JP2020180093A - Powder composition containing reduced coenzyme q10 and antioxidant - Google Patents

Abstract

To provide a powder composition stably containing reduced coenzyme Q10.SOLUTION: A powder composition contains powder with silicon dioxide pores impregnated with vitamin C and amorphous reduced coenzyme Q10.SELECTED DRAWING: Figure 1

Description

The present invention relates to a powder composition containing reduced coenzyme Q10 and an antioxidant of reduced coenzyme Q10.

Coenzyme Q10 is a human-specific ubiquinone having an isoprene unit in the side chain of ubiquinone (2,3-dimethoxy-5-methyl-6-polyprenyl-1,4-benzoquinone), which is a kind of vitamin. Coenzyme Q10 is essential for the production of adenosine triphosphate in mitochondria as coenzyme in the living body. In addition, it has been confirmed to improve immune function and to be effective against heart disease, hypertension, rheumatoid valve disease and the like. Furthermore, its effectiveness against alveolar inflammation has also been studied.

Coenzyme Q10 has high physiological activity and is recommended to be actively ingested on a daily basis as a highly safe substance existing in the living body. However, since coenzyme Q10 is poorly water-soluble and has high crystallinity, it is difficult to formulate it by general emulsification. Further, even if crystalline coenzyme Q10 is orally ingested or drunk as it is, it is hardly absorbed by the living body.
Even if the emulsified composition is prepared once, a phenomenon is observed in which coenzyme Q10 crystallizes within a few days and the emulsified composition is separated or the emulsified composition is solidified. In addition, it is necessary to increase the concentration of coenzyme Q10 in order to ensure the effect as a preparation. However, due to such poor water solubility and high crystallinity, in order to dissolve coenzyme Q10 in edible oil and further disperse it as fine particles in the digestive tract, it is necessary to formulate using a large amount of emulsifier. ..

In order to solve such a problem, a preparation containing a high amount of reduced coenzyme Q10 has been proposed (Patent Document 1).
It is known that there are two types of coenzyme Q10, an oxidized type and a reduced type. It is known that a considerable part of coenzyme Q10 is present in the reduced form in the living body, and the ratio is usually about 40 to 90%. Therefore, reduced coenzyme Q10 is more suitable for oral ingestion. However, since reduced coenzyme Q10 rapidly changes to oxidized coenzyme Q in air, it is difficult to maintain the reduced form in vitro.

Various proposals have been made to stabilize reduced coenzyme Q10 in air.
For example, an acidic crystallization method for crystallization in the presence of a strong acid (Patent Document 2), a formulation containing an antioxidant (Patent Document 3), a formulation containing a polyol (Patent Document 4), and a propylene glycol fatty acid ester are blended. (Patent Document 5), a method of blending wax and a surfactant (Patent Document 6), a method of blending fat and oil and a polyol (Patent Document 7), amino acids (Patent Document 8), and various methods such as a method of blending ascorbic acid and ascorbic acid oxidase into a composition containing coenzyme Q10 (Patent Document 9). Alternatively, there are a method of using reduced CoQ10 as an inclusion body with cyclodextrin (Patent Document 10), a method of using pseudorotaxane with cyclodextrin (Patent Document 11), and the like.

Japanese Unexamined Patent Publication No. 10-109933 International Publication No. 2003/008363 Japanese Unexamined Patent Publication No. 2003-119127 International Publication No. 2003/062182 International Publication No. 2007/05/2802 International Publication No. 2009/025372 JP-A-2010-189437 International Publication No. 2011/046199 JP-A-2016-140351 JP-A-2010-126492 Japanese Unexamined Patent Publication No. 2009-269827

An object of the present invention is to provide a powder composition stably containing reduced coenzyme Q10. Another object of the present invention is to provide a stabilizer for reduced coenzyme Q10, which is used for preparing a powder composition stably containing reduced coenzyme Q10. Another object of the present invention is to provide an orally-administered agent containing a solid dispersion of coenzyme Q10.

The main configuration of the present invention is as follows.
(1) A powder composition containing a powder obtained by impregnating the pores of silicon dioxide with vitamin C and reduced coenzyme Q10, and a powder composition containing an amorphous reduced coenzyme Q10.
(2) The powder composition according to (1), wherein the pores of silicon dioxide have a pore volume of 1.0 to 2.0 mL / g.
(3) The powder composition according to (1) or (2), which contains 0.5 to 2 parts by mass of vitamin C, 40 to 60 parts by mass of silicon dioxide, and 40 to 60 parts by mass of reduced coenzyme Q10 in the powder composition. Stuff.
(4) An oral preparation containing the powder composition according to any one of (1) to (3).
(5) The oral preparation according to (4), which is any one of soft capsules, hard capsules, tablets, and granules.
(6) A stabilizer for reduced coenzyme Q10, which is obtained by impregnating the pores of silicon dioxide with vitamin C.
(7) Production of amorphous reduced coenzyme Q10-containing powder composition including a step of mixing a powder obtained by impregnating the pores of silicon dioxide with vitamin C and reduced coenzyme Q10 powder and heating at 55 to 65 ° C. Method.

In the powder composition of the present invention, the contained reduced coenzyme Q10 keeps the reduced coenzyme Q10 form for a long time in the air and hardly changes to the oxidized form. In addition, because it is amorphous, it exhibits high solubility (dissolution) in water.
Further, the powder composition containing the reduced coenzyme Q10 of the present invention can be used for foods and drinks such as beverages because coenzyme Q10 is dissolved (eluted) in water when dispersed in water. Furthermore, since it is highly soluble in water, its absorbability during oral administration is enhanced, and it is possible to reduce the dose per dose.
Since the powder composition containing the reduced coenzyme Q10 of the present invention contains coenzyme Q10 in a high concentration, it should be in a small dosage form when it is used as a tablet, capsule or granule for oral administration. Is possible. Therefore, the tablet is easy to swallow and has the effect of reducing the burden on the patient.
Further, the stabilizer of reduced coenzyme Q10 in which the pores of fine silicon dioxide of the present invention are impregnated with vitamin C suppresses the oxidation of reduced coenzyme Q10 even under conditions that cannot be suppressed by other antioxidants. Coloring and browning due to oxidation can be suppressed.
Furthermore, the present invention provides a simple method for producing a powder composition containing stable reduced coenzyme Q10.

It is a graph of the test result which confirmed the rate of change of the samples of Examples, Reference Examples and Comparative Examples 1 to 11 from reduced coenzyme Q10 to oxidized coenzyme 10 under room temperature storage conditions. It is a graph of the test result which confirmed the rate of change of the samples of Examples, Reference Examples and Comparative Examples 1, 3, 10 and 11 from reduced coenzyme Q10 to oxidized coenzyme 10 under light-shielded storage conditions at 40 ° C. .. 5 is an X-ray diffraction image of the powder composition of Example and Comparative Example 10.

The present invention relates to a powder composition containing stable reduced coenzyme Q10 (hereinafter referred to as "reduced CoQ10") and a method for producing the same.
The powder composition of the present invention will be specifically described.
The term "vitamin C and / or catechins impregnated in silicon dioxide" as used in the present invention means a state in which vitamin C and / or catechins are adsorbed on a large number of pores present in the silicon dioxide particles.

[Reduced CoQ10]
The reduced CoQ10 referred to in the present invention is also called ubiquinol.
Oxidized coenzyme Q10 (hereinafter referred to as “oxidized CoQ10”) is a compound having the following formula (1-A), and reduced coenzyme Q10 is a compound having the following formula (1-B).

[CoQ10]

In the above formula (1), the formula (1-A) is the oxidized CoQ10, and the formula (1-B) is the reduced CoQ10. Both are compounds that can be converted to each other by oxidation or reduction. Then, the reduced CoQ10 (1-B) is rapidly oxidized to the oxidized CoQ10 (1-A) in the air.

The method for obtaining CoQ10 is not particularly limited, and for example, a method for obtaining CoQ10 by a conventionally known method such as synthesis, fermentation, or extraction from a natural product, and then concentrating the reduced CoQ10 in the effluent by chromatography. Etc. can be adopted. In this case, if necessary, a general reducing agent such as sodium hydride or sodium dithionite (hydrosulfite sodium) is added to the above CoQ10 and contained in the above CoQ10 by a conventional method. Oxidized CoQ10 may be reduced to reduced CoQ10 and then concentrated by chromatography. It can also be obtained by a method of allowing the above-mentioned reducing agent to act on the existing high-purity CoQ10.

[Silicon dioxide]
The silicon dioxide used in the present invention is a compound represented by the composition formula SiO ₂ and has a large number of pores in its structure. Such porous silicon dioxide powder can be used in the present invention. Of these, powders distributed as fine silicon dioxide are preferable.
The fine silicon dioxide used in the present invention refers to a fine powder of silicon dioxide having porosity. The fine powder may have any particle size as long as the average particle size of the powder is 50 μm or less, but the average particle size is preferably 2 to 30 μm. Examples of silicon dioxide include light anhydrous silicic acid, hydrous silicon dioxide, and silicon dioxide. Porous silicon dioxide forms fine pores. The pores of the porous silicon dioxide used have an average pore volume of 0.3 to 3 mL / g, preferably 1.0 to 2.0 mL / g.

The average pore volume of fine silicon dioxide can be measured by a gas adsorption method or a mercury intrusion method.
The following conditions may be adopted as the measurement conditions of the gas adsorption method.
Measuring equipment: Quadruple specific surface area / pore distribution measuring device NOVA-TOUCH type (manufactured by Quantachrome)
Gas used: Nitrogen gas Refrigerant (temperature): Liquid nitrogen (77.35K)
Pretreatment conditions: 6Hr vacuum degassing under heating at 110 ° C Measurement content: Adsorption isotherm Measurement relative pressure: 5 × 10 ^-3 <P / P0 <0.99
Specific surface area: analysis using BET method Pore distribution: analysis using BJH method

The pores of the fine silicon dioxide used in the present invention are preferably those having an average pore volume of 1.0 to 2.0 mL / g. Such porous silicon dioxide is marketed as fine silicon dioxide for preparing tablets for pharmaceuticals and supplements. The fine silicon dioxide may be either an anhydrous type or a water-containing type. Specifically, Silo Page 720, Syricia 250, Syricia 320, Syricia 350, Sycilia 740 (manufactured by Fuji Silysia Chemical Ltd.), Adsolider 101, Adsolider 102 (manufactured by Freund Sangyo Co., Ltd.), Carplex # 67, Carplex FPS. -500 (manufactured by Eponic Japan Co., Ltd.), AEROSIL200FAD, Aerosil 200, Aerosil 300 (manufactured by Nippon Aerosil Co., Ltd.), Sunsphere H-51 (manufactured by AGC SI-Tech Ltd.) and the like. Of these, silo page 720 is preferable.

[Vitamin C]
Vitamin C as used in the present invention refers to ascorbic acid or a salt or derivative of ascorbic acid. For example, ascorbic acid phosphate salts such as sodium ascorbate, ascorbic acid phosphate sodium salt and ascorbic acid phosphate magnesium salt, ascorbic acid fatty acid ester such as ascorbic acid tetraisopalmitic acid ester, ascorbic acid ethyl ether and the like. Ascorbic acid glucosides such as alkyl ether ascorbic acid and -2-glucoside ascorbic acid and their fatty acid esters, ascorbic acid derivatives such as ascorbic acid sulfate ester and tocopheryl ascorbyl phosphate.
Ascorbic acid can be used in the present invention as long as it is a substance having an antioxidant ability. Of these, ascorbic acid or sodium ascorbate is preferable.

The content ratio of vitamin C, reduced CoQ10 and fine silicon dioxide in the powder composition of the present invention is 0.5 to 2 parts by mass of vitamin C, 40 to 60 parts by mass of fine silicon dioxide, and 40 to 60 parts by mass of reduced CoQ10. Is preferable in order to suppress the conversion of reduced CoQ10 to the oxidized form.

[Method for preparing powder composition]
The powder composition of the present invention is prepared by the following steps.
Step 1: Preparation of a powder in which the pores of the fine silicon dioxide are impregnated with vitamin C The fine silicon dioxide, water and vitamin C are mixed to prepare an aqueous vitamin C solution in which the fine silicon dioxide is dispersed. The aqueous solution and fine silicon dioxide are thoroughly stirred and mixed, and then dried. The drying method can be selected by any method. Of these, the freeze-drying method is preferable.
Step 2: Mixing with reduced CoQ10 powder The powder obtained in step 1 in which the pores of the fine silicon dioxide are impregnated with vitamin C and the reduced CoQ10 powder are mixed and stirred so as to be homogeneous.
Step 3: Heating operation The mixture obtained in Step 2 is heated at 50 to 70 ° C, preferably 55 to 65 ° C. The heating time is 5 to 30 minutes, preferably 10 to 20 minutes, and the mixture is heated with stirring.
After the heating is completed, the obtained powder is collected. When the powder is agglomerated, the bound mass may be crushed using a crusher and then sieved to make the particle size of the powder uniform.

In the powder thus obtained, the reduced CoQ10 becomes amorphous, maintains an extremely stable state, and suppresses the change to the oxidized CoQ10.
This is because the powder in which the pores of the fine silicon dioxide are impregnated with vitamin C exerts a strong antioxidant effect on the reduced CoQ10.

The powder composition of the present invention can be blended into foods and drinks as it is, or can be used as a supplement preparation or a pharmaceutical preparation. When it is used as a supplement preparation or a pharmaceutical preparation, it can be made into an oral preparation by adding commonly used additives.

Additives for oral preparations include lactose, crystalline cellulose, sucrose, mannitol, light anhydrous silicic acid, calcium hydrogen phosphate and the like; methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, gelatin, polyvinylpyrrolidone, purulan and the like. Binders; Disintegrants such as croscarmellose sodium, carmellose calcium, crospovidone, low-substituted hydroxypropyl cellulose, pregelatinized starch, partially pregelatinized starch; magnesium stearate, talc, calcium stearate, sucrose fatty acid ester, etc. Lubricants; colorants such as cochineal pigments; flavoring agents such as stevia, aspartame, and fragrances.

Examples of the form of the preparation containing the powder composition of the present invention include oral preparations such as tablets, capsules (soft capsules or hard capsules), granules and fine granules, and sublingual preparations.

The present invention will be specifically described with reference to Examples, Reference Examples, and Comparative Examples.
<1. Preparation of various powder compositions containing reduced CoQ10>
(1) Preparation of powder composition A powder composition was prepared using the commercially available food or pharmaceutical raw materials listed in Table 1 below.

1) Preparation of powder composition of Example An aqueous solution in which 10 mg of vitamin C was dissolved and dispersed in 5 mL of water was prepared. 495 mg of silopage 720 (fine silicon dioxide) was added to this aqueous solution, stirred and mixed, and then freeze-dried by a conventional method. The obtained dried product was pulverized to obtain fine silicon dioxide powder impregnated with vitamin C. The pore volume of silopage 720 was 1.6 mg / mL.
495 mg of the reduced CoQ10 powder was added to 505 mg of this powder and mixed, and then heated on a hot plate heated to 60 ° C. for about 10 minutes to melt the reduced CoQ10. After the completion of heating, if the powder was bound, it was pulverized to obtain the powder composition of the example.

2) Preparation of powder composition of Reference Example An aqueous solution was prepared in which 10 mg of Sanphenone 90LB-OP (catechin) was dissolved and dispersed in 5 mL of water. 495 mg of silopage 720 (fine silicon dioxide) was added to this aqueous solution, stirred and mixed, and then freeze-dried by a conventional method. The obtained dried product was pulverized to obtain fine silicon dioxide powder impregnated with Sanphenon 90LB-OP (catechin).
495 mg of the reduced CoQ10 powder was added to 505 mg of this powder and mixed, and then heated on a hot plate heated to 60 ° C. for about 10 minutes to melt the reduced CoQ10. After the completion of heating, if the powder was bound, it was pulverized to obtain a powder composition of Reference Example.

3) Preparation of fine silicon dioxide impregnated with Vitamin E In order to prepare the powder composition of the comparative example, Riken E Oil 910 or Gamma Bright 90 10 mg as Vitamin E was dissolved and dispersed in 5 mL of ethanol, and a silo was dissolved in this ethanol solution. 495 mg of Page 720 (fine silicon dioxide) was added, stirred and mixed, and then dried under reduced pressure by a conventional method. The obtained dried product was pulverized to obtain fine silicon dioxide powder impregnated with vitamin E.

4) Preparation of powder of Comparative Example Comparative Example 1 was an untreated reduced CoQ10 powder. Comparative Example 2 was prepared by powder mixing (PM) 500 mg of reduced CoQ10 powder with 500 mg of untreated fine silicon dioxide. Comparative Example 3 was prepared by heating and mixing (HM) the powder of Comparative Example 2 under the heating conditions described in Examples. Comparative Example 4 was prepared by powder mixing (PM) 495 mg of reduced CoQ10 powder with 505 mg of fine silicon dioxide impregnated with RIKEN E oil 910 in 3) above. Comparative Example 5 was prepared by heating and mixing (HM) the powder of Comparative Example 4 under the heating conditions described in Examples. Comparative Example 6 was prepared by powder mixing (PM) 495 mg of reduced CoQ10 powder with 505 mg of fine silicon dioxide impregnated with Gamma Bright 90 described in 3) above. Comparative Example 7 was prepared by heating and mixing (HM) the powder of Comparative Example 6 under the heating conditions described in Examples. Comparative Example 8 was prepared by powder mixing treatment (PM) of vitamin C 10 mg, fine silicon dioxide 495 mg, and reduced CoQ10 powder 495 mg. Comparative Example 9 was prepared by heating and mixing (HM) the powder of Comparative Example 8 under the heating conditions described in Examples. Comparative Example 10 was prepared by mixing 505 mg of fine silicon dioxide impregnated with vitamin C in 1) above with 495 mg of reduced CoQ10 powder (PM). Comparative Example 11 was prepared by mixing 505 mg of fine silicon dioxide impregnated with catechin in 2) above with 495 mg of reduced CoQ10 powder (PM).

Table 2 below shows a list of the ingredients and treatments of the comparative examples.

<2. Preservation test 1>
500 mg of each of the powders of Examples, Reference Examples, and Comparative Examples 1 to 11 was collected in a polyethylene bag (unipack) with a sealed seal, and a storage test was conducted using this as a test sample.
(1) Storage at room temperature The sealed bag containing the above sample was left indoors. The room temperature was about 20 ° C., and the humidity and light were not adjusted.

(2) Changes due to storage Reduced CoQ10 turns yellow when it changes to the oxidized form, and turns brown when it is oxidized. This was visually evaluated according to the following criteria. It is also colored by warming (HM) treatment.

The evaluation criteria are as follows.
++++: Brown change ++: Dark yellow to orange ＋: Yellow ±: Slightly colored-: No color change

The visual evaluation results are shown in Table 3 below.

The examples did not change after 7 days of storage. In the reference example, coloring was observed. On the other hand, Comparative Examples 1 to 11 were all colored. In particular, Comparative Examples 1, 4 and 7 had a remarkable degree of coloring.

(3) Measurement of Oxidized CoQ10 Content The amount of CoQ10 in each sample was quantified by the following method.
Preparation of HPLC sample
After weighing each powder, it was dissolved in ethanol containing 0.1% 2,6-Di-tert-butyl-cresol, filtered through a filter, and then diluted with ethanol to prepare a sample for HPLC measurement.

HPLC condition column: Inertsil ODS-3 (3 μm, 50 × 4.6 mm ID, manufactured by GL Science Co., Ltd.)
Eluent: A methanol, B ethanol (A / B 65/35, v / v)
Column temperature: 40 ° C
Detection: UV275 mm (oxidized CoQ10), UV290 nm, (reduced CoQ10)
Flow velocity: 0.6 mL / min

Quantification of Oxidized CoQ10 The content of oxidized CoQ10 in each sample was calculated from the following formula.
Oxidized CoQ10 content (%) = {Oxidized CoQ10 / (Oxidized CoQ10 + Reduced CoQ10)} x 100

(4) Results The measurement results are shown in Table 4 and FIG.

The content of oxidized CoQ10 almost corresponded to the evaluation of coloring.

<3. Preservation test 2>
Based on the results of storage test 1, the effect of storage under high temperature conditions was tested. 500 mg of each of the powders of Examples, Reference Examples, and Comparative Examples 1, 3, 10 and 11 was collected in a polyethylene bag (Unipack) with a sealed seal, and a storage test was conducted using this as a test sample.
The bag containing the above sample was further placed in a light-shielding aluminum bag and sealed.

(1) Storage conditions The sealed bag containing the above sample was stored in a constant temperature bath set at 40 ° C.

(2) Change in color tone due to storage According to Test 1, the change in color tone of reduced CoQ10 was visually evaluated according to the following criteria.
++++: Brown change ++: Dark yellow to orange ++: Yellow ±: Slightly colored-: No color change The visual evaluation results are shown in Table 5 below.

The examples did not change after 7 days of storage. In the reference example, coloring was observed. On the other hand, all the comparative examples were colored. In particular, Comparative Example 1 had a great degree of coloring.

(3) Measurement of Oxidized CoQ10 Content The amount of CoQ10 in each sample was measured in the same manner as above, and the content of oxidized CoQ10 was determined.

(4) Results The measurement results are shown in Table 6 and FIG.

The content of oxidized CoQ10 corresponded to the evaluation of coloring as in Test 1.

From the above storage tests 1 and 2, it is clear that the composition of the present invention is a composition in which reduced CoQ10 is stably retained. Further, it was found that the fine silicon dioxide impregnated with vitamin C used for preparing the composition of the present invention is extremely effective in preventing the oxidation of reduced CoQ10.

<4. Confirmation of crystallinity>
In order to investigate the mechanism of action of the present invention, the crystal state was observed using an X-ray diffractometer. The powder composition of Example 10 and Comparative Example 10 which was a powder mixture was stored at room temperature for 1 week and used as a measurement sample. The measurement conditions are as follows.
Powder X-ray diffractometer: MiniFlex 600 (manufactured by Rigaku)
The X-ray output was 40 kV, 15 mA, and the scan speed was 10 ° / min.

The diffraction pattern is shown in FIG.
From the diffraction pattern of the powder composition of the example, the peak showing the crystal of reduced CoQ10 disappeared. On the other hand, in the composition of Comparative Example 10, a diffraction peak derived from reduced CoQ10 appeared. This confirms that the composition of the present invention is amorphous in reduced CoQ10. That is, it was considered that the powder composition of the present invention was stabilized by the coexistence of reduced CoQ10 as an amorphous substance with vitamin C.

<5. Preparation example using the powder of the example>
(1) Tablets A tablet containing 30% by mass of CoQ10 was prepared by mixing the powder of Examples with crystalline cellulose as an excipient, partially pregelatinized starch as a disintegrant, and calcium stearate as a lubricant, and tableting the mixture.
There were no particular problems in tableting.

(2) Capsules The powder of Examples was mixed with crystalline cellulose as an excipient and calcium stearate as a lubricant and filled in HPMC hard capsules to obtain hard capsules containing 4 to 30% by mass of CoQ10. There were no particular problems in producing hard capsules.

(3) Granules The powder of the example was mixed with maltitol and crystalline cellulose and then granulated by a wet granulation method to obtain granules containing 4 to 30% by mass of CoQ10. There were no particular problems in producing the granules.

Claims (7)

A powder composition containing a powder obtained by impregnating the pores of silicon dioxide with vitamin C and reduced coenzyme Q10, and a powder composition containing an amorphous reduced coenzyme Q10. The powder composition according to claim 1, wherein the pores of silicon dioxide have a pore volume of 1.0 to 2.0 mL / g. The powder composition according to claim 1 or 2, wherein the powder composition contains 0.5 to 2 parts by mass of vitamin C, 40 to 60 parts by mass of silicon dioxide, and 40 to 60 parts by mass of reduced coenzyme Q10. An oral preparation containing the powder composition according to any one of claims 1 to 3. The oral preparation according to claim 4, which is any one of a soft capsule, a hard capsule, a tablet, and a granule. A stabilizer for reduced coenzyme Q10, which is obtained by impregnating the pores of silicon dioxide with vitamin C. A method for producing an amorphous reduced coenzyme Q10-containing powder composition, which comprises a step of mixing a powder obtained by impregnating the pores of silicon dioxide with vitamin C and a reduced coenzyme Q10 powder and heating at 55 to 65 ° C.