WO2006082824A1

WO2006082824A1 - Matrix-type enteric coated sustained release composition

Info

Publication number: WO2006082824A1
Application number: PCT/JP2006/301619
Authority: WO
Inventors: Genji Kawano; Isamu Seto
Original assignee: Nrl Pharma, Inc.
Priority date: 2005-02-03
Filing date: 2006-02-01
Publication date: 2006-08-10
Also published as: JP4050784B2; JPWO2006082824A1

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

Specification

Matrix type enteric / sustained release composition

Technical field

[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. .

Background art

[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.

From such a viewpoint, enteric-coated oral preparations such as enteric-coated tablets and enteric-coated capsules with enteric coatings have been developed!

[0003] Generally, 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.

[0004] On the other hand, in food and feed applications, shellac twein derived from natural products is used as an enteric coating agent.

[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.

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.

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] 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).

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.

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] 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] 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] 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] 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] 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] 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] 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] 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.

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

Disclosure of the invention

[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] 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] That is, the present invention provides

[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] 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] 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] 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] 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] 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] 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] 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] 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] 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] 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] 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] Any one of the above-mentioned [1] to [12] The pharmaceutical comprising the matrix-type enteric 'sustained release composition according to 1;

[15] A feed containing the matrix type enteric / sustained release composition according to any one of [1] to [12];

[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] 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] 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] 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

I will provide a.

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] 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.

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] 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.

Brief Description of Drawings

[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.

FIG. 2 is a graph showing the total amount of ratatopherin absorbed up to 4 hours after ratatopherin administration in rats.

BEST MODE FOR CARRYING OUT THE INVENTION

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, amphiregulin, angiogenin, β-microglobulin, betacellulin,

2

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] 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] 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.

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.

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] 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] 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] 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.

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.

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] 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] 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] 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] 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.

[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.

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] 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.

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] 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] 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] 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] 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.

Hereinafter, the present invention will be described in detail by way of examples, but the present invention is not limited to the examples.

Example

[0046] 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.

[0047] ¾ Example 2: Lactoferrin NaCl-containing sustained release product.

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] 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.). 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 Example 4: Sustained release product containing core isolate.

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 Row 5: Lactoferrin ^ ¾, Contained sustained release.

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] Example 6: Production of a composition for sustained release containing ectoferrin / quenate / calcium lactate

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] Example 7: Making a lactoferrin-containing sustained release composition

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 Example 8: Preparation of oleagin-coated lactoperoxidase pectin mixed powder

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

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] 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.

Example 11 Production of Sustained Release Composition Containing La Feline Z Zanthan Gum Soy Milk

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 Row ί2: Lactoferrin xanthan gum Z Buttermilk powder containing sustained release notification of composition

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] 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%).

[0060] Notification of miB oil-coated ovotransferrin chitosan mixed powder

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.

Example 16: Production of sustained release composition containing ovotransferrin Z chitosan Z soymilk

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] 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.

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] Test Example 2: Dissolution of intestinal fluid _{fistula of exoferrin} / NaCl-containing sustained release composition

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.

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] Test Example 3: Lactoferrin ^ ¾, Contained sustained release 鉬. Stabilization of _adult gastric juice _成

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.

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] 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. 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] Test Example 5: Stable heat treatment of sustained release composition containing lactoferrin ZNaCl in vegetable juice

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.

The ratio of elution after heat treatment to 5.5 mg of lactofrin in 25 mg of sample was expressed as the elution rate (%).

The results are shown in Table 1.

[0067] [Table 1]

Table 1. In vegetable juice

Heat treatment stability of Lac 卜 Ferrin-containing sustained release composition

[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] Trial, Experimental Example 6: Lactoferrin succinate ¾, treatment method of calcium-containing sustained release composition

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.

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.

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.

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] Test Example 7:. Rakutofuerin containing sustained-release Ken鉬Narubutsu stable matter in the gastric juice _{Ώ Η} 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.

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] 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.

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] 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 (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).

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.

It was also confirmed that ratatofurin was eluted in model intestinal fluid containing bile.

[0073] Test Example 10: Lactoferrin Z Xanthan gum Z Soymilk containing sustained release composition treated with pepsin

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.

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] 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.

[0075] Trial, Trial 2: Intestinal Absorption Dynamics Test in Rats

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).

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] 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)).

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)).

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] 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] 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

The scope of the claims

[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] 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] 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] 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] 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] 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] 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] 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] 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] 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] 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] The matrix type enteric / sustained release composition according to claim 11, which is encapsulated in microcapsules, soft capsules or hard capsules.

[13] A food comprising the matrix type enteric / sustained release composition according to any one of claims 1 to 12.

[14] A pharmaceutical comprising the matrix type enteric / sustained release composition according to any one of claims 1 to 12.

[15] A feed comprising the matrix type enteric / sustained release composition according to any one of claims 1 to 12.

[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] 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] 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] 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.