JP6657084B2 - Ghrelin secretagogue - Google Patents

Description

Reference to related application

  This patent application is accompanied by a claim of priority based on Japanese Patent Application No. 2014-130143 filed on June 25, 2014, and the entire disclosure content of such earlier patent application is incorporated herein by reference. Part of this specification.

  The present invention relates to a novel ghrelin secretagogue.

  Anorexia in humans can be due to disease or not. Among them, in particular, anorexia irrespective of illness, for example, in the case of elderly people, social factors such as separation from the spouse or bereavement, retirement, etc., decrease in exercise amount due to aging, mastication by dentures It may be caused by physical factors such as a decrease, cause a malnutrition, and there is a concern that the internal resistance may decrease.

  Neuropeptides Y (NPY), orexins (orexins), motilin (motilin), melanin-concentrating hormone (MCH), and agouti-related proteins (AGRP) include neuropeptides that enhance appetite. ) Are known. Examples of substances that suppress appetite include α-melanocyte-stimulating hormone (α-MSH), corticotropin-releasing factor (CRF), cocaine- and amphetamine-regulation. Transcripts (cocain-and amphetamine-regulated transcript: CART) and cholecystokinin (CCK) are known. These peptides are involved in physiological mechanisms that control gastrointestinal motility and are thought to affect energy homeostasis.

Ghrelin is known as another peptide that enhances appetite. Ghrelin is a 28-residue peptide hormone found in the human stomach as an endogenous ligand for the growth hormone secretagogue receptor (GHSR). Ghrelin has two main molecular forms, active (acyl ghrelin) and inactive (desacyl ghrelin). Activated ghrelin has a structural feature that the third serine is modified (acylated) with octanoic acid. This modification is essential for the expression of ghrelin activity, and active ghrelin has a growth hormone (GH) secretion promoting action, and is expected to prevent muscle synthesis and aging through the GH secretion action. It is also expected to be used for treating illness. Ghrelin is also the only endogenous feeding-promoting factor, and is expected to be used for the treatment of eating disorders (anorexia) through the effect of promoting eating. In addition, recent nonclinical / clinical studies have revealed that they have various effects.
That is, ghrelin has effects such as promotion of fat accumulation, suppression of insulin secretion and suppression of brown adipose tissue function in terms of energy metabolism regulating function, and effects such as promotion of gastrointestinal motility, enhancement of gastric acid secretion, and enhancement of pancreatic exocrine secretion in the digestive system. In terms of the circulatory system, it exerts effects such as suppression of the sympathetic nervous system, vasodilation, increase in cardiac contractility, and protection of cardiomyocytes. Attempts to clinically apply these various physiological effects have already started, including after artificial joint replacement, gastrointestinal cancer surgery, eating disorders, functional dyspepsia, cancer cachexia, chronic heart failure cachexia, chronic renal failure cachexia, chronic renal failure. Clinical trials have been conducted to administer ghrelin to patients with obstructive pulmonary disease (COPD).

  Active ghrelin is rapidly deoctane-oxidized in blood to inactive desacyl ghrelin. It accounts for more than 90% of total ghrelin in circulating plasma and reflects total secretory capacity and metabolic status. Inactive ghrelin has no effect of inducing the promotion of growth hormone secretion, and conversely antagonizes ghrelin and suppresses eating behavior and suppresses gastric fasting during gastrointestinal motility. Therefore, it can be said that the higher the active / inactive ghrelin, the higher the action of the active ghrelin.

  In Patent Document 1, the effect of ghrelin on appetite regulation and its mechanism are elucidated, a novel therapeutic agent for a disease of malnutrition using the same is developed, and a novel dysphagia or metabolism using a ghrelin agonist or antagonist is used. It describes that a therapeutic agent for abnormalities was developed.

  For example, Patent Literature 2 describes that ingestion of specific steroid saponins such as dioscin promotes ghrelin secretion in ghrelin secretory cells isolated from rat stomach.

  On the other hand, in Patent Document 1, when ghrelin and its derivatives are added, it is necessary to newly synthesize a peptide having the same amino acid sequence as human ghrelin. Further, in order to apply the composition to a pharmaceutical preparation, it is necessary to stabilize ghrelins by suppressing the degradation of the hydrophobic modified structure of ghrelin as disclosed in Patent Document 3.

  In Patent Document 2, specific steroid saponins such as diostine that promote ghrelin secretion must be purified again.

  As described above, in order to secrete ghrelin in the body, it is necessary to force anorexia humans to ingest (administer) ghrelin or a known substance that secretes ghrelin. There are / or psychological barriers. Under such a technical situation, it can be said that a new technical means capable of effectively promoting secretion of ghrelin in the body is required.

JP 2010-006823 A JP 2013-227309 A International Publication 2003/006349

  An object of the present invention is to provide a novel ghrelin secretagogue. The present invention also provides a novel, safe and harmless secretion-promoting agent having no side effects, which can exhibit the ghrelin secretion existing in the human body without synthesizing and / or separating and purifying the compound and in a form that is easy to take. It is one purpose to provide.

  Means for Solving the Problems In view of the above problems, the present inventors have conducted intensive studies and obtained the following findings. That is, it has been found that ingestion (administration) of a composition containing specific components such as proteins, lipids and carbohydrates can promote secretion of ghrelin in the body.

That is, the present invention is as follows.
[1] A ghrelin secretagogue comprising a protein hydrolyzate and a fermented milk protein as a protein; a medium-chain fatty acid as a lipid; and a saccharide.
[2] The method according to [1], which contains a protein hydrolyzate and a fermented milk protein as a protein; a medium-chain fatty acid-containing fat, a phospholipid and an oleic acid-containing fat as a lipid; and palatinose (registered trademark) as a saccharide. Ghrelin secretagogue.
[3] The protein hydrolyzate is selected from casein, milk protein concentrate (MPC), whey protein concentrate (WPC), whey protein isolate (WPI), α-lactalbumin, β-lactoglobulin and lactoferrin The ghrelin secretagogue according to [1] or [2], which is a protein hydrolyzate as a raw material.
[4] The ghrelin secretagogue according to any one of [1] to [3], wherein the protein hydrolyzate is a whey protein hydrolyzate.
[5] The ghrelin secretagogue according to any one of [1] to [4], wherein the amount of the protein hydrolyzate is 0.5 to 3 g per 100 ml.
[6] The ghrelin secretion promoter according to any one of [1] to [5], wherein the fermented milk protein is derived from whey excreted from fermented milk.
[7] The ghrelin secretagogue according to any one of [1] to [6], wherein the fermented milk protein is derived from fermented milk obtained by fermenting skim milk with Lactobacillus Bulgaricus, Streptococcus Thermophilus, or a combination thereof. .
[8] The ghrelin secretagogue according to any one of [1] to [7], wherein the fermented milk protein is derived from fresh cheese.
[9] The ghrelin secretagogue according to any one of [1] to [8], wherein the blended amount of the fermented milk protein is 0.5 to 6 g per 100 ml.
[10] The protein hydrolyzate is obtained by hydrolyzing whey protein isolate (WPI) with endo-type protease derived from Bacillus licheniformus and hydrolyzing with trypsin derived from porcine pancreas. , The ghrelin secretagogue according to any one of [1] to [9].
[11] The ghrelin secretagogue according to any one of [1] to [10], wherein the fractionated molecular weight of the protein hydrolyzate is 10,000 or less.
[12] The ghrelin secretagogue according to any one of [1] to [11], wherein the amount of the saccharide is 1 to 15 g per 100 ml.
[13] The ghrelin secretagogue according to any one of [1] to [12], wherein the amount of oleic acid in the lipid is 25% by weight or more of the total fatty acids.
[14] The ghrelin secretagogue according to any one of [1] to [13], wherein the amount of the medium-chain fatty acid is 0.01 to 4 g per 100 ml.
[15] The ghrelin secretagogue according to any one of [1] to [14], wherein the calorific value of the agent is 50 to 150 kcal per 100 ml.
[16] The ghrelin secretagogue according to any one of [8] to [15], wherein the fresh cheese is quark.
[17] The ghrelin secretagogue according to any one of [2] to [16], wherein the phospholipid is milk phospholipid.
[18] The ghrelin secretagogue according to any one of [2] to [17], wherein the blending amount of the phospholipid is 0.01 to 0.5 g per 100 ml.
[19] The ghrelin secretagogue according to any one of [1] to [18], wherein the medium-chain fatty acid is a medium-chain fatty acid having 8 to 14 carbon atoms.
[20] Enhancement of eating, promotion of fat accumulation, suppression of insulin secretion, suppression of brown adipose tissue function, promotion of gastrointestinal motility, enhancement of gastric acid secretion, enhancement of pancreatic exocrine secretion, suppression of sympathetic nervous system, vasodilation, enhancement of cardiac contractility or cardiac muscle cells The ghrelin secretagogue according to any one of [1] to [19] for protection of ghrelin.

  The ghrelin secretion enhancer of the present invention uses components that have been orally ingested for many years, such as proteins, lipids, and carbohydrates, and further contains fermented milk proteins as essential components, so that it can exhibit refreshingness derived from fermented milk. Therefore, the ghrelin secretagogue of the present invention is easy to ingest (administer) continuously, is safe, and has a low risk of side effects. Further, the ghrelin secretagogue of the present invention can be prepared without synthesizing and / or separating and purifying the compound. Furthermore, according to the ghrelin secretagogue of the present invention, ghrelin is secreted in the body, and accordingly, various symptom-improving effects can be exerted. Examples of such effects include actions such as increased eating, promotion of fat accumulation, suppression of insulin secretion, suppression of brown adipose tissue function in relation to the function of regulating feeding and energy metabolism, and promotion of gastrointestinal motility and gastric acid secretion in the digestive system. Actions such as enhancement of hypertension and exocrine pancreatic secretion, and suppression of the circulatory system include sympathetic nervous system suppression, vasodilation, increase in cardiac contractility, and protection of cardiomyocytes.

Detailed description of the invention

As described above, the protein hydrolyzate of the present invention can be provided as a composition containing a protein hydrolyzate and a fermented milk protein as a protein; a medium-chain fatty acid as a lipid; and a saccharide. Further, according to a preferred embodiment of the present invention, the ghrelin secretagogue comprises a protein hydrolyzate and a fermented milk protein as a protein; a medium-chain fatty acid-containing fat, a phospholipid and an oleic acid-containing fat as a lipid; and palatinose as a saccharide. (Registered trademark) .

  Examples of the protein hydrolyzate of the present invention include casein, whey protein (milk protein concentrate (MPC), whey protein concentrate (WPC), whey protein isolate (WPI), α-lactalbumin, β-lactoglobulin ), Milk protein concentrate (MPC), lactoferrin and other milk-derived raw materials. Even if it is a raw material of a protein other than milk, as long as the effects of the present invention can be obtained, it can be used without any particular limitation. The raw material of the protein hydrolyzate may be modified with amino acid residues as necessary to obtain the functional properties (physical properties such as solubility, viscosity, gelation, heat stability, and emulsion stability). In addition, physiological characteristics and the like may be changed. The protein hydrolyzate of the present invention can also be used by subjecting the raw material of the protein hydrolyzate to hydrolysis treatment with an enzyme or the like and fractionating the raw material to a predetermined molecular weight or less as necessary. In addition, a commercially available protein hydrolyzate can be used as long as the same effects as those of the present invention can be obtained.

  For example, in the case of hydrolyzing whey protein with an enzyme, which is one form of the raw material of the protein hydrolyzate of the present invention, commonly used enzymes are not limited to pepsin, trypsin, chymotrypsin, and the like. Other plant-derived proteases (papain, bromelain, actinidain, etc.), purified products of enzymes that hydrolyze known proteins such as microorganism-derived proteases, crude products containing these enzymes, and cells containing these enzymes A crushed material or the like can be used.

For example, a method for preparing a whey protein hydrolyzate, which is one embodiment of the protein hydrolyzate of the present invention, is a preparation method comprising the following steps (1) to (5).
(1) Whey protein isolate (WPI) containing about 90% by weight of protein as dry matter was dissolved in water to contain 8% by weight of protein. (2) The dissolved WPI solution was heated at 85 ° C. for 2 minutes to denature the whey protein. At this time, the pH of the whey protein solution was 7.5. (3) The hydrolysis of the whey protein solution after the heat treatment was performed using 2% by weight of Alcalase 2.4L (Novozymes), an endo-type protease derived from Bacillus licheniformus, based on the weight of whey protein. And reacted at 55 ° C. for 3 hours. (4) Next, PTN6.0S (Novozymes), which is a trypsin derived from swine, was added at 3% by weight based on the weight of whey protein, and reacted at 55 ° C. for 3 hours. When the reaction was completed, the pH of the reaction solution was 7. (5) The obtained reaction solution was centrifuged at 20,000 × g for 10 minutes, and the supernatant was passed through a UF membrane (Millipore) having a molecular weight cut-off of 10,000 and the whey protein hydrolyzed. The product was decomposed.

The blending amount of the protein hydrolyzate of the present invention is determined by mixing other components (fermented milk protein as a protein, medium-chain fatty acid-containing fat and oil as a lipid, phospholipid and oleic acid-containing fat and oil, and palatinose (registered trademark) as a saccharide ) And the like, the disease state, medical condition, age, body weight, use, and the like of the subject to be ingested. For example, as preferable examples of the amount of the protein hydrolyzate, 0.5 to 3 g, 0.75 to 2.8 g, 1 to 2.5 g, 1.25 to 2.25 g, 1.5 ２2.25 g, 1.75 to 2.25, 1.6 to 2.25 or 1.6 to 2.1. It is. Such an amount is particularly preferable when the protein hydrolyzate is a whey protein hydrolyzate.

  As the origin of the fermented milk protein of the present invention, so-called fermented milk (livestock milk such as cow milk, buffalo milk, goat milk, sheep milk, horse milk and / or partially skimmed milk, skim milk, reduced whole milk, reduced milk) Liquid milk prepared by combining one or more kinds of milk raw materials such as skim milk, reduced partially skim milk, butter, and cream, and fermented with a starter such as lactic acid bacteria (in general) can be used. More specifically, as a raw material of the fermented milk protein of the present invention, yogurt, cheese, or the like obtained by fermenting milk with lactic acid bacteria and / or bifidobacteria can be used. As one form of the fermented milk protein of the present invention, a natural cheese from which whey is discharged (reduced) from fermented milk and which is not aged, such as fresh cheese (quark, mascarpone, cream cheese, etc.) can be exemplified. Further, as a starter for producing fermented milk, Lactobacillus bulgaricus, Streptococcus thermophilus can be mainly used, but is not limited thereto, for example, Streptococcus lactis, Streptococcus cremoris, Streptococcus diacetilactis, Enterococcus faecium, Enterococcus fecalis, Lactobalulus Heliceticus, Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus plantarum, Lactobacillus murinus, Lactobacillus reuteri, Lactobacillus brevis, Lactobacillus gasseri, Bifidobacterium longum, Bifidobacterium bifidium, Bifidobacterium bifidum and Bifidobacterium In addition, microorganisms used in producing fermented milk, such as Propionibacterium, can be used in combination. Fermented milk protein of the present invention may be prepared using any fermented milk, preferably quark, or fermentation obtained by fermenting skim milk using Lactobacillus Bulgaricus, Streptococcus Thermophilus or a combination thereof. It is derived from milk, more preferably from fermented milk obtained by fermenting skim milk using Lactobacillus Bulgaricus and Streptococcus Thermophilus.

  As a general method for preparing the fermented milk protein of the present invention, skim milk is first sterilized, and then inoculated with a lactic acid bacterium starter (Lactobacillus bulgaricus, Streptococcus thermophilus) at 0.5 to 5% (w / w). Let it ferment. When the pH of the solution reaches about 4.6, curd is formed and, if desired, the whey is centrifuged, optionally with a separator, before the resulting curd is cooled. As an example of the composition of the fermented milk protein of the present invention, for example, the total solid content is 17 to 19% (w / w), the protein is 11 to 13% (w / w), and the fat is less than 1% (w / w). , Carbohydrates less than 2-8% (w / w) and lactose less than 2% (w / w). In addition, those coagulated using rennet are also included in the fermented milk protein of the present invention. Also, a lactic acid bacterium belonging to Lactococcus, a culture obtained by adding a mixed culture of bacteria of the genus Cremoris and a strain of the genus Leuconostoc to skim milk, removing whey, and obtaining the fermented milk protein of the present invention. Is included. Further, the curd obtained by cutting the curd obtained in the same manner as described above with a cutter and then separating the whey while heating the solution is also included in the fermented milk protein of the present invention. The above-mentioned preparation method is also suitably used in Examples of the present invention.

The amount of the fermented milk protein of the present invention may be determined by mixing other components (protein hydrolyzate as a protein, medium-chain fatty acid-containing fat and oil as a lipid, phospholipid and oleic acid-containing fat and oil, and palatinose (registered trademark) as a saccharide ) And the like, the disease state, medical condition, age, body weight, use, and the like of the subject to be ingested. Preferred examples of the amount of the fermented milk protein include 0.5 to 6 g, 1 to 5 g, 1.5 to 4.5 g, 2 to 4 g, 2.5 to 3.5 g, or 2.75 to 100 ml of the agent. 3.25 g. Such a blending amount is particularly preferable when the fermented milk protein is quark or fermented milk protein derived from fermented milk obtained by fermenting skim milk using Lactobacillus Bulgaricus, Streptococcus Thermophilus or a combination thereof.

As the raw material of the phospholipid of the present invention, one or more known raw materials of a phospholipid such as milk phospholipid, soybean-derived lecithin, and egg yolk lecithin can be used.
The phospholipid of the present invention can be fractionated and purified from raw materials derived from milk, soybeans, eggs and the like. In addition, as long as the effects of the present invention can be obtained, commercially available raw materials containing phospholipids can be used.

  As the phospholipid of the present invention, milk phospholipid is preferable. Milk phospholipids (also called milk lecithin) consist of sphingomyelin (SM), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), phosphatidylserine (PS), and lysophosphatidylcholine (LPC). It is localized only in the fat globule membrane (MFGM). The component composition of the MFGM phospholipid fraction is described in, for example, Bulletin of Japan Dairy Technical Association, Vol. 50: pp. 58-91, 2000.

The blending amount of the phospholipid of the present invention may be determined based on other components (protein hydrolyzate and fermented milk protein as protein, medium-chain fatty acid-containing fat and oleic acid-containing fat as lipid, and palatinose (registered trademark) as saccharide, etc. ) ), The disease state, medical condition, age, body weight, use, etc. of the subject to be ingested. Preferred examples of the blending amount of the phospholipid include 0.01 to 0.5 g, 0.025 to 0.4 g, 0.05 to 0.3 g, 0.06 to 0.2 g, and 0.075 g per 100 ml of the agent. 0.2 g, 0.07 to 0.15 g, 0.07 to 0.12 g, 0.07 to 0.1 g, 0.08 to 0.15 g, 0.08 to 0.12 g or 0.08 to 0 g 0.1 g. Such an amount is particularly preferable when the phospholipid is milk phospholipid.

  The origin and type of other raw materials of the fats and oils of the present invention are not limited as long as the effects of the present invention are not hindered. For example, comparing the intake standards of lipids of the Ministry of Health, Labor and Welfare with the contents of actual intake of lipids, saturated fatty acids (palmitic acid, stearic acid, etc.), monounsaturated fatty acids (oleic acid, etc.), polyunsaturated The blending amount of fatty acids (linoleic acid, linolenic acid, etc.) can be adjusted. In particular, in Japan, it is difficult to increase the intake of monounsaturated fatty acids only by diet, and therefore, it is also preferable to increase the proportion of monounsaturated fatty acids in all fatty acids. Therefore, for example, oleic acid, which is a monounsaturated fatty acid, can be added to the composition of the present invention. Sources of lipids rich in oleic acid include, for example, high oleic high oleic sunflower oil, rapeseed oil, olive oil, high oleic safflower oil, soybean oil, corn oil, palm oil and the like. Nutritionally prepared oils and fats (Nippon Oil & Fats Co., Ltd.) are examples of lipid sources containing oleic acid. Sunflower oil, rapeseed oil, olive oil, and mixtures with olive oil can also be used.

  The oleic acid content in the oleic acid-containing fat or oil of the present invention is not particularly limited as long as the effects of the present invention are not hindered, but is preferably 30% by weight or more, more preferably 40% by weight or more, and further preferably 50% by weight or more. % By weight or more.

In addition, the blending ratio and blending amount of oleic acid in the agent of the present invention may be determined by mixing other components (protein hydrolyzate and fermented milk protein as protein, medium-chain fatty acid-containing fats and phospholipids as lipids, and sugars as It can be appropriately adjusted depending on the content of ( Palatinose (registered trademark), etc.), the disease state, medical condition, age, weight, use, etc. of the ingestion target.

  Preferred examples of the mixing ratio of oleic acid to all fatty acids (total fatty acid composition) in the agent of the present invention are 25% by weight or more, 25 to 95% by weight, 25 to 90% by weight, 25 to 80% by weight, 25 to 25% by weight. 70%, 30-70%, 30-60%, 30-50% or 35-45% by weight. Here, the “total fatty acids” of the present invention means the total amount of free fatty acids and constituent fatty acids in lipids contained in the agent of the present invention.

  Preferred examples of the amount of oleic acid are 0.5 to 8 g, 0.7 to 7 g, 0.8 to 6 g, 1 to 5 g, 1 to 3 g, 1 to 2.2 g, and 1. 2-4 g, 1.4-3 g, 1.6-2 g. Such a compounding amount is particularly preferable when the oleic acid-containing fat or oil is high oleic high oleic sunflower oil.

  The medium-chain fatty acid-containing fats and oils of the present invention include, for example, commercially available mixed oils containing medium-chain fatty acid triglycerides (commercially available medium-chain fatty acid oils). Further, as the medium-chain fatty acid of the present invention, for example, a medium-chain fatty acid having 8 to 14 carbon atoms (preferably a medium-chain saturated fatty acid) can be used, and preferably, caprylic acid, capric acid, lauric acid, or the like is used. .

  The medium-chain fatty acid content in the medium-chain fatty acid-containing fat or oil of the present invention is not particularly limited as long as the effects of the present invention are not impaired, but is preferably 50% by weight or more, more preferably 70% by weight or more, and further preferably Is 90% by weight or more, and more preferably 100% by weight.

The blending ratio and blending amount of the medium-chain fatty acid in the agent of the present invention may be determined based on other components (protein hydrolyzate and fermented milk protein as a protein, phospholipid and oleic acid-containing fats and oils as lipids, and palatinose as saccharides ) (Registered trademark) ), the disease state, medical condition, age, body weight, use, etc. of the subject to be ingested.

  Preferred examples of the mixing ratio of the medium-chain fatty acid to the total fatty acids in the agent of the present invention are 5% by weight or more, 5 to 95% by weight, 10 to 90% by weight, 15 to 80% by weight, 15 to 70% by weight, 20 to 70% by weight, 20 to 60% by weight, 20 to 40% by weight or 20 to 30% by weight.

  Preferred examples of the amount of the medium-chain fatty acid include 0.01 to 4 g, 0.02 to 3 g, 0.05 to 2 g, 0.08 to 1.5 g, and 0.1 to 1.2 g per 100 ml of the agent. , 0.2-1 g, 0.4-0.8 g or 0.4-0.7 g.

  Further, the agent of the present invention preferably further contains a polyunsaturated fatty acid-containing fat or oil as a lipid. As the polyunsaturated fatty acid of the present invention, for example, a polyunsaturated fatty acid having 18 to 24 carbon atoms and an unsaturated degree of 2 to 8, preferably 18 to 22 carbon atoms and an unsaturated degree Polyunsaturated fatty acids having 2 to 8 carbon atoms, more preferably polyunsaturated fatty acids having 18 to 22 carbon atoms and a degree of unsaturation of 2 to 6 can be used, and linoleic acid, linolenic acid, docosahexaene can be used. Known fatty acids such as acid (DHA), eicosapentaenoic acid (EPA) and arachidonic acid can be used. For example, commercially available purified fish oil containing the above fatty acids such as DHA and EPA can be used as a raw material for polyunsaturated fatty acids.

The blending ratio and blending amount of the polyunsaturated fatty acid may be determined according to other components (protein hydrolyzate and fermented milk protein as protein, medium-chain fatty acid-containing fats and oils as lipids, phospholipids and oleic acid-containing fats and oils, and sugars). It can be appropriately adjusted depending on the content of ( Palatinose (registered trademark), etc.), the disease state, medical condition, age, weight, use, etc. of the ingestion target.

  Preferable examples of the blending ratio of the polyunsaturated fatty acid with respect to the total fatty acids in the agent of the present invention are 25 wt% or more, 25 to 90 wt%, 25 to 80 wt%, 25 to 70 wt%, 30 to 70 wt% % Or 30 to 60% by weight. In another preferred example of the blending ratio of the polyunsaturated fatty acid, 10% by weight or more, 10% by weight to 70% by weight, 10% by weight to 60% by weight, 10% by weight to 50% by weight, 10% by weight -40 wt%, 10 wt% -30 wt%, 15 wt% -30 wt% or 15 wt% -20 wt%.

  Preferable examples of the amount of the polyunsaturated fatty acid include 0.01 to 5 g, 0.02 to 4 g, 0.05 to 3 g, 0.08 to 2 g, 0.1 to 1 g, and 0 to 100 g per 100 ml of the agent. .15 to 2 g, 0.2 to 1 g, 0.15 to 0.5 g, 0.2 to 1 g, 0.3 to 0.8 g, 0.4 to 0.6 g, 0.18 to 0.3 g . Such an amount is particularly preferable when the raw material of the polyunsaturated fatty acid is a purified fish oil.

  Since the above-mentioned medium-chain fatty acids and polyunsaturated fatty acids have a unique flavor and the like, it is generally difficult for a person with anorexia to take it as it is. However, in the agent of the present invention, since the fermented milk protein is essential, the refreshingness derived from the fermented milk can also be felt, so that even if the medium-chain fatty acid or the polyunsaturated fatty acid contains a necessary amount, ingestion is not possible. Easy.

  Further, the agent of the present invention preferably further contains a long-chain saturated fatty acid as a lipid. As the long-chain saturated fatty acid of the present invention, for example, a saturated fatty acid having 16 to 24 carbon atoms, preferably a saturated fatty acid having 16 to 22 carbon atoms, more preferably a saturated fatty acid having 16 to 20 carbon atoms, still more preferably Saturated fatty acids having 16 to 18 carbon atoms can be used. Specific examples of such long-chain saturated fatty acids include known fatty acids such as palmitic acid and stearic acid.

  Preferred examples of the mixing ratio of the long-chain saturated fatty acid to the total fatty acids in the agent of the present invention are 15% by weight or more, 15 to 95% by weight, 15 to 90% by weight, 15 to 80% by weight, 15 to 70% by weight. , 15 to 50% by weight, 15 to 30% by weight or 15 to 25% by weight.

  Preferred examples of the amount of the long-chain saturated fatty acid are 0.01 to 5 g, 0.1 to 1 g, 0.15 to 0.8 g, 0.18 to 0.7 g, or 0.35 to 100 ml of the agent. 0.6 g.

It is preferable to mainly use palatinose (registered trademark) as a raw material of the saccharide of the present invention. Sugar alcohols (sorbitol, xylitol, maltitol) can be used instead of or together with Palatinose (registered trademark) . In the case of palatinose (registered trademark) , for example, commercially available palatinose (registered trademark) raw materials such as palatinose (registered trademark) syrup, reduced palatinose (registered trademark) , and palatinose (registered trademark) starch are used. Can be used.

The amount of the saccharide (preferably Palatinose (registered trademark) ) of the present invention is determined by the amount of other components (protein hydrolyzate and fermented milk protein as a protein, medium-chain fatty acid-containing fat and oil as a lipid, phospholipid and oleic acid-containing fat and oil). Oils and fats), the disease state, disease state, age, body weight, use, etc., of the subject to be ingested. Preferred examples of the amount of the carbohydrate in the agent of the present invention are 1 to 15 g, 1.5 to 12 g, 2 to 10 g, 3 to 9 g, 4 to 8 g or 5 to 7 g per 100 ml of the agent.

As a raw material of the saccharide of the present invention, besides Palatinose (registered trademark) , a known saccharide can be blended for the purpose of nutritional design and improvement of palatability. Known dietary fibers can be blended for nutritional design and health promotion. Further, a known saccharide such as dextrin may be blended for the purpose of nutritional design and improvement of directivity.

  In the agent of the present invention, the weight ratio of protein to lipid is preferably from 0.3: 1 to 3: 1, more preferably from 1.4: 1 to 2: 1.

  In the agent of the present invention, the weight ratio of protein to saccharide is preferably 1: 2 to 1:20, more preferably 1: 2 to 1: 4.

  In the agent of the present invention, the weight ratio of lipid to saccharide is preferably 1: 3 to 1: 7, more preferably 1: 4 to 1: 6.

  Further, the calorific value of the agent of the present invention can be arbitrarily adjusted by appropriately adding proteins, lipids and carbohydrates. For example, suitable examples of the calorific value of the agent of the present invention are 50 to 150 kcal, 60 to 140 kcal, 70 to 130 kcal, 80 to 120 kcal or 90 to 110 kcal per 100 ml of the agent.

  In the preparation of the present invention, the energy ratio (caloric value) of protein, lipid and carbohydrate to the whole preparation is not particularly limited as long as the effect of the present invention is not impaired, but is substantially in accordance with the nutritional requirements of the sixth revised Japanese. For example, for example, the energy ratio of protein to the whole agent is 15 to 25%, the energy ratio of lipid to the whole agent is 20 to 30%, and the energy ratio of carbohydrate to the whole agent is 45 to 65%. It can be designed to be.

  In addition to the proteins, lipids, carbohydrates, and dietary fibers described above, water and known raw materials that can be ingested (administered) by humans can be added to the agent of the present invention. For example, from the viewpoint of suppressing side effects, food raw materials, food additives, and the like having a high eating experience can be added. The form of the agent of the present invention may be in any form such as liquid, solid, powder, and gel. Furthermore, the agent of the present invention can be prepared by a known method for producing a nutritional composition.

  The agent of the present invention is preferably constituted in the form of a single oral intake unit. The amount of each component contained in one oral intake unit of the present invention can be set, for example, based on the amount of each of the above components.

  Further, it is preferable that the agent of the present invention is provided in the form of a package in a single oral intake unit. Examples of the unit packaging form per oral intake include a form in which a fixed amount is defined by packs, containers, etc. It may be. Suitable examples of such unit packaging form include supplements, pharmaceutical preparations, and the like.

  The effect of the agent of the present invention can be expected by taking it continuously. As a preferred example of the intake schedule of the agent of the present invention, in the case of a human weighing 60 kg, 200 ml or more per day, 400 ml or more per day, 600 ml or more per day, 800 ml or more per day, 1000 ml or more per day, 1000 ml per day 1200 ml or more, 1600 ml or more per day, or 2000 ml or more per day. In addition, in the case of a human weighing 60 kg, the period is 1 week or more, 2 weeks or more, 3 weeks or more, 4 weeks or more, 6 weeks or more, 8 weeks or more, 12 weeks or more, or 24 weeks or more. Further, for example, continuous ingestion once a week, twice a week, three times a week, four times a week, five times a week, six times a week, or seven times a week It is preferable that

According to another aspect of the present invention, an effective amount of a composition containing a protein hydrolyzate and a fermented milk protein as a protein; a medium-chain fatty acid as a lipid; and a saccharide is administered to a subject in need thereof. There is provided a method of promoting ghrelin secretion, comprising ingesting. According to a preferred embodiment of the present invention, the composition comprises a protein hydrolyzate and a fermented milk protein as proteins; medium-chain fatty acid-containing fats and oils, phospholipid and oleic acid-containing fats and oils as lipids, and palatinose ( (Registered trademark) . According to a preferred embodiment of the present invention, the composition further contains a polyunsaturated fatty acid as a lipid. Further, according to another preferred embodiment of the present invention, the method for promoting ghrelin secretion comprises enhancing eating, promoting fat accumulation, suppressing insulin secretion, suppressing brown adipose tissue function, promoting gastrointestinal motility, enhancing gastric acid secretion, and exocrine pancreas. It is used for hypertension, sympathetic nervous system depression, vasodilation, increased cardiac contractility or protection of cardiomyocytes. Further, according to another preferred embodiment of the present invention, the method for promoting ghrelin secretion comprises enhancing eating, promoting fat accumulation, suppressing insulin secretion, suppressing brown adipose tissue function, promoting gastrointestinal motility, enhancing gastric acid secretion, and exocrine pancreas. It is a method for hyperactivity, sympathetic nervous system depression, vasodilation, increased cardiac contractility or protection of cardiomyocytes.

  According to another preferred embodiment of the present invention, the method for promoting ghrelin secretion is a method for treating a subject. According to still another aspect, the method for promoting ghrelin secretion is a non-therapeutic method except medical practice. The “treatment” of the present invention includes not only treating an established condition / symptom, but also preventing a condition / symptom that may be established in the future. Further, the “effective amount” can be determined according to the intake plan of the ghrelin secretagogue.

  In the method of the present invention, the composition (agent) used for promoting ghrelin secretion can preferably be taken orally. According to a preferred embodiment, the composition can be taken with a meal.

  According to one embodiment of the present invention, there is provided use of a composition containing a protein hydrolyzate and a fermented milk protein as a protein; a medium-chain fatty acid as a lipid; and a saccharide in the production of a ghrelin secretagogue. You. According to another aspect, there is provided use of a composition containing a protein hydrolyzate and a fermented milk protein as a protein; a medium-chain fatty acid as a lipid; and a saccharide for a ghrelin secretagogue. According to yet another aspect, there is provided a composition for promoting ghrelin secretion, comprising a protein hydrolyzate and a fermented milk protein as a protein; a medium-chain fatty acid as a lipid; and a saccharide. Further, according to a preferred embodiment of the present invention, any of the above-mentioned compositions includes a protein hydrolyzate and a fermented milk protein as proteins; medium-chain fatty acid-containing fats and oils as phospholipids, phospholipid and oleic acid-containing fats and oils; Contains Palatinose (registered trademark). According to a more preferred aspect of the present invention, any of the above compositions further contains a polyunsaturated fatty acid as a lipid.

  The subject is not particularly limited as long as it does not interfere with the effects of the present invention, but is preferably a mammal, and more preferably a human.

  Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto. In the following examples,% means% by weight unless otherwise specified. Further, the unit and the measuring method in the specification of the present application follow the rules of Japanese Industrial Standards (JIS).

(Test Example 1)
Twenty-four 7-week-old male C57BL / 6 mice (Japan SLC) were divided into 3 groups of 8 mice each. Specifically, a group to which a powder of the ghrelin secretagogue of the present invention prepared in advance was administered (a ghrelin secretagogue group), a group to which a powder of a control nutrition composition was administered (control group), a standard animal feed ( A group to which the powder of CRF-1) was administered (CRF-1 group).
The nutritional compositions of the ghrelin secretagogue of the present invention and the nutritional composition of the control are as shown in Table 1. Table 2 shows the amounts of the raw materials for protein, sugar, and lipid. The content of oleic acid contained in the ghrelin secretion promoter in the table was 39% in the fatty acid composition.

In each group, blood was collected from the abdominal vena cava after freely feeding for 2 weeks. Blood was collected in a tube containing a protease inhibitor Pefabloc SC (Sigma), which was 1/100 of the blood volume, and mixed by tapping lightly. This was centrifuged at 7000 rpm at 4 ° C. for 2 minutes to separate plasma. To the obtained plasma, 1N HCl was added in an amount of 1/10 of the plasma to obtain a ghrelin concentration measurement plasma.
As the ghrelin concentration, the concentration of acyl ghrelin, which is active ghrelin, was measured. Acyl ghrelin concentration in plasma was measured using an ELISA kit (SCETI: Active Ghrlin ELISA kit). Plasma was diluted 5-fold with an assay buffer, measured, and corrected for the dilution factor to calculate the acylghrelin concentration.

  As a result, the acyl ghrelin concentration of the ghrelin secretagogue group was 82.8 ± 37.7 (fmol / ml), the acyl ghrelin concentration of the control group was 46.9 ± 12.0 (fmol / ml), In addition, the acyl ghrelin concentration of the CRF-1 group was 38.0 ± 18.9 (fmol / ml). As described above, in the ghrelin secretagogue group, the blood activated ghrelin (acyl ghrelin) concentration was significantly increased as compared with the control group and the CRF-1 group.

  In addition, what was prepared according to the procedure of said (1)-(5) of this application was used for the whey protein degradation product in Table 1. Indigestible dextrin was used as a dietary fiber.

  Table 3 shows the composition of all fatty acids in the preparations in Table 1.

Table 4 shows composition examples of milk phospholipids in Table 1.

Table 5 shows the amounts of oleic acid, medium-chain fatty acids, and polyvalent fatty acids in the agents shown in Table 1.

(Test Example 2)
Forty 40 male 9-week-old C57BL / 6 mice (Japan SLC) were divided into 4 groups of 10 mice each. Specifically, a group to which the powder of the ghrelin secretagogue of the present invention prepared in advance in Test Example 1 was administered (a group of ghrelin secretion promoters), and a powder of the control nutritional composition described in Test Example 1 were administered. Group (control group), group to which AIN93G powder as animal purified feed was administered (AIN93G group), group to which powdered AIN93G as animal purified feed to which medium-chain fatty acid triglyceride was added (AIN93G + MCT). (AIN93G + MCT group) was tested. In AIN93G + MCT, the amount of the medium-chain fatty acid per energy was the same as that of the ghrelin secretion promoter of the present invention. In addition, the amounts of vitamins and minerals of the ghrelin secretagogue, AIN93G, and AIN93G + MCT were set to be substantially the same. The nutritional composition and the ghrelin secretagogue of the control in this test example are the same as those shown in Tables 1 and 2.

The compositions of AIN93G and AIN93G + MCT were as follows (Tables 6 and 7).

After each group had free access to food for 2 weeks (fasted overnight), blood was collected from the abdominal vena cava. Blood was collected in a tube containing a protease inhibitor Pefabloc SC (Sigma), which was 1/100 of the blood volume, and mixed by light tapping. This was centrifuged at 7000 rpm at 4 ° C. for 2 minutes to separate plasma. 1N HCl was added to the obtained plasma in an amount of 1/10 of that of the plasma, and used for ghrelin concentration measurement.
The ghrelin concentration was determined by measuring the concentration of the active form, acyl ghrelin. Acyl ghrelin concentration in plasma was measured with an ELISA kit (SCETI: Active Ghrlin ELISA kit).

As a result, the ghrelin secretagogue group had an acyl ghrelin concentration of 274 ± 172 (fmol / ml), the control group had an acyl ghrelin concentration of 89 ± 22 (fmol / ml), and the AIN93G group had an acyl ghrelin concentration of 76 ± 23 (fmol / ml), and the acylghrelin concentration of the AIN93G + MCT group was 110 ± 56 (fmol / ml). The ratio of active ghrelin / inactive ghrelin was 0.75 ± 0.14 in the ghrelin secretagogue group and 0.53 ± 0.16 in the control group.
That is, in the ghrelin secretagogue group, the blood activated ghrelin (acyl ghrelin) concentration was significantly increased as compared with the control group, the AIN93G group, and the AIN93G + MCT group.

(Test Example 3)
Colorectal cancer patients (2) and malignant lymphoma (1) undergoing chemotherapy were ingested with a ghrelin secretagogue. Specifically, three to four courses of 600 mL / day were taken for three days before the start of chemotherapy, and 200 mL / day for four days after the start of chemotherapy. The blood active ghrelin concentration and the inactive ghrelin concentration before and after ingestion of the ghrelin secretagogue were measured, and the ratio of active ghrelin / inactive ghrelin was calculated.

  As a result, the ratio of active ghrelin / inactive ghrelin before and after taking the ghrelin secretagogue increased from 0.137 to 0.206 in one colorectal cancer patient, and increased in another colorectal cancer patient. It rose from 0.116 to 0.272. In patients with malignant lymphoma, the level increased from 0.186 to 0.250.

  The average daily dietary intake (calorie intake) before and after ingestion of the ghrelin secretagogue increased from 1808 kcal to 2304 kcal in one colon cancer patient, and from 1242 kcal to 1624 kcal in a malignant lymphoma patient.

Claims (17)

Medium-chain fatty acid, milk phospholipids and fish oil as the lipid; whey protein hydrolyzate and fermented milk protein as a protein containing palatinose (registered trademark) as well as carbohydrates, ghrelin secretion promoter. The ghrelin secretagogue according to claim 1 , wherein the whey protein hydrolyzate is a raw material protein hydrolyzate selected from whey protein concentrate (WPC) and whey protein isolate (WPI) . The ghrelin secretagogue according to claim 1 or 2 , wherein the blending amount of the whey protein hydrolyzate is 0.5 to 3 g per 100 ml. The ghrelin secretion promoter according to any one of claims 1 to 3 , wherein the fermented milk protein is derived from whey excreted from fermented milk. The ghrelin secretagogue according to any one of claims 1 to 4 , wherein the fermented milk protein is derived from fermented milk obtained by fermenting skim milk using Lactobacillus Bulgaricus, Streptococcus Thermophilus, or a combination thereof. The ghrelin secretagogue according to any one of claims 1 to 5 , wherein the fermented milk protein is derived from fresh cheese. The ghrelin secretagogue according to any one of claims 1 to 6 , wherein the amount of the fermented milk protein is 0.5 to 6 g per 100 ml. The whey protein hydrolyzate is obtained by hydrolyzing a whey protein isolate (WPI) with an endoprotease derived from Bacillus licheniformus and hydrolyzing with trypsin derived from porcine pancreas. Item 8. The ghrelin secretagogue according to any one of Items 1 to 7 . The ghrelin secretagogue according to any one of claims 1 to 8 , wherein the fractional molecular weight of the whey protein hydrolyzate is 10,000 or less. The ghrelin secretagogue according to any one of claims 1 to 9 , wherein the amount of the saccharide is 1 to 15 g per 100 ml. The ghrelin secretagogue according to any one of claims 1 to 10 , wherein the amount of oleic acid in the lipid is 25% by weight or more of the total fatty acids. The ghrelin secretagogue according to any one of claims 1 to 11 , wherein the amount of the medium-chain fatty acid is 0.01 to 4 g per 100 ml. The ghrelin secretagogue according to any one of claims 1 to 12 , wherein the calorific value of the agent is 50 to 150 kcal per 100 ml. The ghrelin secretagogue according to any one of claims 6 to 13 , wherein the fresh cheese is quark. The ghrelin secretagogue according to any one of claims 1 to 14 , wherein the amount of the phospholipid is 0.01 to 0.5 g per 100 ml. The ghrelin secretagogue according to any one of claims 1 to 15 , wherein the medium-chain fatty acid is a medium-chain fatty acid having 8 to 14 carbon atoms. Enhancement of eating, promotion of fat accumulation, suppression of insulin secretion, suppression of brown adipose tissue function, promotion of gastrointestinal motility, enhancement of gastric acid secretion, enhancement of pancreatic exocrine secretion, suppression of sympathetic nervous system, vasodilation, enhancement of cardiac contractility or protection of cardiomyocytes A ghrelin secretagogue according to any one of claims 1 to 16 for use.