JP6253393B2 - Solid composition - Google Patents

Description

  The present invention relates to a solid composition containing hesperidin.

Hesperidin, a kind of flavonoid, is also called vitamin P, and is a substance known to be contained in a large amount in citrus peel and the like. Hesperidin has been reported to have various physiological effects such as strengthening of capillaries, bleeding prevention, blood pressure regulation and the like, and is expected to be used for living bodies.
In order to more effectively express the physiological function of hesperidin, it is important to increase the intake of hesperidin, and it has been proposed to make it in the form of a beverage as a means for easily achieving it ( For example, Patent Document 1).

On the other hand, solid compositions such as tablets and powders are excellent in portability and storage stability, and are in a form suitable for oral intake that can be easily and easily ingested in a small amount per time. In particular, a foaming agent containing a carbonate and an organic acid is a suitable form since it foams by contact with saliva in the mouth when ingested, and a unique refreshing feeling can be obtained.
In addition, foaming agents may be used for the purpose of increasing the absorption rate of oral components. For example, a concentrated green tea plant extract, carbonate, and acid are blended to accelerate absorption by the body and improve bioavailability. A solid water-soluble preparation for forming a foamable composition is known (Patent Document 2).

JP 2011-126849 A Special table 2003-503324 gazette

However, when the present inventors examined to develop a solid composition containing hesperidin, hesperidin was blended into the solid composition, and only the bitterness peculiar to hesperidin was felt as the concentration was increased. In addition, it was found that an astringent feeling different from the bitter taste was felt and the astringent taste remained later.
Accordingly, an object of the present invention is to provide a solid composition containing hesperidin having a good flavor and suppressing astringency and bitterness remaining thereafter.

As a result of intensive studies to solve the above-mentioned problems, the present inventors combined hesperidin with a predetermined amount of carbonate and further an organic acid in a predetermined ratio to generate carbon dioxide gas when ingested, thereby producing hesperidin-specific It has been found that the astringent taste and bitterness remaining after the reduction can be reduced to obtain a solid composition having a good flavor.
That is, the present invention includes the following components (A), (B) and (C):
(A) hesperidin and / or hesperidin derivative,
(B) carbonate,
(C) an organic acid,
The mass ratio of component (A) to component (B) [(B) / (A)] is 0.25 or more, and the equivalent ratio of component (C) to component (B) [(C ) Equivalent / (B) equivalent] is provided in a solid composition of 0.8-3.

  According to the present invention, there is provided a solid composition containing hesperidin having a good flavor, which can suppress the astringent taste and bitterness remaining after hesperidin, and has little salty taste derived from carbonate or organic acid. be able to.

(A) Hesperidin used in the present invention is rutinose (L-rhamnosyl- (α1 → 6) -D-glucose) at the hydroxyl group at the 7-position of hesperetin (5,7,3′-trihydroxy-4′-methoxyflavanone). Is a β-bonded compound.
As the hesperidin derivative of the present invention, a glycoside in which a sugar is bonded to hesperidin, or a methylated product of hesperidin can be used.

  Examples of glycosides in which sugars are bonded to hesperidin include compounds in which 1 to 10 sugars are further bonded to hesperidin. Examples of the sugar include glucose, maltose, fructose, rhamnose, lactose and the like. Among these, from the viewpoint of solubility and solubilizing power, glucosyl hesperidin in which 1 to 10 glucoses are bonded to hesperidin is preferable, and monoglucosyl hesperidin in which 1 glucose is further bonded is preferable. Moreover, the addition number of glucose may have distribution, and the average addition mole number of glucose with respect to 1 mol of hesperidins is 1-10. As described above, hesperidin itself is a glycoside in which hesperetin is used as an aglycone and a sugar is bound thereto. In the present invention, in order to distinguish from this, a substance in which a sugar is further bonded to hesperidin is referred to as a hesperidin sugar adduct.

  These hesperidins and hesperidin sugar adducts can be industrially produced by a known method using chemical synthesis or enzymatic reaction. Hesperidin can also be obtained by extraction from natural products containing it, preferably from plants. These substances are also manufactured and sold as reagents and the like. As an example of commercially available hesperidin, hesperidin “Hamari” manufactured by Hamari Pharmaceutical Co., Ltd. may be mentioned. Examples of commercially available hesperidin sugar adducts include “Hayashibara Hesperidin S” from Hayashibara Bioscience Institute.

  Methyl hesperidin is known to mainly contain chalcone type compounds (1) and flavanone type compounds (2), and examples of the constituents include those having the structures shown below.

(In the formula, R represents a hydrogen atom or a methyl group.)
Here, methyl hesperidin as a pharmaceutical additive and a food additive is mainly handled as a mixture of the compounds (3) and (4).

(In the formula, Gl represents a glucose residue, Rh represents a rhamnose residue, and Gl-2 represents the 2-position of the glucose residue (including 3-position in the case of (3-1)), Rh- 2 represents position 2 of the rhamnose residue.)
Hesperidin methyl chalcone as a cosmetic raw material is handled as a compound represented by (5). In the case of a composition containing a large amount of chalcone type compound, it is also called hesperidin methyl chalcone.

(In the formula, R represents a hydrogen atom or a methyl group.)
The methyl hesperidin used in the present invention may contain both the chalcone type compound (1) and the flavanone type compound (2) shown above, or may contain only one of them.
In the present invention, more preferred methyl hesperidin includes a mixture of compound (3) and compound (4).
Methyl hesperidin is a known method, for example, hesperidin is dissolved in an aqueous sodium hydroxide solution, a corresponding amount of dimethyl sulfate is allowed to act on the alkaline solution, the reaction solution is neutralized with sulfuric acid, and extracted with n-butyl alcohol. It can be produced by distilling off and then recrystallizing with isopropyl alcohol (Saki Bath, Nippon Kagaku Kagaku, 79, 733-6 (1958)), but the production method is not limited to this.
Commercially available methyl hesperidin-containing preparations may be used as methyl hesperidin, for example, “methyl hesperidin” (Alps Yakuhin Kogyo Co., Ltd.), “hesperidin methyl chalcone” (Sigma), “methyl hesperidin” (Hamari Yakuhin Kogyo) Co., Ltd.).

In the solid composition of the present invention, the content of (A) hesperidin and / or hesperidin derivative is preferably 4 to 60% by mass (hereinafter referred to as “%”), more preferably 9 to 60%, and further 10 to 55. %, Further 15 to 50%, and further 15 to 40% is preferable from the viewpoint of the number of tablets necessary for ingesting the flavor and effective amount.
In this specification, “content of component (A)” is defined based on the total amount of hesperidin and hesperidin derivative, and when the hesperidin derivative is a hesperidin sugar adduct, the content of hesperidin sugar adduct is defined as the content of hesperidin sugar adduct. In the case of methyl hesperidin, the content is methyl hesperidin.

  Examples of the carbonate (B) used in the present invention include sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, calcium carbonate, magnesium carbonate, sodium sesquicarbonate, and the like. These may be used alone or in combination of two or more. Can be used in combination.

  In the solid composition of the present invention, the content of (B) carbonate is preferably 3 to 40%, more preferably 5 to 35%, and further 10 to 20%, in terms of flavor and physical properties. (A) It is preferable from the point which contains many components and raises a physiological effect.

  In the solid composition of the present invention, the mass ratio [(B) / (A)] of (A) hesperidin and / or hesperidin derivative and (B) carbonate is set to 0.25 or more. (A) Hesperidin and / or hesperidin derivative and (B) carbonate content mass ratio [(B) / (A)] is 0.27 or more, more 0.3 or more from the viewpoint of astringency and bitterness suppression. Further, 0.35 or more, further 0.4 or more, further 0.5 or more, and further 0.7 or more are preferable. Further, the mass ratio [(B) / (A)] of (A) hesperidin and / or hesperidin derivative and (B) carbonate is 7 or less from the viewpoint of increasing the physiological effect by containing a large amount of component (A). More preferably, it is 6 or less, further 5 or less, further 4 or less, further 3 or less, and further 2 or less.

  In addition, as the organic acid (C) used in the present invention, an edible acid can be used. Examples thereof include organic acids such as citric acid, succinic acid, ascorbic acid, acetic acid, gluconic acid, malic acid, tartaric acid, fumaric acid and adipic acid, and these can be used alone or in combination of two or more. Of these, citric acid or malic acid is preferable, and citric acid is more preferable because of the taste of the organic acid and the texture of the foam generated.

  In the solid composition of the present invention, the content of (C) the organic acid is 5.5 to 50%, more preferably 8 to 30%, and further 10 to 25%. This is preferable from the viewpoint of increasing the physiological effect by containing many components.

In the solid composition of the present invention, the equivalent ratio of (C) organic acid and (B) carbonate [equivalent of (C) / equivalent of (B)] is in the range of 0.8 to 3. The salty taste derived from carbonates and the sourness of organic acids do not protrude, and the flavor balance is good. The equivalent ratio of (C) organic acid to (B) carbonate is 0.9 to 3.0, 0.9 to 2.7, 0.95 to 2.0, Furthermore, 0.95-1.8 is preferable.
In the present invention, the “equivalent ratio” is a value obtained by dividing the equivalent of (C) the organic acid contained in the solid composition by the equivalent of (B) carbonate.

  Further, in the solid composition of the present invention, the ratio (mass ratio) of the total content of (B) carbonate and (C) organic acid to the content of (A) hesperidin in the solid composition [(B ) + (C) / (A)] is in the range of 0.3 to 10, more preferably 0.5 to 5, more preferably 0.7 to 3, and more preferably 0.8 to 2, to reduce the flavor and the number of tablets. From the viewpoint of the content of hesperidin per tablet for efficiently ingesting hesperidin.

  In the solid composition of the present invention, in addition to the above components, minerals (for example, calcium, magnesium, iron, zinc, chromium, selenium, manganese, molybdenum, copper, iodine, Phosphorus, potassium, sodium), vitamins (eg, vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin E, folic acid and their salts, or esters thereof), sweeteners (eg, fructose) Monosaccharides such as glucose, galactose, xylose, tagatose, for example, sucrose, lactose, maltose, trehalose, isomaltoligosaccharide, galactooligosaccharide, fructooligosaccharide, whey oligosaccharide, soybean oligosaccharide, isomaltulose, coupling sugar Such as oligosaccharides, sugar alcohols having 6 to 12 carbon atoms, Karin, sucralose, synthetic sweeteners such as acesulfame potassium), the "(C) an organic acid" other than the acidulant, flavoring, coloring, preservatives, etc. may be appropriately blended.

The solid composition of the present invention generates carbon dioxide in the mouth or in the presence of water. The form is not particularly limited as long as it is solid at room temperature (15 to 25 ° C.), and examples thereof include capsules, granules, powders, tablets, and pills. Among these, tablets and powders that are effervescent tablets are preferable, and chewable tablets are more preferable because they can be taken in a small amount per time and are easy to ingest.
In order to prepare a composition of such a dosage form, if necessary, excipients such as lactose, starches, crystalline cellulose, sucrose, mannitol, light anhydrous silicic acid, calcium hydrogen phosphate; hydroxypropyl methylcellulose, Binding agents such as hydroxypropylcellulose, gelatin, pregelatinized starch, polyvinylpyrrolidone, polyvinyl alcohol, pullulan, methylcellulose, hydrogenated oil; carmellose, carmellose calcium, croscarmellose sodium, crospovidone, corn starch, low-substituted hydroxypropylcellulose Disintegrating agents such as calcium stearate, magnesium stearate, sucrose fatty acid ester, sodium stearyl fumarate, talc, silicon dioxide, etc .; flavoring agents such as stevia, aspartame; Fee, bulking agents, surfactants, dispersants, buffers, preservatives, coating agents, may be combined as appropriate diluents and the like.

The solid composition of the present invention is produced according to a conventional method without any particular limitation. For example, it can be produced by preparing a mixture of (A) hesperidin and / or a hesperidin derivative, (B) carbonate, (C) an organic acid and additives to be added as necessary, and then compression-molding the mixture.
For example, in the case of producing a powder, a mixture of (A) hesperidin and / or hesperidin derivative, (B) carbonate, (C) organic acid and additives added as necessary may be used as it is. May be used after being crushed. The powder preferably passes through the entire size of No. 18 (850 μm) sieve, and the amount remaining on the No. 300 (500 μm) sieve is more preferably 5% or less of the total amount.
For the granule, a dry granulation method, a wet granulation method, or the like is used by mixing a mixture of (A) hesperidin and / or hesperidin derivative, (B) carbonate, (C) organic acid and additives added as necessary. And can be obtained by granulation.
When manufacturing tablets, the raw material powder can be directly compressed and molded (direct powder compression method), or granulated using dry granulation method, wet granulation method, etc. and then compressed (granule compression) Act). Especially, it is preferable to use a direct powder compression method to make a tablet from the point of simplicity of the process.
When a tablet is produced by direct compression and molding, a conventional tableting machine such as a rotary tableting machine or a single-shot tableting machine can be used.
In addition, when a tablet is formed after granulation by a granulation method, an extrusion granulation method using a cylindrical granulator, a spherical granulator, a pelleter, etc., a crushing granulation method using a speed mill, a power mill, etc. A granulated product is produced by dynamic granulation method, stirring granulation method, fluidized bed granulation method, etc., dried and sized, and then the obtained granulated product is compressed by the tableting machine to form tablets. it can. The average particle diameter of the granulated product is preferably 45 μm to 850 μm, and more preferably 100 μm to 500 μm.
The shape of the tablet may be a round tablet or various deformed tablets having a surface shape such as an oval, an oval, or a square.
Moreover, the compression molding pressure at the time of tableting is 100-4000 kg / cm < ² > from points, such as hardness maintenance of a molding, disintegration, etc., for example.

  Further, the weight per tablet of the tablet of the present invention is preferably 0.1 g or more from the viewpoint of simplicity and effectiveness.

[material]
Hesperidin preparation: Hesperidin "Hamari", manufactured by Hamari Pharmaceutical Co., Ltd., Hesperidin content 92%
Glucosyl hesperidin preparation: Hayashibara Hesperidin S, manufactured by Hayashibara Biochemical Laboratory, hesperidin content 17%, monoglucosyl hesperidin content 74%
Methyl hesperidin preparation: methyl hesperidin, manufactured by Alps Pharmaceutical Co., Ltd., methyl hesperidin content 100%
Sodium bicarbonate: Sodium bicarbonate, Wako Pure Chemical Industries, Ltd.
Citric acid: anhydrous citric acid MS, Fuso Chemical Industry Co., Ltd.
Malic acid: Fuso S, Fuso Chemical Industry Co., Ltd.
Dextrin: Dextrin M-SPD, Showa Sangyo Co., Ltd.
Calcium stearate: Orlabrite CA-65, NOF Corporation

[Analysis of hesperidin, methyl hesperidin and hesperidin sugar adducts]
Hesperidin, methyl hesperidin and hesperidin sugar adducts were quantified using a Hitachi high-performance liquid chromatograph, equipped with an intact Cadenza CD-C18 (4.6 mmφ × 150 mm, 3 μm) gradient at a column temperature of 40 ° C. Done by law. The mobile phase A solution was 0.05 mol / L acetic acid aqueous solution, the B solution was acetonitrile, and the solution was fed at 1.0 mL / min. The gradient conditions are as follows.
Time (min) A liquid (%) B liquid (%)
0 85 15
20 80 20
35 10 90
50 10 90
50.1 85 15
60 85 15
The sample injection amount was 10 μL, detection was methyl hesperidin with a wavelength of 360 nm, and hesperidin and hesperidin sugar adduct were quantified with absorbance at a wavelength of 283 nm.

[Analysis of carbonate]
The method for analyzing the content of carbonate in the solid composition is as follows.
0.1 to 0.2 g of a solid composition was sampled, and 10 mL of water and 2 mL of 50% phosphoric acid were added and sealed. After sonication for 10 minutes, the sample was left for 1 hour, the head space gas was subjected to a gas chromatograph, the amount of CO ₂ was determined, and the amount of CO ₂ generated was calculated.
<Gas chromatograph operating conditions>
Model: GC-14B [Shimadzu Corporation]
Detector: TCD
Column: Chromosorb 101, 80-100 mesh
Glass tube, φ3.2mm × 2m
Temperature: Column 50 ° C, inlet and detector 100 ° C
Cell current 75mA
Gas pressure: Helium (carrier gas) 100 kPa
Injection volume: 0.2 mL of headspace gas

[Analysis of organic acids]
The analysis method of the content of the organic acid in the solid composition is as follows.
1 g of the solid composition was sampled, 20 mL of 5% perchloric acid was added, and the mixture was extracted by shaking for 10 minutes. This was made up to 200 mL with water and sonicated for 10 minutes. It used for the high performance liquid chromatograph after filtration.
<High-performance liquid chromatograph operating conditions>
Model: LC-20AD [Shimadzu Corporation]
Detector: UV-visible spectrophotometer SPD-20AV [Shimadzu Corporation]
Column temperature: 40 ° C
Mobile phase: 3 mmol / L perchloric acid reaction solution: 0.2 mmol / L bromthymol blue-containing 15 mmol / L disodium hydrogen phosphate solution Flow rate: mobile phase 1.0 mL / min, reaction solution 1.4 mL / min
Measurement wavelength: 445 nm

[Preparation of chewable tablets]
Examples 1 to 11 and Comparative Examples 1 to 7
Each raw material component was mixed with the composition shown in Table 1. Next, using a single-type tableting machine (manufactured by RIKEN), the tablet was tableted with a tablet weight of 100 mg with a ring-shaped punch having a hole diameter of 7 mm to obtain a chewable tablet.
Examples 2, 9, 10 and 11 are reference examples.

Sensory evaluation was performed by three specialist panels on the product of the present invention and the comparative product obtained above. The evaluation was carried out according to the criteria shown below for the astringent taste specific to hesperidin, the bitter taste specific to hesperidin, and the balance between acidity and saltiness, and the score was determined through consultation. The results are shown in Table 1.
[Astringent taste of aftertaste]
5: Astringent taste of aftertaste is weak 4: Astringent taste of aftertaste is slightly weak 3: Astringent taste of aftertaste is slightly strong 2: Astringent taste of aftertaste is strong 1: Astringent taste of aftertaste is very strong [bitter taste]
5: The bitterness is weak 4: The bitterness is slightly weak 3: The bitterness is slightly strong 2: The bitterness is strong 1: The bitterness is very strong [balance between acidity and salty]
5: Very good balance without protruding sour and salty 4: Good balance without protruding sour and salty 3: Slightly balanced without protruding sour and salty 2: Salty and / or sour Slightly strong and unbalanced 1: Strong salty and / or sour, very poor balance

As is apparent from Table 1, the solid composition containing hesperidin felt the astringent taste and bitterness remaining after hesperidin (Comparative Examples 6 and 7). On the other hand, compared with the comparative product, the astringent taste and bitterness remaining after hesperidin is reduced in the present invention product, and the salty taste derived from carbonate and the sour taste derived from organic acid do not protrude, and the balance of flavor is It was good.
Comparative Examples 1 to 3 in which the ratio of carbonate to hesperidin is outside a certain range have a low effect of reducing the astringency and bitterness remaining after hesperidin, and Comparative Examples 4 and 5 in which the equivalent ratio of organic acid to carbonate is outside the certain range. Then, the saltiness derived from carbonate and the acidity derived from organic acid were strong, and the balance of flavor was bad.

Claims (4)

The following components (A), (B) and (C):
(A) hesperidin and / or hesperidin derivative,
(B) carbonate,
(C) an organic acid,
The mass ratio of component (A) to component (B) [(B) / (A)] is 0.3 or more, and the equivalent ratio of component (C) to component (B) [(C eq] is Ri der 0.8 to 3, wherein the hesperidin derivative is hesperidin sugar adduct or methyl hesperidin der Ru solid composition of equivalents / (B)) of.   The solid composition according to claim 1, wherein the content of (A) hesperidin and / or hesperidin derivative in the solid composition is 4 to 60% by mass.   The solid composition according to claim 1 or 2, wherein the content of the organic acid (C) in the solid composition is 5.5 to 50% by mass. It is an effervescent tablet, The solid composition of any one of Claims 1-3 .