JP6742853B2 - Persistent quercetin glycoside preparation - Google Patents

Description

The present invention relates to a sustained-release quercetin glycoside preparation characterized by containing a prenylated quercetin glycoside. More specifically, a sustained quercetin glycoside preparation capable of maintaining the quercetin conjugate concentration in blood for a long time and decreasing the number of administrations, an oral composition containing them, a food, a drug, or Regarding quasi drugs.

With the recent westernization of lifestyle habits such as high-fat diet and lack of exercise, the increase in so-called lifestyle-related diseases such as diabetes, hypertension, hyperlipidemia, or arteriosclerosis has become one of the major social problems. .. Flavonoids are also being considered as expected as a composition capable of exerting a preventive or ameliorating effect on these various pathological conditions.

In addition, the arteriosclerosis-suppressing action of rutin and quercetin (Non-patent document 1 and patent document 1), the anti-arteriosclerotic action of enzyme-treated isoquercitrin (patent document 2), the antihypertensive action (patent document 3), etc. are reported. Has been done.
As described above, quercetin glycosides are multifunctional, and thus have been attracting attention as a component of functional foods.

Furthermore, many researchers have studied the metabolism and absorption of these flavonoids, and quercetin is absorbed as it is from the intestinal tract, while quercetin glycosides are retained by intestinal bacteria when they reach the intestine. Under the action of β-glucosidase, etc., it is hydrolyzed into quercetin, which is an aglycone, and then absorbed, and then quercetin undergoes glucuronidation by intestinal epithelial cells to become a quercetin conjugate when absorbed. It is thought that it enters the liver via the portal vein, undergoes sulfate conjugation and methylation in the liver, then enters the bloodstream, migrates to peripheral tissues, and is finally excreted in the urine via the kidneys. (Non-patent documents 2, 3, and 4).

However, when quercetin and rutin are orally administered, they are excreted rapidly, and when the dose reaches a certain concentration, further absorption cannot be expected, and therefore its bioavailability is considered to be reduced. There is. Therefore, it has been difficult to maintain the blood concentration of the quercetin conjugate required for the prevention and treatment of various diseases for a long time. For this reason, it is effective to increase the bioavailability of the quercetin conjugate by dividing an appropriate amount into small doses, but the blood concentration of the quercetin conjugate is not long-lasting, and therefore the number of administrations is increased. It is considered necessary to increase the dosage, and therefore, there is a strong demand for the development of a sustained quercetin glycoside preparation having high bioavailability without such drawbacks.

On the other hand, a polyphenol to which a prenyl group is bound has been recently discovered, and its functional analysis is progressing. In particular, it has been suggested that 8-prenylnaringenin contained in hops suppresses the decrease in bone density and the decomposition of skeletal muscle (Non-Patent Document 5,
1470096753674_1.html
reference). In addition, prenylated quercetin (C8-, C5') has also been discovered, and research on its physiological effects is progressing (Non-Patent Document 6,
1470096753674_2.htm
reference). An enzyme that introduces a prenyl group into polyphenol has also been discovered (Patent Document 4).

Kenshiro Fujimoto, Modern Medicine "Natural Antioxidants", Vol.28, No.8, p.129-134 (1996) Food and Development, Vol.33, No.3, p24-26 (1998) Food and Development, Vol.35, No.6, p.8-10 (2000) FOOD Style, Vol.21, No.4, p.81-84 (2000) Vitamin, Vol.87, No.2, p.110-112 (2013) Synthesis, Vol, 44, No. 9, p. 1308-131 (2012)

Special table 2002-524522 gazette WO2006/095675 Pamphlet JP, 2005-272348, A WO2010/147196

An object of the present invention is to provide a sustained quercetin glycoside preparation capable of maintaining the quercetin conjugate concentration in blood for a long time and decreasing the administration frequency, and an oral composition containing them. is there.

As a result of intensive studies to solve the above problems, the present inventors have found that a persistent quercetin glycoside containing a prenylated quercetin glycoside having a prenyl group bonded to the quercetin glycoside. It was found that the use of the preparation in a composition for oral cavity improves the absorbability in the body, is less likely to be metabolized, and can maintain the concentration of the quercetin conjugate in blood for a long time. Was completed.
The present invention has been completed based on such findings, and includes the following embodiments.

That is, the present invention is as follows.
Item 1. A long-acting quercetin glycoside preparation comprising a prenylated quercetin glycoside.
Item 2. Item 2. The sustained-release quercetin glycoside preparation according to Item 1, wherein the prenylated quercetin glycoside is represented by the formula (2).
(Formula 2)


Item 3. Item 2. An oral composition comprising the sustained-release quercetin glycoside preparation according to Item 1 or 2.
Item 4. Item 4. The oral composition according to Item 3, which is a food.
Item 5. Item 4. The oral composition according to Item 3, which is a pharmaceutical product.
Item 6. The oral composition according to Item 3, which is a quasi drug.

According to the present invention, a sustained-release quercetin glycoside preparation characterized by containing a prenylated quercetin glycoside in which a prenyl group is bonded to the quercetin glycoside is used in an oral composition to obtain a conventional quercetin glycoside. As compared with glycosides, it has improved absorption in the body and is less likely to be metabolized, and it has become possible to maintain the quercetin conjugate concentration in blood for a long time.

The prenylated quercetin glycoside of the present invention is represented by (Formula 3).
(Formula 3) Structural formula of prenylated quercetin glycoside

Any quercetin glycoside may be used as long as it satisfies the above structural formula. For example, when referring to sugar, any coupling method including a monosaccharide, a branched structure and a linear structure may be used. In addition, quercetin glycosides in which any or all of these binding methods are mixed may be used.

The prenylated quercetin glycoside of the present invention can be prepared, for example, using the method described in Synthesis 2012; 44(9): 1308-1314.

The present invention also provides a pharmaceutical composition, a food composition, and a cosmetic containing a prenylated quercetin glycoside or a pharmaceutically acceptable salt thereof as an active ingredient. These forms may be a liquid such as an aqueous solution, a suspension or an emulsion, or a paste or a solid such as a powder.

The composition described above can be administered to an individual. In the present invention, an individual means a subject in need of treatment of a disease, and more specifically, a human or non-human primate, a mouse, a rat, a dog, a cat, a horse, And mammals such as cows.

The pharmaceutical composition of the present invention can be prepared for administration by including one or more pharmaceutically acceptable carriers in addition to the above-mentioned active ingredient, and various dosage forms. Can be manufactured in.

The pharmaceutical composition of the present invention can be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or locally) depending on the intended method. The range varies depending on the patient's weight, age, sex, health status, diet, administration time, administration method, excretion rate, severity of disease and the like.

The preferred dose of the pharmaceutical composition of the present invention varies depending on the condition and weight of the patient, the degree of disease, the drug form, the administration route, and the period, but can be appropriately selected by those skilled in the art. However, preferably, the daily dose is 0.001 to 100 mg/kg body weight, more preferably 0.01 to 30 mg/kg body weight. The administration can be carried out once a day or in a plurality of divided doses.

When the prenylated quercetin glycoside of the present invention or a pharmaceutically acceptable salt thereof is used as a food additive, it may be added as it is, or other food, or glucose, fructose, sucrose, maltose, sorbitol, stevioside. , Rubusoside, corn syrup, lactose, citric acid, tartaric acid, malic acid, succinic acid, lactic acid, L-ascorbic acid, d1-α-tocopherol, sodium erythorbate, glycerin, propylene glycol, glycerin fatty acid ester, polyglycerin fatty acid ester, Food additives such as sucrose fatty acid ester, sorbitan fatty acid ester, gum arabic, carrageenan, casein, gelatin, pectin, agar, vitamin Bs, nicotinic acid amide, calcium pantothenate, amino acids, calcium salts, pigments, flavors or preservatives It can be used together with a product and can be appropriately used by a usual method. The amount of the active ingredient mixed can be determined so as to be more suitable depending on the purpose of use (prophylactic, health or therapeutic treatment). Generally, the amount of the prenylated quercetin glycoside of the present invention or a pharmaceutically acceptable salt thereof in the production of food or beverage is 15% by mass or less, preferably 10% by mass or less based on the raw material. Is added in. However, in the case of long-term intake for the purpose of health and hygiene, or for the purpose of controlling health, the above amount can be below the above range, and there is no problem in terms of safety. Therefore, the active ingredient is used in an amount exceeding the above range.

There is no particular limitation on the types of the above foods. Dairy products, various soups, beverages, teas, drinks, alcoholic beverages and vitamin complexing agents are possible, including all other functional foods in the normal sense.

Preparation method of prenylquercetin To 10 g of quercetin (manufactured by Tokyo Kasei), 10 times amount of acetic anhydride was added to 3 times amount of pyridine solvent, reacted at 130 to 140° C. for 1 hour, and purified by a silica gel column. Then, it was reacted at 0° C. for 1.5 hours in the presence of thiophenol (1.2 volumes), imidazole (0.35 volumes) and N-methylpyrrolidone. Subsequently, a coupling reaction was carried out for 2 hours in a solvent of isobutylallyl carbonic acid ester (3 times amount) and tetrahydrofuran at −20° C. to 0° C. using tetrakis(tridenylphosphine)palladium (5 mol %) as a catalyst. Then, the mixture is heated in acetic anhydride at 120 to 130° C. for 1 hour to transfer the prenyl group to C8. Finally, it was deacetylated with 10 times amount of ammonium acetate, refluxed with methanol, and dried by concentration under reduced pressure to prepare 7 g of quercetin having a prenyl group bonded to the C8 position.

Preparation method of prenylated enzyme-treated quercetin 20 g of rutin (manufactured by Tokyo Kasei) was added to 400 mL of water, and the pH was adjusted to 4.9 using a pH adjuster. To this, 0.1 g of rhamnosidase was added to start the reaction, and this was kept at 65° C. for 24 hours. Then, the reaction liquid was cooled to 20° C., and the precipitate generated by cooling was filtered off. The obtained precipitate (solid content) was dried to collect 13.4 g of isoquercitrin.
The above isoquercitrin was prenylated by a procedure similar to that for prenylated quercetin. To this, 50 times the amount of water was added and 4 times the amount of corn starch was added, and 0.1 times the amount of cyclodextrin glucanotransferase was added to start the reaction, and this was adjusted to pH 8.0 at 50°C. The solution obtained after being kept for 24 hours under reduced pressure was concentrated under reduced pressure and then lyophilized to prepare 2 g of prenylated enzyme-treated isoquercitrin.

(Internal absorption/metabolism confirmation test method)
Seven-week-old male C57/BL6 mice were fed with AIN-93M diet and water at room temperature of 23°C for one week. No food is given for 18 hours before sample administration. Prenyl quercetin (PQ), quercetin (Q), enzyme-treated isoquercitrin (E), and prenylated enzyme-treated isoquercitrin (PE) were dissolved in propylene glycol at 5 g/L, and 50 mg/kg body weight was used. It was administered by tube feeding. Plasma was collected after 0.5, 1, 2, 4, 8, 24, and 48 hours, and the concentrations of prenylated quercetin and quercetin metabolized by the HPLC method after β-glucuronidase treatment were measured. The prenylated enzyme-treated isoquercitrin had low absorbability but was difficult to be metabolized, and had the highest plasma concentration after 48 hours (FIG. 2).

Preparation of prenylquercetin (from Synthesis 2012; 44(9): 1308-1314) Results of tests to confirm absorption and metabolism in the body

Claims (5)

A long-acting quercetin glycoside preparation comprising a prenylated quercetin glycoside represented by formula (1) ;
(Formula 1)

In the formula, X represents hydrogen or a prenyl group, at least one X is a prenyl group,
And in the formula, R represents a sugar. An oral composition comprising the sustained-release quercetin glycoside preparation according to claim 1 . The oral composition according to claim 2 , which is a food. The oral composition according to claim 2 , which is a pharmaceutical product. The oral composition according to claim 2 , which is a quasi drug.