Ornithine blood concentration enhancer

Abstract

To provide a material for increasing the level of ornithine in blood when ornithine is ingested.SOLUTION: An agent for increasing the level of ornithine in blood contains catechin as an active ingredient and is used in combination with ornithine or a salt thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an ornithine blood concentration enhancer that enhances the blood concentration of ornithine when ornithine is ingested. [Background technology]

[0002] L-ornithine is a type of amino acid, but exists in the body as a free, non-proteinogenic amino acid. Orally ingested L-ornithine or its salts are absorbed into the body, and various physiological effects have been confirmed in animals and humans when orally ingested. For example, 1) it stimulates the pituitary gland to promote secretion of growth hormone, thereby increasing protein synthesis (Non-Patent Document 1), and has a muscle-building effect (Non-Patent Document 2); 2) it has immune-enhancing effects, such as suppressing the loss of thymus weight due to burns (Non-Patent Document 3), enhancing the activity of macrophages whose activity has been reduced by dexamethasone administration (promoting TNF-α production) (Non-Patent Document 4), and increasing the tumor cell division inhibitory activity of macrophages and the cytotoxic activity of NK cells in animals transplanted with hepatocellular carcinoma (Non-Patent Document 5); and 3) repairing damaged intestinal tracts. It has been reported that: 1) it promotes the production of collagen (Non-Patent Documents 6 and 7); 2) it improves skin quality (complexion, wrinkles, firmness) (Non-Patent Document 9), which is thought to be due to its collagen synthesis promoting effect and wound recovery promoting effect (Non-Patent Document 8), and it also improves the subjective condition of the skin (irritation, dryness), improves the viscoelasticity of the skin, and reduces hidden blemishes (Non-Patent Document 10); 3) it improves sleep and wakefulness due to its anti-stress effect (inhibiting the secretion of cortisol and corticosterone) (Non-Patent Documents 11 and 12) (Non-Patent Document 13); and 4) it increases blood GLP-1 and insulin concentrations (Non-Patent Document 14). Therefore, increasing the blood concentration of ingested ornithine is considered to be significant in terms of effectively exerting the various physiological actions of ornithine.

[0003] On the other hand, Non-Patent Document 15 discloses that when ornithine hydrochloride is orally taken at a dose of 3.0 g / day for three months, the basal concentration of ornithine in plasma does not increase but rather decreases. Therefore, even if ornithine is continuously orally taken, it is not necessarily possible to say that the above-mentioned various physiological effects are effectively exerted.

[0004] It has been reported that the combined use of catechins and ornithine significantly improves ammonia metabolism in hepatocytes compared with the combined use of catechins or ornithine (Patent Document 1). However, it is not known at all that the combined use of catechins and ornithine improves the ornithine concentration in blood. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Patent No. 6469283 [Non-patent literature]

[0006] [Non-Patent Document 1] Nutrition Research. vol.10 239-245, 1990 [Non-patent document 2] Clinical Sports Medicine. vol.22(7) 798-803, 2005 [Non-patent document 3] Nutrition. Vol.15(10) 773-777, 1999 [Non-patent document 4] Journal of leukocyte Biology. vol.67(6) 834-840, 2000 [Non-Patent Document 5] Clinical Science. vol.97(6) 657-669, 1999 [Non-patent document 6] Critical Care Medicine. vol.26(1) 120-125, 1998 [Non-Patent Document 7] Transplantation. vol.63(5) 636-639, 1997 [Non-patent document 8] Journal of Surgical Research. vol.106(2) 299-302, 2002 [Non-Patent Document 9] Food and Development. vol.40(11) 62-64, 2005 [Non-Patent Document 10] Amino Acid Research. vol.6(1) 43-45, 2012 [Non-Patent Document 11] Neuroscience Letters. vol.506(2) 287-291, 2012 [Non-Patent Document 12] BioPsychoSocial Medicine. vol.7(1) 6, 2013 [Non-Patent Document 13] Nutrition Journal. vol.13 53, 2014 [Non-Patent Document 14] Scientific Reports. Vol.6 34665, 2016 [Non-Patent Document 15] Jpn Pharmacol Ther (Pharmacology and Therapy) vol.41 No.8 779-787,2013 Summary of the Invention [Problem to be solved by the invention]

[0007] The present invention relates to providing a material that increases the blood concentration of ornithine when ornithine is ingested. [Means for solving the problem]

[0008] The present inventors have unexpectedly found that when ornithine is ingested, the blood concentration of ornithine can be increased by taking catechins in combination with ornithine.

[0009] That is, the present invention relates to the following 1) to 4). 1) An ornithine blood concentration enhancer that uses catechins as an active ingredient and is used together with ornithine or its salt. 2) An ornithine blood concentration enhancer comprising a combination of catechins and ornithine or a salt thereof. 3) A food for increasing ornithine blood levels, which contains catechins as an active ingredient and is used together with ornithine or its salt. 4) A food for increasing ornithine blood levels, which is a combination of catechins and ornithine or a salt thereof. [Effects of the Invention]

[0010] According to the present invention, when ornithine is ingested, the blood concentration of ornithine can be increased, and the various physiological actions of ornithine can be effectively exerted. [Brief explanation of the drawings]

[0011] [Figure 1] FIG. 1 is a diagram showing an outline of the Phase I intake period and the Phase II intake period. [Figure 2] Blood ornithine concentration after combined intake of catechins and ornithine. [Figure 3] The ratio of ornithine in the blood after catechin intake. DETAILED DESCRIPTION OF THE INVENTION

[0012] In the present invention, "catechins" is a general term that includes non-epi-catechins such as catechin (C), gallocatechin (GC), catechin gallate (Cg), and gallocatechin gallate (GCg), as well as epi-catechins such as epicatechin (EC), epigallocatechin (EGC), epicatechin gallate (ECg), and epigallocatechin gallate (EGCg). In the present invention, at least one of these non-polymer catechins may be contained. In the present invention, the content of catechins is defined based on the total amount of the eight non-polymer catechins. The catechins used in the present invention are generally contained in tea extracts extracted from tea leaves, their concentrates, or purified products thereof, and therefore, those obtained from these are preferably used. Here, "tea extract" refers to a product extracted from tea leaves using water or a hydrophilic organic solvent without being subjected to concentration or purification procedures. The hydrophilic organic solvent may be, for example, an alcohol such as ethanol. A kneader or column may also be used for extraction. Furthermore, a "tea extract concentrate" refers to a product obtained by removing at least a portion of the solvent from a tea extract extracted from tea leaves using water or a hydrophilic organic solvent to increase the concentration of catechins. This concentrate can be prepared, for example, by methods described in JP-A-59-219384, JP-A-4-20589, JP-A-5-260907, JP-A-5-306279, etc. Furthermore, the term "purified tea extract" refers to a product obtained by treating a tea extract or a concentrate thereof with a solvent or adsorbent to increase the purity of catechins in the solid content, and can be prepared, for example, by the methods described in JP-A Nos. 2004-147508, 2007-282568, 2006-160656, and 2008-079609. Examples of tea leaves used for extraction include tea plants selected from the genus Camellia, such as C. sinensis and C. assamica, the Yabukita species, or hybrids thereof. Tea leaves can be broadly classified into unfermented teas, semi-fermented teas, and fermented teas depending on the processing method. Examples of unfermented teas include green teas such as sencha, bancha, tencha, kamairicha, kukicha, bocha, and budcha. Examples of semi-fermented teas include oolong teas such as Tieguanyin, Irodane, Ogongui, and Wuyiyancha. Examples of fermented teas include black teas such as Darjeeling, Assam, and Sri Lanka. These can be used alone or in combination of two or more.

[0013] In the present invention, ornithine can be used in the form of a free form or a salt thereof. Ornithine may be in the L-form, D-form, DL-form, or a mixture thereof, but is preferably in the L-form.

[0014] Examples of ornithine salts include acid addition salts, metal salts, ammonium salts, organic amine addition salts, and amino acid addition salts. Examples of the acid addition salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, and phosphate, and organic acid salts such as acetate, maleate, fumarate, citrate, malate, lactate, α-ketoglutarate, gluconate, and caprylate. Examples of the metal salts include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, and zinc salt. Examples of the ammonium salts include salts of ammonium and tetramethylammonium. Examples of the organic amine addition salts include salts of morpholine and piperidine. Examples of the amino acid addition salts include salts of glycine, phenylalanine, lysine, aspartic acid, and glutamic acid. Among these, sodium salts and hydrochlorides are preferred.

[0015] Ornithine or a salt thereof can be obtained by isolation and purification from plants or animals containing them, chemical synthesis, fermentation production, etc. Alternatively, it may be purchased as a commercially available product.

[0016] The catechins of the present invention are used in combination with ornithine or a salt thereof, and the manner of use may be as a combination drug in which effective amounts of each are formulated in a single dosage form at an appropriate blend ratio, or as a single formulation containing effective amounts of each drug, which may be used simultaneously or separately at intervals.

[0017] In the present invention, the ratio of the combination of catechins and ornithine or a salt thereof can be appropriately selected, but for example, per 1 part by mass of catechins, the amount of ornithine or a salt thereof (converted to free ornithine) is preferably 0.1 parts by mass or more, more preferably 0.5 parts by mass or more, more preferably 1 part by mass or more, more preferably 2 parts by mass or more, and preferably 10 parts by mass or less, more preferably 8 parts by mass or less, more preferably 5 parts by mass or less, more preferably 4 parts by mass or less. Also, the amount is preferably 0.1 to 10 parts by mass, more preferably 0.5 to 8 parts by mass, more preferably 1 to 5 parts by mass, more preferably 2 to 4 parts by mass.

[0018] As shown in the examples below, when catechins are used in combination with ornithine and orally taken for two weeks, the base concentration of ornithine in blood (fasting resting concentration) is significantly improved. This is a completely unexpected effect, considering that in the above-mentioned Non-Patent Document 15, when ornithine hydrochloride is orally taken for three months, the base concentration of ornithine in plasma does not increase but rather decreases. Therefore, when used together with ornithine or a salt thereof, catechins can become an ornithine blood concentration enhancer that can increase the blood concentration of ornithine, and can be used to produce such an ornithine blood concentration enhancer. Furthermore, a combination of catechins and ornithine or a salt thereof can be used to increase the blood concentration of ornithine, can serve as an ornithine blood concentration enhancer, and can also be used to produce an ornithine blood concentration enhancer.

[0019] It should be noted that the "use" of the catechins used together with ornithine or its salt, or the combination of catechins and ornithine or its salt to improve ornithine blood concentration can be used in human or non-human animals, and can be therapeutic or non-therapeutic use.Here, "non-therapeutic" does not include the concept of medical practice, that is, does not include the concept of the method of surgery, treatment or diagnosis of human beings, more specifically, does not include the concept of the method of surgery, treatment or diagnosis that a doctor or the person who is instructed by a doctor carries out on human beings.

[0020] As mentioned above, ornithine enhances protein synthesis by promoting the secretion of growth hormone (Non-Patent Document 1), has muscle-building effects (Non-Patent Document 2), has immune-enhancing effects (Non-Patent Documents 3-5), promotes the repair of damaged intestinal tracts (Non-Patent Documents 6 and 7), improves skin quality (Non-Patent Documents 8-10), improves sleep and wakefulness (Non-Patent Document 13), and increases blood GLP-1 and insulin concentrations (Non-Patent Document 14). Therefore, it is believed that catechins used together with ornithine or its salts, or a combination of catechins and ornithine or its salts, will exert the following effects through increasing the blood concentration of ornithine: promoting secretion of growth hormone, promoting protein synthesis, strengthening muscles, enhancing immunity, promoting intestinal repair, improving skin quality, improving sleep and wakefulness, and increasing blood GLP-1 or insulin concentrations. In other words, the ornithine blood concentration enhancer of the present invention can be used to promote growth hormone secretion, promote protein synthesis, strengthen muscles, enhance immunity, promote intestinal repair, improve skin quality, improve sleep and wakefulness, and increase blood GLP-1 or insulin concentrations. Here, "promoting protein synthesis" refers to the promotion of protein synthesis, which is responsible for muscle synthesis promoted by growth hormone, and "immune enhancement" refers to the enhancement of immunity expected from the suppression of a decrease in thymus weight, activation of macrophages, and an increase in the cytotoxic activity of NK cells. "Promoting intestinal repair" means promoting the recovery of damaged digestive tracts, "improving skin quality" means improving skin viscoelasticity, reducing blemishes, and improving complexion, skin wrinkles, skin firmness, etc., and "improving sleep and awakening" means improving sleep quality, such as subjective ease of falling asleep, maintaining sleep, and increasing sleep duration.

[0021] The ornithine blood concentration enhancer can be an oral pharmaceutical, quasi-drug, supplement, or food product for enhancing the blood concentration of ornithine, or can be a material or preparation to be incorporated into these. In addition to general foods and beverages, the above foods also include foods that are based on the concept of improving blood ornithine concentrations, thereby promoting growth hormone secretion, promoting protein synthesis, strengthening muscles, enhancing immunity, promoting intestinal repair, improving sleep and wakefulness, and increasing blood GLP-1 or insulin concentrations, and are labeled as such as necessary, as well as functional foods, foods for specified health uses, foods for patients, and foods with nutritional functions.

[0022] The above-mentioned medicine (including quasi-drugs) that is compounded with catechins or catechins and ornithine or its salt can be administered in any dosage form.As dosage form, for example, oral administration by tablet, capsule, granule, powder, syrup etc., or parenteral administration by injection, suppository, inhalant, transdermal absorbent, external preparation etc. can be included, but the preferred dosage form is oral administration. To prepare pharmaceutical formulations in such various dosage forms, the catechins of the present invention, or the catechins and ornithine or a salt thereof, may be used in appropriate combination with other pharmaceutically acceptable excipients, binders, bulking agents, disintegrants, surfactants, lubricants, dispersants, buffers, preservatives, flavoring agents, fragrances, coating agents, carriers, diluents, etc., as necessary.

[0023] In addition, the forms of the above-mentioned foods containing catechins or catechins combined with ornithine or its salts include various food compositions such as breads, cakes, noodles, confectioneries, jellies, frozen foods, ice cream, dairy products, and beverages, as well as forms similar to the above-mentioned oral administration formulations (tablets, capsules, syrups, etc.). To prepare various types of food products, the catechins of the present invention, or the catechins and ornithine or a salt thereof, can be used in appropriate combination with other food ingredients, solvents, softeners, oils, emulsifiers, preservatives, flavorings, stabilizers, colorants, antioxidants, moisturizers, thickeners, etc., as needed.

[0024] The content of catechins in the above-mentioned pharmaceuticals (including quasi-drugs) and foods is not particularly limited, but is preferably 0.1% by mass or more, more preferably 1% by mass or more, and even more preferably 3% by mass or more, and is preferably 20% by mass or less, more preferably 10% by mass or less, and even more preferably 5% by mass or less. Further, examples of the content include 0.1 to 20% by mass, 0.1 to 10% by mass, 0.1 to 5% by mass, 1 to 20% by mass, 1 to 10% by mass, 1 to 5% by mass, 3 to 20% by mass, 3 to 10% by mass, and 3 to 5% by mass.

[0025] The content of ornithine or a salt thereof in the pharmaceuticals (including quasi-drugs) and foods is not particularly limited, but is preferably 0.3% by mass or more, more preferably 3% by mass or more, even more preferably 5% by mass or more, even more preferably 9% by mass or more, and is preferably 60% by mass or less, more preferably 30% by mass or less, even more preferably 20% by mass or less, even more preferably 15% by mass or less, calculated as the free ornithine. Further, examples of the content include 0.3 to 60% by mass, 0.3 to 30% by mass, 0.3 to 20% by mass, 0.3 to 15% by mass, 3 to 60% by mass, 3 to 30% by mass, 3 to 20% by mass, 3 to 15% by mass, 5 to 60% by mass, 5 to 30% by mass, 5 to 20% by mass, 5 to 15% by mass, 9 to 60% by mass, 9 to 30% by mass, 9 to 20% by mass, and 9 to 15% by mass.

[0026] In the present invention, the dosage and administration schedule of catechins and ornithine or a salt thereof may be appropriately determined by those skilled in the art according to the species, weight, sex, age, condition, or other factors of the subject. For oral administration, examples of the daily dosage of catechins and ornithine or a salt thereof according to the present invention for an adult are as follows, but are not limited thereto: [Catechins] preferably 100 to 3000 mg / 60 kg body weight, more preferably 250 to 2000 mg / 60 kg body weight, even more preferably 250 to 1000 mg / 60 kg body weight, and still more preferably 250 to 600 mg / 60 kg body weight; [Ornithine (free form equivalent)] preferably 100 to 5000 mg / 60 kg body weight, more preferably 250 to 3000 mg / 60 kg body weight, even more preferably 400 to 2000 mg / 60 kg body weight, even more preferably 500 to 2000 mg / 60 kg body weight, and even more preferably 800 to 1600 mg / 60 kg body weight, The above doses are preferably administered, for example, once a day, or divided into two or three or more doses a day. Furthermore, the subjects for administration or intake are not particularly limited as long as they are animals that need or desire it, but examples include humans that need or desire improved blood ornithine concentrations, muscle strengthening, immune enhancement, promotion of intestinal repair, improvement of sleep and wakefulness, etc. [Example]

[0027] The present invention will be explained in more detail below using examples. Example 1 1. Method (1) Subjects Sixteen healthy adult males (age 22.5±2.8 years) participated in the study.

[0028] (2) Experimental design A total of four measurements were taken per subject. Figure 1 shows an outline of the Phase I intake period (pre-measurement, post-measurement) and Phase II intake period (pre-measurement, post-measurement). In the study, the first measurement (pre-measurement) was conducted on Day 1, and from that day onwards, subjects were asked to consume either a control drink (no catechins or ornithine) or an active drink (containing 538.6 mg of catechins and 1592 mg of ornithine) daily for two weeks. The second measurement (post-measurement) was conducted on the final day of ingestion of the test drink. This study was conducted twice as a crossover study, with a washout period of at least two weeks between each test. All subjects consumed one control drink and one active drink during both intake periods. The study materials were provided in a double-blind manner.

[0029] (3) Measurement Subjects arrived at 8:50 AM on an empty stomach. The experiment began at 9 AM, and blood samples were taken (rest). After blood was taken, subjects consumed either the active drink or the control drink. After 60 minutes of rest, blood samples were taken again (pre-exercise), and then subjects performed 60 minutes of cycling exercise at 75% HRmax intensity (a load was specified for each subject, with the same exercise load for all four measurements). Blood samples were taken again immediately after exercise (post-exercise). The ornithine concentration in the collected blood was measured by LC-MS / MS. All data from subjects obtained in two crossover studies was compiled and analyzed by dividing them into four groups based on the type of test beverage consumed and the period (Pre or Post): Pre-control group, Post-control group, Pre-active group, and Post-active group. At each blood collection time point, a Dunnett's test was performed using the Post-active group as the reference group.

[0030] (4) Test substance Catechins: Tea catechin preparation (catechin composition: EGCg 34.84%, EGC 34.43%, ECG 9.75%, EC 8.54%, GC 6.72%, C 2.93%, GCg 1.69%, Cg 1.1%, contains a small amount of caffeine derived from the raw materials) Ornithine: L-ornithine hydrochloride The composition of the test beverages, including the active ingredients, is shown in Table 1.

[0031] [Table 1]

[0032] 2.Results The blood ornithine concentrations measured in the two tests are shown in Figure 2 (mean ± standard error). At rest and immediately after exercise, the Post-active group had significantly (p<0.05) higher levels than the other three groups, including the Pre-active group.

[0033] Example 2 1. Method (1)Animals Mice (Balb / c, 8 weeks old, Charles River Japan) were pre-bred and acclimatized to treadmill running for one week. During the test period, the mice were given free access to the test food AIN76-compliant powdered diet (10% fat) and water. Twenty mice were divided into two groups (control group and catechin group) to avoid differences in body weight and endurance.

[0034] (2) Test plan During the test period (4 weeks), each test product was administered intragastrically 5 days a week, and exercise training (treadmill running (20 m / min, 30 min / day)) was performed 1 hour later. One hour after intragastric administration of each test product, immediately after running on a treadmill at 25 m / min for 60 min, blood was collected from the abdominal aorta by the anesthesiology department. The blood was mixed with 13% EDTA-2K solution at a ratio of 100:1 and centrifuged at 1200 G for 10 min. The supernatant was then collected and stored at -80°C.

[0035] (3) Measurement of blood ornithine The stored plasma samples were subjected to comprehensive analysis of plasma metabolites using CE-TOFMS (Agilent CE-TOFMS system (Agikent)), and the intergroup abundance ratio of ornithine was measured.

[0036] (4) Test substance Control group: water Catechin group: Catechins (0.2g / kg body weight) aqueous solution Catechins: Tea catechin preparation (Polyphenon 70A; Mitsui Norin Co., Ltd.; catechin content: 77.4% (gallate content: 95.1%); catechin composition: EGCg 55.6%, EGC 2.1%, ECg 12.5%, EC 1.0%, GC 0.5%, GCg 4.9%, C 0.2%, Cg 0.6%; caffeine content: 0.195%; % means mass %). Since the tea catechin preparation contains 0.195% by mass of caffeine, the same amount of caffeine (0.4 mg / kg body weight) was administered to Group 1 (control).

[0037] 2.Results The abundance ratio of ornithine in the blood is shown in Figure 3 (mean ± standard deviation). The catechins group did not have higher levels than the control group. In other words, it was revealed that catechins alone do not increase blood ornithine levels. Therefore, it was revealed that the base concentration of ornithine in the blood does not increase with continued ingestion of ornithine alone or catechins alone, but does increase with the use of catechins together with ornithine.

Claims

1. An ornithine blood concentration enhancer containing catechins as active ingredients and used together with ornithine or a salt thereof, which enhances the blood ornithine concentration at fasting rest during continuous ornithine intake compared to when ornithine is not taken.

2. An ornithine blood concentration enhancer comprising a combination of catechins and ornithine or a salt thereof, which enhances the blood ornithine concentration at fasting rest during continuous ornithine intake compared to when ornithine is not taken.

3. This food contains catechins as an active ingredient and is used together with ornithine or a salt thereof to increase blood ornithine levels, and increases blood ornithine levels at rest on an empty stomach during continuous ornithine intake compared to when ornithine is not taken.

4. This food is for increasing ornithine blood levels and is a combination of catechins and ornithine or a salt thereof, and increases the blood ornithine level during fasting and rest while continuously taking ornithine compared to when ornithine is not taken.

5. The ornithine blood concentration enhancer according to claim 1 or 2, or the ornithine blood concentration enhancer according to claim 3 or 4, which is used to promote growth hormone secretion, promote protein synthesis, strengthen muscles, enhance immunity, promote intestinal repair, improve skin quality, improve sleep and awakening, or increase blood GLP-1 or insulin concentrations.

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