通常の湿式造粒に使用されるもののから適宜選択する ことができ、水溶性の結合剤およびエタノール等の有機溶媒可溶性の結合剤を使用 することができる。また、噴霧する結合剤の量は、組成物乾物当り 10重量％以下、ま たは 1重量％以下が好ましい。  The binder can be appropriately selected from those used in ordinary wet granulation in the industry, and a water-soluble binder and an organic solvent-soluble binder such as ethanol can be used. The amount of the binder to be sprayed is preferably 10% by weight or less, or 1% by weight or less based on the dry matter of the composition.
[0039] 形成された粉末、顆粒、微粒子等の固体形態のマトリックス型腸溶性'徐放性組成 物は、さらに処理して、懸濁液などの別の形態にしてもよい。例えば、上記のようにし て徐放性組成物粉末を形成させた後、この組成物を 0. 5M〜2Mの無機酸塩または 有機酸塩を含有する ρΗ1〜2の酸性溶液に例えば 10分〜 3時間、好ましくは 30分 〜2時間、浸漬した後、この溶液の pHを例えば 3〜9、好ましくは 3〜8に調整して懸 濁液を製造することができる。 [0039] The formed matrix type enteric 'sustained release composition in solid form such as powders, granules, fine particles and the like may be further processed into another form such as a suspension. For example, after forming a sustained-release composition powder as described above, this composition is added to an acidic solution of ρΗ1-2 containing 0.5M to 2M inorganic acid salt or organic acid salt, for example, for 10 minutes to After immersing for 3 hours, preferably 30 minutes to 2 hours, the pH of this solution can be adjusted to 3-9, preferably 3-8, to produce a suspension.
無機酸塩としてはアルカリ金属塩、アルカリ土類金属塩、アンモ-ゥム塩カゝらなる群 力も選択される 1種または 2種以上であることが好ましい。有機酸塩としては、酢酸、ク ェン酸、マレイン酸、フマル酸、酒石酸、コハク酸、エチレンジァミン四酢酸およびコ ンドロイチン硫酸の塩が好ましい。酸性溶液としては、塩酸溶液、乳酸溶液、酢酸溶 液またはクェン酸溶液が好ま U、。  The inorganic acid salt is preferably one or more selected from the group forces of alkali metal salts, alkaline earth metal salts and ammonium salt salts. As the organic acid salt, acetic acid, citrate, maleic acid, fumaric acid, tartaric acid, succinic acid, ethylenediamine tetraacetic acid and chondroitin sulfate are preferred. As the acidic solution, hydrochloric acid solution, lactic acid solution, acetic acid solution or citrate solution is preferred.
[0040] あるいは、前記固体形態の徐放性糸且成物を、 0. 01〜2Mの金属イオンを含有する pH3〜5の酸性溶液に例えば 10分〜 3時間、好ましくは 30分〜 2時間、浸漬した後 、この溶液の pHを例えば 3〜9、好ましくは 3〜8に調整して懸濁液を製造することが できる。 [0040] Alternatively, the sustained-release yarn and composition in the solid form is added to an acidic solution having a pH of 3 to 5 containing 0.01 to 2M metal ions, for example, 10 minutes to 3 hours, preferably 30 minutes to 2 hours. After soaking, the suspension can be prepared by adjusting the pH of the solution to, for example, 3 to 9, preferably 3 to 8.
金属イオンとしてはアルカリ金属、アルカリ土類金属からなる群力 選択される 1種 または 2種以上であることが好ましい。酸性溶液としては、塩酸溶液、乳酸溶液、酢酸 溶液またはクェン酸溶液が好ま Uヽ。  The metal ions are preferably one or more selected from the group power consisting of alkali metals and alkaline earth metals. As the acidic solution, hydrochloric acid solution, lactic acid solution, acetic acid solution or citrate solution is preferred.
[0041] 上記のような懸濁液等の液体を含む形態の場合、長期に保存するためには、この 懸濁液等の液体を 60°C〜100°Cで 1〜60分間加熱処理することにより加熱滅菌を 行うことが好ましい。 [0041] In the case of a form containing a liquid such as a suspension as described above, the liquid such as a suspension is heat-treated at 60 ° C to 100 ° C for 1 to 60 minutes for long-term storage. It is preferable to perform heat sterilization.
[0042] また、前記懸濁液等の液体または粉末等の固体の形態の本発明の組成物は、例 えばヨーグルトやチーズ等の乳製品、野菜ジュース製品、果汁製品、キャンディ一等 の菓子類等の液体、流動性もしくは半流動性、または固体の製品の製造の際に、適 宜添加して使用することができる。 [0042] The composition of the present invention in the form of a liquid such as a suspension or a solid such as a powder includes, for example, dairy products such as yogurt and cheese, vegetable juice products, fruit juice products, candy, etc. In the production of liquid, fluid or semi-fluid or solid products such as confectionery, it can be used with appropriate addition.
[0043] さらに、本発明のマトリックス型腸溶性'徐放性組成物は、粉末、顆粒、錠剤、丸薬、 乳化液、懸濁液、ゲルまたはカプセルに封入された形態など、具体的にはマイクロ力 プセル、ソフトカプセル、ハードカプセルに封入された形態などの任意の形態にして 用いることができる。本発明の組成物のカプセル化は、公知のマイクロカプセル化技 術、ソフトカプセル化技術、ハードカプセルィ匕技術などによって行うことができる。  [0043] Furthermore, the matrix-type enteric 'sustained release composition of the present invention is specifically a microcapsule such as a powder, granule, tablet, pill, emulsion, suspension, gel or capsule encapsulated form. It can be used in any form such as a force capsule, soft capsule, or hard capsule. The encapsulation of the composition of the present invention can be performed by a known microencapsulation technology, soft encapsulation technology, hard encapsulation technology, or the like.
[0044] 上記のようにして、本発明のマトリックス型腸溶性 '徐放性組成物は、そのまま食品 、医薬品、飼料などとして利用する形態で提供してもよぐまた、食品、医薬品、飼料 等に含有させることができる。このようにして利用するために含有させる場合の生理活 性物質の適当な含有量はそれぞれ公知である。  [0044] As described above, the matrix-type enteric 'sustained-release composition of the present invention may be provided as it is as it is used as food, medicine, feed, etc. Also, food, medicine, feed, etc. Can be contained. Appropriate contents of physiologically active substances in the case of containing them for use in this way are known.
[0045] 以下、実施例によって本発明を詳細に説明するが、本発明は実施例に限定される ものではない。  Hereinafter, the present invention will be described in detail by way of examples, but the present invention is not limited to the examples.
実施例  Example
[0046] 実施例 1：脂皙被膜ラクトフエリン/ぺクチン混合粉末の製诰  [0046] Example 1: Preparation of greasy-coated lactoferrin / pectin mixed powder
ラタトフエリン (タツァ'ミルク'バイオ口ジクス社） 16kg,ぺクチン (八宝商会) 4kg、ナ タネ硬化油 (融点 67°C；横関油脂工業 (株)） 2kgをニーダー (カジワラ (株)）にて処 理した。これらの粉末を 10〜50rpmで充分に撹拌混合した後、ジャケットに乾燥蒸 気を注入して品温を 75°Cまで上げ、ナタネ硬化油を融解させた。撹拌混合を続けて 、約 10分間品温を 75°Cに維持した後、徐々に冷却して品温を下げた。ラタトフエリン およびべクチンの粒子表面にナタネ硬化油の被膜を形成させ、脂質被膜ラタトフエリ ン,ぺクチン混合粉末約 21kgを得た。  Ratatohuelin (Tatza 'Milk' Bioguchi Jix Co., Ltd.) 16kg, Pectin (Happo Shokai) 4kg, Rapeseed hardened oil (melting point 67 ° C; Yokoseki Oil & Fat Co., Ltd.) 2kg at Kneader (Kajiwara) Processed. These powders were thoroughly mixed with stirring at 10 to 50 rpm, and then dry steam was injected into the jacket to raise the product temperature to 75 ° C to melt the rapeseed oil. The stirring and mixing were continued, and the product temperature was maintained at 75 ° C. for about 10 minutes, and then gradually cooled to lower the product temperature. A coating of rapeseed oil was formed on the surface of ratatopherin and bectin particles, and about 21 kg of lipid-coated ratatopherin and pectin mixed powder was obtained.
[0047] ¾施例 2：ラクトフエリン NaCl含有徐放件鉬.成物の製诰  [0047] ¾ Example 2: Lactoferrin NaCl-containing sustained release product.
実施例 1で得られた脂質被膜ラ外フェリン/ぺクチン混合粉末 70g、結晶セルロー ス（日本製紙ケミカル (株)） 70g、デキストリン（日澱ィ匕学 (株)） 70gを撹拌混合造粒 機（KOMASA MIC DV)にて処理した。これらの粉末を下部撹拌 300rpm、チヨ ッパー 3, OOOrpmで充分に混合撹拌した後、混合撹拌下、容器上部から 0. 6%グ ァーガム溶液（1M NaCl含有）を噴霧し、造粒を行った。造粒した顆粒を 60°Cの乾 燥機にて 8時間乾燥させ、ラタトフエリン含有徐放性組成物 (ラタトフエリン含量:約 22 %)約 200gを得た。 Mixing and granulating machine 70g of lipid-coated ferroferrin / pectin mixed powder obtained in Example 1, 70g of crystalline cellulose (Nippon Paper Chemicals Co., Ltd.) and 70g of dextrin (Nissho Chemical Co., Ltd.) (KOMASA MIC DV). These powders were thoroughly mixed and stirred at 300 rpm at the bottom and 3 rpm at the tipper, and then 0.6% guar gum solution (containing 1M NaCl) was sprayed from the top of the container with mixing and stirring. Dry granulated granules at 60 ° C After drying for 8 hours in a drier, about 200 g of a sustained release composition containing ratatopherin (ratatopherin content: about 22%) was obtained.
[0048] 実施例 3：脂皙被膜コアイソレート/ベクチン混合粉末の製诰  [0048] Example 3: Production of greasy-coated core isolate / bectin mixed powder
コアイソレート（ラタトフエリン、ラクトパーォキシダーゼ；タツァ ·ミルク ·バイオ口ジクス 社) 16kg、ぺクチン (八宝商会) 4kg、ナタネ硬化油 (融点 67°C ;横関油脂工業 (株)） 2kgを-一ダー（カジワラ (株））にて処理した。これらの粉末を 10〜50rpmで充分に 撹拌混合した後、ジャケットに乾燥蒸気を注入して品温を 75°Cまで上げ、ナタネ硬化 油を融解させた。撹拌混合を続けて、約 10分間品温を 75°Cに維持した後、徐々に 冷却して品温を下げた。コアイソレートおよびぺクチンの粒子表面にナタネ硬化油の 被膜を形成させ、脂質被膜コアイソレート,ぺクチン混合粉末約 21. 1kgを得た。  Co-isolate (ratatoferrin, lactoperoxidase; Taza Milk Milk Bio-Jix) 16kg, Pectin (Happo Shokai) 4kg, Rapeseed oil (melting point 67 ° C; Yokoseki Oil & Fat Co., Ltd.) 2kg (Kajiwara Co., Ltd.). After these powders were sufficiently stirred and mixed at 10 to 50 rpm, dry steam was injected into the jacket to raise the product temperature to 75 ° C. to melt the rapeseed oil. Stirring and mixing were continued, and the product temperature was maintained at 75 ° C for about 10 minutes, and then gradually cooled to lower the product temperature. A coating of rapeseed oil was formed on the surface of coisolate and pectin particles to obtain about 21.1 kg of lipid-coated core isolate and pectin mixed powder.
[0049] ¾施例 4：コアイソレート含有徐放件鉬.成物の製诰  [0049] ¾ Example 4: Sustained release product containing core isolate.
実施例 3で得られた脂質被膜コアイソレート Zぺクチン混合粉末 70g、結晶セル口 ース（日本製紙ケミカル (株)） 70g、デキストリン（日澱ィ匕学 (株)） 70gを撹拌混合造 粒機（KOMASA MIC DV)にて処理した。これらの粉末を下部撹拌 300rpm、チ ョッパー 3, OOOrpmで充分に混合撹拌した後、混合撹拌下、容器上部から 0. 6%グ ァーガム溶液（1M NaCl含有）を噴霧し、造粒を行った。造粒した顆粒を 60°Cの乾 燥機にて 8時間乾燥させ、ラタトフエリン含有徐放性組成物（コアイソレート含量:約 2 2%)約 200gを得た。  Mixing and granulating machine 70g of lipid-coated core isolate Z pectin powder obtained in Example 3, 70g of crystal cell mouth (Nippon Paper Chemical Co., Ltd.) and 70g of dextrin (Nissho Chemical Co., Ltd.) (KOMASA MIC DV). These powders were sufficiently mixed and stirred at the bottom stirring at 300 rpm and the chopper 3, OOO rpm, and then granulated by spraying 0.6% guar gum solution (containing 1M NaCl) from the upper part of the container under mixing stirring. The granulated granule was dried with a dryer at 60 ° C. for 8 hours to obtain about 200 g of a sustained release composition containing ratatopherin (core isolate content: about 22%).
[0050] ¾ 列 5 :ラクトフエリン ^ ¾,含有徐放件鉬.成物の観告  [0050] ¾ Row 5: Lactoferrin ^ ¾, Contained sustained release.
実施例 1と同様にして得られた脂質被膜ラタトフエリン/ベクチン混合粉末 450g、 調製豆乳粉末 (フジプロテインエンジニアリング (株)） 1, 560g、デキストリン 936gを 混合した後、流動層造粒コーティング装置 (フロイント産業)で造粒を行い、ラクトフエ リン Z豆乳含有徐放性組成物（ラタトフエリン含量:約 10%)約 2, 800gを得た。  After mixing 450 g of lipid-coated ratatopherin / bectin powder obtained in the same manner as in Example 1, 1,560 g of prepared soymilk powder (Fuji Protein Engineering Co., Ltd.) and 936 g of dextrin, fluidized bed granulation coating equipment (Freund Sangyo Co., Ltd.) ) To obtain about 2,800 g of a sustained-release composition containing lactoferrin Z soymilk (ratatoferrin content: about 10%).
[0051] 実施例 6 :ラ外フェリン/クェン酸/乳酸カルシウム含有徐放件組成物の製诰  [0051] Example 6: Production of a composition for sustained release containing ectoferrin / quenate / calcium lactate
実施例 1と同様にして得られた脂質被膜ラタトフエリン Zぺクチン混合粉末 70g、ク ェン酸 10g、乳酸カルシウム、結晶セルロース 60g、デキストリン 60gを撹拌混合造粒 機（KOMASA MIC DV)にて処理した。これらの粉末を下部撹拌 300rpm、チヨ ッパー 3, OOOrpmで充分に混合撹拌した後、混合撹拌下、容器上部から 0. 2%力 ルポキシメチルセルロース 'ナトリウム（CMC. Na)溶液を噴霧し、造粒を行った。造 粒した顆粒を 60°Cの乾燥機にて 8時間乾燥させ、ラタトフエリン Zクェン酸 Z乳酸力 ルシゥム含有徐放性組成物（ラタトフエリン含量：約 22%)約 200gを得た。 70 g of lipid-coated ratatopherin Z pectin mixed powder obtained in the same manner as in Example 1, 10 g of citrate, calcium lactate, 60 g of crystalline cellulose, and 60 g of dextrin were processed with a stirring and mixing granulator (KOMASA MIC DV). . These powders are thoroughly mixed and stirred at the bottom stirring at 300rpm and the tipper 3, OOOrpm, then 0.2% force from the top of the container under mixing stirring. It was granulated by spraying a lupoxymethylcellulose 'sodium (CMC. Na) solution. The granulated granule was dried in a dryer at 60 ° C. for 8 hours to obtain about 200 g of a sustained release composition (ratatopherin content: about 22%) containing ratatopherin Z citrate Z lactic acid.
[0052] 実施例 7：ラクトフエリン含有徐放件組成物の製诰 [0052] Example 7: Making a lactoferrin-containing sustained release composition
実施例 1と同様にして得られた脂質被膜ラタトフヱリン Zぺクチン混合粉末 70g、結 晶セルロース 70g、デキストリン 70gを撹拌混合造粒機（KOMASA MIC DV)に て処理した。これらの粉末を下部撹拌 300rpm、チョッパー 3, OOOrpmで充分に混 合撹拌した後、混合撹拌下、容器上部から 0. 2%カルボキシメチルセルロース'ナト リウム (CMC. Na)溶液を噴霧し、造粒を行った。造粒した顆粒を 60°Cの乾燥機にて 8時間乾燥させ、ラタトフヱリン含有徐放性組成物（ラタトフヱリン含量:約 22%)約 20 Ogを得た。  70 g of the lipid-coated ratatofurin Z-pectin mixed powder, 70 g of crystalline cellulose, and 70 g of dextrin obtained in the same manner as in Example 1 were treated with a stirring and mixing granulator (KOMASA MIC DV). After sufficiently mixing and stirring these powders at 300 rpm and chopper 3, OOOrpm at the bottom, 0.2% carboxymethylcellulose sodium (CMC. Na) solution was sprayed from the top of the container with mixing and stirring. went. The granulated granule was dried with a dryer at 60 ° C. for 8 hours to obtain about 20 Og of a sustained release composition containing ratatofurin (ratatofurin content: about 22%).
[0053] ¾施例 8：脂皙被蹬ラクトパーォキシダーゼ ぺクチン混合粉末の製诰  [0053] ¾ Example 8: Preparation of oleagin-coated lactoperoxidase pectin mixed powder
ラクトパーォキシダーゼ (タツァ ·ミルク ·バイオ口ジクス社) 600g、ぺクチン (三晶 (株 ) ) 300g、ナタネ硬化油 (横関油脂工業 (株) ) lOOgをニーダー試験機 (自家製)にて 処理した。これらの粉末を充分に攪拌混合した後、品温を 75°Cまで上げ、ナタネ硬 化油を溶融させた。攪拌混合を続けて、約 10分間品温を 75°Cに維持した後、徐々 に冷却して品温を下げた。ラクトパーォキシダーゼおよびべクチンの粉末粒子表面に ナタネ硬化油の被膜を形成させ、脂質被膜ラクトパーォキシダーゼ Zぺクチン混合 粉末約 950gを得た。  Lactoperoxidase (Tatsumi Milk Bio-Koji Jix Co., Ltd.) 600g, Pectin (Sanki Co., Ltd.) 300g, Rapeseed hardened oil (Yokoseki Oil & Fat Co., Ltd.) lOOg was processed with a kneader tester (homemade) . After sufficiently stirring and mixing these powders, the product temperature was raised to 75 ° C to melt the rapeseed oil. Stirring and mixing were continued, and the product temperature was maintained at 75 ° C for about 10 minutes, and then cooled gradually to lower the product temperature. A coating of rapeseed oil was formed on the surface of the powder particles of lactoperoxidase and bectin, and about 950 g of lipid-coated lactoperoxidase Z pectin mixed powder was obtained.
[0054] 実施例 9：ラクトパーォキシダーゼ含有徐放性組成物の製造  Example 9: Production of sustained release composition containing lactoperoxidase
実施例 8と同様にして得られた脂質被膜ラクトパーォキシダーゼ /ぺクチン混合粉 末 340g、調製豆乳粉末 500g、キトサン乳酸塩（(株)共和テクノス） 160gを攪拌混合 造粒機（KOMASA MIC DV)にて処理した。これらの粉末を下部攪拌 300rpm、 チョッパー 3, OOOrpmで充分に混合攪拌した後、混合攪拌下、容器上部から 17重 量0 /0ツエイン'エタノール溶液 450gを添カ卩し、造粒を行った。造粒した顆粒を 60°Cの 乾燥機にて 8時間乾燥させ、ラクトパーォキシダーゼ含有徐放性組成物 (ラタトフエリ ン含有量:約 21%)約 995gを得た。 A lipid-coated lactoperoxidase / pectin mixed powder 340 g obtained in the same manner as in Example 8, 500 g of prepared soymilk powder, and 160 g of chitosan lactate (Kyowa Technos Co., Ltd.) were stirred and mixed. Granulator (KOMASA MIC DV ). These powders lower stirring 300 rpm, chopper 3, it was thoroughly mixed and stirred OOOrpm, under mixing agitation, to添Ka卩17 by weight 0/0 zein 'ethanol 450g from the container top, and granulation was performed. The granulated granule was dried with a dryer at 60 ° C. for 8 hours to obtain about 995 g of a sustained release composition containing lactoperoxidase (ratatopherin content: about 21%).
[0055] 実施例 10：脂皙被膜ラクトフエリン/キサンタンガム混合粉末の製诰 ラタトフエリン (タツァ'ミルク'バイオ口ジクス社） 12kg,キサンタンガム (太陽ィ匕学 (株 ) ) 6kg、ナタネ硬化油 (横関油脂工業 (株) ) 2kgをニーダー（ (株)カジワラ）にて処理 した。これらの粉末を 10〜50rpmで充分に攪拌混合した後、ジャケットに乾燥蒸気を 注入して品温を 75°Cまで上げ、ナタネ硬化油を溶融させた。攪拌混合を続けて、約 10分間品温を 75°Cに維持した後、徐々に冷却して品温を下げた。ラクトパーォキシ ダーゼおよびべクチンの粉末粒子表面にナタネ硬化油の被膜を形成させ、脂質被 膜ラタトフエリン/キサンタンガム混合粉末約 19. 5kgを得た。 [0055] Example 10: Preparation of greasy-coated lactoferrin / xanthan gum mixed powder Ratatophelin (Tatsumi's Milk Biotech Company) 12 kg, xanthan gum (Taiyo Chemical Co., Ltd.) 6 kg, rapeseed hydrogenated oil (Yokoseki Oil & Fat Co., Ltd.) 2 kg were treated with a kneader (Kajiwara Co., Ltd.). These powders were thoroughly stirred and mixed at 10 to 50 rpm, and then dry steam was injected into the jacket to raise the product temperature to 75 ° C. to melt the rapeseed oil. Stirring and mixing were continued, and the product temperature was maintained at 75 ° C for about 10 minutes, and then gradually cooled to lower the product temperature. A coating of rapeseed oil was formed on the surface of the powder particles of lactoperoxidase and bectin to obtain about 19.5 kg of lipid-coated ratatopherin / xanthan gum mixed powder.
[0056] 実施例 11 :ラ外フエリン Zキサンタンガム Z豆乳含有徐放性組成物の製造  Example 11 Production of Sustained Release Composition Containing La Feline Z Zanthan Gum Soy Milk
実施例 10と同様にして得られた脂質被膜ラタトフエリン/キサンタンガム混合粉末 3 40g、調製豆乳粉末 500g、キトサン乳酸塩（(株)共和テクノス） 160gを攪拌混合造 粒機にて処理した。これらの粉末を下部攪拌 300rpm、チョッパー 3, OOOrpmで充 分に混合攪拌した後、混合攪拌下、容器上部から 17重量％ツエイン Z83重量％ェ タノール溶液 450gを添加し、造粒を行った。造粒した顆粒を 60°Cの乾燥機にて 8時 間乾燥させ、ラタトフエリン Zキサンタンガム Z豆乳含有徐放性組成物 (ラタトフエリン 含有量:約 21%)約 995gを得た。  Lipid-coated ratatopherin / xanthan gum mixed powder 340 g, prepared soymilk powder 500 g, and chitosan lactate (Kyowa Technos Co., Ltd.) 160 g obtained in the same manner as in Example 10 were treated with a stirring and mixing granulator. These powders were thoroughly mixed and stirred at 300 rpm at the bottom and 3 rpm at the chopper, and then 450 g of a 17 wt% Zane Z83 wt% ethanol solution was added from the top of the container under mixing and granulation. The granulated granule was dried with a dryer at 60 ° C for 8 hours to obtain about 995 g of a sustained release composition containing ratatopherin Z xanthan gum Z soymilk (ratatopherin content: about 21%).
[0057] ¾ 列 ί2 :ラクトフエリン キサンタンガム Zバターミルクパウダー含有徐放件 成物 の觀告  [0057] ¾ Row ί2: Lactoferrin xanthan gum Z Buttermilk powder containing sustained release notification of composition
実施例 10と同様にして得られた脂質被膜ラタトフエリン/キサンタンガム混合粉末 1 OOg、キトサン乳酸塩 ( (株）共和テクノス） 50g、バターミルクパウダー（タツァ ·ミルク · ノ ィォロジタス社) 50gを攪拌混合造粒機にて処理した。これらの粉末を下部攪拌 30 Orpm、チョッパー 3, OOOrpmで充分に混合攪拌した後、混合攪拌下、容器上部か ら 17重量％ッェイン Z83重量％エタノール溶液 140gを添カ卩し、造粒を行った。造粒 した顆粒を 60°Cの乾燥機にて 8時間乾燥させ、ラタトフエリン Zキサンタンガム Zバタ 一ミルクパウダー含有徐放性組成物（ラタトフヱリン含有量:約 28%)約 210gを得た。  1 OOg of lipid-coated ratatopherin / xanthan gum mixed powder obtained in the same manner as in Example 10; 50 g of chitosan lactate (Kyowa Technos); Processed by machine. These powders were sufficiently mixed and stirred at the bottom stirring 30 Orpm and chopper 3, OOOrpm, and then granulated by adding 140g of 17wt% Zane Z83wt% ethanol solution from the top of the container under mixing stirring. . The granulated granules were dried with a dryer at 60 ° C. for 8 hours to obtain about 210 g of a sustained release composition containing ratatopherin Z xanthan gum Z butter milk powder (ratatofurin content: about 28%).
[0058] 実施例 13 :脂皙被膜ラクトフェリン/カラギーナン混合粉末の製诰 [0058] Example 13: Making a greasy-coated lactoferrin / carrageenan mixed powder
ラタトフエリン (タツァ'ミルク'バイオ口ジクス社） 12kg,カラギーナン (伊那食品工業 (株) ) 6kg、ナタネ硬化油 (横関油脂工業 (株) ) 2kgをニーダー（ (株)カジワラ）にて 処理した。これらの粉末を 10〜50rpmで充分に攪拌混合した後、ジャケットに乾燥 蒸気を注入して品温を 75°Cまで上げ、ナタネ硬化油を溶融させた。攪拌混合を続け て、約 10分間品温を 75°Cに維持した後、徐々に冷却して品温を下げた。ラタトフエリ ンおよびカラギーナンの粉末粒子表面にナタネ硬化油の被膜を形成させ、脂質被膜 ラタトフエリン/カラギーナン混合粉末約 19. 5kgを得た。 Ratatohuelin (Tatza 'Milk' Bioguchi Jix Co., Ltd.) 12 kg, Carrageenan (Ina Food Industry Co., Ltd.) 6 kg, and rapeseed hydrogenated oil (Yokoseki Oil & Fat Co., Ltd.) 2 kg were treated with a kneader (Kajiwara Co., Ltd.). These powders are thoroughly stirred and mixed at 10 to 50 rpm and then dried in a jacket. Steam was injected to raise the product temperature to 75 ° C, and the rapeseed oil was melted. Stirring and mixing were continued, and the product temperature was maintained at 75 ° C for about 10 minutes, and then gradually cooled to lower the product temperature. A coating of rapeseed oil was formed on the surface of ratatopherine and carrageenan powder particles to obtain about 19.5 kg of lipid-coated ratatopherin / carrageenan mixed powder.
[0059] 実施例 14 :ラクトフエリン/カラギーナン/豆乳含有徐放件組成物 Example 14: Sustained release composition containing lactoferrin / carrageenan / soy milk
実施例 13と同様にして得られた脂質被膜ラタトフエリン/カラギーナン混合粉末 34 Og、調製豆乳粉末 500g、キトサン乳酸塩（(株)共和テクノス） 160gを攪拌混合造粒 機にて処理した。これらの粉末を下部攪拌 300rpm、チョッパー 3, OOOrpmで充分 に混合攪拌した後、混合攪拌下、容器上部から 17重量％ツエイン Z83重量％ェタノ ール溶液 450gを添加し、造粒を行った。造粒した顆粒を 60°Cの乾燥機にて 8時間 乾燥させ、ラタトフエリン Zカラギーナン Z豆乳含有徐放性組成物 (ラタトフエリン含有 量:約 21 %)約 990gを得た。  Lipid-coated ratatopherin / carrageenan mixed powder 34 Og, prepared soymilk powder 500 g, and chitosan lactate (Kyowa Technos Co., Ltd.) 160 g obtained in the same manner as in Example 13 were treated with a stirring and mixing granulator. These powders were sufficiently mixed and stirred with a lower stirring speed of 300 rpm and a chopper of 3, OOO rpm, and then 450 g of a 17 wt% Tween Z83 wt% ethanol solution was added from the upper portion of the container and granulated. The granulated granule was dried with a dryer at 60 ° C. for 8 hours to obtain about 990 g of a sustained release composition containing ratatopherin Z carrageenan Z soymilk (ratatopherin content: about 21%).
[0060] miB 脂皙被蹬オボトランスフェリン キトサン混合粉末の觀告  [0060] Notification of miB oil-coated ovotransferrin chitosan mixed powder
オボトランスフェリン (カナダ'イノバテック社） 120g、キトサン乳酸塩（(株）共和テク ノス) 60g、ナタネ硬化油 (横関油脂工業 (株) ) 20gをニーダー試験機 (自家製)にて 処理した。これらの粉末を充分に攪拌混合した後、品温を 75°Cまで上げ、ナタネ硬 化油を溶融させた。攪拌混合を続けて、約 10分間品温を 75°Cに維持した後、徐々 に冷却して品温を下げた。ラクトパーォキシダーゼおよびべクチンの粉末粒子表面に ナタネ硬化油の被膜を形成させ、脂質被膜ラクトパーォキシダーゼ Zぺクチン混合 粉末約 190gを得た。  120 g of ovotransferrin (Canada Innovatech), 60 g of chitosan lactate (Kyowa Technos Co., Ltd.), and 20 g of rapeseed oil (Yokoseki Oil & Fat Co., Ltd.) were treated with a kneader tester (homemade). After sufficiently stirring and mixing these powders, the product temperature was raised to 75 ° C to melt the rapeseed oil. Stirring and mixing were continued, and the product temperature was maintained at 75 ° C for about 10 minutes, and then cooled gradually to lower the product temperature. A coating of rapeseed oil was formed on the surface of the powder particles of lactoperoxidase and bectin, and about 190 g of lipid-coated lactoperoxidase Z pectin mixed powder was obtained.
[0061] 実施例 16 :オボトランスフェリン Zキトサン Z豆乳含有徐放性組成物の製造  Example 16: Production of sustained release composition containing ovotransferrin Z chitosan Z soymilk
実施例 15と同様にして得られた脂質被膜オボトランスフェリン/キトサン混合粉末 1 70g、調製豆乳粉末 830gを攪拌混合造粒機にて処理した。これらの粉末を下部攪 拌 300rpm、チョッパー 3, OOOrpmで充分に混合攪拌した後、混合攪拌下、容器上 部から 17重量％ッェイン Z83重量％エタノール溶液 500gを添カ卩し、造粒を行った。 造粒した顆粒を 60°Cの乾燥機にて 8時間乾燥させ、オボトランスフェリン Zキトサン Z 豆乳含有徐放性組成物（ラタトフエリン含有量:約 10%)約 990gを得た。  70 g of the lipid-coated ovotransferrin / chitosan mixed powder 170 and 830 g of the prepared soymilk powder obtained in the same manner as in Example 15 were processed by a stirring and mixing granulator. These powders were thoroughly mixed and stirred with a lower stirring speed of 300 rpm and chopper 3, OOO rpm, and granulated by adding 500 g of 17 wt% Zane Z83 wt% ethanol solution from the upper part of the container under mixing and stirring. . The granulated granule was dried with a dryer at 60 ° C. for 8 hours to obtain about 990 g of a sustained release composition containing ovotransferrin Z chitosan Z soymilk (ratatopherin content: about 10%).
[0062] 試験例 1 :ラ外フェリン /NaCl含有徐放件組成物の胃液 PHでの安定件 実施例 2と同様にして製造したラタトフエリン ZNaCl含有徐放性組成物 250mgを モデル胃液（0. 2%NaCl、 70mMHCl、 pHl. 2) lOmL中に分散させ、 37°Cで 1時 間緩やかに回転混合した後、遠心分離を行い、上清液を回収した。上清液中のラタ トフエリン濃度を高速液体クロマトで測定した。 [0062] Test Example 1: Stable release of exoferrin / NaCl-containing sustained release composition in gastric fluid PH Ratatopherin ZNaCl-containing sustained-release composition 250 mg produced in the same manner as in Example 2 was dispersed in model gastric juice (0.2% NaCl, 70 mM HCl, pH l. 2) lOmL, and gently rotated at 37 ° C for 1 hour. After mixing, the mixture was centrifuged and the supernatant was collected. Ratatopherin concentration in the supernatant was measured by high performance liquid chromatography.
モデル胃液中へのラタトフエリンの溶出は殆ど認められな力つた。したがって、本発 明のラタトフエリン含有徐放性組成物が胃液 pH中で安定であることが確認された。  The dissolution of ratatopherin into the model gastric juice was almost unnoticeable. Accordingly, it was confirmed that the sustained release composition containing ratatopherin of the present invention is stable in gastric juice pH.
[0063] 試験例 2：ラ外フェリン /NaCl含有徐放件組成物の腸液 ΌΗでの溶解件 [0063] Test Example 2: Dissolution of intestinal fluid fistula of exoferrin / NaCl-containing sustained release composition
実施例 2と同様にして製造したラタトフエリン ZNaCl含有徐放性組成物 250mgを モデル腸液（50mM リン酸二水素カリウム、 24mM NaOH、 pH6. 8) lOmL中に 分散させ、 37°Cで 1時間緩やかに回転混合した後、遠心分離を行い、上清液を回収 した。上清液中のラクトフ リン濃度を高速液体クロマトで測定した。  Disperse 250 mg of ratatopherin ZNaCl-containing sustained release composition prepared in the same manner as in Example 2 in model intestinal fluid (50 mM potassium dihydrogen phosphate, 24 mM NaOH, pH 6.8) lOmL, and gently at 37 ° C for 1 hour After rotary mixing, centrifugation was performed and the supernatant was collected. The lactofrin concentration in the supernatant was measured by high performance liquid chromatography.
上清中のラタトフエリン濃度は 5mgZmLであった。これは、処理した組成物 250m gに含まれるラタトフエリン (約 55mg)の約 91%が溶出されたことになり、本発明のラタ トフエリン/ NaCl含有徐放性組成物が腸液 pHでラタトフエリンを放出することが確認 された。  The ratatopherin concentration in the supernatant was 5 mgZmL. This means that about 91% of ratatopherin (about 55 mg) contained in 250 mg of the treated composition was eluted, and the ratatopherin / NaCl-containing sustained release composition of the present invention releases ratatopherin at intestinal pH. It was confirmed.
[0064] 試験例 3：ラクトフエリン ^ ¾,含有徐放件鉬.成物の胃液 ΏΗでの安定件 [0064] Test Example 3: Lactoferrin ^ ¾, Contained sustained release 鉬. Stabilization of adult gastric juice 成
実施例 5と同様にして製造したラタトフエリン/豆乳含有徐放性組成物 500mgをモ デノレ胃液（0. 2% NaCl, 70mM HC1、 pHl. 2) lOmL中に分散させ、 37°Cで 1 時間緩やかに回転混合した後、遠心分離を行い、上清液を回収した。上清液中のラ タトフェリン濃度を高速液体クロマトで測定した。  500 mg of sustained release composition containing ratatopherin / soy milk prepared in the same manner as in Example 5 was dispersed in 10 mL of modelole gastric juice (0.2% NaCl, 70 mM HC1, pHl. 2), and gently stirred at 37 ° C for 1 hour. Then, the mixture was centrifuged, and the supernatant was collected. The ratoferrin concentration in the supernatant was measured by high performance liquid chromatography.
モデル胃液中へのラタトフエリン溶出は殆ど認められな力つた。したがって、本発明 のラタトフエリン Z豆乳含有徐放性組成物が胃液 PH中で安定であることが確認され た。  Elution of ratatopherin into the model gastric juice was almost unnoticeable. Therefore, it was confirmed that the sustained release composition containing ratatopherin Z soymilk of the present invention is stable in gastric fluid PH.
[0065] 試験例 4：ラ外フェリン/豆乳含有徐放件組成物の腸液 ΌΗでの溶解件 [0065] Test Example 4: Dissolution of intestinal fluid phlegm with a sustained release composition containing exoferrin / soy milk
実施例 5と同様にして製造したラタトフエリン/豆乳含有徐放性組成物 500mgをモ デル腸液（50mM リン酸二水素カリウム、 24mM NaOH、 pH6. 8) lOmL中に分 散させ、 37°Cで 1時間緩やかに回転混合した後、遠心分離を行い、上清液を回収し た。上清液中のラクトフ リン濃度を高速液体クロマトで測定した。 上清中のラタトフエリン濃度は 4. 7gZmLであった。これは、処理した組成物 500m gに含まれるラタトフエリン (約 50mg)の約 94%が溶出されたことになり、本発明のラタ トフエリン Z豆乳含有徐放性組成物力 腸液 PHでラタトフエリンが溶出することが確 f*i¾ れ 。 500 mg of sustained release composition containing ratatopherin / soy milk prepared in the same manner as in Example 5 was dispersed in 10 mL of model intestinal fluid (50 mM potassium dihydrogen phosphate, 24 mM NaOH, pH 6.8) at 37 ° C, and 1 After gently rotating and mixing for a period of time, the mixture was centrifuged and the supernatant was collected. The lactofrin concentration in the supernatant was measured by high performance liquid chromatography. The ratatopherin concentration in the supernatant was 4.7 gZmL. This means that about 94% of ratatopherin (about 50 mg) contained in 500 mg of the treated composition was eluted, and ratatopherin was dissolved in the intestinal fluid PH of ratatopherin Z soymilk-containing sustained release composition of the present invention. Is sure f * i¾.
[0066] 試験例 5：野菜ジュース中におけるラクトフエリン ZNaCl含有徐放性組成物の加熱処 理安定件  [0066] Test Example 5: Stable heat treatment of sustained release composition containing lactoferrin ZNaCl in vegetable juice
実施例 2と同様にして製造したラタトフエリン/ NaCl含有徐放性組成物 25mgを巿 販野菜ジュース (グリコ乳業 (株）「野菜 &くだもの」；野菜汁 35%+果汁 65%、 pH4) lmLに懸濁させ、 65°C、 75°C、 85°C、 95°Cで各々 30分間、ヒートブロック中で加熱 処理した。加熱処理後、遠心分離を行い、上清液を回収した。上清液中のラクトフエ リンを高速液体クロマトで測定した。  25 mg of ratatopherin / NaCl-containing sustained-release composition produced in the same manner as in Example 2 was suspended in 1 mL of commercially available vegetable juice (Glico Dairy Co., Ltd. “Vegetable &Fruit”; vegetable juice 35% + fruit juice 65%, pH 4) It was made turbid and heat-treated in a heat block at 65 ° C, 75 ° C, 85 ° C and 95 ° C for 30 minutes each. After the heat treatment, centrifugation was performed and the supernatant was collected. The lactoferrin in the supernatant was measured by high performance liquid chromatography.
試料 25mg中のラクトフ リン 5. 5mgに対する加熱処理後に溶出した割合を、溶出 率（％)として表した。  The ratio of elution after heat treatment to 5.5 mg of lactofrin in 25 mg of sample was expressed as the elution rate (%).
結果を表 1に示す。  The results are shown in Table 1.
[0067] [表 1] [0067] [Table 1]
表 1 . 野菜ジュース中における  Table 1. In vegetable juice
ラク 卜フエリン含有徐放性組成物の加熱処理安定性  Heat treatment stability of Lac 卜 Ferrin-containing sustained release composition
Figure imgf000022_0001
Figure imgf000022_0001
[0068] これからわかるように、加熱処理によるラタトフエリンのマトリツスカ の溶出は殆どな かった。したがって、本発明のラタトフエリン含有徐放性組成物は野菜ジュース中で の 65°C〜95°C、 30分間の加熱処理に安定であることが確認された。  [0068] As can be seen, there was almost no elution of ratatopherin Matritska by heat treatment. Therefore, it was confirmed that the ratatopherin-containing sustained-release composition of the present invention is stable in heat treatment at 65 ° C. to 95 ° C. for 30 minutes in vegetable juice.
[0069] 試,験例 6 :ラクトフエリン クヱン酸 ¾,酴カルシウム含有徐放件 成物の処理 法  [0069] Trial, Experimental Example 6: Lactoferrin succinate ¾, treatment method of calcium-containing sustained release composition
実施例 6と同様にして得られたラタトフヱリン/タエン酸/乳酸カルシウム含有徐放 性組成物 25mgを 0. IN HC1溶液（lMNaCl含有） 0. 5mLに分散させ、 30分間放 置後、 0. IN NaOH溶液 0. 5mLをカ卩えて中和した。中和後、 70°C、 30分間の加 熱処理を行った。遠心分離後、上清を回収し、沈澱は純水 lmLに分散させ、ビート ビータ一（和研薬)で処理し、ラタトフエリンを抽出した。加熱処理なしのものをコント口 ールとした。 25 mg of sustained release composition containing ratatofurin / taenoic acid / calcium lactate obtained in the same manner as in Example 6 was dispersed in 0.5 mL of 0.1 HC1 solution (containing 1M NaCl) and released for 30 minutes. After placing, 0.5 mL of 0. IN NaOH solution was added and neutralized. After neutralization, heat treatment was performed at 70 ° C for 30 minutes. After centrifugation, the supernatant was collected, and the precipitate was dispersed in 1 mL of pure water and treated with beet beater (Waken Yakuhin) to extract ratatopherin. The one without heat treatment was used as the control console.
加熱処理後の上清に約 8%のラタトフエリンの溶出が認められた力 殆ど沈澱部分 に残存していた。その中の約 70%が破砕により溶出されてきた。  About 8% ratatopherin elution was observed in the supernatant after the heat treatment, and almost all of the force remained in the precipitate. About 70% of them have been eluted by crushing.
一方、加熱処理なしのコントロールでは、上清に約 4%程度のラタトフエリンの溶出 が認められたが、殆ど大部分が沈澱部分に残存していた。その中の約 86%が破砕 により溶出されてきた。  On the other hand, in the control without heat treatment, elution of about 4% ratatopherin was observed in the supernatant, but almost all remained in the precipitate. About 86% of them have been eluted by crushing.
以上から、ラタトフエリン/タエン酸/乳酸カルシウム含有徐放性組成物は ρΗ1〜2 において 1M NaCl存在下で処理することにより、中性 pH付近における 70°C、 30 分間の加熱処理に対して安定であることが分った。従って、このように加熱滅菌処理 された組成物は、別途殺菌されたヨーグルト等の乳製品や野菜ジュース等に添加す ることが可能である。  Based on the above, the sustained release composition containing ratatopherin / taenoic acid / calcium lactate is stable against heat treatment at 70 ° C for 30 minutes near neutral pH by treatment in the presence of 1M NaCl at ρΗ1-2. I found that there was. Therefore, the composition sterilized by heating can be added to sterilized dairy products such as yogurt or vegetable juice.
[0070] 試験例 7：ラクトフエリン含有徐放件鉬.成物の胃液 ΏΗでの安定件 [0070] Test Example 7:. Rakutofuerin containing sustained-release Ken鉬Narubutsu stable matter in the gastric juice Ώ Η of
実施例 7と同様にして製造したラタトフエリン含有徐放性組成物 (ラタトフエリン含量： 22%) 250mgを、モデル胃液（0. 2% NaCl、 70mM HC1、 pHl. 2)に各々 0、 0 . 25、 0. 50、 0. 75、 1. 0Mの NaClを添加した溶液 10mL中に分散させ、 37。Cで 1 時間緩やかに回転混合した後、遠心分離を行い、上清液を回収した。上清液中のラ タトフェリン濃度を高速液体クロマトで測定した。  Ratatopherin-containing sustained-release composition produced in the same manner as in Example 7 (ratatopherin content: 22%) 250 mg was added to model gastric fluid (0.2% NaCl, 70 mM HC1, pHl. 2) at 0, 0.25, Disperse in 10 mL of a solution supplemented with 0.50, 0.75, 1.0 M NaCl 37. After gently rotating and mixing at C for 1 hour, the mixture was centrifuged and the supernatant was collected. The ratoferrin concentration in the supernatant was measured by high performance liquid chromatography.
NaCl濃度が 0〜0. 5Mでは濃度依存的にラタトフエリンの溶出が認めらた力 NaC 1濃度が 0. 75M以上ではラタトフエリンの溶出は認められな力つた。したがって、本発 明の徐放性組成物の胃液 pH中での安定性にイオン強度が関係することが確認され た。  The strength at which elution of ratatopherin was observed in a concentration-dependent manner at a NaCl concentration of 0 to 0.5 M. The elution of ratatopherin was observed at a NaC 1 concentration of 0.75 M or more. Therefore, it was confirmed that the ionic strength is related to the stability of the sustained release composition of the present invention in the gastric juice pH.
[0071] 試験例 8：ラ外フェリン含有徐放件組成物の腸液 ΌΗでの溶解件 [0071] Test Example 8: Dissolution of intestinal fluid phlegm with a composition containing sustained release of exogenous ferrin
実施例 7と同様にして製造したラタトフエリン含有徐放性組成物 (ラタトフエリン含量： 22%) 250mgを、モデル腸液（50mM リン酸二水素カリウム、 24mM NaOH, p H6. 8)【こ各 0、 0. 25、 0. 50、 0. 75、 1. 0Mの NaClを添カ卩した溶液 10mL中【こ 分散させ、 37°Cで 1時間緩やかに回転混合した後、遠心分離を行い、上清液を回収 した。上清液中のラクトフ リン濃度を高速液体クロマトで測定した。 Ratatopherin-containing sustained release composition produced in the same manner as in Example 7 (ratatopherin content: 22%) 250 mg of model intestinal fluid (50 mM potassium dihydrogen phosphate, 24 mM NaOH, pH 6. 8) [each 0, 0 25, 0.50, 0.75, 1.0 In a 10 mL solution supplemented with NaCl After dispersing and gently rotating and mixing at 37 ° C for 1 hour, the mixture was centrifuged and the supernatant was collected. The lactofrin concentration in the supernatant was measured by high performance liquid chromatography.
何れの場合においても、 NaCl濃度に関係なくラタトフエリンの溶出が認められた。し たがって、本発明の徐放性組成物の腸液 pHでのラタトフエリンの溶出にはイオン強 度は関係しな 、ことが確認された。  In either case, elution of ratatopherin was observed regardless of the NaCl concentration. Therefore, it was confirmed that the ionic strength is not related to the elution of ratatopherin at the intestinal pH of the sustained-release composition of the present invention.
[0072] 試験例 9 :ラ外フェリン/豆乳粉末含有徐放件組成物のペプシン処理に針する安定 性 [0072] Test Example 9: Stability of a controlled release composition containing exoferrin / soymilk powder to pepsin treatment
実施例 5と同様にして製造したラ外フェリン Z豆乳粉末含有徐放性組成物 (ラタト フェリン含量： 10%) lgを水 5mLに懸濁し、 0. 4mgZmLペプシン溶液（ρΗ2 ; 1Ν 塩酸溶液で調整） 5mLを加え、 37°Cで 30分間処理した。対照として、ペプシンを含 まない pH2溶液（1N 塩酸溶液で調整）を加え、同様に処理した。処理後、遠心分 離を行い、沈殿を 3%胆汁 Z50mM炭酸水素ナトリウム溶液 (モデル腸液） lOmLに 分散させ、 37°Cで 60分間処理した。次いで、遠心分離を行い、上清液を回収し、溶 出されてきた上清液中のラタトフエリンを高速液体クロマト (HPLC)で測定した。  Sustained release composition containing extra-feroferin Z soymilk powder produced in the same manner as in Example 5 (ratatoferrin content: 10%) 1 g was suspended in 5 mL of water and adjusted with 0.4 mg ZmL pepsin solution (ρΗ2; 1Ν hydrochloric acid solution) 5mL was added and treated at 37 ° C for 30 minutes. As a control, a pH 2 solution containing no pepsin (adjusted with a 1N hydrochloric acid solution) was added and treated in the same manner. Centrifugation was performed after the treatment, and the precipitate was dispersed in 10 mL of 3% bile Z50 mM sodium bicarbonate solution (model intestinal fluid) and treated at 37 ° C for 60 minutes. Subsequently, centrifugation was performed, the supernatant was collected, and ratatopherin in the supernatant that had been dissolved out was measured by high performance liquid chromatography (HPLC).
ペプシン処理後の上清液中のラタトフエリン濃度は、対照の上清液中のラタトフエリ ン濃度とほぼ同じであった。従って、本発明のラタトフエリン Z豆乳粉末含有徐放性 組成物は、胃液中に存在するペプシンに対して安定であることが確認された。  The ratatopherin concentration in the supernatant after pepsin treatment was almost the same as the ratatopherin concentration in the control supernatant. Therefore, it was confirmed that the sustained release composition containing ratatopherin Z soymilk powder of the present invention is stable against pepsin present in gastric juice.
また、胆汁を含むモデル腸液においてラタトフヱリンが溶出されてくることが確認さ れた。  It was also confirmed that ratatofurin was eluted in model intestinal fluid containing bile.
[0073] 試験例 10：ラクトフエリン Zキサンタンガム Z豆乳含有徐放性組成物のペプシン処理- に する 定件  [0073] Test Example 10: Lactoferrin Z Xanthan gum Z Soymilk containing sustained release composition treated with pepsin
実施例 9と同様にして製造したラクトパーォキシダーゼ含有徐放性組成物 (ラタトパ 一ォキシダーゼ含量： 21%) lgを用いて、試験例 9と同様にペプシン処理に対する 安定性を調べた。  The stability to pepsin treatment was examined in the same manner as in Test Example 9 using the lactoperoxidase-containing sustained-release composition produced in the same manner as in Example 9 (ratatopa-oxidase content: 21%) lg.
ペプシン処理後の上清液中のラクトパーォキシダーゼ濃度は、対照の上清液中の ラクトパーォキシダーゼ濃度とほぼ同じであった。従って、本発明のラクトパーォキシ ダーゼ含有徐放性組成物は、胃液中に存在するペプシンに対して安定であることが 確認された。 また、胆汁を含むモデル腸液においてラタトフヱリンが溶出されてくることが確認さ れた。 The concentration of lactoperoxidase in the supernatant after pepsin treatment was almost the same as the concentration of lactoperoxidase in the control supernatant. Therefore, it was confirmed that the lactoperoxidase-containing sustained-release composition of the present invention is stable against pepsin present in gastric juice. It was also confirmed that ratatofurin was eluted in model intestinal fluid containing bile.
[0074] 試験例 11：ラクトパーォキシダーゼ含有徐放性組成物のペプシン処理に対する安定 性  [0074] Test Example 11: Stability of a sustained release composition containing lactoperoxidase to pepsin treatment
実施例 11と同様にして製造したラタトフエリン Zキサンタンガム Z豆乳粉末含有徐 放性組成物（ラタトフエリン含量： 21%) lgを用いて、試験例 9と同様にペプシン処理 に対する安定性を調べた。  Ratatophelin Z xanthan gum Z soymilk powder-containing sustained release composition (ratatopherin content: 21%) lg produced in the same manner as in Example 11 was used to examine the stability against pepsin treatment in the same manner as in Test Example 9.
ペプシン処理後の上清液中のラタトフエリン濃度は、対照の上清液中のラタトフエリ ン濃度とほぼ同じであった。従って、本発明のラタトフヱリン Zキサンタンガム Z豆乳 粉末含有徐放性組成物は、胃液中に存在するペプシンに対して安定であることが確 f*i¾ れ 。  The ratatopherin concentration in the supernatant after pepsin treatment was almost the same as the ratatopherin concentration in the control supernatant. Therefore, it can be confirmed that the sustained release composition containing ratatofolin Z xanthan gum Z soymilk powder of the present invention is stable against pepsin present in the gastric juice.
また、胆汁を含むモデル腸液においてラタトフヱリンが溶出されてくることが確認さ れた。  It was also confirmed that ratatofurin was eluted in model intestinal fluid containing bile.
[0075] 試,験 2 :ラットに: ける腸管吸収動能試験  [0075] Trial, Trial 2: Intestinal Absorption Dynamics Test in Rats
8週齢の Wistar系雄性ラット 30頭を 5頭ずつ 6群に分け、胃内投与 3群（対照： 2群、 実験： 1群)および十二指腸内投与 3群 (対照： 2群、実験： 1群)を形成した。  Thirty 8-week-old male Wistar rats were divided into 6 groups each of 5 rats, 3 groups (control: 2 groups, experiment: 1 group) and 3 groups (control: 2 groups, experiment: 1) Group).
胃内投与および十二指腸内投与の各々の対照の 2群には裸のラクトフ リン（「粉 末 LF」）を生理食塩水に溶解して投与し（30mgZkg、 300mgZkg)、実験群には 実施例 5で製造したラタトフエリン,豆乳含有徐放性組成物（「腸溶性 LF」 )を生理食 塩水に懸濁して投与した (ラタトフエリンとして 30mgZkg)。投与 1時間前（「Pre」 )か ら投与 4時間後まで 1時間ごとに胸管リンパ液を採取し、 ELISA法にてラタトフエリン を定量した。結果を図 1に示す。  Naked lactofurin (“powder LF”) was dissolved in physiological saline (30 mgZkg, 300 mgZkg) and administered to the two groups of controls for intragastric administration and intraduodenal administration. The sustained release composition containing ratatopherin and soy milk (“enteric LF”) prepared in 1 was suspended in physiological saline and administered (30 mgZkg as ratatopherin). Chest lymphatic fluid was collected every hour from 1 hour before administration (“Pre”) to 4 hours after administration, and ratatopherin was quantified by ELISA. The results are shown in Figure 1.
[0076] 胃内投与群における胸管リンパ液中に移行したラクトフ リン総量を比較すると、対 照群では投与 1時間後をピークに、その後暫時減少するのに対して、実験群では投 与 4時間後まで高レベルを維持した (図 1、パネル (A) )。  [0076] When the total amount of lactofrin transferred into the thoracic lymph fluid in the intragastric group was compared, the control group peaked at 1 hour after administration and decreased for a while, whereas the experimental group received 4 hours of administration. It remained high until later (Figure 1, Panel (A)).
一方、胃を経由せず十二指腸内に投与した群における胸管リンパ液中に移行した ラタトフヱリン総量を比較すると、同じ投与量の実験群 (ラタトフヱリンとして 30mgZkg )と対照のラタトフエリン 30mgZkg投与群は投与直後から 4時間後まで、ほぼ同じ濃 度の経時的変化を示した (図 1、パネル (B) )。また、投与量が 10倍の対照のラ外フ エリン 300mgZkg投与群では約 10倍の濃度の経時的変化を示した（図 1、パネル（ C) )。 On the other hand, when comparing the total amount of ratatofurin transferred into the thoracic lymph fluid in the group administered into the duodenum without going through the stomach, the experimental group with the same dose (30 mgZkg as ratatofurin) and the control ratatopherin 30 mgZkg group received 4 Until the time is almost the same dark The degree of change over time was shown (Figure 1, Panel (B)). In addition, the control dose of 10-fold dose of the 300 mgZkg extra-laferin group showed a 10-fold concentration change over time (Fig. 1, Panel (C)).
その結果、投与直後から 4時間後までの総量を比較すると、胃内投与の実験群 (ラ クトフヱリンとして 30mgZkg)においては、対照のラタトフヱリン 300mgZkg投与群 の約 2倍の値となった（図 2)。ラタトフエリン/豆乳含有徐放性組成物のラタトフエリン 含量が裸のラタトフエリン 10分の 1であることから、徐放性組成物のラタトフエリンは裸 のラクトフ リンの約 20倍多ぐ腸管力も吸収されたことが明らかになった。また、対照 のラタトフエリン 30mgZkg投与群に対しては、約 15倍多く腸管力も吸収されたことが 明らかになった。  As a result, when the total dose from immediately after administration to 4 hours later was compared, the experimental group (30 mgZkg as lactoferrin) in the intragastric administration was about twice as large as the control ratatofurin 300 mgZkg administration (Figure 2). . The ratatopherin content of the sustained release composition containing ratatopherin / soy milk is one-tenth that of the naked ratatopherin. It was revealed. In addition, it was revealed that the intestinal force was absorbed about 15 times more in the control ratatopherin 30mgZkg administration group.
[0077] 以上の結果から、裸のラタトフエリンが胃内で消化を受けるのに対して、本発明の徐 放性組成物中のラタトフエリンは、胃内での消化に抵抗性であり、小腸からのラタトフ エリンの吸収効率を向上させる効果があることが判明した。  [0077] From the above results, naked ratatopherin is digested in the stomach, whereas ratatopherin in the sustained-release composition of the present invention is resistant to digestion in the stomach, It was found that there is an effect of improving the absorption efficiency of ratatopherin.
[0078] この出願は、平成 17年 2月 3日出願の日本特許出願、特願 2005— 27145に基づ くものであり、特願 2005— 27145の明細書及び特許請求の範囲に記載された内容 は、すべてこの出願明細書に包含される。 [0078] This application is based on Japanese Patent Application No. 2005-27145 filed on Feb. 3, 2005, and described in the specification and claims of Japanese Patent Application No. 2005-27145. All the contents are included in this application specification.

Claims

請求の範囲 The scope of the claims
[1] 生理活性物質、ゲル化物質、塩基性有機化合物および賦形剤を含有するマトリック ス型腸溶性 '徐放性組成物であって、生理活性物質が、タンパク質、ポリペプチド、 ペプチドまたは微生物であり、生理活性物質およびゲル化物質が、脂質被膜で被覆 された粉末粒子であり、かつ、これらの成分またはその他の付加的な成分が、アル力 リ金属、アルカリ土類金属、マンガン、銅、鉄、亜鉛およびコバルトからなる群力ゝら選 択される 1種または 2種以上の元素を含有することを特徴とするマトリックス型腸溶性' 徐放性組成物。  [1] A matrix type enteric 'sustained release composition containing a physiologically active substance, a gelling substance, a basic organic compound and an excipient, wherein the physiologically active substance is a protein, polypeptide, peptide or microorganism And the bioactive substance and the gelling substance are powder particles coated with a lipid coating, and these components or other additional components are alkali metal, alkaline earth metal, manganese, copper A matrix-type enteric 'sustained-release composition characterized by containing one or more elements selected from the group consisting of iron, zinc and cobalt.
[2] 有機酸、無機酸塩および結合剤力 なる群力 選択される 1種または 2種以上をさ らに含む、請求の範囲 1記載のマトリックス型腸溶性 ·徐放性組成物。  [2] The matrix-type enteric / sustained-release composition according to claim 1, further comprising one or more selected organic acids, inorganic acid salts, and binder power.
[3] 生理活性物質およびゲル化物質の脂質被膜粉末粒子の脂質の含有量が、生理活 性物質およびゲルィ匕物質の脂質被膜粉末粒子の全重量を基準として 1重量％〜90 重量％である、請求の範囲 1記載のマトリックス型腸溶性 ·徐放性組成物。  [3] The lipid content of the lipid-coated powder particles of the physiologically active substance and the gelling substance is 1% to 90% by weight based on the total weight of the lipid-coated powder particles of the physiologically active substance and the gely substance The matrix type enteric / sustained release composition according to claim 1.
[4] 生理活性物質およびゲル化物質の脂質被膜粉末粒子の脂質の含有量が、生理活 性物質およびゲルィ匕物質の脂質被膜粉末粒子の全重量を基準として 5重量％〜20 重量％である、請求の範囲 1記載のマトリックス型腸溶性 ·徐放性組成物。  [4] The lipid content of the lipid-coated powder particles of the physiologically active substance and the gelling substance is 5% to 20% by weight based on the total weight of the lipid-coated powder particles of the physiologically active substance and the gely substance. The matrix type enteric / sustained release composition according to claim 1.
[5] 前記元素が、ナトリウム、カリウム、カルシウム、マグネシウム力もなる群力も選択され る 1種または 2種以上を含む、請求の範囲 1〜3のいずれか 1項記載のマトリックス型 腸溶性，徐放性組成物。  [5] The matrix type enteric, sustained-release according to any one of claims 1 to 3, wherein the element includes one or more selected from the group power including sodium, potassium, calcium, and magnesium power. Sex composition.
[6] ゲル化物質が、カラギーナン、アルギン酸、フコィダン、硫酸ガラクタン、キサンタン ガム、カルボキシメチルセルロース、ぺクチン、アラビアガム、ジエランガム、納豆菌ガ ム、大豆水溶性多糖類、寒天、デンプン、ファーセルラン、トラカントガム、ゼラチン、 タマリンド種子ガム、ローカストビーンガム、グァーガム、キチン、キトサン力もなる群か ら選択される 1種または 2種以上である、請求の範囲 1〜5のいずれか 1項記載のマト リックス型腸溶性 ·徐放性組成物。  [6] The gelling substances are carrageenan, alginic acid, fucoidan, galactan sulfate, xanthan gum, carboxymethylcellulose, pectin, gum arabic, dielan gum, natto germ, soybean water-soluble polysaccharides, agar, starch, farcellulan, Matrix type according to any one of claims 1 to 5, which is one or more selected from the group consisting of tracant gum, gelatin, tamarind seed gum, locust bean gum, guar gum, chitin and chitosan force. Enteric / sustained release composition.
[7] 賦形剤が、セルロース、結晶セルロース、デキストリン、バターミルクパウダー、カゼ イン、豆乳粉末、大豆粉末、脱脂ミルク、野菜粉末、果汁粉末からなる群から選択さ れる 1種または 2種以上である、請求の範囲 1〜6のいずれか 1項記載のマトリックス 型腸溶性，徐放性組成物。 [7] The excipient is one or more selected from the group consisting of cellulose, crystalline cellulose, dextrin, buttermilk powder, casein, soymilk powder, soybean powder, skim milk, vegetable powder, and fruit juice powder. The matrix according to any one of claims 1 to 6, Type enteric and sustained release composition.
[8] 塩基性有機化合物が、豆乳粉末、キトサン、ポリリジン、ポリアルギニン、ポリグルタ ミン、アルギニン、グルタミン、ヒスチジン、リジン、オル二チン、ダルコサミンからなる群 力も選択される 1種または 2種以上である、請求の範囲 1〜7のいずれか 1項記載の マトリックス型腸溶性 ·徐放性組成物。  [8] The basic organic compound is one or more selected from the group power consisting of soymilk powder, chitosan, polylysine, polyarginine, polyglutamine, arginine, glutamine, histidine, lysine, ornithine, darcosamine The matrix type enteric / sustained release composition according to any one of claims 1 to 7.
[9] 有機酸が、酢酸、クェン酸、マレイン酸、フマル酸、酒石酸、コハク酸、エチレンジァ ミン四酢酸、コンドロイチン硫酸、およびそれらの塩力 なる群力 選択される 1種また は 2種以上である、請求の範囲 2〜8のいずれか 1項記載のマトリックス型腸溶性.徐 放性組成物。  [9] The organic acid is acetic acid, citrate, maleic acid, fumaric acid, tartaric acid, succinic acid, ethylenediaminetetraacetic acid, chondroitin sulfate, and their salt strength. The matrix-type enteric / sustained release composition according to any one of claims 2 to 8.
[10] 無機酸塩が、アルカリ金属塩、アルカリ土類金属塩、アンモ-ゥム塩カゝらなる群から 選択される 1種または 2種以上である、請求の範囲 2〜9のいずれか 1項記載のマトリ ックス型腸溶性 ·徐放性組成物。  [10] Any one of claims 2 to 9, wherein the inorganic acid salt is one or more selected from the group consisting of alkali metal salts, alkaline earth metal salts and ammonium salt salts. The matrix type enteric / sustained release composition according to 1.
[11] 粉末、カプセルに封入されている形態、錠剤、顆粒、丸薬、乳化液、懸濁液または ゲルの形態である、請求の範囲 1〜10のいずれ力 1項記載のマトリックス型腸溶性' 徐放性組成物。 [11] The matrix-type enteric agent according to any one of claims 1 to 10, which is in the form of powder, encapsulated form, tablet, granule, pill, emulsion, suspension or gel. Sustained release composition.
[12] マイクロカプセル、ソフトカプセルまたはハードカプセルに封入されている、請求の 範囲 11記載のマトリックス型腸溶性 ·徐放性組成物。  [12] The matrix type enteric / sustained release composition according to claim 11, which is encapsulated in microcapsules, soft capsules or hard capsules.
[13] 請求の範囲 1〜 12の ヽずれか 1項記載のマトリックス型腸溶性 ·徐放性組成物を含 有する食品。 [13] A food comprising the matrix type enteric / sustained release composition according to any one of claims 1 to 12.
[14] 請求の範囲 1〜 12の ヽずれか 1項記載のマトリックス型腸溶性 ·徐放性組成物を含 有する医薬。  [14] A pharmaceutical comprising the matrix type enteric / sustained release composition according to any one of claims 1 to 12.
[15] 請求の範囲 1〜 12の ヽずれか 1項記載のマトリックス型腸溶性 ·徐放性組成物を含 有する飼料。  [15] A feed comprising the matrix type enteric / sustained release composition according to any one of claims 1 to 12.
[16] 請求の範囲 1記載のマトリックス型腸溶性 ·徐放性組成物用の素材組成物であって 、生理活性物質とゲル化物質とが脂質被膜で被覆されて ヽることを特徴とする素材 組成物。  [16] A material composition for a matrix-type enteric / sustained-release composition according to claim 1, wherein the physiologically active substance and the gelling substance are covered with a lipid film. Material Composition.
[17] 脂質被膜の脂質の含有量が、素材組成物の重量を基準として 1重量％〜90重量 %である、請求の範囲 16記載の素材組成物。 [17] The raw material composition according to claim 16, wherein the lipid content of the lipid coating is 1% by weight to 90% by weight based on the weight of the raw material composition.
[18] 請求の範囲 16または 17記載の素材組成物の製造方法であって、生理活性物質と ゲル化物質と脂質を含む被膜材とを一緒にして混合物を生成する工程、前記混合 物を加熱して脂質を融解させる工程、前記混合物中で前記生理活性物質およびゲ ル化物質に前記被膜材を付着させる工程、および前記生理活性物質およびゲルィ匕 物質の表面に前記被膜材カゝらなる被膜を形成させる工程を含むことを特徴とする方 法。 [18] A method for producing a raw material composition according to claim 16 or 17, wherein the bioactive substance, the gelling substance and the coating material containing lipid are combined to form a mixture, and the mixture is heated. A step of melting the lipid, a step of attaching the coating material to the physiologically active substance and the gelling substance in the mixture, and a coating comprising the coating material on the surface of the physiologically active substance and the gelling substance A method characterized by including a step of forming a film.
[19] 請求の範囲 1記載のマトリックス型腸溶性'徐放性組成物の製造方法であって、生 理活性物質、ゲル化物質、塩基性有機化合物および賦形剤を含有し、かつ、これら の成分またはその他の付カ卩的な成分に由来するアルカリ金属またはアルカリ土類金 属を含有する、組成物の構成成分を一緒にして混合物を生成する工程、前記混合 物に結合剤を噴霧して造粒する工程、および前記造粒物を乾燥させる工程を含むこ とを特徴とする方法。  [19] A method for producing a matrix-type enteric 'sustained release composition according to claim 1, comprising a physiologically active substance, a gelling substance, a basic organic compound and an excipient, and A step of combining components of the composition containing an alkali metal or an alkaline earth metal derived from the above components or other auxiliary components to form a mixture, and spraying the mixture with a binder And granulating, and drying the granulated product.
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