JP2023000201A - oral composition - Google Patents

Abstract

To provide a composition for reducing the levels of glycated albumin and/or inhibiting the saccharification of albumin.SOLUTION: Searching for a composition for reducing the levels of glycated albumin and/or inhibiting the saccharification of albumin, the inventors have found out that maclurin or a glycoside thereof has the effect of reducing the levels of glycated albumin and/or inhibiting the saccharification of albumin, completing this invention.SELECTED DRAWING: None

Description

The present invention relates to oral compositions containing maclulin or its glycosides.

Albumin is a protein that exists in important tissues and body fluids such as blood in vivo and performs various functions. Albumin is abundant in blood, and is known to play a role in transporting nutrients and metabolites, maintaining osmotic pressure, and the like (Non-Patent Document 1). In addition, it is known that when the amount of albumin in the blood decreases, the resistance to infections weakens and the efficacy of antibiotic administration decreases, suggesting that albumin also plays a role in the body's defense against infections. (Non-Patent Document 2).

However, when albumin binds to blood glucose (saccharification) and becomes glycoalbumin, the normal function of albumin is lost, and albumin cannot fully perform its original role as described above. Since albumin is a protein that is easily glycated, there has been a demand for the development of a composition that inhibits glycation of albumin and reduces glycoalbumin.

“Chikuba Surgery/Gastroenterology/Proctology Hospital NST No. 32 February 2017 issue”, [online], [searched June 1, 2021], Internet <URL: http://www.chikubageka.jp/ assets/files/pdffolder/nsletter32.pdf > Hiroshi Shibata, "Media Milk Seminar No. 15 December 2007 issue", [online], [searched June 1, 2021], Internet <URL: https://www.j-milk.jp/report/media /f13cn00000000v2a-att/berohe000000k29r.pdf＞

The present invention has been made in view of the background described above, and an object of the present invention is to provide a composition for reducing glycoalbumin and/or inhibiting glycation of albumin.

In searching for a composition that reduces glycoalbumin or inhibits glycation of albumin, the present inventors found that maclurin or its glycoside has the effect of reducing glycoalbumin and/or the effect of inhibiting glycation of albumin. The present inventors have found that it works, and have completed the present invention.

That is, the present invention is as follows.
[1] An oral composition for reducing glycoalbumin containing maclurin or a glycoside thereof.
[2] An oral composition for lowering glycoalbumin containing maclurin or a glycoside thereof as an active ingredient.
[3] The oral composition for lowering glycoalbumin according to [1] or [2], wherein the maclulin or its glycoside is rhodanthenone B.
[4] The oral composition for reducing glycoalbumin according to [1] or [2], wherein the maclulin or its glycoside is derived from mangosteen pericarp.
[5] An oral composition for suppressing glycation of albumin containing maclurin or its glycoside.
[6] An oral composition for suppressing glycation of albumin containing maclurin or its glycoside as an active ingredient.
[7] The oral composition for lowering glycoalbumin according to [5] or [6], wherein the maclulin or its glycoside is rhodanthenone B.
[8] The oral composition for reducing glycoalbumin according to [5] or [6], wherein the maclurin or its glycoside is derived from mangosteen pericarp.

The composition of the present invention exhibits an effect of reducing glycoalbumin and/or an effect of suppressing glycation of albumin.

[1. Macrulin or its glycoside]
The oral composition of the present invention is characterized by containing maclurin or its glycoside. Macrulin or its glycoside contained in the oral composition of the present invention may be purified from plants, chemically synthesized, or commercially available reagents. You may use the containing plant.

Rhodantenone B is particularly preferable as maclurin or its glycoside used in the present invention, because higher effects can be obtained. Rhodantenone B is a kind of maclulin glycoside compound. When a plant containing rhodanthenone B is used as rhodanthenone B, it is preferable to use mangosteen, and it is particularly preferable to use the pericarp of mangosteen, because higher effects can be obtained.

Mangosteen means Garcinia mangostana, which is a plant belonging to the genus Fukugi of the family Fukugiaceae. The mangosteen pericarp means the skin portion of the mangosteen fruit. When mangosteen pericarp is used, parts such as fruits and seeds may be included along with the pericarp. As the mangosteen peel used in the oral composition of the present invention, for example, pulverized products such as powder and granules, squeezed products, and extracts can be used. The squeezed product or extract may be in the form of liquid or slurry, but is preferably used as a dry powder. Among these, pulverized products and extracts are preferred, and extracts are particularly preferred, from the viewpoint of the effects of the present invention. In the present invention, the extract is a concept that includes dry powder of the extract (a powder obtained by drying the extract).

Examples of mangosteen peel extracts include extracts, diluted or concentrated solutions thereof, and dry powders thereof. Solvents used for extraction include, for example, water; lower alcohols such as methanol, ethanol, isopropanol and butanol; lower esters such as ethyl acetate and methyl acetate; acetone; Among these, from the viewpoint of the effect of the present invention, water, ethanol or hydrous ethanol are preferred, and water is particularly preferred. In addition, the obtained extract may be pulverized by spray drying, freeze drying, etc., if necessary, and excipients may be added when pulverizing.

[2. Glycoalbumin decrease or albumin glycation suppression]
(decrease in glycoalbumin)
In the present invention, glycoalbumin reduction means improvement in blood glycoalbumin level, and is a concept including reduction in blood glycoalbumin level and inhibition of increase in blood glycoalbumin level. That is, by ingesting the oral composition of the present invention, an effect of reducing the amount of glycoalbumin in the blood or an effect of suppressing an increase in the amount of glycoalbumin in the blood can be obtained compared to when the composition is not ingested. can.

The oral composition of the present invention can be used as an oral composition for lowering glycoalbumin, and such an oral composition contains maclurin or its glycoside to reduce the amount of glycoalbumin or increase the amount of glycoalbumin. is not particularly limited as long as it can be distinguished from other products as a product in terms of suppressing the The present invention includes any one displaying the function of suppressing the decrease or elevation of glycoalbumin. The oral composition for reducing glycoalbumin of the present invention may display maclurin or its glycoside as an active ingredient. is not limited to For example, the active ingredient may not be specified. In addition, even general foods that are manufactured and sold with indications of uses are included in the scope of the present invention. For example, the scope of the present invention also includes foods and the like that are sold with personal testimonials of those who ingested the foods that refer to reduction or suppression of glycoalbumin increase on their websites. Foods with functional claims containing maclurin or its glycosides as ingredients involved in functionality based on the scientific basis of scientific evidence showing that glycoalbumin decreases or increases, and suppresses the glycation of proteins in the blood. Foods with function claims whose function is to be reported are also included in the scope of the present invention, because the reported labeling substantially means suppression of decrease or increase in glycoalbumin.

Specific examples of the oral composition for lowering glycoalbumin include packaging of the product, etc. that "has a function to lower glycoalbumin", "has a function to improve glycoalbumin", and "suppresses an increase in glycoalbumin". The foods listed in can be exemplified.

(Inhibition of glycation of albumin)
In the present invention, the inhibition of glycation of albumin is a concept including the effect of inhibiting glycation of blood albumin. That is, by ingesting the oral composition of the present invention, it is possible to obtain the effect of suppressing the saccharification of blood albumin as compared to the case of not ingesting the composition.

The oral composition of the present invention can be used as an oral composition for suppressing glycation of albumin. It is not particularly limited as long as it can be distinguished from other products. is included in the scope of the present invention. The oral composition for suppressing glycation of albumin of the present invention may be labeled with maclurin or its glycoside as an active ingredient. is not limited to For example, the active ingredient may not be specified. In addition, even general foods that are manufactured and sold with indications of uses are included in the scope of the present invention. For example, the scope of the present invention also includes a food product that is sold with a home page or the like containing a testimonial about inhibition of albumin saccharification as a personal impression of a person who has taken the product. In addition, based on the scientific basis of functionality, such as papers showing suppression of glycation of albumin, it is a food with function claims that contains maclurin or its glycoside as a functional component, and has the function of suppressing glycation of blood proteins. Foods with function claims that are subject to notification labeling are also included in the scope of the present invention because the notification labeling substantially means inhibition of saccharification of albumin.

A specific example of an oral composition for inhibiting glycation of albumin is a food labeled on the packaging of the product, etc., such as "having a function of inhibiting glycation of albumin."

(Regarding saccharification reaction and glycoalbumin)
Glycation refers to a series of chemical reactions in which sugars in the body combine with proteins, lipids, etc., and finally produce compounds called end-products of glycation (AGEs). When simply saying "anti-glycation", it generally means suppression of production of AGEs.

On the other hand, glycoalbumin is one of the early reaction products in the saccharification reaction. Although it is easily misunderstood, suppression of the production of AGEs does not necessarily mean that the production of glycoalbumin, which is a prophase reaction product, is also suppressed. This is because the flow of the saccharification reaction is complicated and diverse. The flow of the saccharification reaction will be described below.

The saccharification reaction can be roughly divided into three stages: the “early reaction” in which glycated proteins are produced, the “intermediate reaction” in which saccharification intermediate reactants are produced, and the “late reaction” in which late AGEs-producing reactants are produced. be done. The first reaction produces a Schiff base, and the Amadori rearrangement reaction produces an Amadori compound having a ketoamine structure. HbA1c (hemoglobin A1c), glycoalbumin, and the like are known as Amadori compounds.

In the intermediate reaction, glyoxal (GO), 3-DG (deoxyglucosone), etc. are produced as saccharification intermediates. 3-DG is a compound produced from an Amadori compound, but glyoxal is a compound produced by the oxidation reaction of glucose and is not related to the previous reaction. Thus, in the saccharification reaction, there is also a pathway that proceeds without going through the early reaction (production of the early reaction product).

In late-stage reactions, diverse reaction pathways lead to the production of various substances instead of a single substance. Examples thereof include carboxymethylarginine (CMA), pentosidine, pyraline, carboxymethyllysine (CML), pyropyridine, crossrin, etc. These compounds are collectively called AGEs.

Thus, since the saccharification reaction in vivo is multi-path and multi-step, even if suppression of specific AGEs is observed, the production of all precursors is not suppressed, and the production is suppressed. Some precursors are inhibited and others are uninhibited. For example, it is known that the main precursors of pentosidine, which is one of AGEs, are pentose and vitamin C. Therefore, when the production of pentosidine is suppressed, it can be predicted that the precursors of pentose and vitamin C are suppressed. It is unknown and cannot be determined without actual testing.

[3. Oral composition]
The oral composition of the present invention is, for example, pharmaceuticals (including quasi-drugs), functional foods such as food with function claims, food for specified health use, food with nutrient function claims, etc. whose efficacy has been approved by a predetermined organization. It can be used as a so-called health food or the like. Among them, it is preferably used as a food with function claims or a food for specified health uses, and particularly preferably as a food with function claims.

Forms of the oral composition of the present invention include tablets, capsules, powders, granules, liquids, granules, rods, plates, blocks, solids, rounds, pastes, creams, and caplets. shape, gel, chewable tablet, stick, and the like. It may be in the form of ice, jelly, cookie, cake, chocolate, PET bottle drink, and the like. Among these, tablets, capsules, powders, granules, rounds, and chewable tablets are preferred, and tablets are particularly preferred.

The oral composition of the present invention can be produced by a known method by adding other ingredients such as maclulin or its glycoside, if necessary.

When the oral composition of the present invention is in the form of a tablet, a round tablet, or a chewable tablet, it is preferable to add one or more of excipients, lubricants, and fluidizing agents. This enhances the moldability and improves the storage stability of the produced agent. In particular, storage stability can be further enhanced by using excipients and lubricants.

Excipients are added to improve the handling or molding of the composition, or to facilitate administration. Excipients that can be used in the present invention are not particularly limited. Substituted hydroxypropyl cellulose, hydroxypropyl cellulose, refined sucrose, light anhydrous silicic acid, calcium silicate, titanium oxide, precipitated calcium carbonate and the like. These may be used individually by 1 type, and may use 2 or more types together.

Lubricants are used to reduce friction between the punches of a tableting machine and tablets when compressing powder for tablets, and to prevent tableting failures such as sticking. The lubricant that can be used in the present invention is not particularly limited as long as it is a component that can achieve the above purpose. Stearyl sodium, sucrose fatty acid ester, talc, polyethylene glycol, vegetable oil, hardened oil and the like. These may be used individually by 1 type, and may use 2 or more types together.

A fluidizer is used to improve the fluidity of mixed powder and granules. The fluidizing agent that can be used in the present invention is not particularly limited, and examples thereof include silicon dioxide, aluminum silicate, magnesium aluminosilicate, calcium phosphate, magnesium carbonate, and magnesium oxide. These may be used individually by 1 type, and may use 2 or more types together. In the present invention, commercial products can be used as excipients, lubricants, and fluidizers.

The content of maclurin or its glycoside in the oral composition of the present invention may be appropriately contained within the range in which the effect is exhibited. For example, the oral composition of the present invention can contain 0.00005 to 10% by mass, preferably 0.0005 to 1% by mass, of maclurin or its glycoside in terms of dry mass. It is more preferable to contain 0.001 to 0.1% by mass.

The intake of maclurin or its glycosides in the present invention is not particularly limited, but the intake of maclurin or its glycosides should be 16 μg or more per day for adults in order to enjoy the effect more effectively. , more preferably 80 µg or more, and even more preferably 160 µg or more.

The oral composition of the present invention may be appropriately designed so that the daily intake of maclurin or its glycoside is the above intake, and it may be in a form in which the above intake is taken at one time. Alternatively, the intake amount may be divided into a plurality of times and ingested. That is, for example, it can be contained in one container or divided into a plurality of containers of 2 to 4 for one day.

EXAMPLES The present invention will be described in more detail below based on examples, but the present invention is not limited to these.

[Glycoalbumin decrease (albumin glycation inhibition) test]
A placebo-controlled, randomized, double-blind, parallel-group study was conducted in healthy adult males and females for the purpose of evaluating the effect of oral ingestion of rhodanthenone B on blood glycoalbumin by the method described below.

<1. Test food>
Test foods of Examples or Comparative Examples were produced by the methods described below.

(Example)
After mixing fine silicon dioxide, calcium stearate, microcrystalline cellulose, maltose, and safflower pigment with an aqueous extract of mangosteen peel (containing rhodanthenone B), tableting was performed using a tableting machine, and tablets of 300 mg per tablet (implemented Example) was manufactured. The amount of rhodanthenone B contained per tablet was 80 μg (0.027%). Two tablets of the example (the recommended daily intake in the test described later) were packed in a plain aluminum individual package (160 µg of rhodanthenone B per recommended daily intake). Table 1 shows the calorie and nutritional component values per recommended daily intake of the tablets of Examples.

(Comparative example)
Caramel pigment was substituted for the water extract of mangosteen peel so as to be indistinguishable from the tablet of the example in terms of appearance. 300 mg per tablet tablet (comparative example) was produced by the same method. Two tablets of the comparative example were packed in a plain aluminum individual package. Table 1 shows the calorie and nutritional component values per recommended daily intake of the tablet of Comparative Example.

<2. Selection of subjects>
Paid volunteers were recruited as subjects, and 90 subjects (60 males and 30 females) who satisfied the following selection criteria and did not meet the exclusion criteria were included as subjects by the principal investigator.

Selection criteria:
(1) Healthy men and women aged between 30 and 65 at the time of informed consent.
(2) Subjects with a fasting blood glucose level of 125 mg/dL or less and a HbA1c level of 6.4% or less at the screening test.
(3) Subjects who have received a sufficient explanation of the purpose and content of the study, have the ability to consent, and who have fully understood the study, voluntarily applied for participation, and agreed to participate in the study in writing.

Exclusion Criteria:
(1) During the test period, it is possible to stop taking drugs, quasi-drugs, supplements, and health foods (including foods for specified health uses and foods with function claims) that may affect blood sugar levels and glycation. those who cannot.
(2) smokers;
(3) Subjects who have declared that they have an allergy to the ingredients of the test food.
(4) Excessive alcohol intake exceeding about 20 g/day in terms of pure alcohol, or those who have a habit of drinking 4 days or more a week.
(5) Subjects who are unable to abstain from alcohol 2 days before the screening test or each test.
(6) Subjects whose daily average sleep time is less than 6 hours.
(7) shift workers or late-night workers;
(8) Subjects with serious liver disease, kidney disease, gastrointestinal disease, heart disease, respiratory disease, endocrine disease, thyroid disease, adrenal disease, or other metabolic disease, or under treatment.
(9) Those who have chronic diseases and are undergoing treatment.
(10) Subjects with a history of gastrointestinal disease or gastrointestinal surgery that affects digestion and absorption.
(11) Subjects who are judged to be unsuitable as subjects based on the blood test performed in the screening test.
(12) Subjects who are pregnant, intend to become pregnant during the test period, or are breast-feeding.
(13) Subjects who have collected or donated more than 200 mL of blood within 1 month or 400 mL of blood within 3 months prior to the date of consent acquisition.
(14) Subjects with a history of drug dependence or alcohol dependence or a current medical history.
(15) Subjects who are currently participating in studies involving the intake of other foods or using pharmaceuticals, studies involving the application of cosmetics or pharmaceuticals, those who have participated in other clinical studies within one month of obtaining informed consent, and those who intend to participate. Someone.
(16) In addition, those who are judged to be inappropriate as subjects by the principal investigator.

<3. Test method>
This study was conducted as a placebo-controlled, randomized, double-blind, parallel group comparison study (allocated ratio: 1:1) for a total of 10 weeks, consisting of a pre-observation period (2 weeks) and an intake period (8 weeks). The principal investigator enrolled the subjects according to the inclusion and exclusion criteria, and the statistical analysis manager allocated the subjects equally to each group in consideration of gender, age, etc. The two allocated groups were assigned to the example intake group and the comparative example intake group by a controller not directly related to the study. Furthermore, the controller created and sealed a table (key code) describing the allocation results, and sealed it up until the key code was disclosed after the analysis subjects were determined, thereby ensuring blinding.

During the test period, 1 bag (2 grains) of the test food (Example food for the Example intake group, Comparative example food for the Comparative example intake group) was ingested once a day with 100 mL of water or lukewarm water. let me

During the test period, do not use medicines or health foods that may affect blood sugar levels or saccharification, lead the same lifestyle as before the start of the test, do not consume large amounts of alcohol, and do not drink alcohol for more than 6 hours every day. During the study period, subjects were instructed to take precautions such as getting enough sleep and avoiding participation in other studies. In addition, as precautions for each test, avoiding alcohol intake from 2 days before all tests and avoiding eating and drinking other than water after 21:00 on the day before all tests were explained. Subjects were to use drugs with the permission of the principal investigator or study subinvestigator, except in an emergency.

[Measurement of glycoalbumin and HbA1c]
Blood tests were performed three times in total: a pre-intake test (hereinafter referred to as pre-intake), a 4-week post-ingestion test (hereinafter 4-weeks after intake), and an 8-week post-ingestion test (hereinafter 8-weeks after intake). and HbA1c were measured.

<4. Results>
(Persons subject to analysis)
The number of subjects enrolled in this study was 90 (60 males and 30 females), and the study was started with 90 subjects without dropouts after randomization. During the test period, 3 subjects withdrew from the test food group for reasons other than the test food, resulting in a total of 87 subjects completing the test. In addition, after the end of the study, 7 subjects who met the rejection criteria were found, so 80 subjects (52 males, 28 females) were analyzed. The reasons for the rejection criteria and the number of patients were as follows.
(1) 3 subjects who observed changes in their lifestyle habits compared to before the start of the test (1 subject of the example intake group, 2 subjects of the comparative example intake group)
(2) 1 subject who was found to have violated alcohol intake (1 subject in the example intake group)
(3) 2 subjects who were allowed to ingest the forbidden food for a long period of time (2 subjects in the comparative example intake group)

(Changes in glycoalbumin and HbA1c)
In this test, healthy adult males and females aged 30 to 65 years old took the tablet of the example containing 160 µg/day of rhodanthenone B or the tablet of the comparative example containing no rhodanthenone B once a day for 8 consecutive weeks. A placebo-controlled, randomized, double-blind, parallel-group study was conducted. Table 2 shows the results.

As is clear from Table 2, the Example intake group showed a significant decrease in glycoalbumin compared to the Comparative Example intake group. From this, it was clarified that oral ingestion of rhodanthenone B reduces glycoalbumin (saccharification of albumin is suppressed). On the other hand, no significant difference in HbA1c was observed between the Example intake group and the Comparative Example intake group. Glycoalbumin and HbA1c are both Amadori compounds, but the results were contrasting.

[Production Examples 1 to 3] (Production of tablets)
As shown in Table 3, after mixing Rhodantenone B and other raw materials, tableting was performed using a rotary tableting machine to produce tablets of Production Examples 1 to 7. Tablets were manufactured to have a tablet diameter of 8 mmφ, a tablet thickness of 4.5 mm, a weight of 300 mg, and a hardness of 5 kgf or more. By ingesting two of the tablets described in Production Examples 1 to 3 per day, an excellent effect of lowering glycoalbumin (inhibiting saccharification of albumin) can be obtained.

[Production Examples 4 to 9] (Production of powdered beverage)
As shown in Table 4, after mixing rhodanthenone B and other raw materials, fluidized bed granulation was performed using a granulator to produce granular powdered beverages described in Production Examples 4 to 9. The produced powdered beverage was filled in an aluminum pouch so that 3 g per bag. By ingesting 3 g of the powdered beverages described in Production Examples 4 to 9 once a day, an excellent effect of reducing glycoalbumin (inhibiting saccharification of albumin) can be obtained.

INDUSTRIAL APPLICABILITY The oral composition of the present invention is highly industrially useful because it can be used as food such as food with function claims.

Claims (2)

An oral composition for lowering glycoalbumin containing maclurin or its glycoside. An oral composition for suppressing glycation of albumin containing maclurin or its glycoside.