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WO2006016595A1 - Complexe de lactoférine et méthode pour le produire - Google Patents

Complexe de lactoférine et méthode pour le produire Download PDF

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Publication number
WO2006016595A1
WO2006016595A1 PCT/JP2005/014623 JP2005014623W WO2006016595A1 WO 2006016595 A1 WO2006016595 A1 WO 2006016595A1 JP 2005014623 W JP2005014623 W JP 2005014623W WO 2006016595 A1 WO2006016595 A1 WO 2006016595A1
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WO
WIPO (PCT)
Prior art keywords
complex
powder
acid
aqueous solution
ratatopherin
Prior art date
Application number
PCT/JP2005/014623
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English (en)
Japanese (ja)
Inventor
Genji Kawano
Isamu Seto
Hirohiko Shimizu
Kozue Fujimura
Original Assignee
Nrl Pharma, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nrl Pharma, Inc. filed Critical Nrl Pharma, Inc.
Priority to JP2006531672A priority Critical patent/JP4195486B2/ja
Publication of WO2006016595A1 publication Critical patent/WO2006016595A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/40—Transferrins, e.g. lactoferrins, ovotransferrins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/142—Amino acids; Derivatives thereof
    • A23K20/147—Polymeric derivatives, e.g. peptides or proteins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • 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
    • A23L33/19—Dairy proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

  • Ratatofu phosphorus complex and method for producing the same
  • the present invention relates to a complex of ratatopherin and a polyelectrolyte, a method for producing the same, and a lactoferrin material composition which can be used for medicine, food, feed, etc. containing this complex, and further, the material Relating to medicine, food, feed etc. More specifically, a ratatopheline complex capable of efficiently exerting a physiological activity, a ratatopheline material composition, having enhanced stability in the presence of water and in gastric juice, entericity, and stability to heat treatment in an aqueous system.
  • the present invention relates to a method for producing them, and medicines, foods and feeds using this composition. Background art
  • Ratatophelin is a glycoprotein with a molecular weight of about 80,000 which is mainly present in the milk of mammals and is also found in neutrophils, tears, saliva, nasal discharge, bile, semen and the like.
  • Ratatoferrin belongs to the transferrin family because it binds iron.
  • Physiological activities of ratatofurin include antibacterial activity, iron absorption control activity, cell proliferation activation activity, hematopoietic activity, anti-inflammatory activity, antioxidative activity, phagocytosis activity, antiviral activity, bifidobacteria growth promotion activity, antifungal activity. It is known to have effects on cancer, cancer metastasis, and translocation.
  • ratatophelin has lipid metabolism improving and analgesic effects.
  • ratatophelin is a multifunctional physiologically active protein that exhibits various functions, and is expected to be used for applications such as medicines and foods for the recovery or improvement of health, and it contains ratatopheline. Food is already commercially available.
  • ratatofu phosphorus used in food and the like is a powder which is mainly separated from milk or dairy products and is spray-dried or freeze-dried. In dry powder form, ratatopherin is stable at room temperature for about 1 to 2 years.
  • ratatophelin is unstable when dissolved in water.
  • ratatoferin is used in medicine, food or feed, etc. in the presence of water, modification due to its three-dimensional structure being broken during storage or modification due to aggregation with a coexistent substance occurs, resulting in ratatopherin It loses its physiological activity. Therefore, ratatohuelin has water Can not be stored for a long time in the existing state.
  • ratatopheline powder is used as it is as a powder in order to enable long-term storage of several months or more. It was limited to any one of whether it was used as a tablet formulated in a dry powder state with the addition of excipients and the like.
  • Patent Document 2 Patent No. 2688098, Non-Patent Document 1
  • Patent Document 2 Patent No. 2688098, Non-Patent Document 1
  • this method can not improve the thermal stability of the ratatopheline-containing solution at near neutral pH.
  • ratatophelin when ratatophelin is orally taken, it is hydrolyzed by the acid protease pepsin, which is present in gastric juice, to be decomposed into a peptide, so that ratatophelin molecules can almost reach the intestinal tract as the ratatopheline molecule.
  • ratatophelin receptor is present in the small intestine mucosa in the digestive tract, and recently, ratatophelin is taken up by intestinal epithelial cells and is involved in gene expression in the nucleus, and inflammatory site is It has been reported that it controls the development. Therefore, the physiological activity of ratatophelin In order to exert it, it is necessary to allow ratatopheline to reach the intestinal tract without undergoing hydrolysis by pepsin in gastric juice.
  • enteric ratatopherin tablets obtained by coating enteric films on uncoated tablets pressed with tablet in dry powder state without using water by adding an excipient etc. to health support It is sold as a food.
  • Ratatofu-phosphorin raw material yarn which is stable to heat treatment near neutral pH while being able to sufficiently exert its physiological activity, and pharmaceuticals, food and feed using it. He was an unknown force.
  • Polyelectrolytes have been used as thickeners, dispersion stabilizers, adhesives, protective colloids, and the like in various technical fields including food, pharmaceuticals, and formulated feeds.
  • gelled ones adsorb ratatopherin, and this property has been utilized for the purification of extranuclear phosphorus.
  • a method of preparing a gel composition of a protein with excellent thermal stability that can be used as a food and drink material by heating a protein such as casein and a gelling agent containing ratatoferin as an active ingredient (patented) Reference 4: JP-A-8-98655), a method for producing a folate-lactophrins complex useful as a food or drink or a pharmaceutical material by mixing folate or the like with ratatophelin (Patent Document 5: JP-A-2001-106) 238640), ratatofurin by adding a polyvalent inorganic acid (phosphoric acid or sulfuric acid) or an organic acid (taenic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, ethylenediamine tetraacetic acid or chondroitin sulfate) to a solution of ratatofurin.
  • a method for stabilizing (Patent Document 6: WO99Z06065) has been reported.
  • Non-patent Document 4 a polyion complex is formed by mixing polymer electrolyte solutions having charges of opposite signs to each other. It is unknown if it is enteric.
  • Patent Document 1 Japanese Patent Application Laid-Open No. 2-108629
  • Patent Document 2 Patent No. 2688098
  • Patent Document 3 JP-A-61-246198
  • Patent Document 4 Japanese Patent Application Laid-Open No. 08-098655
  • Patent Document 5 Japanese Patent Application Publication No. 2001-238640
  • Patent Document 6 WO 99 Z 606 6065
  • Patent Document 7 Japanese Patent Application Laid-Open No. 2002-161050
  • Patent Document 8 Japanese Patent Application Laid-Open No. 2002-322088
  • Patent Document 9 Japanese Patent Application Laid-Open No. 2002-326950
  • Patent Document 10 Japanese Patent Application Laid-Open No. 2003-089629
  • Patent Document 11 Japanese Patent Application Laid-Open No. 2003-137808
  • Patent Document 12 Japanese Patent Application Laid-Open No. 2003-137809
  • Non Patent Literatures Abe, H “baito, H” iya awa, H “Tamura, Y .: Journal of dairy science (1991) 74 (1), 65-71
  • Non-patent literature 2 New food material effective utilization technology series No. 6 “Ratatofu ⁇ ⁇ ⁇ ”, Inc. (Inc.) Confectionery General Technology Center published, March 2000
  • Non-Patent Document 3 Biochemical Dictionary, Tokyo Chemical Co., Ltd., April 1984
  • Non-patent document 4 Polymer assembly, published by Academic Press Center, January 1983
  • the present invention provides improved stability in the presence of water and in gastric juice, entericity, and thermal stability of ratatofu phosphorus to heat treatment in an aqueous system, resulting in preservation in the presence of water.
  • the stability is excellent, and ratatoferin reaches the intestinal tract and is eluted or released without being (or reduced in degradation) degraded by pepsin in gastric juice, so it is efficiently absorbed by the body and sufficiently bioactive.
  • a ratatopheline material composition having a feature that it can be used to perform a process involving heating such as heat sterilization in food, medicine, feed and the like, and a method for producing the same
  • ratatopherin is mixed with a polyelectrolyte in an aqueous solution to form a water-insoluble complex with the polyelectrolyte.
  • ratatopherin is mixed with a polyelectrolyte in an aqueous solution to form a water-insoluble complex with the polyelectrolyte.
  • the polyelectrolytes are casein, gelatin, acidic egg white proteins, acidic whey proteins, poly L-glutamic acid, carboxymethylcellulose, carrageenan, alginic acid, fucoidan, galactan sulfate, xanthan gum, pectin, gum arabic Lyacrylic acid, polymethacrylic acid, dielan gum, natto bacteria gum, soybean water-soluble polysaccharide, agar, starch, furcellane, tracanth gum, heparin, hyaluronic acid, chondroitin, Heparan sulfate, dermatan sulfate, keratan sulfate, chondroitin sulfate, carboxymethyl starch, carboxymethyl amylose, buttermilk powder, acid soluble soy proteins, soy milk, chitosan, glycol chitosan, polylysine, polyglutamine, polyarginine, polyethylene
  • the complex according to any one of the
  • An aqueous solution of a polymer base is dispersed in an aqueous solution by dispersing a powder containing a lipid coating coated exoferrin and a powder containing a lipid coating coated polymeric acid in an aqueous solution.
  • a ratatophile material composition comprising the complex according to any one of the items (1) to (8);
  • the basic substance is also selected from soy milk, chitosan, polylysine, polyarginine, polyarginine, polydaltamin, sodium hydrogencarbonate, arginine, glutamine, histidine, lysine, dulcosamine, sodium carbonate, or a group of one or two.
  • the ratatofelin material composition as described in (10) above.
  • the above binder is one or more selected from the group consisting of zein, shellac, water-soluble soybean polysaccharide, carboxymethyl cellulose, alginic acid, guar gum and carboxymethyl cellulose. (10) or the composition of the ratatofelin raw material as described in (11).
  • a pharmaceutical composition comprising the material composition according to any one of the above (9) to (12) in an amount effective to exert the physiological activity of ratatopherin;
  • a feed comprising the material composition according to any one of the above (9) to (12) in an amount effective to exert the physiological activity of ratatopherin;
  • a method for producing a complex of ratatopherin and a polymer electrolyte which is obtained by mixing an aqueous solution containing ratatopherin and an aqueous solution containing a polymer electrolyte at normal temperature or under heating.
  • a method for producing a complex of ratatofuline and a polymer electrolyte which comprises mixing an aqueous solution containing ratatofurin with an aqueous solution containing a polymer electrolyte which is a polymeric acid at room temperature or under heating, Then, an aqueous solution containing a polymer electrolyte which is a polymer base is added to form a complex of ratatopherin, a polymer acid and a polymer base, and the obtained complex is recovered.
  • a method for producing a complex of ratatopherin and a polymer electrolyte which comprises preparing a powder containing ratatopherin and a polymer electrolyte, dispersing the powder in an aqueous solution, and heating at normal temperature or under heating.
  • a method comprising mixing to form a complex, and recovering the obtained complex;
  • a method for producing a complex of ratatopherin and a polymer electrolyte which comprises preparing a powder containing ratatopherin and a polymer electrolyte which is a polymer acid, and dispersing the powder in an aqueous solution to obtain a mixture at room temperature. Alternatively, they are mixed under heating, and then an aqueous solution or powder containing a polymer electrolyte which is a polymer base is added, and mixed under normal temperature or heating to form a complex of ratatophenin, a polymer acid and a polymer base.
  • a powder coating containing a lipid coating and a powder coating containing LaFerrin and a lipid coating Raw material for preparing a complex of ratatofluorine and a polyelectrolyte, which is contained in a container separately or in a mixed state with a powder containing a coated polyelectrolyte.
  • the ratatopherin complex and the raw material composition of the present invention are water insoluble in a normal state, and have good storage stability even in the presence of water.
  • ratatophein contained in the complex and the material composition of the present invention does not elute in gastric juice and does not undergo degradation by pepsin or its degradation is reduced.
  • the complex In the digestive tract containing bile acids such as lipase and deoxycholic acid, that is, in the intestine containing bile etc., the complex can be easily eluted or released, so it is efficiently absorbed by the body. It is possible to exert physiological activity.
  • Bile is classified into hepatobile and gallbladder bile, which generally have the following composition.
  • the term "bile” in the context of the present invention also includes both of these and experimentally used model bile (3 wt.% Bile (Wako Pure Chemical Industries or equivalent bile powder), 50 mM sodium bicarbonate).
  • the composite and material composition of the present invention is stable to heat treatment at around the acidic pH (pH 3.5) to near neutral pH, and therefore, it can be used in the production of food, medicine, feed and the like. It can be advantageously used in carrying out processes involving heating, such as heat sterilization, and as a result of the restriction on production being relaxed, it can be applied to a wide variety of products.
  • the composite and the material composition of the present invention are advantageous in terms of production because they can be easily produced in a simple process.
  • the food, medicament and feed containing the ratatopheline complex or ratatophelin raw material composition of the present invention are not limited to those in a dry state, and even in the form in which water is present, the physiological activity of ratatofurin is obtained. It can be maintained for a long period of time, and even if it is heat-treated, it can sufficiently retain the physiological activity of ratatopheline, so the storage stability and usefulness of food, medicine and feed itself are improved. Significantly improved.
  • FIG. 1 is a view showing the pH dependence of pepsin degradation of ratatophelin.
  • “latatopherin” also includes the natural ratatopherin molecule itself, gene recombinant ratatofurin, and functional equivalents of ratatofurin such as active fragments of ratatofurin. The presence or absence of iron ion or its content, regardless of the species from which it originates.
  • “the ratatophelin raw material composition” is a composition containing ratatopheline, which can be used as a raw material of other products such as food, medicine, feed and the like, and the physiological activity or characteristics of ratatopherin. Means a material composition to be used for at least one purpose of exerting it in the product in which it is used.
  • polyelectrolyte refers to a substance that dissociates in an aqueous solution to form polyions (macroions) and counterions (microions), and is a polymeric acid, a polymeric base or ampholytic polymer.
  • Molecular Electrolyte! /, Misalignment May be Synthetic or Natural! /, Misalignment! / ,.
  • the polymer electrolyte used in the composite, material composition and the like of the present invention includes, among arbitrary polymer electrolytes, physiologically acceptable polymer electrolytes or salts thereof, especially for food and medical use etc. Depending on the application, one or two or more may be selected as appropriate.
  • polyelectrolytes used as food additives are preferred in terms of availability, price and Z or safety.
  • casein gelatin, Acidic egg white proteins (ovalbumin, conalbumin, ovomucoid, ovoglobulin
  • polymer electrolyte used in the present invention when there is one type of polymer electrolyte, a polymer acid which dissociates in an aqueous solution to form polyanion (for example, an acidic protein, Acidic polypeptides and acidic polysaccharides) are preferred.
  • a polymer acid which dissociates in an aqueous solution to form polyanion for example, an acidic protein, Acidic polypeptides and acidic polysaccharides
  • these polyelectrolytes the use of a strongly acidic polyelectrolyte is particularly resistant to acid dissociation and pepsin degradation as compared with a complex with a weakly acidic electrolyte, and the complex is can get.
  • weakly acidic polyelectrolytes are particularly preferred.
  • a polymeric acid that dissociates in an aqueous solution to form polyanion and a polymeric base that dissociates in an aqueous solution to form a polycation (for example, basic protein, base It is preferred to include both a sex polypeptide and a basic polysaccharide).
  • a complex of ratatopheline and a polymeric acid may be abbreviated as a binary complex in particular.
  • a complex of ratatopheline, a polymeric acid and a polymeric base may be abbreviated as a ternary complex.
  • a complex of ratatofulin and a polyelectrolyte (herein, simply referred to as The term “complex” or “complex” is sometimes referred to as polyelectrolyte salt of ratatopheline. This is formed, for example, by mixing an aqueous solution containing ratatopherin with an aqueous solution containing polyelectrolyte at normal temperature or under heating.
  • the binary composite is formed by mixing an aqueous solution containing ratatopheline with an aqueous solution containing a polymeric acid at normal temperature or under heating.
  • an aqueous solution containing ratatoferin and an aqueous solution containing a polymeric acid are mixed under normal temperature or heating, and then an aqueous solution containing a polymeric base is added to the mixture. It is formed by mixing.
  • aqueous solution in the context of the present invention also includes water itself, examples being water as well as saline, physiologically acceptable buffers etc. Also, “solution” does not require that the solute be completely dissolved, and does not need to be liquid in a strict sense. Thus, in the context of the present invention, a “solution” may contain dispersed or suspended substances or it may be in the form of a yogurt or sherbet etc.
  • the temperature for heating is generally about 40 ° C. to 120 ° C., preferably 50 ° C. to 90 ° C., and most preferably in the range of 50 ° C. to 65 ° C. is there. Below 40 ° C., certain polyelectrolytes such as agar tend to solidify. On the other hand, when the temperature exceeds 65 ° C., the physiological activity of ratatoferin is easily inactivated for a long period of time when the temperature exceeds 100 ° C., the physiological activity is almost lost.
  • the specific temperature can be appropriately selected according to the selected polymer electrolyte.
  • the time for carrying out the mixing is not particularly limited as long as the outer shell phosphorus and the polymer electrolyte are sufficiently mixed to form a complex. Temperature conditions to be adopted, size of reactor, shape of mixing means It can be selected appropriately according to the situation.
  • the state of the complex thus formed varies depending on the type, concentration, mixing ratio, pH and the like of ratatopherin and polyelectrolyte, and is in the form of a colloidal precipitate, sol or gel.
  • the binary complex is in the form of a hydrophilic hydrogel
  • the ternary complex is in the form of a dewatering precipitate.
  • the two-component complex is formed by binding to the basic group of ratatopheline molecule by a high molecular weight acid bond, and the acidic group of ratatopheline becomes free, so the complex as a whole is considered to be a negative charge.
  • the binary complex hydrogen bonds water molecules It is thought that it takes in to form a hydrogel and does not precipitate at high concentrations.
  • the ternary complex a polymer base is formed by ionic bonding to a free acidic group of the binary complex, charge is lost and water molecules are released. It is considered to be in the form of a well-dehydrated precipitate, so that the precipitate fraction and the supernatant fraction will be separated even by natural sedimentation.
  • These complexes are in the form of a powder, for example, through a drying process such as lyophilization or spray drying.
  • the ternary complex is excellent in separation property and drying efficiency, and is advantageous in production.
  • the complex of the present invention is prepared as a powder containing ratatopherin and a polyelectrolyte, and the powder is dispersed in an aqueous solution to form a complex, and the obtained complex is recovered. It can also be manufactured by collecting.
  • a powder containing ratatofuran and a polymeric acid can be prepared, and this powder can be dispersed in an aqueous solution to form a complex.
  • a powder containing extraferrin and a polymeric acid is prepared, this powder is dispersed in an aqueous solution, mixed at normal temperature or under heating, and then containing a polymeric base. The aqueous solution or powder can be added and mixed at normal temperature or under heating to form a complex.
  • a powder containing ratatopheline and a polyelectrolyte may be prepared, for example, by mixing a powder containing lactoferrin and a powder containing a polyelectrolyte at normal temperature or under heating. Can.
  • the powder containing ratatophenin and the powder containing the polymer electrolyte are each coated with a lipid film in advance.
  • the coating with a lipid film may be separately performed before mixing the ratatopherin-containing powder and the polymer electrolyte-containing powder, or may be performed after mixing both powders.
  • ratatopherin in a powder containing ratatopherin is coated with a film (sometimes referred to as “lipid film”) consisting of a film material containing a lipid as a main component, and a polymer
  • lipid film any of fats and oils, waxes and complex lipids may be acceptable as long as they are acceptable for food and medicine use.
  • naturally occurring animal or vegetable fats or oils or Examples thereof include hydrogenated oils (such as hydrogenated beef tallow oil, hydrogenated fish oil, hydrogenated rapeseed oil, hydrogenated soybean oil, hydrogenated palm oil, olive cured oil, and hydrogenated peanut oil).
  • a lipid having a melting point in the range of 30 to 90 ° C. more preferably a lipid having a melting point of 40 to 80 ° C. is used.
  • lipids having similar melting points more preferably, lipids of the same composition are used.
  • the composite of the present invention is a powder containing ratatofurin and a polymer electrolyte, or a mixture of a powder containing ratatopherin and a powder containing a polymer electrolyte (preferably a lipid film).
  • the powder is stored in the form of a mixture of powder containing extra-ferrin particles coated with a powder and powder containing a polyelectrolyte coated with a lipid film, and the powder is dispersed in an aqueous solution at the time of use.
  • the complexes of the present invention can be prepared at the time of use and used.
  • the step of separately preparing the ratatoferrin aqueous solution and the polymer electrolyte aqueous solution can be omitted, and the formation of dams when Z or the powder is dispersed in the aqueous solution can be prevented, and the operability can be improved. It is advantageous.
  • the ratatofelin-containing powder and the polymer electrolyte-containing powder are separately stored in a container, mixed when necessary, and combined with the aqueous solution.
  • the present invention can be provided as a raw material product for preparing a complex of ratatopherin according to the present invention and a polyelectrolyte.
  • the powder containing ratatopherin and the powder containing the polymer electrolyte may be provided as a raw material product which is contained in a container in an already mixed state and, if necessary, combined with an aqueous solution, .
  • powders containing ratatoferin coated with a lipid coating and powders containing a polyelectrolyte coated with a lipid coating are preferred.
  • Recovery of the formed complex can be performed by conventional means.
  • ratatopheline: polymer electrolyte 4: 1 to 1: 4 (weight ratio)
  • ratatopheline: polymer acid 5: 1 to L: 5 (weight ratio)
  • the complex formed by the method as described above, after being recovered from the reaction vessel, is in the form as it is, ie, in the form of a colloidal precipitate, sol or gel, particularly in the form of hydrogel or precipitate.
  • the complexes formed may be further processed to other forms such as powders, emulsified suspensions and the like.
  • the complex formed in the form of a colloidal precipitate is separated by centrifugation or the like, and this complex is further lyophilized, a sol or
  • the formed complex in the form of a gel can be lyophilized as it is.
  • the precipitate collected by centrifugation etc. is freeze-dried and pulverized to form powder, or the binary complex in the form of hydrogel is freeze-dried as it is, It can be milled into powder form.
  • the ratatoferrin complex of the present invention can be used in the form of a powder and further in the form of being enclosed in a capsule, specifically in the form of being enclosed in a microcapsule, a soft capsule or a hard capsule.
  • the capsule of the material of the present invention can be carried out by known microcapsule technology, soft capsule technology, hard capsule technology and the like.
  • the material composition of the present invention may be a complex of various forms as described above, or may be a tablet or a granule with or without the additional component described later in the complex.
  • the latatopherin material composition of the present invention can be made into any form such as pill and the like. Methods of processing to such forms are known in the art of formulation technology.
  • the material composition of the present invention may contain, in addition to the ratatofelin-polyelectrolyte complex, other additional components generally used in the art, Those skilled in the art may appropriately select the type of the components and the amount to be added according to the form of the specific material composition to be manufactured, the application, etc. and the properties of the product to which the material composition is to be applied. it can.
  • plasticizers for example, plasticizers, excipients, emulsifiers, stabilizers; vitamin A, vitamin B, vitamin B, vitamin
  • Vitamins such as Tamine B, Vitamin B, Vitamin C, and Vitamin E; Cozym Q, ⁇ -li Lipid-soluble or water-soluble general nutritional ingredients such as norenic acid, EPA, DHA; medicinal ingredients with analgesic activity such as morphine, codeine, dihydrocodin, cetylmorphine, other medicinal ingredients; and Z or lactic acid bacteria, La Examples include components for improving intestinal flora such as oligosaccharides.
  • Examples of the raw material composition include a raw material composition in the form of powder or granules containing the binary composite (or ternary composite) of the present invention, a basic substance, and a binder.
  • the basic substance referred to here may be a low molecular weight polymer or a high molecular weight substance as long as it has an effect of neutralizing gastric acid and raising the pH to 3 or more when the complex is brought into contact with gastric juice.
  • Specific examples of the basic substance suitable for use in the present invention include soymilk, chitosan, polylysine, polyarginine, polyglutamine, sodium hydrogencarbonate, arginine, glutamine, histidine, lysine, darcosamine, carbonate Sodium etc. are mentioned.
  • the binder may be one generally used, and examples thereof include Tween, shellac, water-soluble soybean polysaccharide, carboxymethylcellulose, alginic acid, guar gum, carboxymethyl cellulose and the like.
  • the basic substance and the binder can be used by appropriately selecting one or two or more kinds.
  • the ratatofu-phosphorus raw material composition of the present invention can be contained in food, medicine, feed and the like.
  • the appropriate content of lactoflavin when it is contained in medicine, food, feed and the like is known.
  • Example 3 Production of a lactoferrin-one strength raginan complex
  • a solution of 6 g of carrageenan (Ina Foods) in 500 mL of pure water is added to a solution of 10 g of ratatofelin (Tatza 'milk' BIO mouth Zix's) in 1 L of pure water, and mixed for 30 minutes. Formed.
  • the obtained gel-like solution was dried as it was with a lyophilizer (Kowa Vacuum Technology Co., Ltd.) to obtain about 14 g of the extraferrin complex of the present invention.
  • the precipitate was dried as it was with a lyophilizer (Kyowa Vacuum Technology Co., Ltd.) to obtain about 1.7 g of the lactoferrin complex of the present invention.
  • Example 5 Production of a capsule containing a lactoferrin material composition
  • Ratatohurin complex in a dry powder form produced in the same manner as in Examples 1 to 4 is used as a ratatopheline raw material composition as it is, 1 part by weight of ratatopheline raw material composition, 10 parts by weight of microcrystalline cellulose, and rapeseed oil 0.5 parts by weight was mixed, and 150 mg of this powder mixture was filled in a node capsule.
  • the capsule can be used as a pharmaceutical composition or a health supplement.
  • Example 6 Production of an ice cream containing a lactoferrin material composition
  • Each of ratatofutorin complex in the form of a dry powder prepared in the same manner as in Examples 1 to 4 was used. As it is, it was used as ratatohuelin raw material composition. A small amount of butter, emulsion stabilizer and flavor was added to 1 L of milk, 300 g of skimmed milk powder, 300 g of sugar and 1 L of water, and after mixing and dissolving, it was homogenized with a homogenizer. An ice cream was prepared by adding 2 g of any ratatopheline material composition and subjecting it to an ice cream freezer.
  • Example 3 1 L of milk, 100 g of skimmed milk powder, 10 g of sugar, ratatopherin complex in dry powder form prepared as in Example 3 (used as it is as a ratatopherin raw material composition) 2 g of butter, stabilizer and flavor added to a small amount of water Then, the mixture was dissolved and homogenized with a homogenizer. It was cooled after heat sterilization at 78 ° C. for 3 minutes and then at 98 ° C. for 2 seconds. After holding at 39 ° C., a lactic acid bacteria starter was added and fermented to prepare yogurt.
  • Example 8 Lactoferrin material for containing pet ⁇ ! Notice of fees
  • Ratatofurin complex in the form of ratatofurin ingredient composition 3g, corn flour 100g, fish meal 30g, yeast extract 10g, beef tallow 2g, soy flour 25g, Fratatooligosaccharide 20g, dextrin 10g, as dried powder form prepared in Example 3.
  • a small amount of sodium chloride was mixed, sufficiently mixed while adding water little by little using a kneader, and granulated with a twin-screw extrusion granulator. Furthermore, the obtained granules were dried at 40 ° C. overnight to produce a pet food.
  • Test, Test Example ⁇ Heat resistance test
  • ratatophein complex 10 mg prepared in Example 1 was dispersed in 10 mM Tris-HCl buffer (pH 7.0) 1. Om, and heated at 80 ° C. for 30 minutes. After heat treatment with heat, centrifugation at 10,000 rpm for 10 minutes was carried out, the precipitate was dissolved in 1 M NaCl, and ratatopherin in the supernatant liquid was analyzed by high performance liquid chromatography to find that it corresponds to about 6 mg ZmL of ratatopherin. Was detected.
  • naked ratatopherin as a control (lactopherin used as a raw material in Example 1 (Tatza 'milk' Bio-Physics Co., Ltd.)) 10 mg of 10 mM Tris-HCl buffer (pH 7.0) 1. Dissolve in O mL, 80 ° Heated at C for 30 minutes. After the formed precipitate was removed by centrifugation, the supernatant liquid was measured for ratatopherin by high performance liquid chromatography, and the peak for ratatopherin was hardly detected. In addition, the precipitate was extracted with 1 M NaCl, and the rat's extract of ratatopheline was measured by high performance liquid chromatography. Foremost was an undetectable force.
  • Test Example 2 Stabilization with gastric juice PH
  • the ratatofurin complex 1 g prepared in Example 1 is dispersed in 100 mL of a model gastric fluid (0.2% sodium chloride, 70 mM HCl, pH 1.2), and left at 37 ° C. for 2 hours, and then the supernatant liquid is recovered at a high speed. It was measured by liquid chromatography. As a result, almost no peak generated by elution of ratatophein was observed, and it was confirmed that the ratatophelin complex of the present invention was stable in gastric juice pH.
  • a model gastric fluid (0.2% sodium chloride, 70 mM HCl, pH 1.2
  • Test, Test Example 3 Stabilizing needle needle for pepsin treatment
  • Example 3 After 0.15 g of the ratatopheline complex prepared in Example 3 is added to 100 g of commercially available plain yoghurt and thoroughly stirred and mixed in a mixer, 500 mg of the mixture is placed in a 1.5 mL Ezbend Ruf tube to obtain 0.4 mg ZmL pepsin solution ( ⁇ 2 ) Carried out at 500 ° C for 30 minutes at 37 ° C. Thereafter, centrifugation (10, OOO rpm, 10 minutes) was performed to recover the supernatant and the precipitate, respectively. The precipitate was dispersed in 500 L of 40 mM deoxycholic acid. SDS-PAGE was performed using this precipitate and the supernatant as samples, and the presence or absence of degradation of ratatopheline was examined.
  • the ratatopheline complex of the present invention is stable to pepsin.
  • 0.1 mg of naked ratatopherin was subjected to the same treatment as above, and the degradation of ratatoferrin was observed in SDS-PAGE.
  • mice Sixteen 5-week-old ICR male mice were randomly divided into two groups of eight each, and a control group was fed with a standard diet for rat 'mouse (CE, 2 from CLEA Japan), and the experimental group was A feed containing 0.2% of ratatopheline complex prepared in the same manner as in Example 1 or 2 was given to CE-2 and the animals were reared for 4 weeks. Body weight was measured every three days during this breeding period.
  • CE rat 'mouse
  • the blood fat content was 25% (P 0 0. 05) and the blood free fatty acid value was 30% (P 0 0. 05), respectively, as determined by oral administration of ratatopheline complex, as measured for blood components. It has dropped significantly.
  • the experimental group to which the ratatofu phosphate material composition was administered showed a tendency to increase the total blood cholesterol level compared to the control group, but the increase was due to the HDL cholesterol strength 0% It became clear that it was because it rose (P ⁇ 0. 01).
  • the ratatophelin raw material composition of the present invention is safe for the living body, and at least exerts the physiological action of Lafrin, which improves lipid metabolism, sufficiently in a small amount.
  • a solution of 5 g of xanthan gum (Taiyo Engineering Co., Ltd.) in 500 mL of pure water is added to a solution of 10 g of ratatofelin (Tatza 'milk', BIOguchi Zix Co., Ltd.) dissolved in 1 L of pure water, Mix for minutes to allow complex formation.
  • the obtained gel was dried as it was with a lyophilizer (Kowa Vacuum Technology Co., Ltd.) to obtain about 14 g of the La complex of the present invention.
  • Example 12 Fat-coated lactoferrin powder and fat-coated CMC sodium powder Preparation of lactoferrin-CMC complex
  • Example 13 Lipid-coated lactoferrin powder and lipid-coated vectin powder as raw materials
  • Example 15 Production of Lactoferrin Xanthan Gum Chitosan Complex Starting from Fat Coated Lactoferrin Powder, Fat Coated Xanthan Gum Powder and Chitosan Mixed powder (Ratatofuerin 60 weight 0/0, xanthan gum 30 weight 0/0 and 10 wt% rapeseed hardened oil) of Ratatofuerin coated with rapeseed hardened oil (Kawaken Fine Chemicals Co., Ltd.) and hexa Ntangamu a 10 g, 0 of LOOmL. The mixture was charged into a mixer containing a 001N lactic acid solution, and stirred and mixed to form a binary complex. Next, 100 mL of a 0.
  • Example 16 Report of Lactoferrin-Pectin-Chitosan Complex Starting from Fat-Coated Lactoferrin Powder, Fat-Coated Vectin Powder, and Chitosan
  • m Production of a lactoferrin- 1-Pectin-acid-soluble soybean protein complex, which is based on a lipid-coated lactoferrin powder, a lipid-coated ⁇ pectin powder, and a highly acceptable protein.
  • ratatopheline 60% by weight, pectin 30% by weight and rapeseed oil 10% by weight are introduced into a mixer containing 1 L of 0.10 N aqueous solution of 001 N citric acid, and the mixture is stirred to mix to form a binary composite (latatopheline- (Pectin complex) was formed.
  • the resulting precipitate is collected by centrifugation and dried with a lyophilizer (Kyowa Vacuum Technology Co., Ltd.), About 120 g of ratatophelin complex of the present invention was obtained.
  • Example 18 Production of a Lactoferrin-Containing Lactoferrin Powder, a Lipid-Coated Vectin Powder and Soymilk The manufacture of a lactoferrin-containing granule
  • Test Example 5 Enteric dissolution test
  • ratatoferin complex (ratatoferin content: 60%) prepared in Example 10 was dispersed in 10 ml of model bile (3 wt% bile (Wako Pure Chemical Industries, Ltd., 50 mM aqueous sodium hydrogen carbonate solution (pH 8)) at 37 ° C. I processed it for 1 hour. After centrifugation, ratatopherin in the supernatant fluid was measured by high performance liquid chromatography, and a peak corresponding to about 5.9 mg ZmL of ratatopherin was detected. As a control, 100 mg of ratatoferrin complex was dispersed in 10 mL of pH 6. 8 (phosphate buffer), treated in the same manner, and ratatopholine in the supernatant fluid was measured by high performance liquid chromatography. It was a force.
  • model bile 3 wt% bile (Wako Pure Chemical Industries, Ltd., 50 mM aqueous sodium hydrogen carbonate solution (pH 8)
  • ratatopherin of the present invention liberates ratatopheline in bile near neutral pH and exhibits enteric solubility, but does not contain bile! /, Ratatopherin near neutral pH liberates It became clear that it was water insoluble.
  • ratatopheline complex prepared in Example 10 in an Eppendorf tube, 1 OmM Tris-HCl buffer (pH 7.0) 1. Add OmL, and block heater (IWAKI; THERM 0 A to UMI BATH) It was heated at 75 ° C. for 30 minutes. After heat treatment with heat, centrifugation at 10,000 rpm for 10 minutes was carried out to dissolve the precipitate in model bile, and ratatopherin of the supernatant fluid was measured by high performance liquid chromatography to find that ratatopherin was about 4.8 mg ZmL (recovery: about 80% The peak corresponding to) was detected.
  • Test Example 7 A sputum-dependent test for pepsin degradation of lactoferrin
  • ratatopherin solution was added to 500 ⁇ L of each pepsin solution of ⁇ and treated at 37 ° C. for 30 minutes.
  • each pH solution not containing pepsin was added and treated in the same manner. After the reaction, centrifugation was performed, and ratatopherin in the supernatant was measured by HPLC.
  • ratatophein-l-pectin-chitosan complex lOOmg prepared in the same manner as in Example 16 had a pH of 2.0, a pH of 3.0, a pH of 3.5, a pH of 4.0, a pH of 4.5, and a pH of 5.0.
  • the solution was dispersed in 5 mL, the pH was measured, and adjusted to each pH.
  • These solutions were covered with 5 mg of 0.4 mg Z mL of pepsin solution of each pH and treated at 37 ° C. for 30 minutes.
  • pepsin solution instead of pepsin solution, each pH solution not containing pepsin was coated and treated in the same manner.
  • the residual rate of ratatophein in pepsin treatment was determined from the ratio of the concentration of residual ratatofurin after pepsin treatment to the concentration of ratatophein in the control at each pH.
  • ratatofulin complex prepared in Example 10 Fifty mg of the ratatofulin complex prepared in Example 10 was dispersed in 5 mL of a 0.2 mg / mL pepsin solution (pH 3, hydrochloric acid) and treated at 37 ° C. for 30 minutes. After centrifugation, the precipitate was extracted with model bile, and the ratatopherin of the extract was measured by high performance liquid chromatography to obtain a peak corresponding to about 3.6 mg ZmL of ratatopherin (about 60% recovery). On the other hand, 50 mg of naked ratatopherin powder is dissolved in 5 ml of 0.2 mg / mL pepsin solution (pH 3, hydrochloric acid), treated at 37 ° C. for 30 minutes, and centrifuged for the supernatant liquid. The peak corresponding to lactoferrin was almost completely degraded.
  • Test Example 9 Heat resistance test, Test (3) 100 mg of the ratatopheline complex prepared in Example 16 was placed in an Eppendorf tube, 1 mL of a 0. 001 N aqueous solution of citric acid was added, and heat treatment was performed at 75 ° C. for 30 minutes using a block heater. After cooling, centrifugation was performed, and 10 mL of model bile was added to the obtained precipitate, and elution was performed at 37 ° C. for 1 hour. Thereafter, centrifugation was carried out, and the lactoferrin in the supernatant liquid was measured by high performance liquid chromatography to obtain a peak corresponding to about 3.3 mg ZmL (recovery rate: 72%) of ratatopherin.
  • Test Test: In Rats: Intestinal Absorption Kinetics Test in Rats
  • naive lactoferrin was dissolved in physiological saline for intragastric administration (300 mg Z kg) in the control group.
  • the extracellular ferritin-containing granules produced in the above were suspended in physiological saline and administered intragastrically (30 mg Z kg of ratatofelin).
  • thoracic duct lymph fluid and venous blood were collected every hour, and ratatoferin was quantified by ELISA method.
  • ratatopheline in plasma was measured, ratatopheline was detected in the plasma in only 1 case out of 5 in the control group and in 3 cases out of 5 in the experimental group (concentration of about 50 to 200 ng ZmL).
  • the complex of the present invention is resistant to digestion in the stomach and has an effect of improving the absorption efficiency of ratatoferrin from the small intestine.
  • Example 19 Raw material of lactoferrin-Pectin complex soymilk powder
  • Ratatopherin-Pectin complex lOOg prepared in the same manner as in Example 13 and prepared soybean milk powder (Fuji Protein Engineering Co., Ltd.) lOOg is placed in a No-speed mixer (Fukae Powder Tech Co., Ltd.), 25 wt% tween (84% by weight ethanol solution containing Showa Sangyo Co., Ltd. (Kouka Chemical Co., Ltd.) (75 g of 84% by weight ethanol in which 25 g of tween is dissolved) 10 g of 10 g was sprayed and granulated. It was dried at 40 ° C. for 8 hours to obtain about 210 g of a raw material composition in the form of granules.
  • Ratatopherin- xanthan gum complex lOOg prepared in the same manner as in Example 9 and conditioned soybean milk powder (Fuji Protein Engineering Co., Ltd.) lOOg was placed in a No-Speed Mixer (Fukae Bowtech Co., Ltd.), and 25 wt. An 84% by weight ethanol solution (Showa Sangyo Co., Ltd.) was mixed and granulated by spraying 100 g of ethanol solution. It was dried at 40 ° C. for 8 hours to obtain about 215 g of a raw material composition in the form of granules.
  • Example 21 A material in the form of granules obtained from a lactoferrin-one pectin complex chitosan
  • Ratatoferin-Pectin complex lOOg prepared in the same manner as in Example 13 and chitosan (Kyowa Technos Co., Ltd.) lOOg are placed in an i-speed mixer (Fukae Powder Technology Co., Ltd.), 25 wt% tween (Showa Sangyo Co., Ltd.) Granulation was carried out by spraying 100 g of an 84% by weight ethanol solution (Sanka Kagaku Co., Ltd.) containing K.K. Dry at 40 ° C for 8 hours to obtain about 21 lg of material composition in granular form
  • i-speed mixer Frukae Powder Technology Co., Ltd.
  • 25 wt% tween Showa Sangyo Co., Ltd.
  • Granulation was carried out by spraying 100 g of an 84% by weight ethanol solution (Sanka Kagaku Co., Ltd.) containing K.K. Dry at 40 ° C for 8 hours to obtain about 21 lg of material
  • Example 22 Production of a complex of a chew-shaped bear made from La ferella ferin-Xanthan gum complex and chitosan
  • Ratatopheline-Xanthan gum complex lOOg prepared in the same manner as in Example 9 and Kitosan (Kohan Technos Co., Ltd.) lOOg are placed in a speed mixer (Fukae Powder Tech Co., Ltd.), 25 wt% tween (Showa Sangyo The solution was granulated by spraying 1 OOg of an 84 wt% ethanol solution (Sanka Chemical Co., Ltd.) containing Drying at 40 ° C. for 8 hours gave about 210 g of a complex in the form of granules
  • Example 23 Preparation of chewable particulate form using a complex of exo-ferin, 1-pectin-chitosan and chitosan
  • Example 24 Lactoferrin-Pectin-Chitosan Complex ⁇ 3 ⁇ 4, Powder Preparation of Granule Particles 3 ⁇ 4
  • Ratatoferin- 1-Pectin-chitosan complex lOOg prepared in the same manner as in Example 16 and prepared soymilk powder (Fuji Protein Engineering Co., Ltd.) lOOg was placed in a No-Speed Mixer (Fukae Bauttech Co., Ltd.), An 84% by weight ethanol solution containing Twain (Showa Sangyo Co., Ltd.) was granulated by spraying 100 g of a 100 g ethanol solution. It was dried at 40 ° C. for 8 hours to obtain about 210 g of a material composition in the form of granules.
  • Example 25 Powdered powder made from a complex of exo-ferin, pectin-chitosan and chitosan as raw materials
  • Example 26 13 ⁇ 4% of the grain-shaped particles made from the exo-pherin-pectin-chitosan complex and chitosan
  • Ratatopherin- 1-Pectin-chitosan complex lOOg and chitosan 100g prepared in the same manner as in Example 16 were placed in an I-speed mixer (Fukae Powder Technology Co., Ltd.), and 30% by weight shellac ( It was granulated by spraying 100 g of an anhydrous ethanol solution containing Gifu Shellac Co., Ltd.). It was dried at 40 ° C. for 8 hours to obtain about 210 g of a raw material composition in the form of granules.
  • Test Example 12 Stability against pepsin treatment (4)
  • EXAMPLE 1 100 mg of ratatopherin-xanthan gum complex prepared in the same manner as in Example 9 was dispersed in 5 mL of a pH 3.5 solution, and the pH was measured and adjusted to pH 3.5. This solution was covered with 5 mL of 0.4 mg / mL pepsin solution (pH 3.5) and treated at 37 ° C. for 30 minutes. As a control, instead of pepsin solution, pH 3.5 solution was added and treated similarly. After the reaction, centrifugation was performed to recover the supernatant and the precipitate. The precipitate was dissolved in 10 mL of model bile and centrifuged to collect supernatant. The concentration of ratatopherin in the above sample was measured by HPLC.
  • the residual rate of ratatopheline in the ratatopheline complex at pepsin treatment at pH 3.5 was about 80%. Therefore, it has been revealed that the ratatophelin complex of the present invention is pepsin-quenching.

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Abstract

L'invention concerne un complexe lactoférrine qui possède une excellente stabilité au stockage en présence de l'eau grâce aux améliorations dans la stabilité de la lactoférrine en présence d'eau et de liquide gastrique, sa solubilité dans le tube intestinal et sa stabilité thermique pendant un traitement thermique dans un système aqueux, dans lequel la lactoférrine peut accéder au tube intestinal sans être digérée par la pepsine contenu dans le liquide gastrique et est efficacement absorbée in vivo pour exercer toute son activité physiologique, et qui peut être avantageusement employée dans une étape thermique comme la pasteurisation thermique dans la production d'aliments, de médicaments, d'aliments pour animaux, etc.; une composition matérielle contenant le complexe; et une méthode pour produire ce complexe. Ce complexe lactoférrine est un complexe de lactoférrine avec un électrolyte de haut poids moléculaire.
PCT/JP2005/014623 2004-08-10 2005-08-10 Complexe de lactoférine et méthode pour le produire WO2006016595A1 (fr)

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