WO2016117525A1 - リン吸収抑制用組成物 - Google Patents
リン吸収抑制用組成物 Download PDFInfo
- Publication number
- WO2016117525A1 WO2016117525A1 PCT/JP2016/051353 JP2016051353W WO2016117525A1 WO 2016117525 A1 WO2016117525 A1 WO 2016117525A1 JP 2016051353 W JP2016051353 W JP 2016051353W WO 2016117525 A1 WO2016117525 A1 WO 2016117525A1
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- composition
- present
- bone
- phosphorus
- ppi
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Classifications
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
- A23C9/00—Milk preparations; Milk powder or milk powder preparations
- A23C9/12—Fermented milk preparations; Treatment using microorganisms or enzymes
- A23C9/13—Fermented milk preparations; Treatment using microorganisms or enzymes using additives
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
- A23C19/00—Cheese; Cheese preparations; Making thereof
- A23C19/06—Treating cheese curd after whey separation; Products obtained thereby
- A23C19/068—Particular types of cheese
- A23C19/076—Soft unripened cheese, e.g. cottage or cream cheese
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/20—Milk; Whey; Colostrum
Definitions
- the present invention relates to a composition for suppressing phosphorus absorption, comprising fermented milk products and oligosaccharides as active ingredients.
- the present invention also relates to a composition for treating or preventing a disease caused by excessive phosphorus uptake, which contains fermented milk products and oligosaccharides as active ingredients.
- Proton pump inhibitor a potent gastric acid secretion inhibitor
- PPI Proton pump inhibitor
- GOS is an indigestible carbohydrate that is difficult to digest in the small intestine and ferments in the large intestine.
- PPI was subcutaneously administered in a short period of time
- the combination of lactic acid bacteria fermented product and GOS was orally administered in a short period of time, thereby absorbing calcium. It was reported that the bone strength was further improved (Non-patent Document 2).
- the present inventors administered PPI subcutaneously for a long period of time, and when the combination of lactic acid bacteria fermented product and GOS was administered for a long period of time in a state where the secretion of gastric acid was decreased (the pH of gastric juice was increased), The effect of this deteriorated phosphorus on metabolism was examined experimentally.
- the present invention is composed of (nutrition) ingredients that have been proven to be excellent in safety and taste from a long dietary experience, and can be ingested over a long period of time.
- Fermented lactic acid bacteria (fermented milk products) and GOS It is an object of the present invention to provide a composition for treating or preventing osteoporosis containing a combination as an active ingredient, and a composition for improving phosphorus metabolism (particularly for suppressing excessive phosphorus uptake). To do.
- Another object of the present invention is to provide a composition for treating or preventing a disease caused by excessive phosphorus uptake, which contains a combination of a fermented lactic acid bacterium and GOS as an active ingredient.
- the present inventors have conducted intensive research to solve the above-mentioned problems. Specifically, the combination of lactic acid bacteria fermented products (fermented dairy products) and GOS for a long period of time in rats with PPI administered and gastric acid secretion decreased and in a healthy state without PPI administration. Orally administered, the effects on phosphorus metabolism, calcium metabolism, bone strength, etc. were studied experimentally. As a result, in rats, the combination of fermented dairy products and GOS was orally administered over a long period of time, resulting in increased bone strength, both in a state of reduced gastric acid secretion and in a healthy state. Clarified about what to do.
- a composition for suppressing phosphorus absorption comprising fermented milk products and oligosaccharides as active ingredients.
- oligosaccharide is an oligosaccharide containing galactose as a constituent sugar.
- composition according to [2] wherein the oligosaccharide is a galactooligosaccharide.
- the composition of the present invention can suppress an increase in phosphorus absorption accompanying a decrease in gastric acid secretion. Therefore, oral administration of the composition of the present invention (which may also include the concept of enteral administration) suppresses an increase in phosphorus absorption in subjects with decreased gastric acid secretion, such as the elderly. Can improve metabolic abnormalities and return excessive phosphorus uptake to the normal range. In addition, by orally administering the composition of the present invention, diseases caused by excessive phosphorus uptake can be improved (treatment, prevention, etc.).
- the composition of the present invention contains fermented dairy products and oligosaccharides, which have been proven to be excellent in safety and taste from a long dietary experience, so there are no problems of side effects. Can be administered orally over a long period of time.
- the present invention provides a composition for suppressing phosphorus absorption, which contains fermented milk products and oligosaccharides as active ingredients.
- the present invention also relates to a composition for treating and / or preventing a disease caused by excessive phosphorus uptake, comprising fermented milk products and oligosaccharides as active ingredients. Excessive uptake of phosphorus into the body is caused, for example, by an increase in pH due to a decrease in gastric acid secretion.
- the composition of the present invention significantly suppresses excessive phosphorus uptake into the body caused by an increase in pH due to a decrease in gastric acid secretion, and improves abnormalities in phosphorus metabolism.
- the composition for suppressing phosphorus absorption of the present invention can also be expressed as a composition for suppressing absorption of phosphorus, a phosphorus absorption inhibitor, and the like.
- the composition for suppressing phosphorus absorption of the present invention can be orally administered to a subject whose gastric acid secretion is decreased and / or a subject whose gastric juice pH is increased. That is, the present invention relates to a composition for suppressing phosphorus absorption, which is used for administration to a subject having decreased secretion of gastric acid and / or a subject having increased pH of gastric juice.
- the composition for suppressing phosphorus absorption according to the present invention is a composition for suppressing phosphorus absorption containing fermented milk products and oligosaccharides as active ingredients, and the secretion of gastric juice is reduced in the subject of administration (intake).
- “administration” can also be referred to as “intake”.
- whether or not the secretion of gastric acid has decreased can be determined by measuring the pH of gastric juice. That is, the pH of gastric juice is measured, and when the pH is increased, it can be determined that the secretion of gastric acid has decreased.
- subjects whose gastric acid secretion is decreased and / or subjects whose gastric fluid pH is increased are preferably subjects whose gastric fluid pH is preferably 9 to 2, more preferably 8 to 2, even more preferably 7 to 2. It can mention, but it is not limited to these.
- the method of measuring the pH of gastric juice is well known to those skilled in the art. For example, a method of measuring by inserting a wired micro-pH glass electrode into the stomach nasally (Pharma.
- Examples of the subject whose gastric acid secretion is decreased and / or the subject whose pH of gastric juice is increased include a subject who orally administered PPI for a long period of time. That is, the composition for suppressing phosphorus absorption of the present invention can be used for oral administration to subjects who have been orally administered PPI for a long period of time.
- Other examples of subjects whose gastric acid secretion has decreased and / or whose gastric juice pH has increased include elderly people, gastrectomy patients, H2 blocker-administered patients, and the like.
- examples of the long term include, but are not limited to, preferably 1 week or more and 30 years or less, more preferably 2 weeks or more and 20 years or less, and further preferably 3 weeks or more and 10 years or less.
- the suppression of phosphorus absorption refers to a decrease in phosphorus uptake into the body, and can also be expressed as "improving a state where phosphorus is excessively absorbed into the body".
- the composition for suppressing phosphorus absorption of the present invention can be used for the treatment or prevention of diseases caused by excessive phosphorus uptake (diseases caused by enhanced absorption of phosphorus).
- the composition for treating and / or preventing a disease caused by excessive absorption of phosphorus comprising the fermented milk product of the present invention and an oligosaccharide as active ingredients, is a composition for treating a disease caused by excessive phosphorus uptake. It can also be expressed as a (drug) agent for treatment and / or prevention.
- the composition for the treatment and / or prevention of diseases caused by excessive phosphorus uptake of the present invention is orally administered to a subject having decreased gastric acid secretion and / or a subject having increased gastric fluid pH. be able to.
- the present invention relates to treatment and / or prevention of diseases caused by excessive phosphorus uptake, which are used for oral administration to subjects with decreased secretion of gastric acid and / or subjects with increased pH of gastric juice. It relates to a composition for one side.
- the composition for treatment and / or prevention of diseases caused by excessive phosphorus uptake according to the present invention is a composition resulting from excessive phosphorus uptake containing fermented milk products and oligosaccharides as active ingredients.
- a composition for treatment and / or prevention of a disease wherein in the subject of administration (intake), whether secretion of gastric juice is decreased and / or pH of gastric juice is increased
- intake in the subject of administration
- a method comprising a step of determining whether or not It can also be expressed as a “composition of”.
- “disease caused by excessive phosphorus uptake” can be expressed as “disease caused by excessive intake of phosphorus”, “disease caused by increased absorption of phosphorus”, and the like.
- the “disease caused by excessive phosphorus uptake” is preferably caused by absorption of phosphorus due to a decrease in gastric acid secretion, an increase in gastric pH, long-term (oral) administration of PPI, or the like. Although it becomes excessive and the disease which arises by it can be mentioned, It is not limited to these. That is, more specifically, as a disease that develops due to excessive uptake of phosphorus caused by decreased secretion of gastric acid, increased pH of gastric juice, or long-term administration of PPI, cardiovascular disease Examples include, but are not limited to, ectopic calcification and osteoporosis.
- the present inventors have found that excessive intake of phosphorus can be suppressed by orally ingesting fermented milk products and oligosaccharides over a long period of time. Therefore, the composition of the present invention can be used daily for a long period of time for subjects who need it (particularly subjects whose gastric acid secretion is decreased, subjects whose gastric juice pH is increased, subjects who have been administered PPI for a long period of time). Can be administered orally. That is, the present invention relates to a composition for suppressing phosphorus absorption, which is used for daily oral administration to a subject in need thereof for a long period of time.
- the present invention also provides a composition for the treatment and / or prevention of diseases caused by excessive phosphorus uptake, which is used for daily oral administration over a long period of time to a subject in need thereof.
- the long term period is, for example, preferably 1 week or longer, more preferably 2 weeks, still more preferably 3 weeks or longer (for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 weeks).
- the present invention is not limited to these.
- the composition of the present invention contains fermented dairy products and oligosaccharides, which have been proven to be excellent in safety and taste from a long dietary experience, so there are no problems of side effects. Can be administered orally over a long period of time. Therefore, in the present invention, there is no upper limit on the period of administration, but for example, it is preferably 30 years or less, more preferably 20 years or less, and even more preferably 10 years or less. Not.
- oligosaccharide refers to oligosaccharide and refers to a compound in which 2 to 20 sugars are glycosidically bonded.
- examples of oligosaccharides include dairy oligosaccharide, isomaltooligosaccharide, fructooligosaccharide, galactooligosaccharide, xylo-oligosaccharide, soybean oligosaccharide, nigerooligosaccharide, gentio-oligosaccharide, lactose, sucrose, maltose, trehalose, palatinose and the like. Can be, but is not limited to.
- the composition of this invention is acidic, it is preferable to use the oligosaccharide of the property which does not produce attenuation
- an oligosaccharide such as a galactooligosaccharide
- An oligosaccharide containing galactose as a constituent saccharide refers to a compound in which 2 to 20 saccharides are glycoside-bonded, and the saccharide constituting this compound includes one or a plurality of galactoses.
- Galactooligosaccharides are known as sugars that are contained in breast milk and have the effect of increasing the number of bifidobacteria in the intestine and are difficult to digest and absorb.
- Galactooligosaccharide is produced by the action of “ ⁇ -galactosidase ( ⁇ -D-galactoside galactohydrolase, EC3.2.1.23, cryptococcus yeast) from lactose, in the standard of food for specified health use (standard standard type) system.
- ⁇ -galactosidase ⁇ -D-galactoside galactohydrolase, EC3.2.1.23, cryptococcus yeast
- the galactooligosaccharide is not particularly limited as long as it meets this definition.
- Galactoligosaccharide can be obtained by a commercial (industrial) production method. And, as a method for producing galactooligosaccharide, for example, there can be mentioned a method in which lactose is allowed to act on ⁇ -galactosidase (mainly derived from microorganisms such as Cryptococcus laurentii, Bacillus circulans, etc.) having a high ability to transfer galactose (Sayairi Hayato, The function of galactooligosaccharide and its application to food, FOODSTYLE (21, 1998, 2, 76-78) are not limited to this.
- ⁇ -galactosidase mainly derived from microorganisms such as Cryptococcus laurentii, Bacillus circulans, etc.
- FOODSTYLE The function of galactooligosaccharide and its application to food, FOODSTYLE (21, 1998, 2, 76-78) are not limited to this.
- the composition of the present invention is partly prepared using a fermented milk product.
- the fermented milk product is obtained by fermenting milk or milk containing non-fat milk solid content of the same degree using lactic acid bacteria, bifidobacteria, propionic acid bacteria, etc. (starter, etc.).
- milk or milk containing non-fat milk solid content of the same degree as this for example, livestock milk (whole milk) such as cow's milk, buffalo milk, goat milk, sheep milk and horse milk, these Partial skim milk, skim milk, reduced full fat milk, reduced partial skim milk, reduced skim milk, full fat milk powder, partial skim milk powder, skim milk powder, full fat concentrated milk, partial skim milk concentrate, skim concentrated milk, casein, whey , Whey protein, whey related products (whey protein concentrate (WPC), whey protein isolate (WPI), etc.), milk protein concentrate (MPC), butter, buttermilk, cream, etc.
- livestock milk whole milk
- cow's milk buffalo milk, goat milk, sheep milk and horse milk
- these Partial skim milk skim milk, reduced full fat milk, reduced partial skim milk, reduced skim milk, full fat milk powder, partial skim milk powder, skim milk powder, full fat concentrated milk, partial skim milk concentrate, skim concentrated milk, casein, whey , Whey protein,
- the fermented milk product is preferably fermented milk (such as yogurt), cheese (such as aged cheese, non-aged cheese (fresh cheese), or processed cheese), cheese food, or whey (whey) fermented product. More preferred are fermented milk and cheese, still more preferred are yogurt and non-aged cheese, and particularly preferred is yogurt, but is not limited thereto.
- whey-related products include concentrated whey with concentrated whey, whey powder with dried whey, and major whey proteins after being concentrated by ultrafiltration (UF).
- Whey Protein Concentrate hereinafter also referred to as “WPC”
- Whey protein isolate Whey Protein Isolate: hereinafter
- Whey Protein isolate was obtained by selective fractionation of the main protein of whey (low fat / high protein), whey, etc. by ion-exchange resin method or gel filtration method Desalted by desalting after desalting by nanofiltration (NF), electrodialysis, etc.
- Milk protein concentrate (Milk-Protein-Concentrate: hereinafter also referred to as "MPC") obtained by concentrating skim milk by the MF method or the UF method and drying is similar to WPC and WPI. The amount is reduced and the amount of casein and whey protein is relatively enhanced.
- fermented milk means “milk or milk containing non-fat milk solids equivalent to or higher than this is fermented with lactic acid bacteria or yeast, pasty or liquid, or frozen. (Ministry Ordinance Article 38, No. 38 on ingredient standards for milk and dairy products).
- fermented milk is not particularly limited as long as it is included in this definition.
- cheese means “milk, milk containing a non-fat milk solid content equal to or higher than this, or liquid milk prepared by combining two or more kinds with fermentation, enzyme addition or acid addition. And the whey removed from the resulting curd ”.
- the cheese may be either solidified or non-solidified.
- the cheese may be either a matured product (aged cheese) or a non-aged product (non-aged cheese).
- lactic acid bacteria belonging to the genus Lactobacillus, Streptococcus, Lactococcus, Leuconostoc, Pediococcus, etc. can be used, preferably the Lactobacillus genus, Streptococcus genus, Lactic acid bacteria belonging to the genus Lactococcus can be used, and more preferably, lactic acid bacteria belonging to the genus Lactobacillus and Streptococcus can be used, but are not limited thereto. More specifically, Lactobacillusobadelbrueckiibrusubsp.
- Lactobacillus delbrueckii subsp More preferably, Lactobacillus delbrueckii subsp.
- Bulgaricus, Lactobacillus gasseri, Lactobacillus helveticus, Lactobacillus plantarum, Streptococcus thermophilus, Lactococcus lactis, Lactococcus cremoris, more preferably Streptococcus thermophilus can be used, and particularly preferably, Lactobacillus delbrueckii subsp.
- Bulgaricus, Streptococcus thermophilus can be used. I can't. And in this invention, these microorganisms (starter) can be used combining 1 type (s) or 2 or more types.
- fermented milk such as yogurt
- cheese can also be obtained using a well-known manufacturing method.
- the composition (mass unit) can include, for example, a total solid content of 17 to 19%, a protein of 11 to 13%, a fat of 1% or less, and a carbohydrate of 2 to 8%. However, it is not limited to this.
- compositions of the present invention are usually prepared as a mixture of oligosaccharides, fermented dairy products, and other optional ingredients, for example, those divided into those containing oligosaccharides and those containing fermented dairy products. It may be prepared in the form of When prepared in a form divided into those containing oligosaccharides and those containing fermented milk products, it is desirable to administer those containing oligosaccharides and those containing fermented milk products simultaneously (orally).
- the concentration of oligosaccharide contained in the total solid content (100% by mass) is preferably 0.1 to 10% by mass, more preferably 0.2 to 8% by mass, still more preferably 0.3 to 6% by mass, Particularly preferred is 0.4 to 6% by mass.
- the concentration of the fermented milk product contained in the total solid content (100% by mass) is preferably 5 to 98% by mass, more preferably 10 to 97% by mass, and further preferably 15 to 96%. % By mass, particularly preferably 18 to 96% by mass.
- the total solid content means the mass (including the mass of liquid fats and oils) after being dried in a desiccator at 20 ° C. in a dry atmosphere (of powder feed) It does not mean the mass of such a water-containing solid content).
- the administration (intake) amount of the oligosaccharide is preferably 0.1 mg to 2 g, more preferably 0.5 mg to 1.5 g, still more preferably 1 mg to 1 g in solid content per kg body weight per day. 1 g, particularly preferably 5 mg to 0.5 g.
- the composition of the present invention is preferably 100 mg to 10 g, more preferably 200 mg to 7.5 g, still more preferably 300 mg in solid content per kg body weight per day as the administration (intake) amount of fermented dairy products. -5 g, particularly preferably 500 mg to 2.5 g.
- the amount of oligosaccharide administered to a human in terms of solid content per day is preferably 0.01 to 20 g, more preferably 0.05 to 15 g, still more preferably 0.1 to 10 g, particularly preferably. 0.5g to 5g.
- the composition of the present invention has a solid content per day, preferably 1 g to 100 g, more preferably 2 g to 75 g, still more preferably 3 g to 50 g, particularly preferably as a dosage of fermented dairy products to humans. 5g to 25g.
- composition of the present invention can be administered to a subject (patient or the like) in need of administration in a lump sum, before meals, after meals, between meals and / or before going to bed, etc., or divided and administered. You can also In addition, since the composition of the present invention can individually determine the dose according to the age, body weight, and administration purpose of the subject (patient etc.) requiring the administration, the dose is not necessarily as described above. It is not limited within the numerical range.
- the mass ratio of fermented dairy product / oligosaccharide is preferably 1 to 49, more preferably 1 to 30, still more preferably 2 to 9, and particularly preferably 3 to 8.
- the composition of the present invention includes pharmaceuticals (pharmaceutical compositions, nutritional pharmaceutical compositions, drugs, enteral nutritional agents, pharmaceutical additives, etc.), foods and beverages (food and beverage compositions, nutritional compositions, special-purpose foods, nutritional functional foods). , Health foods, food additives (food additives, etc.), cosmetics and the like.
- the composition of the present invention can be used by adding (compounding) to pharmaceuticals, foods and drinks, cosmetics, etc. and / or used in combination with pharmaceuticals, foods and drinks, cosmetics and the like. Thereby, it is possible to impart a phosphorus absorption inhibitory effect and a therapeutic effect and / or a preventive effect on diseases caused by excessive phosphorus uptake to pharmaceuticals, foods and drinks, cosmetics and the like.
- composition of the present invention When the composition of the present invention is used as a medicine (form of a medicine), it can be administered in various forms.
- administration form include oral administration or enteral administration (nasal tube, gastric fistula, intestinal fistula, etc.) of pharmaceuticals such as enteral nutrients and liquids.
- the composition of the present invention can be processed into a tablet, capsule, granule, powder, syrup preparation or the like for administration.
- the main ingredients are excipients, binders, disintegrants, lubricants, flavoring agents, solubilizers, suspension agents, coating agents, solvents, isotonic agents.
- compositions examples thereof include, but are not limited to, those produced using known adjuvants in the technical field of pharmaceutical preparations such as These various preparations may contain an appropriate amount of calcium, and may further contain an appropriate amount of vitamins, minerals, organic acids, sugars, amino acids, peptides, and the like.
- the dose and administration method can be appropriately selected according to the age, weight, administration purpose (symptoms), etc. of the subject (patient etc.) requiring the administration. it can.
- the effective dose of the composition of the present invention is, for example, 5 mg ⁇ 1500 mg, preferably 10 mg to 1000 mg, more preferably 20 mg to 750 mg, more preferably 30 mg to 500 mg, in particular, per kg body weight at a time.
- it can be appropriately selected from 50 mg to 250 mg.
- the effective dose of the composition of the present invention per patient is, for example, 0.5 g to 150 g, preferably 1 g to 100 g, more preferably 2 g to 75 g, still more preferably 3 g to 50 g, particularly preferably per patient.
- the composition of the present invention is, for example, 5 mg to 1500 mg, preferably 10 mg to 1000 mg, more preferably 20 mg to 750 mg, more preferably 30 mg to 500 mg per kg body weight at a time as an effective dose and administration method.
- composition of the present invention can be administered to a subject (such as a patient) in need of administration in a lump sum, before meal, after meal, between meals and / or before going to bed, etc. It can also be administered.
- the composition of the present invention can individually adjust the number of effective administrations according to the state of each subject while observing the state after actual administration to the subject and the trend of blood tests. it can.
- the composition of the present invention When using the composition of the present invention as a food or drink (in the form of a food or drink), it can be taken in various forms.
- the ingestion form include oral intake or enteral intake (eg, nasal tube, gastric fistula, intestinal fistula) of foods and drinks such as dairy products and liquid foods.
- the composition of the present invention can be processed and ingested into liquid, pasty, solid, powdered and other foods and beverages, and actually added (mixed) to various foods and beverages. And / or in combination with various foods and drinks.
- these foods and beverages preferably, water, beverages, confectionery (including desserts, etc.), dairy products, liquid foods (including foods and beverages with high nutritional value), infant formulas, instant foods, More preferably water, beverages, confectionery, dairy products, liquid foods, infant formula, more preferably confectionery, dairy products, liquid foods, particularly preferably dairy products, It is not limited to these. That is, more specifically, milk, soft drinks, fermented milk, yogurt, cheese, bread, biscuits, crackers, pudding, jelly, ice cream, pizza crust, prepared milk powder, liquid food, food for the sick, nutritional food, Examples include frozen foods, food compositions, processed foods, and other commercially available foods. These various foods and drinks can also be provided as meals at various schools, nursing homes, and welfare facilities.
- the intake amount and intake method can be appropriately selected. It is preferable that the active ingredient can be taken orally directly as it is.
- the composition of the present invention includes dairy products, liquid foods, and the like as forms thereof, but may be, for example, a fruit juice type beverage, a milk shake type beverage, or the like. It may be a powdered food that can be dissolved and dispersed in water or the like.
- the composition of the present invention has an effective intake amount of solid content per day, for example, 0.5 g to 150 g, preferably 1 g to 100 g, more preferably 2 g to 75 g, still more preferably 3 g to 50 g, Particularly preferred is 5 to 25 g.
- the composition of the present invention can be administered to a subject who needs to take it in a lump sum, before meals, after meals, between meals and / or before going to bed, etc., or in divided doses. it can.
- the composition of the present invention can be used as a substitute for meals, or can be used as a supplement to meals.
- the composition of the present invention When the composition of the present invention is used as a medicine or a food or drink, it can be produced by a method well known to those skilled in the art. If it is an expert, the mixing process of mixing the composition of this invention or its processed material with another component, a sterilization process, a fermentation process, a concentration process, a shaping
- the pH can be set to 2 to 6, for example, preferably 3 to 5.
- composition of the present invention when used as various dairy products, it can be produced by methods well known to those skilled in the art.
- yogurt a preparation process for a starter for culturing lactic acid bacteria, and if necessary, blending (adding) galactooligosaccharide, then mixing raw ingredients such as milk ingredients, and mixing the starter with the raw milk Fermentation process to hold at a predetermined temperature, cooling process to lower the fermented milk to a predetermined temperature, and mixing process to mix the galactooligosaccharide after crushing or atomizing the fermented milk as necessary
- it can be produced by a method that undergoes a flavoring step, a filling step, and the like in which a fragrance or a flavor substance is blended.
- a starter for example, a mixture of lactic acid bacteria belonging to the genus Lactobacillus and lactic acid bacteria belonging to the genus Streptococcus can be used, and a mixture of Lactobacillus delbrueckii subsp. Bulgaricus and Streptococcus thermophilus can be preferably used.
- the preparation process of the starter as described above, the preparation process of the raw material milk as described above, the fermentation process as described above, the production process of the cheese curd containing the rennet, the cutting process of the cheese curd, the cheese It can be produced by a method that goes through a whey discharging process, a salting process, an aging process, and the like.
- lactic acid bacteria belonging to the genus Lactobacillus can be used as the starter, and preferably, Lactobacillus delbrueckii subsp. Bulgaricus, Lactobacillus helveticus can be used.
- the nutritional composition can be adjusted by further adding additional nutrients.
- additional nutrients include proteins, carbohydrates, lipids, peptides, amino acids, dietary fiber, vitamins, minerals, organic acids, organic bases, fruit juices, flavors, artificial sweeteners (eg, aspartame, etc.) ) Etc. can be used.
- the protein for example, full milk powder, skim milk powder, partially skim milk powder, full fat concentrated milk, skim concentrated milk, partially skimmed concentrated milk, casein, whey powder, whey protein, whey protein concentrate, whey protein isolate , ⁇ -casein, ⁇ -casein, ⁇ -casein, ⁇ -lactoglobulin, ⁇ -lactalbumin, lactoferrin, soy protein, egg protein, meat protein, etc., and their degradation products, butter, cream, whey, whey minerals
- milk-derived components such as non-protein nitrogen, sialic acid, phospholipid, and lactose can be used.
- sugars for example, sugars such as sucrose, glucose, fructose and honey, processed starches (dextrin (maltodextrin, resistant dextrins, etc.), soluble starch, British starch, oxidized starch, starch ester, starch ether Etc.), dietary fiber, etc. can be used.
- fat for example, lard, fish oil, etc.
- these fractionated oils, hydrogenated oils, transesterified oils and other animal fats palm oil, safflower oil, corn oil, rapeseed oil, coconut oil, these fractionated oils
- Vegetable oils such as hydrogenated oils and transesterified oils can be used.
- a champignon extract having a fecal odor reducing effect is, for example, 0.005 to 0.5% by weight
- a carotenoid preparation having a nutrition enhancing effect for example, ⁇ -carotene, ⁇ -carotene, lycopene
- Including lutein can be blended (added) at 0.00001 to 0.0002% by weight, for example.
- catechin, polyphenol, etc. can also be mix
- carnitine having an effect of enhancing lipid metabolism can be added.
- Carnitine is a biological trace component made from lysine and methionine in the liver and kidney, and its production amount is known to decrease with age. Carnitine has been shown to play an important role in the metabolism of nutrients, such as the delivery of long-chain fatty acids to muscle cells.
- Dietary fiber is classified into water-soluble dietary fiber and insoluble dietary fiber, and both can be used.
- the indigestible oligosaccharides lactulose, lactitol, and raffinose can be used.
- Physiological functions of indigestible oligosaccharides include the effect of improving the intestinal environment by reaching the large intestine as it is undigested, contributing to the activation and proliferation of intestinal bifidobacteria.
- Lactulose is a synthetic disaccharide composed of galactose and fructose and is used as a basic drug for the treatment of hyperammonemia (Bircher, J. et al., Lancet i: 890, 1965).
- Lactitol ( ⁇ -galactosyl-sorbitol) is the second generation of lactulose and is comparable to lactulose in clinical effects of chronic hepatic encephalopathy (Lanthier, PL. And Morgan, M., Gut, 26 : 415, 1985; Uribe, M., et al., Dig. Dis. Sci., 32: 1345, 1987; Heredia, D. et al., J. Hepatol, 7: 106, 1988; patRiggio, O., et al., Dig. Dis. Sci., 34: 823, 1989), used as a drug for the treatment of hyperammonemia.
- pectin protopectin, pectinic acid, pectinic acid
- guar gum enzyme degradation products tamarind seed gum, etc. that have an effect of improving lipid metabolism (lowering action of cholesterol and lowering of neutral fat)
- the guar gum enzyme degradation product has been shown to have an inhibitory effect on the increase in blood glucose level and an insulin saving effect (Kazuhiko Yamatoya et al., Journal of Japanese Society of Nutrition and Food, 46: 199, 1993).
- water-soluble dietary fiber konjac glucomannan, alginic acid, low-molecular alginic acid, psyllium, gum arabic, seaweed polysaccharide (cellulose, lignin-like substance, agar, carrageenan, alginic acid, fucodyne, laminarin) ), Microbial gums (welan gum, curdlan, xanthan gum, gellan gum, dextran, pullulan, lamb gum), other gums (seed-derived locust bean gum, tamarind gum, tara gum, sap-derived Karaya gum, tragacanth gum), etc.
- polydextrose, indigestible dextrin, maltitol and the like can be used.
- cellulose, hemicellulose, lignin, chitin, chitosan, soybean dietary fiber, wheat bran, pine fiber, corn fiber, beet fiber, etc. can be used as insoluble dietary fiber.
- insoluble dietary fiber As a physiological function of insoluble dietary fiber, there is an effect of increasing the number of defecations and increasing the amount of stool by increasing the amount of indigestible material in the large intestine and shortening the passage time.
- vitamins for example, vitamin A, carotene, vitamin B group, vitamin C, vitamin D group, vitamin E, vitamin K group, vitamin P, vitamin Q, niacin, nicotinic acid, pantothenic acid, biotin, inositol, choline, Folic acid or the like can be used.
- vitamins for example, vitamin A, carotene, vitamin B group, vitamin C, vitamin D group, vitamin E, vitamin K group, vitamin P, vitamin Q, niacin, nicotinic acid, pantothenic acid, biotin, inositol, choline, Folic acid or the like can be used.
- vitamins for example, vitamin A, carotene, vitamin B group, vitamin C, vitamin D group, vitamin E, vitamin K group, vitamin P, vitamin Q, niacin, nicotinic acid, pantothenic acid, biotin, inositol, choline, Folic acid or the like can be used.
- vitamins for example, vitamin
- minerals for example, calcium, potassium, magnesium, sodium, copper, iron, manganese, zinc, selenium and the like can be used, and trace elements derived from natural products, for example, copper, zinc, selenium, manganese of mineral yeast Further, chromium, copper gluconate, zinc glucone and the like can also be used.
- organic acids that can be used include malic acid, citric acid, lactic acid, and tartaric acid.
- both chemically synthesized components and components derived from natural products can be used.
- the foodstuff containing the target component can also be mix
- These components can be used by blending at least one or a combination of two or more.
- the composition of the present invention has an osmotic pressure of, for example, 300 to 1000 ⁇ mOsm / L, preferably 300 to 750 ⁇ mOsm / L.
- the viscosity is, for example, 1 to 40 ⁇ cp (mPa ⁇ s), preferably 3 to 20 ⁇ cp.
- the composition of the present invention has, for example, 0.5 to 3 kcal / mL as calories, preferably 1 to 2.5 kcal / mL, more preferably 1 to 2 kcal / mL.
- the form of the composition of the present invention may be solid, liquid, gel or semi-solid.
- the composition of the present invention can be produced by a known method in the fields of beverages, dairy products, liquid foods and enteral nutrients.
- the composition (raw material liquid) is preliminarily heat sterilized, and after cooling as necessary, aseptically filling the container (for example, Ultra-high temperature (UHT) sterilization (eg 130-145 ° C, 1-10 seconds), high-temperature (HTST) sterilization (eg 100-130 ° C, 1-60 seconds) and aseptic filling (packaging)
- UHT Ultra-high temperature
- HTST high-temperature sterilization
- Packaging aseptic filling
- a method of sterilization by heating together with the container after filling the composition (raw material liquid) into the container for example, retort method, autoclave method)
- Etc can be used.
- a homogenized product based on the composition (a material obtained by homogenizing a raw material liquid or a sterilizing liquid) is again subjected to heat sterilization (e.g. UHT (sterilization method or high temperature (HTST) sterilization method) after cooling and then filling aseptically, or filling into cans or soft bags, then heat sterilizing with the container, etc. it can.
- heat sterilization e.g. UHT (sterilization method or high temperature (HTST) sterilization method
- the homogenized product based on the composition is, for example, vacuum-evaporated or freeze-concentrated, if necessary, and then spray-dried or freeze-dried, for example. Etc. can be used.
- composition of the present invention can also be expressed as (1) to (11) below as its use.
- a method for suppressing phosphorus absorption comprising a step of (orally) administering (ingesting) a fermented dairy product and an oligosaccharide or a composition containing them to a subject.
- Fermented dairy products and oligosaccharides for use in suppressing phosphorus absorption comprising a step of blending a fermented milk product, an oligosaccharide, and a pharmaceutically acceptable carrier.
- a composition comprising fermented dairy products and oligosaccharides, which is used for addition to pharmaceuticals (pharmaceutical compositions) or foods and drinks (food and beverage compositions) and used to suppress phosphorus absorption.
- nutritional pharmaceutical compositions, pharmaceuticals, pharmaceuticals, food and beverage compositions, food and beverage products nutritional compositions, special-purpose foods, nutritional functional foods, health foods, etc.
- a method for treating and / or preventing a disease caused by excessive phosphorus uptake comprising a step of administering to a subject a fermented milk product and an oligosaccharide, or a composition containing these.
- a method for producing a composition for treating and / or preventing a disease caused by excessive phosphorus uptake comprising a step of blending a fermented milk product, an oligosaccharide and a pharmaceutically acceptable carrier .
- a composition comprising fermented dairy products and oligosaccharides, which is used for addition to pharmaceuticals or foods and drinks, and for treatment and / or prevention of diseases caused by excessive phosphorus uptake. .
- Fermented dairy products and oligosaccharides or compositions containing these pharmaceutical compositions, nutritional pharmaceutical compositions, pharmaceuticals, pharmaceuticals, food and beverage compositions, food and beverage products, nutritional compositions, special-purpose foods, nutritional functional foods, health Excessive phosphorus in pharmaceutical compositions, nutritional pharmaceutical compositions, pharmaceuticals, pharmaceuticals, food and beverage compositions, food and beverage products, nutritional compositions, special-purpose foods, functional nutritional foods, health foods, etc.
- Test materials and test methods 1.1. Feed For fermented milk, lactic acid bacteria (Lactobacillus bulgaricus and Streptococcus thermophilus isolated from Meiji Bulgaria yogurt plain) were cultured using skim milk as a medium, and the obtained culture was freeze-dried. The freeze-dried fermented milk was prepared (manufactured) by electron beam sterilization with 10-kGy. On the other hand, the galactooligosaccharide (GOS) raw material (Cup-Oligo) had a GOS content of 73% by weight. AIN93M (Ca content: 0.5% by weight, phosphorus content: 0.3% by weight) was used as a control food.
- lactic acid bacteria Lacobacillus bulgaricus and Streptococcus thermophilus isolated from Meiji Bulgaria yogurt plain
- the freeze-dried fermented milk was prepared (manufactured) by electron beam sterilization with 10-kGy.
- the galactooligosaccharide (GOS) raw material
- the test meal (YG meal) of fermented milk and GOS ingredients is prepared by replacing part of casein with freeze-dried fermented milk and part of sucrose (5% by weight) with GOS. Using. At this time, the Ca, phosphorus, and crude protein concentrations were adjusted to be equal between the control diet and the test diet (YG diet). The concentration of the crude protein was calculated by nitrogen content ⁇ 6.38 measured by Kjeldahl method. Table 1 shows the composition of the fermented milk and GOS raw material test food (YG food) and control food.
- test method All groups (control group, PPI group, YG group, YG + PPI group) were fed a control diet or YG diet (test feed) for 12 weeks only during the dark period. At this time, in the control group and the PPI group, the pair feeding method was applied to match the intake of the test feed in the YG group and the YG + PPI group. In the PPI group and the YG + PPI group, PPI was subcutaneously administered to the rats at a dose of 20 mg / kg-BW every day 1 hour before the start of the dark period.
- Bone including the femur, generally consists of two types of structural parts, “cortical bone” and “cancellous bone”, and the proportion of these two types of structures varies depending on the type of bone.
- cortical bone is a hard and dense structure covering the surface of the bone.
- cancellous bone is a mesh-like structure in which small thin bones are intricately combined.
- the “cortical bone density” is the bone density (the amount of bone per unit volume (unit area)) of the “cortical bone” portion.
- the “cancellous bone density” is the bone density (the amount of bone per unit volume (unit area)) of the “cancellous bone” portion.
- total bone density is the bone density (the amount of bone per unit volume (unit area)) of the above-mentioned “cortical bone” and “cancellous bone”. These are all indicators of bone strength.
- the “cortical bone width” is the thickness of the cortical bone.
- MMICA minimum section second moment
- cross-sectional secondary pole moment is one of the indices of the strength of the cross-section that represents the strength against twisting.
- PMICA cross-sectional secondary pole moment
- the imaging conditions were tube voltage: 80 kV, tube current: 100 ⁇ A, magnification: 6.96, voxel size: 14.368 ⁇ 14.368 ⁇ 14.368 ⁇ m.
- a 0.1 mm thick brass plate filter was used.
- trabecular bone is a basic unit in cancellous bone, and is a sponge-like portion stretched vertically and horizontally like a mesh. Here, bone metabolism is fostering compared to cortical bone.
- the “bone marrow” is a gap between trabecular bones. Here, red blood cells, white blood cells, platelets and the like are produced.
- the “trabecular width” is the thickness of the trabecular bone, and the “number of trabecular bones” is the number of trabecular bones per unit length.
- the “trabecular gap” is the width of the gap between two trabeculae.
- Each numerical value can be quantitatively calculated, for example, by analyzing the three-dimensional structure of the trabecular bone from a bone tomographic image obtained by ⁇ CT.
- the “star volume” is an index of osteoporosis, and is a volume in a range that can be seen from any place without being blocked in all directions. For example, if the linear continuity of the bone marrow space is maintained, the star volume of the bone marrow space increases. Further, if the linear continuity of the trabecular bone is maintained, the star volume of the trabecular bone increases. That is, in the analysis of the star volume, the star volume of the bone marrow space and the star volume of the trabecular bone are obtained, and those numerical values are used as an index for osteoporosis.
- Node strut analysis is a method of evaluating trabecular structure by regarding trabecular structure as a structure with only points and lines. Image processing is applied to the trabecular image, and the trabecular structure is skeletonized. And expressed in two dimensions. Next, the node (terminating point of 3 or more trabeculae), terminus (terminal point that is not coupled with other trabecular bones), cortex (joining point between trabecular bone and cortical bone) is obtained, then node, terminus , Connect the cortex, find the total skeletal line length, and use each value as an indicator of changes in the internal structure of the trabecular bone.
- a three-point bending test was performed using a bone strength tester (Bone Strength Tester model TK-252C, Muromachi Kikai Co., Ltd.) using the right femur that had undergone CT imaging and ⁇ CT imaging of Lacita. That is, place the right femur on a support device (spacing: 15 mm), apply force until the bone breaks at a constant speed of 5 mm / min, perpendicular to the center of the femur, breaking energy, rigidity, The maximum load was calculated.
- breaking energy in the three-point bending test means the total energy required for the test sample to break when a load is applied to the test sample.
- Rigidity is the degree of difficulty of deformation against bending and twisting forces. That is, when the deformation with respect to the force is small, the rigidity increases, and when the deformation is large, the rigidity decreases. These are all indicators for the strength of the test sample.
- Ca accumulation (mg / 3 days) is calculated by "Apparent Ca absorption"-"Ca excretion in urine"
- the Ca accumulation rate (%) was calculated by [[apparent Ca absorption amount] ⁇ “urine Ca excretion amount]] /“ Ca intake amount ” ⁇ 100.
- phosphorus parameters were also calculated in the same manner as Ca.
- Test results 2.1 Body weight At the end of the study, the body weight of the control group was 340.6 ⁇ 5.2 g, the body weight of the PPI group was 347.3 ⁇ 4.2 g, the body weight of the YG group was 348.5 ⁇ 4.1 g, and the body weight of the YG + PPI group was 348.6 ⁇ 5.5 g. At this time, there was no significant difference in body weight between these groups.
- Table 4 shows the measurement results of the bone density and bone strength of the femur by X-ray CT and the measurement results of the three-point bending test.
- the total bone density, cortical bone density, cancellous bone density, and cortical bone thickness of the femur were significantly reduced by PPI (Comparison between “control group” and “PPI group” in Table 2, “YG group” A comparison between the “YG + PPI group” showed that the P-value (PPI) in the two-way analysis of variance was 0.0008 to 0.0113, both less than 5% and significantly decreased.)
- the total bone density, cortical bone density, cancellous bone density, and cortical bone thickness of the femur were significantly increased by the YG diet (Comparison between “control group” and “YG group” in Table 2, “PPI group” A comparison between the “YG + PPI group” showed that the P-value (feed) in the two-
- administration of YG diet significantly increased the minimum moment of inertia and the moment of inertia of the section. Furthermore, in the three-point bending test, administration of PPI significantly reduced femoral stiffness and maximum load, but had no effect on fracture energy. On the other hand, administration of YG diet showed a tendency to significantly increase the fracture energy and the maximum load and increase the stiffness of the femur (P value: 0.0576).
- the femoral stiffness decreased by the administration of PPI, but the YG group (311 ⁇ 11) and the YG + PPI group (309 ⁇ 8) In comparison, the femoral stiffness did not change with PPI administration. That is, when the stiffness of the femur decreases due to PPI, the stiffness of the femur increases due to the YG diet, and the administration of the YG + PPI diet tends to offset the effect of PPI (Interaction value: 0.0611). ) was recognized. From these results, it was revealed that the bone strength was improved (increased) by the YG diet both in the normal state where PPI was not administered and in the case where the bone strength was decreased when PPI was administered.
- Table 5 shows the measurement results of the microstructure of the femur by ⁇ CT.
- administration of PPI had no effect on trabecular bone density, trabecular number, or trabecular gap of cancellous bone, but showed a tendency to reduce trabecular width (P value: 0.0549).
- administration of the YG diet significantly improved (increased) the trabecular density, number of trabeculae, and trabecular gap of cancellous bone, but had no effect on trabecular width.
- the YG diet improves the bone structure of the sea surface bones of the femur both in normal cases where PPI is not administered and in bone strength where PPI is administered became. Therefore, it was suggested that the composition of the present invention can be used effectively for the treatment and prevention of diseases such as osteoporosis where bone structure deteriorates.
- Table 6 shows the measurement results of cortical bone morphology of the femur by ⁇ CT.
- the administration of PPI significantly reduced the cortical bone volume, the ratio of cortical bone volume, the average cortical bone width, the minimum cross-section second moment, and the density-weighted minimum cross-section second moment.
- administration of YG diet significantly increased cortical bone volume, cortical bone volume ratio, average cortical bone width, minimum cross-section second moment, and density-weighted minimum cross-section second moment.
- the YG diet improves (increases) the bone density of cortical bone and increases the sea level of the femur in both normal cases where PPI is not administered and when bone strength is reduced when PPI is administered. It was revealed that the bone structure of the bone was improved.
- the YG diet has no effect on phosphorus balance, but when the gastric acid decreased due to the administration of PPI, the YG diet decreased the phosphorus absorption. The same tendency was observed in the amount of phosphorus absorbed at 12 weeks, the rate of phosphorus absorption, and the amount of urinary phosphorus excreted at 4 weeks and 12 weeks. From these results, it was clarified that administration of the YG diet has an effect of reducing phosphorus absorption, and has an effect of normalizing phosphorus absorption when phosphorus absorption abnormally increases.
- a composition containing a combination of fermented milk products and oligosaccharides has an effect of improving bone strength, an effect of improving bone density, and an effect of suppressing phosphorus absorption (an effect of normalizing phosphorus metabolism). It was done. So far, it has never been known that the combination of fermented milk products and oligosaccharides has any effect on phosphorus metabolism. In other words, in the present invention, long-term effects were evaluated and verified for the first time by orally administering (orally ingesting) fermented milk products and oligosaccharides for 12 weeks in elder rats aged 11 weeks.
- the inventors found for the first time that the combination of fermented milk products and oligosaccharides has the effect of normalizing abnormalities in phosphorus metabolism (excessive phosphorus uptake) when gastric acid is reduced.
- the combination of a fermented milk product and an oligosaccharide has a particularly excellent bone strength improving effect and bone density improving effect. Therefore, by orally administering the composition of the present invention, it is possible to improve bone strength and bone density while normalizing abnormalities of phosphorus metabolism, and it has a very beneficial effect especially for those who have decreased gastric acid. It became clear to bring.
- the combination of the fermented milk product and the oligosaccharide which is a composition of the present invention
- excessive phosphorus uptake caused by an increase in pH accompanying a decrease in gastric acid secretion is suppressed. Absorption can be returned to the normal range. That is, the composition of the present invention can improve abnormalities of phosphorus metabolism.
- the composition of the present invention can ameliorate diseases caused by excessive phosphorus uptake.
- the composition of the present invention is composed of ingredients that have been proven to be excellent in safety and taste from a long eating experience. Can be administered for a long time.
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Abstract
Description
〔1〕発酵乳製品とオリゴ糖を有効成分として含む、リン吸収抑制用組成物。
〔2〕オリゴ糖が、ガラクトースを構成糖として含むオリゴ糖である、前記〔1〕に記載の組成物。
〔3〕オリゴ糖が、ガラクトオリゴ糖である、前記〔2〕に記載の組成物。
〔4〕発酵乳製品が、Lactobacillus属に属する乳酸菌および/またはStreptococcus属に属する乳酸菌を用いて得られた発酵乳製品である、前記〔1〕~〔3〕のいずれかに記載の組成物。
〔5〕発酵乳製品が、ヨーグルトおよび/または非熟成チーズである、前記〔1〕~〔4〕のいずれかに記載の組成物。
〔6〕胃酸の分泌が低下した対象および/または胃液のpHが上昇した対象へ経口投与する(経口摂取させる)ために用いられる、前記〔1〕~〔5〕のいずれかに記載の組成物。
〔7〕少なくとも4週間以上に亘って毎日で経口投与する(経口摂取させる)ために用いられる、前記〔1〕~〔6〕のいずれかに記載の組成物。
〔8〕食品添加剤として(食品に添加するために)用いられる、前記〔1〕~〔7〕のいずれかに記載の組成物。
〔9〕リン吸収抑制用組成物の製造における発酵乳製品とオリゴ糖の使用。
(1)発酵乳製品とオリゴ糖、またはこれらを含む組成物を対象に(経口)投与する(摂取させる)工程を含む、リン吸収の抑制方法。
(2)リン吸収抑制のために使用するための、発酵乳製品とオリゴ糖。
(3)発酵乳製品とオリゴ糖と薬学的に許容される担体を配合する工程を含む、リン吸収抑制用組成物の製造方法。
(4)発酵乳製品とオリゴ糖を含む、医薬品(医薬組成物)または飲食品(飲食組成物)への添加に用いられ、かつリン吸収抑制に用いられる組成物。
(5)発酵乳製品とオリゴ糖、またはこれらを含む組成物を、医薬組成物、栄養医薬組成物、医薬品、薬剤、飲食組成物、飲食品、栄養組成物、特別用途食品、栄養機能食品、健康食品などに添加(配合)する工程を含む、医薬組成物、栄養医薬組成物、医薬品、薬剤、飲食組成物、飲食品、栄養組成物、特別用途食品、栄養機能食品、健康食品などに、リン吸収抑制効果を付与する方法。
(6)発酵乳製品とオリゴ糖、またはこれらを含む組成物を対象に投与する工程を含む、リンの過剰な取り込みに起因する疾患の治療や予防の両方またはいずれか一方のための方法。
(7)リンの過剰な取り込みに起因する疾患の治療や予防の両方またはいずれか一方のための組成物の製造における、発酵乳製品とオリゴ糖の使用。
(8)リンの過剰な取り込みに起因する疾患の治療や予防の両方またはいずれか一方のために使用するための、発酵乳製品とオリゴ糖。
(9)発酵乳製品とオリゴ糖と薬学的に許容される担体を配合する工程を含む、リンの過剰な取り込みに起因する疾患の治療や予防の両方またはいずれか一方のため組成物の製造方法。
(10)発酵乳製品とオリゴ糖を含む、医薬品または飲食品への添加に用いられ、かつリンの過剰な取り込みに起因する疾患の治療や予防の両方またはいずれか一方のために用いられる組成物。
(11)発酵乳製品とオリゴ糖、またはこれらを含む組成物を医薬組成物、栄養医薬組成物、医薬品、薬剤、飲食組成物、飲食品、栄養組成物、特別用途食品、栄養機能食品、健康食品などに添加する工程を含む、医薬組成物、栄養医薬組成物、医薬品、薬剤、飲食組成物、飲食品、栄養組成物、特別用途食品、栄養機能食品、健康食品などに、リンの過剰な取り込みに起因する疾患の治療や予防の両方またはいずれか一方の効果を付与する方法。
なお、本明細書において引用された全ての先行技術文献は、参照として本明細書に組み入れられる。
1.1.飼料
発酵乳では、脱脂乳を培地として、乳酸菌(明治ブルガリア ヨーグルト プレーンから分離した、Lactobacillus bulgaricusとStreptococcus thermophilus)を培養し、この得られた培養物を凍結乾燥した。そして、この凍結乾燥した発酵乳を、10-kGyで電子線滅菌して調製(製造)した。一方、ガラクトオリゴ糖(GOS)原料(Cup-Oligo)では、GOSの含有量が73重量% であった。
対照食には、AIN93M(Caの含有量:0.5重量%、リンの含有量:0.3重量%)を用いた。発酵乳とGOS原料の試験食(YG食)には、カゼインの一部を発酵乳の凍結乾燥物で置換し、ショ糖の一部(5重量%)をGOSで置換して作製したものを用いた。このとき、対照食と試験食(YG食)で、Ca、リン、粗タンパク質の濃度を同等になるように調整した。なお、粗タンパク質の濃度は、ケルダール法で測定した窒素含量×6.38で算出した。
発酵乳とGOS原料の試験食(YG食)および対照食の組成を表1に示した。
11週齢のWistar系オスラット(日本SLCから購入した)の32匹を用いた。これらラットを、明暗サイクルが12時間の室温(25℃)の部屋において、ステンレス代謝ケージで個別に飼育した。これらラットを1週間で馴化した後に、それぞれの体重が群間で均一になるように8匹ずつ、以下の4群に分けた。ここで、PPIは、オメプラゾールナトリウム(Omepral Injection 20、アストラゼネカ社)である。
- Control(対照)群(対照食の給与および溶媒の投与)
- PPI群(対照食の給与およびPPIの投与)
- YG群(YG食の給与および溶媒の投与)
- YG+PPI群(YG食の給与およびPPIの投与)
全部の群(対照群、PPI群、YG群、YG+PPI群)に、対照食やYG食(試験飼料)を12週間に亘って、暗期の時間帯のみで給与した。このとき、対照群およびPPI群では、ペアフィーディング法を適用し、YG群およびYG+PPI群における試験飼料の摂取量に合わせた。そして、PPI群およびYG+PPI群では、暗期の開始の1時間前に毎日、PPIを20 mg/kg-BWの用量で、前記のラットに皮下投与した。なお、予備試験として、PPIを20 mg/kg-BWの用量で、成熟ラットに皮下投与したときには、胃液のpHがベースラインのpH:1.8 ± 0.2に対して、皮下投与してから2~5時間後のpH:7.0 ± 0.2、9~12時間後のpH:2.5 ± 0.3となり、有意に高い数値を示すことを確認した。また、対照群およびYG群では、同様の方法として、暗期が始まる1時間前に毎日、生理食塩水を20 mg/kg-BWの用量で、前記のラットに皮下投与した。なお、全部の群に、試験期間中において、イオン交換水を自由摂取させた。
動物用CT装置であるラシータ(LCT-100M、アロカ社)を用いて、1 mm の間隔で、各ラットの右大腿骨の画像を撮影した。そして、ラシータソフトウェア(version 1.31)を用いて、これら撮影した画像を解析し、皮質骨密度、海綿骨密度、全骨密度、皮質骨幅、最小断面二次モーメント(MMICA) 、断面二次極モーメント (PMICA) を算出した。大腿骨をはじめとする骨は、一般に「皮質骨」と「海綿骨」という2種類の構造部から成り立っており、骨の種類によって、この2種類の構造の割合は異なっている。ここで、皮質骨は、骨の表面部を覆っている硬くて緻密な構造である。一方、海綿骨は、小さな細い骨が複雑に組み合わさった網目状の構造である。そして、「皮質骨密度」とは、「皮質骨」の部分の骨密度(単位体積(単位面積)あたりの骨の量)である。「海綿骨密度」とは、上記の「海綿骨」の部分の骨密度(単位体積(単位面積)あたりの骨の量)である。「全骨密度」とは、上記の「皮質骨」の部分と「海綿骨」の部分を合わせたものの骨密度(単位体積(単位面積)あたりの骨の量)である。これらは、いずれも骨の強度を示す指標となる。また、「皮質骨幅」とは、皮質骨の厚みである。骨の太さが同じであれば、皮質骨の幅が厚いほど、力学的な強度が高まる傾向にあることが知られている。さらに、「最小断面二次モーメント(MMICA)」とは、曲げに対する強さを表す断面の強度の指標の一つである。丸棒のような部材に対して、曲げを生じるように荷重を掛けたときに、その曲げの荷重に対する強さの指標となる。このとき、断面二次モーメントが大きいほど、曲げに対して強いこととなる。つまり、複数の骨について、最小の断面二次モーメントを比較することで、曲げに対する強さを相対的に比較できる。一方、「断面二次極モーメント(PMICA)」とは、捻じれに対する強さを表す断面の強度の指標の一つである。丸棒のような部材に対して、捻じれを生じる(一端を固定した状態のままで、反対側の端を回転させる)ように荷重を掛けたときに、その捻じれの荷重に対する強さの指標となる。実際には、断面二次極モーメントは部材の断面の半径と荷重の負荷の大きさによって決まる。このとき、断面二次極モーメントが大きいほど、捻じれに対して強いこととなる。つまり、複数の骨について、荷重の負荷を同じ条件に設定し、断面二次極モーメントを比較することで、捻じれに対する強さを相対的に比較できる。
μCT(ScanXmate-L080、コムスキャンテクノ社)を用いて、2 mm の長さで、各ラットの右大腿骨の成長板から0.5 mm の離れた場所の画像を撮影した。μCTでは、通常のCTに比べて、撮影の視野は狭いが、分解能(最終的に認識できる最少の寸法)が高いことが特徴である。μCTでは、試料を非破壊の状態で、その内部構造を詳細に観察でき、実際の条件次第では、1~10μmの形状を判別できる。この撮影条件は、管電圧:80 kV、管電流:100 μA、倍率:6.96、ボクセルサイズ:14.368 × 14.368 × 14.368 μmとした。そして、ビームハードニング効果を減弱させるために、0.1 mmの厚さの真鍮板フィルターを用いた。TRI/3D-BON ソフトウェア(ラトックシステムエンジニアリング社)を用いて、骨梁の骨密度(BV/TV,%)、骨梁幅(Tb.Th,μm)、骨梁数(Tb.N,mm-1)、骨梁間隙(Tb.Sp,μm)、骨髄空間のスターボリューム(V*m.space,mm3)、骨梁のスターボリューム(V*tr,mm3)、組織の体積当たりのノード(Nd:3個以上の骨梁の結合点)の数(N.Nd/TV)、組織の体積当たりのターミナス(Tm:他の骨梁と結合のない端点)の数(N.Tm/TV)、組織の体積当たりのコーテックス(Ct:皮質骨との結合点)の数(N.Ct/TV)、組織の体積当たりの骨の解析部分の総骨格線長(TSL/TV)、総体積(Tt.V,mm3)、皮質骨体積(Ct.V,mm3)、皮質骨体積の割合(Ct.V/Tt.V,%)、平均の皮質骨幅(Ct.Th,mm)、最小断面モーメント(Imin,mm5)、密度重みづけ最小断面モーメント(Imin Dn,mm (mm2))を算出した。ここで、「骨梁」とは、海綿骨における基本的な単位であり、網目のように縦横に張り巡らされた、スポンジ状の部分である。ここでは、皮質骨に比べて、骨代謝が盛んである。また、「骨髄」とは、骨梁の間隙である。ここでは、赤血球、白血球、血小板などが生産される。「骨梁幅」とは、骨梁の厚さであり、「骨梁数」とは、単位長さ当たりの骨梁の個数である。「骨梁間隙」とは、2つの骨梁の間隙の幅である。これらは、いずれも、海綿骨の強度を示す指標となる。そして、それぞれの数値は、例えば、μCTで得られる骨の断層の画像から、骨梁の三次元構造を解析することで定量的に算出できる。さらに、「スターボリューム」とは、骨粗鬆化の指標であり、任意の箇所から全方向において遮ることなく見渡せる範囲の体積である。例えば、骨髄空間の直線的な連続性が保たれていると、骨髄空間のスターボリュームは大きくなる。また、骨梁の直線的な連続性が保たれていると、骨梁のスターボリュームは大きくなる。つまり、スターボリュームの解析では、骨髄空間のスターボリュームと骨梁のスターボリュームを求めて、それらの数値を骨粗鬆化の指標として用いることとなる。また、ノードストラット解析とは、骨梁構造を点と線のみの構造体と見なし、骨梁構造を評価する方法であり、骨梁像に対して画像処理を施し、骨梁構造を骨格化させて、二次元的に表現する。次いで、ノード(3個以上の骨梁の結合点)、ターミナス(他の骨梁と結合の無い末端点)、コーテックス(骨梁と皮質骨との結合点)を求めてから、ノード、ターミナス、コーテックスを連結し、総骨格線長を求めて、それぞれの数値を骨梁の内部構造の変化の指標として用いる。
ラシータのCT撮影とμCT撮影を行った右大腿骨を用いて、骨強度試験機(Bone Strength Tester model TK-252C、室町機械社)による三点曲げ試験を行った。すなわち、右大腿骨を支持器具(間隔:15mm)の上に置いて、大腿骨の中央部へ垂直に、5 mm/minの定速で、骨が折れるまで力を加え、破断エネルギー、剛性、最大荷重を算出した。ここで、三点曲げ試験における「破断エネルギー」とは、被験試料に対して荷重を掛けたときに、被験試料が破断に至るまでに要した総エネルギーをいう。また、「剛性」とは、曲げや捻じりの力に対する変形しにくさの度合いである。つまり、力に対する変形が小さいときには、剛性は大きくなり、変形が大きいときには、剛性は小さくなる。これらは、いずれも、被験試料の強度を示す指標となる。
湿式灰化装置(Multiwave3000、パーキンエルマー社)を用いて、試験飼料、糞、尿を濃硝酸の存在下で灰化してから、ICP装置(ICP-S7500、島津製作所社)を用いて、Ca、リンを測定した。そして、見かけのCaの吸収量(mg/ 3 days)は、「Ca摂取量」-「糞中のCa排泄量」によって算出し、見かけのCa吸収率(%)は、[「Ca摂取量」-「糞中のCa排泄量」]/「Ca摂取量」×100によって算出し、Ca蓄積量(mg/ 3 days)は、「見かけのCa吸収量」-「尿中のCa排泄量」によって算出し、Ca蓄積率(%)は、[「見かけのCa吸収量」-「尿中のCa排泄量」]/「Ca摂取量」×100によって算出した。このとき、Caと同様に、リンのパラメーターも算出した。
全部のデータを、平均値±標準誤差で評価した。そして、全部のデータを、Bartlett検定により、等分散性を確認した。ここで、データに等分散性が認められた場合、PPIと食事の二要因で、二元配置分散分析を行った。さらに、二元配置分散分析において、交互作用が有意であった場合(Interaction値が0.05以下の場合)、Tukey-Kramer多重検定を行った。一方、データに等分散性が認められなかった場合、Kruskal-Wallis 検定を行った後に、Steel-Dwass 多重検定を行った。このとき、P<0.05を統計的に有意であると見なした。なお、エクセル統計2012(社会情報サービス社)を用いて、統計解析を行った。そして、表7と表8において、異種の符号間で統計的に有意差があるときに、「a」、「b」、「c」の符号を付与した。
2.1.体重
試験終了時には、対照群の体重が340.6 ± 5.2 g、PPI群の体重が347.3 ± 4.2 g、YG群の体重が348.5 ± 4.1 g、YG + PPI群の体重が348.6 ± 5.5 gであった。このとき、これら群間の体重に有意差は認められなかった。
X線CTによる大腿骨の骨密度や骨強度の測定結果と、三点曲げ試験の測定結果を表4に示した。ここで、PPIによって、大腿骨の全骨密度、皮質骨密度、海綿骨密度、皮質骨厚は有意に低下した(表2の「対照群」と「PPI群」の比較、「YG群」と「YG+PPI群」の比較で、二元配置分散分析におけるP値(PPI)が0.0008~0.0113であり、いずれも5%未満で、有意に低下したことが示された。)。一方、YG食によって、大腿骨の全骨密度、皮質骨密度、海綿骨密度、皮質骨厚は有意に増加した(表2の「対照群」と「YG群」の比較、「PPI群」と「YG+PPI群」の比較で、二元配置分散分析におけるP値(飼料)が0.0001以下であり、いずれも5%未満で、有意に増加したことが示された。)。また、PPIの投与では、最小断面二次モーメントを有意に低下させ、断面二次極モーメントを低下させる傾向(P値:0.0623)が認められた。一方、YG食の投与では最小断面二次モーメントおよび断面二次極モーメントを有意に増加させた。さらに、三点曲げ試験において、PPIの投与では、大腿骨の剛性および最大荷重を有意に低下させたが、破断エネルギーには影響が認められなかった。一方、YG食の投与では、破断エネルギーおよび最大荷重を有意に増加させ、大腿骨の剛性を増加させる傾向(P値:0.0576)が認められた。なお、対照群(310±11)とPPI群(274±4)の比較では、PPIの投与によって、大腿骨の剛性は低下したが、YG群(311±11)とYG+PPI群(309±8)の比較では、PPIの投与によって、大腿骨の剛性は変化しなかった。すなわち、本来なら、PPIによって、大腿骨の剛性が低下するところ、YG食によって、大腿骨の剛性が増加することで、YG+PPI食の投与では、PPIの影響が相殺される傾向(Interaction値:0.0611)が認められた。これらの結果から、PPIを投与していない健常時と、PPIを投与した骨強度の低下時と、いずれにおいても、YG食によって、骨強度が向上(増加)されることが明らかとなった。
μCTによる大腿骨の微細構造の測定結果を表5に示した。ここで、PPIの投与では、海綿骨の骨梁の骨密度、骨梁数、骨梁間隙に影響が認められなかったが、骨梁幅を低下させる傾向(P値:0.0549)が認められた。一方、YG食の投与では、海綿骨の骨梁の骨密度、骨梁数、骨梁間隙を有意に向上(増加)させたが、骨梁幅には影響が認められなかった。また、スターボリューム解析において、PPIの投与では、骨髄空間のスターボリューム、骨梁のスターボリュームのいずれにも影響が認められなかった。一方、YG食の投与では、骨髄空間のスターボリュームを有意に低下させ、骨梁のスターボリュームを有意に増加させた。さらに、ノードストラット解析において、PPIの投与では、いずれの指標にも影響が認められなかった。一方、YG食の投与では、ノードの数、コーテックスの数、総骨格線長を有意に増加させ、ターミナスの数を低下させる傾向(P値:0.0955)が認められた。これらの結果から、PPIを投与していない健常時と、PPIを投与した骨強度の低下時と、いずれにおいても、YG食によって、大腿骨の海面骨の骨構造が改善されることが明らかとなった。したがって、骨粗鬆症などの骨構造が悪化する疾患の治療や予防のために、本発明の組成物を有効に使用できることが示唆された。
Caの出納の結果を表7に、リンの出納の結果を表8に示した。ここで、PPIの投与では、Caの出納に有意な影響が認められなかった。一方、YG食の投与では、4週目のCa吸収と、4週目と12週目の尿中Ca排泄を有意に増加した。また、PPI群では、4週目のリン吸収量とリン吸収率が有意に増加した。一方、YG群では、4週目のリン吸収量もリン吸収率も有意に増加しなかった。このとき、YG+PPI群では、PPI群に比べて、リン吸収量もリン吸収率も有意に減少した。したがって、健常時においては、YG食によって、リン出納は何も影響されないが、PPIの投与に伴う胃酸の低下時においては、YG食によって、リン吸収を低下させることが明らかとなった。そして、12週目のリン吸収量、リン吸収率、4週目と12週目の尿中リン排泄量にも、これと同様な傾向が認められた。これらの結果から、YG食の投与では、リン吸収を低下させる効果があり、リン吸収が異常に増加した場合において、リン吸収を正常化させる効果があることが明らかとなった。
Claims (9)
- 発酵乳製品とオリゴ糖を有効成分として含む、リン吸収抑制用組成物。
- オリゴ糖が、ガラクトースを構成糖として含むオリゴ糖である、請求項1に記載の組成物。
- オリゴ糖が、ガラクトオリゴ糖である、請求項2に記載の組成物。
- 発酵乳製品が、Lactobacillus属に属する乳酸菌および/またはStreptococcus属に属する乳酸菌を用いて得られた発酵乳製品である、請求項1~3のいずれか1項に記載の組成物。
- 発酵乳製品が、ヨーグルトおよび/または非熟成チーズである、請求項1~4のいずれか1項に記載の組成物。
- 胃酸の分泌が低下した対象および/または胃液のpHが上昇した対象へ経口投与するために用いられる、請求項1~5のいずれか1項に記載の組成物。
- 少なくとも4週間以上に亘って毎日で経口投与するために用いられる、請求項1~6のいずれか1項に記載の組成物。
- 食品添加剤として用いられる、請求項1~7のいずれかに記載の組成物。
- リン吸収抑制用組成物の製造における発酵乳製品とオリゴ糖の使用。
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- 2016-01-19 JP JP2016527489A patent/JP6058223B2/ja active Active
- 2016-01-19 WO PCT/JP2016/051353 patent/WO2016117525A1/ja active Application Filing
- 2016-01-19 SG SG11201705549YA patent/SG11201705549YA/en unknown
- 2016-01-19 CN CN201680005369.9A patent/CN107105688B/zh active Active
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JPWO2016117525A1 (ja) | 2017-04-27 |
CN107105688B (zh) | 2021-03-19 |
TW201634054A (zh) | 2016-10-01 |
CN107105688A (zh) | 2017-08-29 |
SG11201705549YA (en) | 2017-08-30 |
TWI692360B (zh) | 2020-05-01 |
JP6058223B2 (ja) | 2017-01-11 |
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