JP6004130B1 - Coenzyme Q10-containing composition, method for producing the same, and coenzyme Q10 combination preparation using the composition - Google Patents

Abstract

[PROBLEMS] To easily and easily obtain a granular coenzyme Q10-containing composition without requiring complicated operations in the process of emulsification or solubilization or extremely strict preparation and management. Effectively improves bioabsorbability. [MEANS FOR SOLVING PROBLEMS] (A) Coenzyme Q10, (B) One or more water-soluble polymeric substances selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and polyvinyl alcohol, (C) Water-soluble shaping And a coenzyme Q10-containing composition comprising an agent and (D) an alkyl sulfate salt of vitamin B1. [Selection figure] None

Description

  The present invention has a high solubility in water and can improve the bioabsorption rate of coenzyme Q10, and can also improve the ease of formulation, and coenzyme Q10 powder that can be suitably used as pharmaceuticals, foods, cosmetics and the like. The present invention relates to a composition, a production method thereof, and a coenzyme Q10 combination preparation using the powder composition.

  Coenzyme Q10 exists in mitochondria in cells in the living body, is a coenzyme that creates energy necessary for life activity, and is involved in mitochondrial electron transfer. Coenzyme Q10 has been attracting attention as a pharmaceutical, food, and cosmetic because it acts as an antioxidant in vivo. On the other hand, coenzyme Q10 is a poorly water-soluble component with low solubility in water. It is known as an inferior component.

  Since coenzyme Q10 is a low-melting powder, it is generally inferior in handleability. For this reason, conventionally, it has been mostly used as a soft capsule, and it is difficult to produce processed foods such as tablets and other dosage forms. Met. Various proposals have been made for this problem. For example, the following Patent Documents 1 to 8 having an emulsification step can be exemplified.

  In Japanese Patent No. 5256041 (Patent Document 1) and Japanese Patent No. 5140585 (Patent Document 2), an O / W / O emulsion containing a water-soluble polymer and coenzyme Q10 is dried to obtain a high spherical shape. It is described that powder particles of a certain degree can be obtained, exhibit high content stability and water dispersibility, and avoid tableting troubles.

  Further, International Publication No. 2007/125915 (Patent Document 3) discloses that a fine droplet of coenzyme Q10 emulsified in an aqueous solution of alginate collides with a fine droplet of a calcium salt aqueous solution, thereby producing a fine amorphous material. It is disclosed that a calcium alginate gel containing high quality coenzyme Q10 is formed, dried and recovered as coenzyme Q10 powder. And it is described that this coenzyme Q10 powder shows rapid disintegration in the intestinal tract after oral administration, and shows excellent absorbability in the body.

  In Japanese Patent No. 5343002 (Patent Document 4), a glycerin fatty acid ester, a sucrose fatty acid ester, a sorbitan fatty acid ester, a lecithin, and a saponin are used as a surfactant, gum arabic, and erythritol. However, it is difficult to say that it is in line with the nature-oriented trend that has been increasing among consumers in recent years because a surfactant is an essential component.

  In Japanese Patent No. 5292105 (Patent Document 5) and Japanese Patent No. 5159117 (Patent Document 6), coenzyme Q10 is crystallized in an aqueous alcohol solution containing a surfactant of HLB6 or higher and a water-soluble polymer. It is disclosed that coenzyme Q10 granules having high fluidity and handleability can be obtained.

  In JP2013-32301A (Patent Document 7), coenzyme Q10 melted in fats and oils is emulsified and dispersed in an aqueous solution containing a surfactant of HLB12 or higher and a water-soluble excipient, and then dried. A method for producing coenzyme Q10 powder to be powdered is disclosed.

  Japanese Patent No. 5690809 (Patent Document 8) does not require a high shearing force like a high-pressure emulsifier or a homomixer by dropping and dispersing coenzyme Q10 dissolved in an organic solvent in an aqueous solution of protein or amino acid. It discloses that an emulsion of coenzyme Q10 can be obtained by the production process.

  As is clear from the examples, most of the techniques described in the above-mentioned patent documents include a step of emulsifying coenzyme Q10 heated and melted in an aqueous solution of a water-soluble polymer such as gum arabic or a surfactant. Cost. This generally requires an emulsification operation using a high-pressure emulsifier or a homomixer, but as is well known, a mixer such as a homomixer has a shearing force that is high enough to cut a water-soluble polymer. In the emulsification step, coenzyme Q10 must be prepared into sufficiently fine emulsified droplets before the water-soluble polymer is cleaved and its colloid protective action is impaired. This lacks the robustness of the manufacturing process, and it cannot be said that it has sufficient industrial applicability. In Patent Document 8, a method that does not use a high shearing force for emulsification is proposed, but very strict management is required in the residual solvent, and it is difficult to avoid an increase in quality control cost.

  Japanese Patent Application Laid-Open No. 2005-328839 (Patent Document 9) discloses that a poorly water-soluble functional component containing coenzyme Q10 is dissolved in alcohol and then introduced into an aqueous solution of a surfactant or cyclodextrin. It is disclosed to obtain a solubilized solution. However, in this method, the form of the coenzyme Q10-containing preparation obtained is limited to a liquid.

  Furthermore, as a technique for formulating coenzyme Q10, a technique considering the blending of organic acids has also been proposed. For example, in Japanese Patent No. 3549197 (Patent Document 10), a dry powder of coenzyme Q10 obtained by emulsification in an aqueous solution of a water-soluble polymer and spray-drying has a content stability in the presence of an organic acid. Patent No. 3754625 (Patent Document 11) describes that the content stability of coenzyme Q10 decreases in the presence of gelatin and a vitamin B1 derivative by adding an organic acid. It is described that it can be prevented.

Japanese Patent No. 5256041 Japanese Patent No. 5140585 International Publication No. 2007/125915 Japanese Patent No. 5343002 Japanese Patent No. 5292105 Japanese Patent No. 5159117 JP2013-32301A Japanese Patent No. 5690809 JP 2005-328839 A Japanese Patent No. 3549197 Japanese Patent No. 3754625

  The present invention has been made in view of the above circumstances, and does not require complicated operations or extremely strict preparation, management, etc. by the step of emulsification or solubilization, and it is easy and simple to produce a granular material excellent in stability. An object is to obtain a coenzyme Q10-containing composition and to effectively improve the bioabsorbability of coenzyme Q10.

  As a result of intensive studies to achieve the above object, the present inventors have found that a granular composition is formed by spray drying from a solution in which coenzyme Q10 is dispersed together with a water-soluble polymer substance and a water-soluble excipient. It was found that a specific water-soluble polymer substance was used and an alkyl sulfate salt of vitamin B1 was blended when producing the product. That is, fundamentally different from the above-described conventional technique that undergoes an emulsification or solubilization step, the present invention does not substantially utilize the phenomenon of emulsification or solubilization, and a water-soluble polymer substance, a water-soluble excipient, and A powdery composition can be obtained satisfactorily from a solution in which coenzyme Q10 is dispersed together with the alkyl sulfate of vitamin B1, and amorphous coenzyme Q10 is confirmed in the obtained composition. As a result, it was found that the water solubility was greatly improved and the bioabsorbability was excellent, and the present invention was completed.

Therefore, this invention provides the following coenzyme Q10 containing composition, the manufacturing method of this composition, and the various formulation which mix | blended this composition.
[1] (A) Coenzyme Q10, (B) One or more water-soluble polymer substances selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and polyvinyl alcohol, (C) Water-soluble excipient And (D) a coenzyme Q10-containing composition comprising an alkyl sulfate salt of vitamin B1.
[2] For 100 parts by mass of (A) coenzyme Q10, (B) 100-500 parts by mass of water-soluble polymer substance, (C) 100-500 parts by mass of water-soluble excipient, (D) vitamins [1] A coenzyme Q10-containing composition comprising 1 to 100 parts by mass of an alkyl sulfate of B1.
[3] The coenzyme Q10-containing composition according to [1] or [2], wherein the alkyl sulfate of (D) vitamin B1 is thiamine lauryl sulfate or thiamine cetyl sulfate.
[4] The water-soluble excipient (C) is dextrin, glucose, mannose, galactose, fructose, psicose, xylose, arabinose, trehalose, maltose, isomaltose, isomaltulose, isotrehalose, cellobiose, lactose, sucrose, Fructooligosaccharide, galactooligosaccharide, dairy oligosaccharide, inulin, N-acetylglucosamine, raffinose, erythritol, isomalt, lactitol, maltitol, mannitol, sorbitol, xylitol, reduced palatinose, reduced water candy, alanine, proline, glycine, threonine, Coenzyme Q10 of any one of [1] to [3], which is one or more selected from lysine, arginine, aspartic acid, glutamic acid, cysteine, ornithine Containing composition.
[5] (A) The coenzyme Q10-containing composition according to any one of [1] to [4], wherein at least a part of coenzyme Q10 is contained in an amorphous state.
[6] A method for producing the coenzyme Q10-containing composition according to any one of [1] to [5] as a powdery composition, the water-soluble polymer substance of (A) coenzyme Q10 and (B) above A coenzyme Q10 comprising: a water-soluble excipient of (C), an aqueous dispersion containing (D) an alkyl sulfate of vitamin B1 and ethanol, and spray-dried. A method for producing the composition.
[7] A coenzyme Q10-dispersed ethanol solution is prepared by dispersing and dissolving the coenzyme Q10 of (A) in ethanol together with the alkyl sulfate of vitamin B1 of (D), and water-soluble shaping of (C) above An aqueous excipient solution is prepared by dissolving the agent in water. At that time, the water-soluble polymer substance (B) is blended and dissolved in either the ethanol solution or the aqueous solution, and then the coenzyme Q10 ethanol solution and The method for producing an enzyme Q10-containing composition according to [6], wherein the excipient aqueous solution is mixed, spray-dried and granulated to obtain a granular composition.
[8] A coenzyme Q10 combination preparation comprising the coenzyme Q10-containing composition according to any one of [1] to [5], which is formulated as a pharmaceutical, health food or cosmetic.
[9] The coenzyme Q10 combination preparation according to [8], which is prepared or formulated in any form selected from soft capsules, hard capsules, tablets, granules, and powders.
[10] The coenzyme Q10-containing preparation according to [8], wherein the coenzyme Q10-containing composition is dissolved or dispersed in a base or a solvent and dispensed or formulated into a jelly, liquid, lotion, cream or ointment.

  Here, the emulsification and solubilization used in the above-mentioned conventional method generally refers to an operation to make two different phases of water and oil discontinuous but uniform or fine, depending on the degree of uniformity or fineness in this operation. It is said that the degree of achievement of a property required for the composition changes, and the strength of the property increases as the property is uniform or fine. For example, the solubility of coenzyme Q10 after pulverizing this emulsion becomes higher as the average particle size of the oil droplets containing coenzyme Q10 in the emulsion is more uniform and finer. Therefore, the conventional method requires extremely strict adjustment and control in the operation of emulsification and solubilization, and as described above, this is a factor that impairs the robustness of the manufacturing process. In contrast, in the present invention, even if the two phases are not only heterogeneous but also coarse, the supersaturated solubility, the dissolution rate, and the absorbability in the body achieved by these are not significantly reduced. It is a robust product that can stably obtain a coenzyme Q10-containing composition, and sufficiently meets the industrial demand for productivity.

  The present invention also provides a coenzyme Q10 granule having good handling properties, stability, and oral absorbability, as in the above Patent Documents 1 and 2, which is a costly production process (O / Regardless of (W / O emulsification, dehydration, powder / liquid separation, powder washing), it is possible to provide a simple and low cost and small environmental load.

  Furthermore, in the present invention, as described in Patent Documents 10 and 11, good content stability can be obtained without requiring special consideration for the blending of organic acids. For example, exudation and color spots can be prevented even at a temperature of 40 ° C. or higher. It can be stored without any occurrence. Furthermore, in the production method of the present invention, coenzyme Q10 is dispersed in a water-containing ethanol solution in the presence of vitamin B1 alkyl sulfate. Unlike Patent Document 9, vitamin B1 alkyl sulfate is water-soluble. Is low and has low emulsifying properties, it does not dissolve coenzyme Q10 transparently, but does not emulsify. That is, in the present invention, by using vitamin B1 alkyl sulfate, an amorphous material having a high water solubility and a high absorbability in the body without passing through a single-phase state or a uniform fine emulsified state as a uniform solution. A powder containing high quality coenzyme Q10 is obtained, which is an invention based on a phenomenon completely different from the technique described in Patent Document 9.

  According to the present invention, it is possible to obtain a coenzyme Q10 granule having high solubility in water, excellent bioabsorption, and easy formulation, without requiring a strict and complicated process such as an emulsification process. The enzyme Q10 can be easily and satisfactorily applied to pharmaceuticals, foods and cosmetics.

2 is a graph showing the particle size distribution of a powdered coenzyme Q10-containing composition obtained in Example 1. FIG. 2 is a polarizing microscope photograph of the powdery coenzyme Q10-containing composition obtained in Example 1. FIG. It is a polarizing microscope photograph of coenzyme Q10 bulk powder. 6 is a polarizing microscope photograph of the mixed powder obtained in Comparative Example 8. It is a graph which shows the result of the elution test to water. It is a graph which shows the result of the X ray diffraction measurement of coenzyme Q10 bulk powder. 2 is a graph showing the results of X-ray diffraction measurement of the powdery coenzyme Q10-containing composition obtained in Example 1. FIG. It is a graph which shows the result of a pharmacokinetic test.

Hereinafter, the present invention will be described in detail.
As described above, the coenzyme Q10-containing composition of the present invention comprises (A) coenzyme Q10, (B) a water-soluble polymer substance, (C) a water-soluble excipient, and (D) an alkyl sulfate salt of vitamin B1. It contains.

  A commercial product can be used as the (A) coenzyme Q10, and the blending amount thereof is not particularly limited, but is preferably 8 to 33% by mass, more preferably 13 to 28% of the composition. It is 18 mass%, More preferably, it is 18-23 mass%. If the amount of coenzyme Q10 is less than 8% by mass, the intake of the coenzyme Q10 composition will increase in order to administer an appropriate amount, which may impair the ease of drinking and administration of the preparation. Application to cosmetics, etc. may be difficult. On the other hand, if it exceeds 33% by mass, the content of the above-mentioned other components is inevitably reduced, making it difficult to produce a powder or the like, and obtaining sufficient water solubility and bioabsorbability. May be difficult. Furthermore, there is a risk that the stability to temperature may be impaired, and there may be inconveniences such as the storage conditions of the coenzyme Q10 composition being limited to a cold place and the expiration date being short.

  The (B) water-soluble polymer substance is applicable to pharmaceuticals, foods, cosmetics, etc. In the present invention, from the viewpoints of solubility in water-containing ethanol solution, heat resistance and heat-dependent viscosity change, One or more of hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), and polyvinyl alcohol (PVA) are used.

  (B) Although the compounding quantity of a water-soluble polymeric substance is not restrict | limited in particular, It is preferable to set it as 100-500 mass parts with respect to said (A) coenzyme Q10 of 100 mass parts, More preferably It is 130-300 mass parts, More preferably, it is 175-225 mass parts. When the blending amount of the water-soluble polymer substance is less than 100 parts by mass, the yield of the powder is reduced due to the binding property derived from coenzyme Q10 when spray-dried and pulverized to increase productivity. May be lower. On the other hand, when the amount exceeds 500 parts by mass, agglomerates (mamasko) are likely to be formed at the time of re-dissolution of the granular material obtained by spray drying, and there is a high possibility that inconvenience such as rapid supersaturation dissolution cannot be obtained. Become.

  As the above-mentioned (C) water-soluble excipient, those having a solid state that does not flow at 20 ° C. and having a solubility in 100 g of water at 20 ° C. of 10 to 300 g are used. For example, saccharides and amino acids are suitable. Used for. Specifically, as saccharides, dextrin, glucose, mannose, galactose, fructose, psicose, xylose, arabinose, trehalose, maltose, isomaltose, isomaltulose, isotrehalose, cellobiose, lactose, sucrose, fructo-oligosaccharide, galactooligosaccharide, Examples include dairy oligosaccharides, inulin, N-acetylglucosamine, raffinose, erythritol, isomalt, lactitol, maltitol, mannitol, sorbitol, xylitol, reduced palatinose, reduced water candy, etc., and one or more of these are used. be able to.

  Examples of amino acids include alanine, proline, glycine, threonine, lysine, arginine, aspartic acid, glutamic acid, cysteine, ornithine, and one or more of these can be used. Of course, one or more of these amino acids can be used in combination with one or more of the above saccharides.

  Here, (C) the above-mentioned “water-soluble excipient that is a solid that does not flow at 20 ° C. and has a solubility in 100 g of water at 20 ° C. of 10 g to 300 g” is, for example, powdered In the obtained coenzyme Q10 composition, it is a property necessary for production as a granule or for a water-soluble excipient to be a water-conducting route and to dissolve quickly in water or the digestive tract. When a fluid fluid at 20 ° C. is used as the water-soluble excipient, it may be difficult to produce the coenzyme Q10 composition as a powder that is easy to handle. In addition, more preferable solubility is 15-260g with respect to 100g of water in 20 degreeC, More preferably, it is 20-220g. If the solubility of the water-soluble excipient is less than 10 g, aggregates (mamasko) are likely to be formed during re-dissolution, and rapid supersaturation dissolution may not be obtained. On the other hand, if it exceeds 300 g, when the powder is obtained by spray drying, the powder will be dissolved by the water remaining in the powder, making it difficult to produce a powder that is easy to handle. There is a case.

  The blending amount of the water-soluble excipient (C) is not particularly limited, but is preferably 100 to 500 parts by mass, more preferably 100 parts by mass of the (A) coenzyme Q10. Is 130 to 300 parts by mass, more preferably 175 to 225 parts by mass. When the blending amount of the water-soluble excipient is less than 100 parts by mass, there is not a sufficient water-conveying route in the coenzyme Q10 composition obtained by pulverization, so that an agglomerate (maco) is easily formed during re-dissolution. In other words, rapid supersaturated dissolution may not be obtained. On the other hand, if it exceeds 500 parts by mass, the intake of the coenzyme Q10 composition increases for administration of an appropriate amount, which may cause inconveniences such as impairing ease of swallowing and administration of the preparation.

  Next, the alkyl sulfate of (D) vitamin B1 is not particularly limited, but thiamine lauryl sulfate and thiamine cetyl sulfate are preferably used because of their availability.

  The blending amount of the alkyl sulfate of (D) vitamin B1 is not particularly limited, but is preferably 1 to 100 parts by mass with respect to 100 parts by mass of the (A) coenzyme Q10. Preferably it is 2-25 mass parts, More preferably, it is 4-10 mass parts. In the present invention, as described above, the use of this vitamin B1 alkyl sulfate together with the (B) water-soluble polymer substance and (C) water-soluble excipient substantially eliminates the phenomenon of emulsification or solubilization. Therefore, it is possible to obtain a composition in the form of a granular material and the like, and to obtain good water solubility and bioabsorbability. In this case, when the blending amount of the alkyl sulfate of vitamin B1 is less than 1 part by mass, it may be difficult to obtain good water solubility and bioabsorbability. On the other hand, when the amount exceeds 100 parts by mass, when the powder is dried by spray drying, only a crystal of the salt of the fatty alcohol sulfate of vitamin B1 is separated and a uniform composition cannot be obtained. In some cases, the amount of the water-containing ethanol solution to be provided increases and the productivity is impaired.

  Here, the alkyl sulfate of (D) vitamin B1 does not act as a surfactant, but it is preferable that the composition of the present invention does not contain fats and oils and a surfactant. Oils and fats (for example, medium-chain fatty acid triglycerides, safflower oil, linseed oil, fish oil, pork fat, edible fats and oils), anionic surfactants (for example, sodium dodecyl sulfate, etc.) together with alkyl sulfate of vitamin B1 in the composition ) And nonionic surfactants (eg, polysorbates, polyglycerin fatty acid esters, sucrose fatty acid esters, organic acid monoglycerides, propylene glycol fatty acid esters, hydrogenated castor oil, lecithins, etc.) In this case, coenzyme Q10 is preferentially taken into these oils and surfactants in the water-containing ethanol solution used for spray drying, and then only the crystal of coenzyme Q10 is separated when spray dried and powdered. Inconveniences such as inability to obtain a uniform composition may occur.

  The coenzyme Q10-containing composition of the present invention does not go through the steps of emulsification and solubilization in a water-containing ethanol solution used for spray-drying when it is made into a powder by using the (D) vitamin B1 alkyl sulfate. In the present invention, in the aqueous ethanol solution used for spray-drying, the coenzyme Q10 contains the above-mentioned coenzyme Q10. It is preferable to contain in the state which is not emulsified at all.

  In the coenzyme Q10-containing composition of the present invention, known additives in addition to the above components may be used in accordance with the dosage form for final products such as pharmaceuticals, health foods, and cosmetics. It can mix | blend suitably in the range which does not carry out. For example, appropriate amounts of sweeteners, colorants, preservatives, lubricants, thickeners, stabilizers, antioxidants, bleaches, fragrances, acidulants, seasonings, pH adjusters, and other various manufacturing agents Can be blended.

  The form of the coenzyme Q10-containing composition of the present invention is not particularly limited, but is preferably in the form of a granular material. In this case, although not particularly limited, it is preferable that at least a part of the (A) coenzyme Q10 is contained in an amorphous state, whereby the water solubility can be further improved. . In this case, the higher the proportion of amorphous, the better. Specifically, it is preferably 10% or more of (A) coenzyme Q10, more preferably 20% or more. Moreover, although there is no restriction | limiting in an upper limit, it can be 99% or less realistically. In addition, (A) Coenzyme Q10 and part or all of the alkyl sulfate of (D) vitamin B1 may be in an amorphous state. Usually, in the present invention, although not particularly limited, At least a part of both the enzyme Q10 and the alkyl sulfate of (D) vitamin B1 is in an amorphous state.

  When the method for producing a coenzyme Q10-containing composition of the present invention is, for example, a granular composition, (A) coenzyme Q10, (B) water-soluble polymer substance, (C) A method of spray-drying an aqueous dispersion containing the water-soluble excipient of (D), the alkyl sulfate of vitamin B1 of (D), and ethanol is suitably employed. In this case, the (A) coenzyme Q10 is dispersed or dissolved in ethanol together with the (D) vitamin B1 alkyl sulfate to prepare a coenzyme Q10-dispersed ethanol solution, while the (C) water-soluble excipient is added. Prepare aqueous solutions of excipients by dissolving in water, and when these are further prepared, blend the water-soluble polymer substance (B) with either an ethanol solution or an aqueous solution depending on the type (solubility). Then, a method is preferably employed in which the coenzyme Q10 ethanol solution and the aqueous excipient solution are mixed to form an aqueous dispersion containing ethanol and granulated by spray drying.

  The coenzyme Q10-containing composition of the present invention can be a coenzyme Q10 preparation such as pharmaceuticals, health foods or cosmetics. For example, hard capsules and soft capsules filled with the coenzyme Q10-containing composition of the present invention produced in a powder form, powders, granules and tablets produced from the powdered coenzyme Q10-containing composition, the powder form A coenzyme Q10 preparation such as a solution, lotion, cream, ointment, jelly or the like in which the coenzyme Q10-containing composition is dissolved or dispersed can be obtained. In this case, various preparations produced from the composition of the present invention can achieve good bioavailability by coenzyme Q10 being absorbed into the living body by oral or percutaneous ingestion. In the case where the preparation is dissolved in a liquid, the preparation containing coenzyme Q10 at a high concentration can be easily produced because it dissolves well in water.

  Examples and Comparative Examples are shown below to show the effects of the present invention more specifically, but the present invention is not limited to the following Examples.

[Example 1]
2 g of coenzyme Q10 bulk powder and 0.08 g of thiamine lauryl sulfate were dispersed and dissolved in 110 g of ethanol to obtain a coenzyme Q10-dispersed ethanol solution. At this time, the coenzyme Q10 bulk powder and thiamine lauryl sulfate were uniformly dissolved in ethanol. On the other hand, 4 g of hydroxypropylcellulose (HPC) and 3.92 g of maltose were dissolved in 240 g of water to obtain an aqueous HPC / maltose solution (excipient aqueous solution). While the HPC maltose aqueous solution was stirred at room temperature at 100 rpm with a propeller mixer, the coenzyme Q10-dispersed ethanol solution was added thereto to obtain a mixed solution. In this mixture, coenzyme Q10 was precipitated and dispersed as fine crystals. This mixed solution is spray-dried at a temperature of 140 ° C. using a spray dryer (spray dryer, manufactured by Tokyo Rika Kikai Co., Ltd., SD-1000), and a powdery coenzyme Q10-containing composition having a median diameter d50 = 15.41 μm. Got. The particle size distribution diagram is shown in FIG.

[Example 2]
A mixed solution was prepared in the same manner as in Example 1 except that hydroxypropylmethylcellulose (HPMC) was used instead of HPC. In this mixture, coenzyme Q10 was precipitated and dispersed as fine crystals. In the same manner as in Example 1, this mixed solution was spray-dried to obtain a powdery coenzyme Q10-containing composition.

[Example 3]
2 g of coenzyme Q10 bulk powder and 0.08 g of thiamine lauryl sulfate were dispersed and dissolved in 60 g of ethanol to obtain a coenzyme Q10 dispersed ethanol solution. On the other hand, 4 g of HPC and 3.92 g of maltose were dissolved in 130 g of water to obtain an HPC / maltose aqueous solution (excipient aqueous solution). Thereafter, the same operation as in Example 1 was performed to obtain a powdery coenzyme Q10-containing composition. Table 1 shows the state of each process. Regarding the preparation of the dispersion liquid, the uniformly suspended liquid: ◯ and the aggregate precipitated: x. Regarding the preparation of the powder, amorphized powder: ◯, powder with many crystals: Δ, sticky powder and difficult to recover: x. Regarding the state of dissolution when the obtained powder was added to water, it was easily dissolved: ◯, dissolved but aggregated: Δ, not dissolved: x.

[Example 4]
A powdery coenzyme Q10-containing composition was obtained in the same manner as in Example 3 except that thiamine lauryl sulfate was changed to 0.1 g, HPC was changed to 2.5 g, and maltose was changed to 5.4 g. The state of each process is shown in Table 1 as in Example 3.

[Example 5]
A powdery coenzyme Q10-containing composition was obtained in the same manner as in Example 3 except that thiamine lauryl sulfate was changed to 0.1 g, HPC was changed to 8 g, and maltose was changed to 9.9 g. The state of each process is shown in Table 1 as in Example 3.

[Example 6]
A powdery coenzyme Q10-containing composition was prepared in the same manner as in Example 3 except that 0.2 g of thiamine lauryl sulfate, 100 g of ethanol, HPMC was changed to HPMC, maltose was changed to 3.8 g, and water was changed to 190 g. I got a thing. The state of each process is shown in Table 1 as in Example 3.

[Example 7]
A powdery supplement was prepared in the same manner as in Example 3 except that 0.4 g of thiamine lauryl sulfate, 100 g of ethanol, polyvinyl pyrrolidone (PVP) for HPC, 3.6 g of maltose and 190 g of water were changed. An enzyme Q10-containing composition was obtained. The state of each process is shown in Table 1 as in Example 3.

[Example 8]
A powdery coenzyme Q10-containing composition was obtained in the same manner as in Example 3 except that 0.02 g of thiamine lauryl sulfate, 90 g of ethanol, 3.98 g of maltose and 3.98 g of water were changed to 180 g of water. It was. The state of each process is shown in Table 1 as in Example 3.

[Example 9]
A powdery coenzyme Q10-containing composition was obtained in the same manner as in Example 3, except that 0.06 g of thiamine lauryl sulfate, 90 g of ethanol, 3.94 g of maltose and 3.94 g of water were changed to 160 g of water. It was. The state of each process is shown in Table 1 as in Example 3.

[Example 10]
A powdery coenzyme Q10-containing composition was obtained in the same manner as in Example 3 except that 2 g of thiamine lauryl sulfate, 120 g of ethanol, 8 g of HPC, 8 g of maltose, and 240 g of water were changed to 240 g. . The state of each process is shown in Table 1 as in Example 3.

[Example 11]
A powdery coenzyme Q10-containing composition was obtained in the same manner as in Example 3 except that 0.1 g of thiamine lauryl sulfate, 8 g of HPC, and 9.9 g of maltose were changed. The state of each process is shown in Table 1 as in Example 3.

[Comparative Example 1]
A powdery coenzyme Q10-containing composition was obtained in the same manner as in Example 1 except that thiamin lauryl sulfate was not added, ethanol was changed to 60 g, maltose was changed to 4 g, and water was changed to 130 g. The state of each step is shown in Table 2 as in Example 3.

[Comparative Example 2]
2 g of the coenzyme Q10 bulk powder was dispersed and dissolved in 60 g of ethanol to obtain a coenzyme Q10 dispersed ethanol solution. On the other hand, 4 g of HPC and 3.92 g of maltose were dissolved in 130 g of water to obtain an HPC / maltose aqueous solution (excipient aqueous solution). Thereafter, the same operation as in Example 1 was performed to obtain a powdery coenzyme Q10-containing composition. The state of each process is shown in Table 2 in the same manner as in Example 3.
0.08 g of thiamine lauryl sulfate was mixed with 9.92 g of the obtained powder to obtain a mixed powder.

[Comparative Example 3]
A powdery coenzyme Q10-containing composition was obtained in the same manner as in Example 1 except that ethanol was changed to 60 g, HPC was changed to 4 g of gum arabic, and water was changed to 130 g. The state of each process is shown in Table 2 in the same manner as in Example 3. As shown in the table, precipitation of aggregates was observed in the mixed solution in the preparation of the dispersion.

[Comparative Example 4]
2 g of coenzyme Q10 bulk powder and 0.08 g of thiamine lauryl sulfate were dispersed and dissolved in 60 g of ethanol to obtain a coenzyme Q10 dispersed ethanol solution. On the other hand, 0.4 g of carboxyvinyl polymer and 7.52 g of maltose were dissolved in 130 g of water and the pH was adjusted with sodium hydroxide to obtain an aqueous carboxyvinyl polymer / maltose solution (excipient aqueous solution). Thereafter, the same operation as in Example 1 was performed to obtain a powdery coenzyme Q10-containing composition. The state of each step is shown in Table 2 as in Example 3. As shown in the table, precipitation of aggregates was observed in the mixed solution in the preparation of the dispersion.

[Comparative Example 5]
2 g of coenzyme Q10 bulk powder and 2 g of soybean lecithin (emulsifier) were dispersed and dissolved in 100 g of ethanol to obtain a coenzyme Q10-dispersed ethanol solution. On the other hand, 4 g of HPC and 2 g of maltose were dissolved in 190 g of water to obtain an HPC / maltose aqueous solution (excipient aqueous solution). Thereafter, the same operation as in Example 1 was performed, but it was difficult to recover the powdered coenzyme Q10-containing composition by stickiness.

[Comparative Example 6]
2 g of the coenzyme Q10 bulk powder was dispersed and dissolved in 60 g of ethanol to obtain a coenzyme Q10 dispersed ethanol solution. On the other hand, 4 g of HPC, 2 g of maltose and 2 g of polysorbate 80 (emulsifier) were dissolved in 130 g of water to obtain an aqueous HPC / maltose / polysorbate aqueous solution (excipient aqueous solution). Thereafter, the same operation as in Example 1 was performed, but it was difficult to recover the powdered coenzyme Q10-containing composition by stickiness.

[Comparative Example 7]
2 g of the coenzyme Q10 bulk powder was dispersed and dissolved in 60 g of ethanol to obtain a coenzyme Q10 dispersed ethanol solution. On the other hand, 4 g of HPC, 2 g of maltose and 2 g of sucrose stearate (HLB = about 16, emulsifier) were dissolved in 130 g of water to obtain an aqueous HPC / maltose / sucrose stearate aqueous solution (excipient aqueous solution). Thereafter, the same operation as in Example 1 was performed to obtain a powdery coenzyme Q10-containing composition. The state of each process is shown in Table 2 in the same manner as in Example 3.

[Comparative Example 8]
2 g of coenzyme Q10 bulk powder and 0.1 g of thiamine lauryl sulfate were dispersed and dissolved in 60 g of ethanol to obtain a coenzyme Q10 dispersed ethanol solution. On the other hand, 7.9 g of maltose was dissolved in 130 g of water to obtain a maltose aqueous solution (excipient aqueous solution). Thereafter, the same operation as in Example 1 was performed to obtain a powdery coenzyme Q10-containing composition. The state of each process is shown in Table 2 in the same manner as in Example 3. As shown in the table, precipitation of aggregates was observed in the mixed solution in the preparation of the dispersion.

[Confirmation of crystal state]
The coenzyme Q10 bulk powder and the powdered coenzyme Q10-containing composition of Example 1 and Comparative Example 8 were observed with a polarizing microscope to examine the crystal state. A polarizing microscope photograph is shown in FIG. 2 (Example 1), FIG. 3 (raw powder), and FIG. 4 (Comparative Example 8). As shown in FIG. 2, in the powder of Example 1, there are a large number of particles that do not show birefringence indicating a crystalline substance, and about 99% of coenzyme Q10 and thiamine lauryl sulfate are non-existent. It was confirmed that it was contained in a crystalline state. On the other hand, as shown in FIG. 3 and FIG. 4, in the mixed powder containing the coenzyme Q10 bulk powder and the powdered coenzyme Q10-containing composition of Comparative Example 2, birefringence showing a crystalline substance clearly appears. Most of them were confirmed to be crystalline.

[Water solubility test of coenzyme Q10]
About the powdery coenzyme Q10 containing composition of the said Examples 3-11 and Comparative Examples 1-4, 7, and 8, the solubility to water was measured with the following method. The results are shown in Tables 1 and 2.
<Measurement method>
The powder and water to be tested were weighed so that coenzyme Q10 was 100 μg / mL with respect to water, and the powder was put into water and stirred. The water was collected and filtered through a membrane filter having a pore size of 0.45 μm. The solubility of coenzyme Q10 was calculated | required by removing by liquid chromatography on the following conditions by using the following filtrate as a sample solution except the first 1 mL of filtrate.
[Analysis test conditions]
High performance liquid chromatograph: Shimadzu Prominence
Detector: UV absorptiometer (measurement wavelength: 270 nm)
Column: ODS column φ4.6 × 150 mm Particle size 5 μm
Column temperature: 40 ° C
Mobile phase: Methanol / ethanol mixture (25:75)
Flow rate: Adjusted so that the retention time is 6.4 minutes Injection volume: 10 μL

  As shown in Tables 1 and 2, the coenzyme Q10-containing compositions of Examples 1 to 11 according to the present invention are excellent in workability when produced into powder, and the obtained powder is dissolved in water. It was confirmed that it was excellent in property.

[Formulation example] (Tablet)
After mixing and sieving 600 g of the coenzyme Q10-containing composition obtained in Example 2, 300 g of powdered reduced maltose water candy and 288 g of crystalline cellulose, 12 g of calcium stearate was added and mixed, and a 9 mmφ mortar was attached. When tableting was performed at 25 rpm for about 1 hour using a rotary tableting machine, tablets without tableting trouble or bleeding of coenzyme Q10 could be stably obtained. The obtained tablets were packaged in aluminum zippers and stored at 40 ° C. and 75% RH for 1 month. The coenzyme Q10 content was 99.6% immediately after the preparation.

[Elution test of coenzyme Q10 in water]
A hard capsule (HPMC capsule size: No. 2) was filled with 250 mg of the powder obtained in Example 3 and Comparative Example 1, and an elution test was performed under the following conditions and method. The results are shown in Table 3 and FIG. As shown in Table 3 and FIG. 5, it was confirmed that the powdered coenzyme Q10-containing composition of Example 3 according to the present invention was excellent in elution into water.
[Elution conditions]
Temperature: 37 ° C
Elution time: 90 minutes Test solution: 900 mL of purified water
Stirring speed: 50 rpm
Test method:
The test solution was collected at each time point of 5, 10, 20, 30, 60, and 90 minutes after elution was started by the dissolution tester under the above conditions, and filtered through a membrane filter having a pore size of 0.45 μm. The first filtrate was removed, and the next filtrate was used as a sample solution.
[Analysis test conditions]
High performance liquid chromatograph: Shimadzu Prominence
Detector: UV absorptiometer (measurement wavelength: 270 nm)
Column: ODS column φ4.6 × 150 mm Particle size 5 μm
Column temperature: 40 ° C
Mobile phase: Methanol / ethanol mixture (25:75)
Flow rate: Adjusted so that the retention time is 6.4 minutes Injection volume: 10 μL

[X-ray diffraction test]
X-ray diffraction measurement was performed on the powder obtained in Example 1 and coenzyme Q10 bulk powder using an X-ray diffractometer. The results are shown in FIG. 6 (raw powder) and FIG. 7 (Example 1), respectively. As shown in FIGS. 6 and 7, in the powder of Example 1, the peak observed in the raw powder decreased, and it was confirmed that amorphization occurred.

[Pharmacokinetic study]
75 mg / kg b of an aqueous solution (containing 0.5% carboxymethyl cellulose) in which the coenzyme Q10 bulk powder or the powder prepared in Example 2 is dispersed in 7-week-old male SD rats fasted from 14 hours before administration The _{urine was} administered by oral gavage so that _{Aw 0-24h} (area under the blood concentration-time curve), C _max , and T _max were measured. The results are shown in Table 4 and FIG. As shown in Table 4 and FIG. 8, both C _max and AUC increased in the powder administration group prepared in Example 2 as compared with the coenzyme Q10 bulk powder administration group.

Claims (10)

  (A) coenzyme Q10, (B) one or more water-soluble polymer substances selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and polyvinyl alcohol, (C) a water-soluble excipient, and ( D) A coenzyme Q10-containing composition comprising an alkyl sulfate salt of vitamin B1.   100 parts by mass of (A) coenzyme Q10, (B) 100-500 parts by mass of water-soluble polymer substance, (C) 100-500 parts by mass of water-soluble excipient, (D) alkyl of vitamin B1 The coenzyme Q10-containing composition according to claim 1, comprising 1 to 100 parts by mass of sulfate.   3. The coenzyme Q10-containing composition according to claim 1, wherein the alkyl sulfate of (D) vitamin B1 is thiamine lauryl sulfate or thiamine cetyl sulfate.   (C) The water-soluble excipient is dextrin, glucose, mannose, galactose, fructose, psicose, xylose, arabinose, trehalose, maltose, isomaltose, isomaltulose, isotrehalose, cellobiose, lactose, sucrose, fructooligosaccharide, Galactooligosaccharide, dairy oligosaccharide, inulin, N-acetylglucosamine, raffinose, erythritol, isomalt, lactitol, maltitol, mannitol, sorbitol, xylitol, reduced palatinose, reduced water candy, alanine, proline, glycine, threonine, lysine, arginine The coenzyme Q1 according to any one of claims 1 to 3, wherein the coenzyme Q1 is one or more selected from among aspartic acid, glutamic acid, cysteine and ornithine. Containing composition.   (A) The coenzyme Q10-containing composition according to any one of claims 1 to 4, wherein at least a part of the coenzyme Q10 is contained in an amorphous state.   A method for producing the coenzyme Q10-containing composition according to any one of claims 1 to 5 as a powdery composition, the coenzyme Q10 of (A) above, the water-soluble polymer substance of (B), A coenzyme Q10-containing composition prepared by spray-drying an aqueous dispersion containing (C) a water-soluble excipient, (D) an alkyl sulfate salt of vitamin B1 and ethanol. Manufacturing method.   The coenzyme Q10 of (A) is dispersed and dissolved in ethanol together with the alkyl sulfate of vitamin B1 of (D) to prepare a coenzyme Q10-dispersed ethanol solution, and the water-soluble excipient of (C) is added to water. The aqueous solution of the excipient is prepared by dissolving the water-soluble polymer substance (B) in either one of these ethanol solutions or aqueous solutions, and then the coenzyme Q10 ethanol solution and the above-mentioned shaping. The method for producing an enzyme Q10-containing composition according to claim 6, wherein the composition is mixed with an aqueous solution of the agent, spray-dried and granulated to obtain a granular composition.   A coenzyme Q10 combination preparation, wherein the coenzyme Q10-containing composition according to any one of claims 1 to 5 is blended and formulated or formulated as a pharmaceutical, health food or cosmetic.   The coenzyme Q10 combination preparation according to claim 8, which is prepared or formulated in any form selected from soft capsules, hard capsules, tablets, granules, and powders.   9. The coenzyme Q10 combination preparation according to claim 8, wherein the coenzyme Q10-containing composition is dissolved or dispersed in a base or a solvent, and is formulated or formulated into a jelly, liquid, lotion, cream or ointment.