Coenzyme q10-containing composition, absorption promoter and absorption promotion method for coenzyme q10, sustained release improver for coenzyme q10, and method for improving sustained release property

Abstract

A purpose of the present invention is to provide a coenzyme Q10-containing composition the improves bioabsorbability of coenzyme Q10, particularly reduced coenzyme Q10.　The coenzyme Q10-containing composition contains coenzyme Q10 and an emulsifying starch, and a weight ratio of the emulsifying starch to the coenzyme Q10 is 0.4-5.0, preferably 1.0-5.0.

Description

Coenzyme Q10-containing composition, coenzyme Q10 absorption enhancer and absorption enhancement method, and coenzyme Q10 sustained-release enhancer and sustained-release enhancement method

[0001] The present invention relates to a coenzyme Q10-containing composition, a coenzyme Q10 absorption enhancer and method for enhancing absorption, and a coenzyme Q10 sustained-release enhancer and method for enhancing sustained-release.

[0002] Coenzyme Q is an essential component widely distributed in living organisms, from bacteria to mammals, and is known as a component of the mitochondrial electron transport chain in living cells. In humans, the main component is coenzyme Q10, which has a repeating structure of 10 coenzyme Q side chains, and in living organisms, approximately 40 to 90% of it is usually present in the reduced form. The physiological effects of coenzyme Q include activation of energy production by mitochondrial activation, activation of cardiac function, stabilization of cell membranes, and cell protection by antioxidant action.

[0003] Most of the coenzyme Q10 currently manufactured and sold is oxidized coenzyme Q10, but in recent years, reduced coenzyme Q10 (hereinafter sometimes referred to as "QH"), which shows higher oral absorbability than oxidized coenzyme Q10, has also appeared on the market and is being used.

[0004] Reduced coenzyme Q10 is easily oxidized, which results in high storage costs and limits the range of applicable product forms. In particular, there has been a demand for a solid composition containing reduced coenzyme Q10 and having excellent oxidation stability that can be applied in the form of granules, hard capsules, tablets, etc.

[0005] Patent Document 1 discloses that reduced coenzyme Q10 exhibits the phenomenon of crystalline polymorphism, and reports that a specific crystalline form among these crystalline polymorphs (hereinafter referred to as "Form II crystal") is significantly more stable and has higher oxidation stability than conventional reduced coenzyme Q10 (hereinafter referred to as "Form I crystal"), and also has other superior physical properties.

[0006] However, although the Form II crystal of reduced coenzyme Q10 of Patent Document 1 exhibits higher oxidation stability than the conventional Form I crystal, further stabilization is desired for application in hard capsule or tablet form.

[0007] In contrast to this, Patent Document 2 discloses a solid composition containing Form II crystals of reduced coenzyme Q10, an emulsifier, and an antioxidant.

[0008] International Publication No. WO 2012 / 176842 International Publication No. WO 2023 / 176871

[0009] The solid composition described in Patent Document 2 can suppress the reduction of reduced coenzyme Q10 due to oxidation during storage.

[0010] However, compared with conventional capsules in which reduced coenzyme Q10 is dissolved in oil such as olive oil, the above-mentioned solid composition does not provide sufficient absorption of reduced coenzyme Q10 in the body, and there is room for further improvement. Also, it has been desired to improve the sustained release of reduced coenzyme Q10, that is, to extend the time that reduced coenzyme Q10 can exist in the body without being decomposed or metabolized, so that it can act for a long time.

[0011] In view of the above-mentioned conventional circumstances, the present invention aims to provide a coenzyme Q10-containing composition that improves the bioabsorbability of coenzyme Q10, particularly reduced coenzyme Q10. It also aims to provide an absorption enhancer and an absorption enhancement method for increasing the absorbability of coenzyme Q10. It also aims to provide a sustained-release enhancer and a sustained-release enhancement method for increasing the sustained-release of coenzyme Q10.

[0012] The present inventors have discovered that a composition combining an emulsifying starch such as starch sodium octenyl succinate with coenzyme Q10, and further adjusting the weight ratio of the two components to fall within a specific range, exhibits high bioabsorbability of coenzyme Q10, and furthermore, improves the sustained release of coenzyme Q10 in the body, thereby completing the invention.

[0013] That is, the gist of the present invention is as follows: (1) A Coenzyme Q10-containing composition containing Coenzyme Q10 and an emulsifying starch, wherein the weight ratio of the emulsifying starch to the Coenzyme Q10 is 0.4 to 5.0. (2) The Coenzyme Q10-containing composition according to (1) above, wherein the weight ratio is 1.0 to 5.0. (3) The Coenzyme Q10-containing composition according to (1) or (2) above, wherein the emulsifying starch is starch sodium octenyl succinate. (4) The Coenzyme Q10-containing composition according to any one of (1) to (3) above, wherein the Coenzyme Q10 is reduced Coenzyme Q10. (5) The Coenzyme Q10-containing composition according to any one of (1) to (4) above, which is in a solid form. (6) The Coenzyme Q10-containing composition according to any one of (1) to (5) above, wherein the viscosity of the emulsifying starch at 30°C is 10 to 200,000 mPa·s. (7) The Coenzyme Q10-containing composition according to (3) above, wherein the content of octenylsuccinic acid groups in the starch sodium octenylsuccinate is greater than 0 to 5.0%. (8) The Coenzyme Q10-containing composition according to any one of (1) to (7) above, further comprising one or more emulsifiers selected from the group consisting of glycerin fatty acid esters, sucrose fatty acid esters, water-soluble polysaccharides, retinol fatty acid esters, propylene glycol fatty acid esters, sorbitan fatty acid esters, and polysorbates. (9) The coenzyme Q10-containing composition according to any one of (1) to (8), wherein, when orally administered to rats, the relative value of the AUC (area under the blood concentration-time curve) of coenzyme Q10 at 8 to 24 hours after administration to the AUC (area under the blood concentration-time curve) of coenzyme Q10 at 0 to 4 hours after administration is 2.1 or more. (10) The coenzyme Q10-containing composition according to any one of (1) to (8), wherein, when orally administered to humans, the relative value of the AUC (area under the blood concentration-time curve) of coenzyme Q10 at 24 to 72 hours after administration to the AUC (area under the blood concentration-time curve) of coenzyme Q10 at 0 to 12 hours after administration is 3.5 or more. (11) A coenzyme Q10 absorption enhancer comprising starch sodium octenyl succinate as an active ingredient. (12) The absorption enhancer according to (11), wherein the coenzyme Q10 is reduced coenzyme 10.(13) A sustained-release enhancer for coenzyme Q10, comprising starch sodium octenylsuccinate as an active ingredient. (14) A method for enhancing the absorption of coenzyme Q10, comprising the step of allowing coenzyme Q10 and an emulsifying starch to coexist, wherein the weight ratio of the emulsifying starch to the coenzyme Q10 in the coexisting state is 0.4 to 5.0. (15) A method for improving the sustained-release of coenzyme Q10, comprising the step of allowing coenzyme Q10 and an emulsifying starch to coexist, wherein the weight ratio of the emulsifying starch to the coenzyme Q10 in the coexisting state is 0.4 to 5.0. This specification incorporates the disclosures of Japanese Patent Application No. 2024-104358, from which the present application claims priority.

[0014] The Coenzyme Q10-containing composition of the present invention can exhibit high Coenzyme Q10 absorption and excellent sustained-release properties in vivo. Furthermore, the absorption enhancer of the present invention can enhance the absorption of Coenzyme Q10 by mixing with Coenzyme Q10. Furthermore, according to the absorption-enhancing method of the present invention, the coexistence of Coenzyme Q10 and emulsifying starch at a predetermined ratio can enhance the absorption of Coenzyme Q10. Furthermore, the sustained-release enhancer of the present invention can enhance the sustained-release of Coenzyme Q10 by mixing with Coenzyme Q10. Furthermore, according to the sustained-release improving method of the present invention, the coexistence of Coenzyme Q10 and emulsifying starch at a predetermined ratio can enhance the sustained-release of Coenzyme Q10.

[0015] 1 is a graph showing the AUC (area under the blood concentration-time curve) of total coenzyme Q10 over 24 hours when the test compositions of Example 1 and Comparative Examples 1 to 5 are orally administered to rats by gavage. 2 is a graph showing the change in blood concentration of total coenzyme Q10 over 24 hours when the test compositions of Example 1 and Comparative Examples 1 to 5 are orally administered to rats by gavage. 3 is a graph showing the AUC (area under the blood concentration-time curve) of total coenzyme Q10 over 24 hours when the test compositions of Examples 2 to 3 and Comparative Examples 6 to 8 are orally administered to rats by gavage. 4 is a graph showing the change in blood concentration of total coenzyme Q10 over 24 hours when the test compositions of Examples 2 to 3 and Comparative Examples 6 to 8 are orally administered to rats by gavage. 5 is a graph showing the AUC (area under the blood concentration-time curve) of total coenzyme Q10 over 24 hours when the test compositions of Example 4 and Comparative Examples 9 to 13 are orally administered to rats by gavage. 1 is a graph showing the change in blood concentration of total coenzyme Q10 over 24 hours when the test compositions of Example 4 and Comparative Examples 9 to 13 are orally administered to rats. 2 is a graph showing the AUC (area under the blood concentration-time curve) of total coenzyme Q10 over 24 hours when the test compositions of Examples 5 to 6 and Comparative Examples 14 to 17 are orally administered to rats. 3 is a graph showing the change in blood concentration of total coenzyme Q10 over 24 hours when the test compositions of Examples 5 to 6 and Comparative Examples 14 to 17 are orally administered to rats. 4 is a graph showing the change in blood concentration of total coenzyme Q10 up to 72 hours when the test compositions of Example 16 and Comparative Example 18 are administered to humans.

[0016] The present invention will be described in detail below based on the embodiments. The Coenzyme Q10-containing composition of the present invention is characterized by containing Coenzyme Q10 and emulsifying starch, and the weight ratio of the emulsifying starch to the Coenzyme Q10 is 0.4 to 5.0.

[0017] <Coenzyme Q10> Coenzyme Q10 can be oxidized coenzyme Q10, reduced coenzyme Q10, or a mixture thereof. However, the composition according to this embodiment preferably contains reduced coenzyme Q10, which exhibits higher oral absorption, as the main component. Here, "main component" means that the proportion of reduced coenzyme Q10 relative to the total amount of coenzyme Q10 is, for example, 50% by weight or more, usually 60% by weight or more, preferably 70% by weight or more, more preferably 80% by weight or more, even more preferably 90% by weight or more, particularly preferably 95% by weight or more, and particularly preferably 98% by weight or more.

[0018] Reduced coenzyme Q10 can be obtained by known methods, such as synthesis, fermentation, extraction from natural products, and optionally combining these methods with a reduction reaction. Preferably, reduced coenzyme Q10 can be obtained by reducing oxidized coenzyme Q10, such as existing high-purity coenzyme Q10, or a mixture of oxidized coenzyme Q10 and reduced coenzyme Q10, with a common reducing agent, such as sodium hyposulfite, sodium borohydride, or ascorbic acid.

[0019] Reduced coenzyme Q10 exists in two crystalline polymorphs, Form I and Form II, and both are applicable. Specifically, Form I crystals are crystalline forms of reduced coenzyme Q10 that have a melting point of around 48°C and exhibit characteristic peaks at diffraction angles (2θ±0.2°) of 3.1°, 18.7°, 19.0°, 20.2°, and 23.0° in powder X-ray (Cu-Kα) diffraction, while Form II crystals are crystalline forms of reduced coenzyme Q10 that have a melting point of around 52°C and exhibit characteristic peaks at diffraction angles (2θ±0.2°) of 11.5°, 18.2°, 19.3°, 22.3°, 23.0°, and 33.3° in powder X-ray (Cu-Kα) diffraction.

[0020] In one embodiment of the present invention, reduced coenzyme Q10 (QH) is preferably used in the form II crystal of reduced coenzyme Q10 (QH Form II crystal) because of its high stability against oxidation.

[0021] The QH Form II crystal may consist solely of Form II crystal, or may be a QH crystal or crystalline solid containing Form II crystal as the main component, where "main component" means that Form II crystal accounts for preferably 80% by weight or more, more preferably 90% by weight or more, more preferably 95% by weight or more, and most preferably 98% by weight or more of the total amount of QH.

[0022] In one embodiment of the present invention, the content of coenzyme Q10, preferably reduced coenzyme Q10, in the composition (coenzyme Q10 weight / total composition weight) is not particularly limited, but is usually about 0.1% by weight or more, preferably about 0.5% by weight or more, more preferably about 1% by weight or more, particularly preferably about 2% by weight or more, and even more preferably about 5% by weight or more. The upper limit is not particularly limited, but is, for example, 63% by weight or less, 50% by weight or less, preferably 49% by weight or less, more preferably 48% by weight or less, particularly preferably 47% by weight or less, and even more preferably 46% by weight or less.

[0023] <Emulsifying starch> Emulsifying starch is a type of modified starch that has been given emulsifying properties by introducing a lipophilic group into hydrophilic starch, and has both the viscosity adjusting function and emulsifying function of starch. By including it in the composition of the present invention, the bioabsorbability of Coenzyme Q10 can be improved. Without being bound by theory, it is presumed that the reason for the improved absorbability of Coenzyme Q10 is that the inclusion of emulsifying starch causes the composition of the present invention to gel in vivo, thereby allowing Coenzyme Q10 to remain in the body for a longer period of time.

[0024] Furthermore, by incorporating a predetermined weight ratio of emulsifying starch, the coenzyme Q10-containing composition according to one embodiment of the present invention can improve the sustained release of coenzyme Q10 when administered to a living body, thereby maintaining high blood coenzyme Q10 concentrations for extended periods of time. In other words, the time during which coenzyme Q10 can be present in the body without being decomposed or metabolized can be extended compared to when coenzyme Q10 is ingested alone. The sustained release can be evaluated, for example, by the relative value of the AUC (area under the blood concentration-time curve) of coenzyme Q10 immediately after administration to the AUC of coenzyme Q10 after a certain time has elapsed since administration. The higher this relative value, the better the sustained release. "Immediately after administration" can be, for example, the period from administration to one-sixth of the total test period. "After a certain time has elapsed since administration" can be the period from one-third of the total test period to the end of the test. Therefore, the sustained-release properties may be evaluated by the relative value of the AUC (area under the blood concentration-time curve) of coenzyme Q10 from one-third of the test period to the end of the test, relative to the AUC of coenzyme Q10 from one-sixth of the test period after administration. The test period is typically set to within 24 hours in rat studies and within 72 hours in human studies. Therefore, even if test data from longer periods are available, data up to 24 hours in rat studies or 72 hours in human studies can be used as the data for the entire test period. In tests using other organisms, the entire test period may also be the period until the blood coenzyme Q10 concentration after administration of a test substance containing coenzyme Q10 and emulsifying starch reaches one-fifth of the maximum blood concentration (Cmax) after administration of the test substance. In other words, even if there is test data for a period longer than the time required for the blood concentration of coenzyme Q10 to reach one-fifth of the maximum blood concentration (Cmax) after administration of the test substance, the total test period can be set as the time required for the blood concentration of coenzyme Q10 to reach one-fifth of Cmax.Specifically, when a Coenzyme Q10-containing composition according to one embodiment of the present invention is orally administered to a rat, the relative value of the AUC (area under the blood concentration-time curve) of Coenzyme Q10 8 to 24 hours after administration to the AUC (area under the blood concentration-time curve) of Coenzyme Q10 0 to 4 hours after administration is 2.1 or more, 2.2 or more, 2.5 or more, 3.0 or more, or 3.5 or more. Furthermore, when a Coenzyme Q10-containing composition according to one embodiment of the present invention is orally administered to a human, the relative value of the AUC (area under the blood concentration-time curve) of Coenzyme Q10 24 to 72 hours after administration to the AUC (area under the blood concentration-time curve) of Coenzyme Q10 0 to 12 hours after administration is 3.5 or more, 4.0 or more, 4.5 or more, 5.0 or more, 5.5 or more, 6.0 or more, or 6.5 or more. Furthermore, when the Coenzyme Q10-containing composition according to one embodiment of the present invention is orally administered to rats and organisms other than humans, the relative value of the AUC (area under the blood concentration-time curve) of Coenzyme Q10 from one-third of the total test period to the end of the test is higher than that when a test substance not containing emulsifying starch is administered.

[0025] The sustained-release properties may also be evaluated by the time required for a certain relative AUC value to be reached relative to the AUC after a certain time has elapsed after administration; the longer this time, the better the sustained-release properties can be evaluated. Specifically, when the Coenzyme Q10-containing composition according to one embodiment of the present invention is orally administered to rats, the time required for the AUC (area under the blood concentration-time curve) of Coenzyme Q10 to reach 40% of its AUC relative value 24 hours after administration is 6 hours or more, 6.2 hours or more, 6.4 hours or more, 6.6 hours or more, 6.8 hours or more, 7 hours or more, 7.2 hours or more, or 7.4 hours or more. Specifically, when the Coenzyme Q10-containing composition according to one embodiment of the present invention is orally administered to humans, the time required for the AUC (area under the blood concentration-time curve) of Coenzyme Q10 to reach 40% of its AUC relative value 72 hours after administration is 23 hours or more, 24 hours or more, 25 hours or more, or 25.5 hours or more.

[0026] Furthermore, the sustained release property may be evaluated by the relative value of the blood concentration of Coenzyme Q10 after a certain time has elapsed to that after a certain time has elapsed after administration, and the higher this relative value, the better the sustained release property can be evaluated. Specifically, in the Coenzyme Q10-containing composition according to one embodiment of the present invention, when orally administered to rats, the relative value of the blood concentration of Coenzyme Q10 8 hours after administration to that after 1 hour after administration is 1.5 or more, 2.0 or more, 2.5 or more, 3.0 or more, 3.5 or more, 4.0 or more, or 4.5 or more. Furthermore, in one embodiment of the present invention, when orally administered to a human, the relative value of the blood concentration of coenzyme Q10 60 hours after administration to the blood concentration of coenzyme Q10 4 hours after administration is 0.3 or more, 0.5 or more, 1 or more, 1.5 or more, 2 or more, 2.5 or more, 3 or more, 3.5 or more, 4 or more, 4.5 or more, 5 or more, or 5.5 or more.

[0027] The emulsifying starch used in this embodiment is not particularly limited as long as it is edible and has emulsifying properties. Examples include natural starch esterified with a carboxylic acid having an alkyl group attached thereto or its salt, and dextrin obtained by partially hydrolyzing these esterified starches while retaining their emulsifying properties. Specific examples include starch sodium octenyl succinate, hydroxypropyl starch, oxypropanol starch, etc. Among these, starch sodium octenyl succinate is particularly preferred because it has excellent properties for enhancing the bioabsorbability and sustained release of coenzyme Q10. While both α-type and β-type emulsifying starch can be used, α-type is preferred. Even β-type starch can be pregelatinized before use.

[0028] Starch sodium octenylsuccinate can be obtained by octenylsuccinating starch or modified starch using a conventional method. Specifically, it can be obtained by reacting starch with octenylsuccinic anhydride. Commercially available products such as Amycol Nyuka D (product name, derived from waxy corn, manufactured by Nippon Starch Chemical Co., Ltd.), PURITY GUM 2000 (product name, derived from waxy corn, manufactured by Ingredion), PURITY GUM BE (product name, derived from waxy corn, manufactured by Ingredion), N-CREAMER 46 (product name, derived from waxy corn, manufactured by Ingredion), CAPSUL (product name, derived from waxy corn, manufactured by Ingredion), and NATIONAL 912 (product name, derived from waxy corn, manufactured by Ingredion) can also be used. Although both α-type and β-type starch sodium octenyl succinate are applicable, it is preferable to use α-type. Even if it is β-type, it can be pregelatinized before use.

[0029] The viscosity of the emulsifying starch contributes to the degree of gelation of the composition in vivo, and is appropriately set from that perspective. The lower limit of the viscosity of the emulsifying starch at 30°C is not particularly limited, but is, for example, 10 mPa·s or more, preferably 30 mPa·s or more, more preferably 50 mPa·s or more, particularly preferably 100 mPa·s or more, and most preferably 150 mPa·s or more. The upper limit of the viscosity of the emulsifying starch at 30°C is not particularly limited, but is, for example, 200,000 mPa·s or less, preferably 100,000 mPa·s or less, more preferably 10,000 mPa·s or less, more preferably 3,000 mPa·s or less, particularly preferably 1,000 mPa·s or less, and most preferably 500 mPa·s or less. The viscosity of the emulsifying starch at 30°C is, for example, in the range of 10 to 200,000 mPa·s, preferably in the range of 30 to 3,000 mPa·s, and particularly preferably in the range of 100 to 1,000 mPa·s, or 10 to 1,000 mPa·s, or 10 to 300 mPa·s. When the viscosity of the emulsifying starch is within the above range, disintegration properties when formed into tablets are appropriately suppressed, and the effects of improving the absorption and sustained release of coenzyme Q10 can be further enhanced. The disintegration properties can be evaluated using, for example, a disintegration tester.

[0030] In this specification, the viscosity of the emulsifying starch at 30°C refers to a value obtained by preparing a starch slurry having an emulsifying starch concentration of 20% by weight, heating the slurry until the temperature reaches 80°C, holding the slurry at 80°C for 5 minutes after the temperature reaches 80°C, and then cooling the slurry to 30°C and measuring the viscosity with a B-type viscometer.

[0031] The proportion of octenylsuccinic acid groups in starch sodium octenylsuccinate is appropriately set from the viewpoint of maintaining the emulsion stability of the coenzyme Q10-containing composition of the present invention. Specifically, the proportion of octenylsuccinic acid groups in starch sodium octenylsuccinate is preferably in the range of more than 0 to 5.0%, and particularly preferably in the range of more than 0 to 3.0%.

[0032] The proportion of octenylsuccinic acid groups in the above-mentioned starch sodium octenylsuccinate can be calculated by the method described in the Food Additives Standards, 9th Edition (https: / / www.mhlw.go.jp / stf / seisakunitsuite / bunya / kenkou_iryou / shokuhin / syokuten / kouteisho9e.html).

[0033] In the Coenzyme Q10-containing composition of the present invention, the content of emulsifying starch in the composition (weight of emulsifying starch / weight of total composition) is not particularly limited, and although it varies depending on the formulation of the composition, it is usually about 0.1% by weight or more, preferably about 0.5% by weight or more, more preferably about 1% by weight or more, and particularly preferably about 5% by weight or more. The upper limit is not particularly limited, but is 84% ​​by weight or less, preferably 80% by weight or less, more preferably 78% by weight or less, and particularly preferably 75% by weight or less.

[0034] Furthermore, in the Coenzyme Q10-containing composition of the present invention, the weight ratio of emulsifying starch to Coenzyme Q10 (emulsifying starch weight / Coenzyme Q10 weight) is within the range of 0.4 to 5.0. It is preferably within the range of 0.6 to 5.0, more preferably within the range of 1.0 to 5.0, more preferably within the range of 1.1 to 4.0, and even more preferably within the range of 1.2 to 3.0. Furthermore, the weight ratio may be 1.5 to 3.0, or even 1.7 to 3.0. If the weight ratio is less than 0.4, the effects of the emulsifying starch in improving the absorption and sustained release of Coenzyme Q10 cannot be obtained. Furthermore, if the weight ratio exceeds 5.0, an unpleasant taste due to the emulsifying starch may occur.

[0035] The substances other than coenzyme Q10 and emulsifying starch contained in the composition of the present invention are not particularly limited, but examples thereof include excipients, disintegrants, lubricants, binders, emulsifiers, pigments, anti-aggregating agents, absorption promoters, solubilizers, stabilizers, fragrances, oils and fats, surfactants, higher fatty acids, ethanol, water, active ingredients other than coenzyme Q10, antioxidants, etc.

[0036] In addition, the form of the composition of the present invention is not particularly limited and can be appropriately selected as needed.Specific examples include oral preparations such as tablets, powders, chewable tablets, pills, capsules, granules, fine granules, sustained-release preparations, suspensions, emulsions, syrups, and elixirs, and parenteral preparations such as injections, suppositories, liniments, and patches.However, since Coenzyme Q10 has excellent oral absorbability, oral preparations are particularly preferred.Furthermore, the Coenzyme Q10-containing composition of the present invention can also be in the form of capsules in which Coenzyme Q10 is dissolved in an oil component and encapsulated in a capsule.However, when it is made into a solid composition such as granules or tablets, which have traditionally had the problem of low bioabsorbability and sustained release of Coenzyme Q10, the emulsifying starch's effect of improving Coenzyme Q10's absorption and sustained release is particularly utilized, so a solid Coenzyme Q10-containing composition is preferred.The use of solid compositions such as granules and tablets will be described in detail below.

[0037] The form of the solid coenzyme Q10-containing composition according to the present invention is not particularly limited, and examples thereof include powder, granules, tablets, and hard capsules.

[0038] The type of emulsifier other than emulsifying starch to be added to the solid coenzyme Q10-containing compound is not particularly limited. For example, an emulsifier with an HLB of 1 to 17, preferably 2 to 16, can be used. Two or more emulsifiers can be used in combination. Specific examples of emulsifiers suitable for use in the solid coenzyme Q10-containing compound include one or more emulsifiers selected from the group consisting of glycerin fatty acid esters, sucrose fatty acid esters, water-soluble polysaccharides, retinol fatty acid esters, propylene glycol fatty acid esters, sorbitan fatty acid esters, and polysorbates.

[0039] When using reduced coenzyme Q10 as coenzyme Q10, from the viewpoint of the oxidation inhibitory effect on reduced coenzyme Q10, among the above-mentioned emulsifiers, emulsifiers that are not powdery or flaky are preferably used. Examples of emulsifiers that are not powdery or flaky include emulsifiers that are liquid, sol-like, gel-like, or soft solid, and more preferred are emulsifiers that are liquid, viscous liquid, viscous liquid, paste, pellet, waxy mass, wax, soft solid, or semi-solid. As the emulsifier, emulsifiers that have the above properties at 50 ° C are preferred, and emulsifiers that have the above properties at 25 ° C are most preferred.

[0040] Examples of emulsifiers that are not powdery or flaky include emulsifiers whose melting onset temperature, measured with a differential scanning calorimeter (DSC) at a temperature rise rate of 1°C / min or more and 20°C / min or less, is 50°C or less, preferably 40°C or less, and more preferably 25°C or less.

[0041] From another perspective, examples of the emulsifier include those having a viscosity, measured using a Brookfield viscometer at a rotation speed of 10 rpm and a sample temperature of 50° C., of 150,000 mPa·s or less, preferably 100,000 mPa·s or less, 50,000 mPa·s or less, more preferably 30,000 mPa·s or less, and most preferably 25,000 mPa·s or less. There is no particular lower limit to the viscosity as long as it is greater than 0 mPa·s, but it is more preferably 1 mPa·s or more, particularly preferably 5 mPa·s or more, and most preferably 10 mPa·s or more.

[0042] Specific examples of such emulsifiers include one or more selected from the group consisting of monoglycerin, polyglycerin, sorbitan, polyoxyethylene sorbitan, sucrose, propylene glycol, polypropylene glycol, ethylene glycol, and polyethylene glycol, ester compounds of fatty acids which may have a substituent, and lecithin.

[0043] The number of glycerin units in polyglycerin may be 2 or more, and preferably 2 to 10. Examples include diglycerin, triglycerin, tetraglycerin, pentaglycerin, hexaglycerin, and decaglycerin.

[0044] The number of oxyethylene units in polyoxyethylene sorbitan may be 2 or more, preferably 10 or more and 30 or less, and more preferably 15 or more and 25 or less.

[0045] The number of propylene glycol units in the polypropylene glycol may be 2 or more, and preferably 2 or more and 10 or less.

[0046] The number of ethylene glycol units in the polyethylene glycol may be 2 or more, and preferably 2 or more and 10 or less.

[0047] Examples of the fatty acid which may have a substituent include a linear or branched monovalent or divalent fatty acid having from 4 to 24 carbon atoms. Examples of the substituent include a hydroxyl group and an acetoxy group. The number of substituents is preferably two or less. Specific examples of the fatty acid which may have a substituent include lauric acid, oleic acid, caprylic acid, stearic acid, behenic acid, ricinoleic acid, succinic acid, and diacetyltartaric acid.

[0048] In the ester compound of the polyol and the fatty acid, the number of fatty acids bonded to one molecule of the polyol is not particularly limited, and can be adjusted appropriately depending on the HLB of the target emulsifier.

[0049] When reduced coenzyme Q10 is used as coenzyme Q10, from the viewpoint of inhibiting oxidation, the number of fatty acids bonded to one molecule of polyol can be, for example, 12 or less, preferably 10 or less, more preferably 7 or less, more preferably 6 or less, more preferably 5 or less, more preferably 3 or less, more preferably 2 or less, and more preferably 1.

[0050] Specific examples of the ester compounds of the polyols and the fatty acids include diglycerol monooleate, monoglycerol monocaprylate, diglycerol monocaprylate, decaglycerol pentaoleate, tetraglycerol pentaoleate, pentaglycerol trioleate, decaglycerol monolaurate, hexaglycerol monocaprylate, hexaglycerol monooleate, pentaglycerol monostearate, tetraglycerol tristearate, decaglycerol monobehenate, mono-diglycerol monostearate, monoglycerol monooleate, glycerol monostearate succinate, and monoglycerol succinate. Examples of suitable glycerin include serine, glyceryl diacetyltartarate monostearate, propylene glycol monooleate, sorbitan monooleate, sorbitan monostearate, sorbitan tristearate, monoglyceryl monolaurate, diglyceryl monolaurate, diglyceryl monomyristate, tetraglyceryl pentastearate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate, condensed pentaglyceryl ricinoleate, sucrose stearate, sucrose erucate, and sucrose oleate.

[0051] When reduced coenzyme Q10 is used as coenzyme Q10, the fatty acid in the ester compound of the polyol and the fatty acid is more preferably an unsaturated fatty acid, from the viewpoint of inhibiting oxidation thereof. Examples of the unsaturated fatty acids include crotonic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, gadoleic acid, eicosenoic acid, erucic acid, nervonic acid, linoleic acid, eicosadienoic acid, docosadienoic acid, α-linolenic acid, γ-linolenic acid, pinolenic acid, α-eleostearic acid, β-eleostearic acid, mead acid, dihomo-γ-linolenic acid, eicosatrienoic acid, stearidonic acid, arachidonic acid, eicosatetraenoic acid, adrenic acid, bosseopentaenoic acid, eicosapentaenoic acid, osbondo acid, sardine acid, tetracosapentaenoic acid, docosahexaenoic acid, herring acid, ricinoleic acid, and condensed ricinoleic acid, of which oleic acid, condensed ricinoleic acid, linoleic acid, and erucic acid are more preferred, and oleic acid is particularly preferred.

[0052] From another viewpoint of inhibiting oxidation of reduced coenzyme Q10, the ester compound of the polyol and the fatty acid is more preferably a glycerin fatty acid ester or polyglycerin fatty acid ester that satisfies any one of the following: 1) a glycerin fatty acid ester or polyglycerin fatty acid ester containing an ester of a fatty acid having 8 or less carbon atoms, 2) a polyglycerin fatty acid ester containing an ester of a fatty acid having 9 to 14 carbon atoms and having 2 or more glycerin units, and 3) a polyglycerin fatty acid ester containing an ester of a fatty acid having 15 to 18 carbon atoms and having 5 or more glycerin units. In this case, the fatty acid may be a saturated fatty acid or an unsaturated fatty acid.

[0053] Specific examples of the ester compounds of the polyol and the unsaturated fatty acid include monoglycerol monooleate, monoglycerol mono-dioleate, monoglycerol dioleate, monoglycerol mono-dioleate, diglycerol monooleate, diglycerol monodioleate, diglycerol dioleate, diglycerol trioleate, triglycerol monooleate, triglycerol dioleate, triglycerol trioleate, triglycerol tetraoleate, tetraglycerol monooleate, tetraglycerol dioleate, and triglycerol tetraoleate. Tetraglycerin Tetraoleate, Tetraglycerin Tetraoleate, Tetraglycerin Pentaoleate, Pentaglycerin Monooleate, Pentaglycerin Dioleate, Pentaglycerin Trioleate, Pentaglycerin Tetraoleate, Pentaglycerin Pentaoleate, Pentaglycerin Hexaoleate, Hexaglycerin Monooleate, Hexaglycerin Dioleate, Hexaglycerin Trioleate, Hexaglycerin Tetraoleate, Hexaglycerin Pentaoleate, Hexaglycerin Hexaoleate, Heptaolein Hexaglycerin, Decaglycerin Monooleate, Decaglycerin Dioleate, Decaglycerin Trioleate, Decaglycerin Tetraoleate, Decaglycerin Pentaoleate, Decaglycerin Hexaoleate, Decaglycerin Heptaoleate, Decaglycerin Octaoleate, Decaglycerin Nonaoleate, Decaglycerin Decaoleate, Decaglycerin Dodecaoleate, Diacetoglycerin Monooleate, Glycerin Monooleate Lactate, Glycerin Monooleate Succinate, Glycerin Monooleate Citrate, Diacetoglycerin Glyceryl monooleate, sucrose oleate, propylene glycol monooleate, sorbitan monooleate, sorbitan dioleate, sorbitan trioleate, polyoxyethylene sorbitan monooleate, phosphatidylcholine monooleate monopalmitate, phosphatidylcholine dilinoleate, monoglyceryl monoerucate, monoglyceryl mono-dierucate, monoglyceryl dierucate, monoglyceryl monoerucate, diglyceryl monoerucate, diglyceryl monoerucate, diglyceryl monodierucate, diglyceryl dierucate,Diglyceryl Trierucate, Triglyceryl Monoerucate, Triglyceryl Dierucate, Triglyceryl Trierucate, Triglyceryl Tetraerucate, Tetraglyceryl Monoerucate, Tetraglyceryl Dierucate, Tetraglyceryl Trierucate, Tetraglyceryl Tetraerucate, Tetraglyceryl Pentaerucate, Pentaglyceryl Monoerucate, Pentaglyceryl Dierucate, Pentaglyceryl Trierucate, Pentaglyceryl Tetraerucate Pentaglycerin, Pentaglycerin Pentaerucate, Pentaglycerin Hexaerucate, Hexaglycerin Monoerucate, Hexaglycerin Dierucate, Hexaglycerin Trierucate, Hexaglycerin Tetraerucate, Hexaglycerin Pentaerucate, Hexaglycerin Heptaerucate, Decaglycerin Monoerucate, Decaglycerin Dierucate, Decaglycerin Trierucate, Decaglycerin Tetraerucate Glycerin, Decaglycerin Pentaerucate, Decaglycerin Hexaerucate, Decaglycerin Heptaerucate, Decaglycerin Octaerucate, Decaglycerin Nonaerucate, Decaglycerin Decaerucate, Decaglycerin Dodecaerucate, Diacetoglycerin Monoerucate, Glycerin Monoerucate Lactate, Glycerin Monoerucate Succinate, Glycerin Monoerucate Citrate, Glycerin Monoerucate Diacetyltartarate, Sucrose Ester Examples of the esters of glyceryl esters include glyceryl esters of carboxylic acid, propylene glycol monoerucate, sorbitan monoerucate, sorbitan dierucate, sorbitan trierucate, condensed monoglycerol ricinoleate, condensed diglycerol ricinoleate, condensed triglycerol ricinoleate, condensed tetraglycerol ricinoleate, condensed pentaglycerol ricinoleate, condensed hexaglycerol ricinoleate, condensed heptaglycerol ricinoleate, and condensed decaglycerol ricinoleate.

[0054] From the viewpoint of inhibiting oxidation of reduced coenzyme Q10, polyoxyethylene sorbitan fatty acid esters are also preferably used as the ester compounds of the polyols and the fatty acids.

[0055] Specific examples of the polyoxyethylene sorbitan fatty acid ester include polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, and polyoxyethylene sorbitan monostearate.

[0056] The water-soluble polysaccharides may be those derived from natural products or those obtained by chemical synthesis, and examples thereof include pectin, guar gum, carrageenan, alginic acid, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, xanthan gum, dextran, etc. Among these, pectin is particularly preferred. By including the water-soluble polysaccharides, the absorbability of coenzyme Q10 in the body can be further improved.

[0057] When a solid composition containing an emulsifier is used in combination with an oily ingredient (e.g., vegetable oil, essential oil, animal fat, fish oil, fat-soluble active ingredient, etc.), the emulsifier contained in the solid composition preferably has an HLB of less than 10.0, more preferably less than 8.0, and particularly preferably less than 6.0. By using an ester of a polyol and an unsaturated fatty acid having an HLB of less than 6.0 as an emulsifier, coenzyme Q10 in the solid composition can be stably preserved even under conditions of less than 50% relative humidity, where pharmaceuticals and foods are often stored, and this is preferred.

[0058] Specific examples of the esters of polyols and unsaturated fatty acids having an HLB of less than 6.0 include monoglycerol monooleate, monoglycerol mono-dioleate, monoglycerol dioleate, monoglycerol mono-diglycerol monooleate, tetraglycerol pentaoleate, hexaglycerol pentaoleate, decaglycerol pentaoleate, decaglycerol decaoleate, sorbitan monooleate, sorbitan trioleate, propylene glycol monooleate, monoglycerol monooleate citrate, sucrose oleate, decaglycerol erucate, and sucrose erucate.

[0059] Examples of lecithin include soybean lecithin, egg yolk lecithin, and enzymatically decomposed soybean lecithin.

[0060] It is particularly preferable to use an emulsifier that is acceptable for food, cosmetics, and / or pharmaceuticals.

[0061] Adding an emulsifier other than emulsifying starch to a solid coenzyme Q10-containing compound can enhance the bioabsorbability of coenzyme Q10 via the emulsifying starch. In particular, when the weight ratio of emulsifying starch to coenzyme Q10 is relatively low (0.4 to less than 1.0), bioabsorbability equivalent to or greater than that obtained when no emulsifier is added and the weight ratio of emulsifying starch is high can be obtained. Therefore, in such cases, an emulsifier is preferably used in combination.

[0062] When the composition of the present invention contains reduced coenzyme Q10 such as Form II crystals, the composition preferably contains an antioxidant to ensure oxidation stability in a solid dosage form. Here, the type of antioxidant is not particularly limited. Two or more antioxidants may be used in combination. Specific examples of antioxidants are preferably solid at room temperature, and include one or more antioxidants selected from the group consisting of ascorbic acid, ascorbate, erythorbic acid, and erythorbate.

[0063] The counter ions of ascorbate and erythorbate are not limited, but can each independently be one or more metal salts selected from the group consisting of sodium salts, potassium salts, calcium salts, and magnesium salts.

[0064] It is particularly preferable to use an antioxidant that is acceptable for use as a food or pharmaceutical product. As the antioxidant, ascorbic acid salts are preferred, and one or more selected from sodium ascorbate and calcium ascorbate are particularly preferred.

[0065] The solid composition preferably further contains a binder, which can be used to bind the components, such as coenzyme Q10, emulsifier, and antioxidant, to form a solid composition.

[0066] The type of binder is not limited. Two or more binders may be used in combination. Specific examples of binders include one or more selected from celluloses and starches.

[0067] Examples of celluloses include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose, carboxymethyl cellulose, crystalline cellulose, cellulose powder, methyl cellulose, ethyl cellulose, and salts thereof. Particularly preferred binders are one or more selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and sodium carboxymethyl cellulose.

[0068] Examples of starches include wheat starch, potato starch, sweet potato starch, corn starch, dextrin, hydroxypropyl starch, starch acetate, oxidized starch, and partially pregelatinized starch.

[0069] It is particularly preferable to use a binder that is acceptable for food or pharmaceutical use.

[0070] The solid coenzyme Q10-containing composition of this embodiment is a solid composition at 25°C. The solid composition of this embodiment can be in any form, such as granules, powder, flakes, tablets, or capsules, but is preferably in granule or tablet form. The term "granular" refers to any form formed by combining primary particles of materials containing coenzyme Q10 (e.g., reduced coenzyme Q10), emulsifying starch, and, if necessary, substances other than coenzyme Q10 and emulsifying starch, such as antioxidants and emulsifiers, through a granulation process, and includes granules. The dimensions of the granular composition are not limited, but can be, for example, granules with a longest diameter of 0.20 mm or more and 2.0 mm or less.

[0071] The term "tablet-form" refers to any shape formed primarily for tablet use, and its shape and size are not particularly limited. Examples of tablet shapes include round, oval, triangular, and rectangular shapes. In the case of round shapes, the diameter may be 7 to 16 mm, preferably 13 to 16 mm, and the thickness may be 4 to 8 mm, preferably 5 to 7 mm. The weight per tablet of the tablet-form composition may be, for example, 200 to 1600 mg, preferably 900 to 1200 mg. The shape of the tablet can be appropriately changed, for example, depending on the shape of the punch or die used in a tablet press or the shape of the mold. The term "capsule-form" refers to a shape in which the granular, powdered, or flake-form coenzyme Q10-containing composition is enclosed in an oral capsule.

[0072] The solid composition according to this embodiment can be produced with high yield and has good handling characteristics, even when a liquid, sol, gel, or soft solid emulsifier is used as the emulsifier. For example, in the case of a solid composition produced by agitation granulation, the composition exhibits a transmittance of 50% or more, preferably 60% or more, more preferably 70% or more, more preferably 80% or more, and particularly preferably 90% or more through a mesh with an opening of 710 μm. The size of the mesh opening is usually adjusted according to the expected particle size, but in the case of granules obtained by extrusion granulation, a mesh with an opening of 3.0 mm or the like can be used.

[0073] The solid composition according to this embodiment preferably contains reduced coenzyme Q10 in a crystalline state, and the crystallinity of the reduced coenzyme Q10 (the proportion of the total amount of reduced coenzyme Q10 present in the composition that is present as crystals) is typically 50% or more, preferably 70% or more, more preferably 80% or more, more preferably 85% or more, more preferably 90% or more, and particularly preferably 95% or more.

[0074] The crystallinity of the reduced coenzyme Q10 contained in the solid composition can be calculated by measuring the heat of crystalline fusion by DSC analysis, and using the theoretical heat of fusion calculated from the content of reduced coenzyme Q10 in the composition and the measured heat of fusion data according to the following formula: Crystallinity (%) = (measured heat of fusion / theoretical heat of fusion) x 100

[0075] In the solid composition according to this embodiment, the blending ratio of each component can be appropriately set depending on the dosage form, etc.

[0076] When the solid composition according to this embodiment contains an antioxidant, the antioxidant is contained in an amount of, for example, 1 part by weight or more and 9,900 parts by weight or less per 100 parts by weight of coenzyme Q10. The lower limit of the content of the antioxidant per 100 parts by weight of coenzyme Q10 is preferably 20 parts by weight or more, more preferably 50 parts by weight or more, and more preferably 55 parts by weight or more. The upper limit of the content of the antioxidant per 100 parts by weight of coenzyme Q10 is preferably 5,000 parts by weight or less, more preferably 1,000 parts by weight or less, more preferably 500 parts by weight or less, more preferably 200 parts by weight or less, and more preferably 120 parts by weight or less.

[0077] When the solid composition according to this embodiment contains an emulsifier other than emulsifying starch, the emulsifier is contained in an amount of, for example, 1 to 9,900 parts by weight per 100 parts by weight of coenzyme Q10. The lower limit of the amount of emulsifier per 100 parts by weight of coenzyme Q10 is preferably 3 parts by weight or more, more preferably 5 parts by weight or more, and more preferably 8 parts by weight or more. The upper limit of the amount of emulsifier per 100 parts by weight of coenzyme Q10 is preferably 5,000 parts by weight or less, more preferably 1,000 parts by weight or less, more preferably 500 parts by weight or less, more preferably 200 parts by weight or less, more preferably 150 parts by weight or less, more preferably 100 parts by weight or less, more preferably 50 parts by weight or less, and more preferably 30 parts by weight or less.

[0078] The lower limit of the content of the antioxidant in the solid composition according to this embodiment is, for example, 1% by weight or more, preferably 2% by weight or more, more preferably 4% by weight or more, and more preferably 5% by weight or more, and the upper limit of the content is, for example, 99% by weight or less, preferably 90% by weight or less, preferably 80% by weight or less, more preferably 70% by weight or less, and more preferably 60% by weight or less.

[0079] The content of the emulsifier other than the emulsifying starch in the solid composition according to this embodiment is not particularly limited, but the lower limit of the emulsifier content is, for example, 0.5% by weight or more, preferably 0.7% by weight or more, and more preferably 0.9% by weight or more, and the upper limit of the content is, for example, 99% by weight or less, preferably 50% by weight or less, more preferably 30% by weight or less, more preferably 25% by weight or less, more preferably 20% by weight or less, more preferably 15% by weight or less, and more preferably 10% by weight or less. When using an emulsifier in a form other than powder or flake, for example, one or more emulsifiers selected from liquid, sol, gel, and soft solid forms, it is usually difficult to obtain a solid composition with good handleability in high yield. However, if the content of the emulsifier in the solid composition according to this embodiment is, for example, 50% by weight or less, preferably 30% by weight or less, and more preferably 25% by weight or less, it is possible to obtain a composition with good handleability in high yield.

[0080] When the solid composition according to this embodiment contains a binder, the lower limit of the binder content in the solid composition is, for example, 1% by weight or more, preferably 10% by weight or more, and more preferably 20% by weight or more, and the upper limit of the binder content is, for example, 80% by weight or less, preferably 70% by weight or less, and more preferably 60% by weight or less.

[0081] The solid composition of this embodiment more preferably contains, for example, 1 part by weight or more, preferably 3 parts by weight or more, more preferably 5 parts by weight or more, particularly preferably 8 parts by weight or more, and even more preferably 10 parts by weight or more of binder per 100 parts by weight of coenzyme Q10.

[0082] The solid composition according to this embodiment preferably does not contain porous calcium silicate, which may have an average particle size of 18 to 32 μm, a loose bulk density of 0.07 to 0.15 g / ml, and an oil absorption of 300 to 550 ml / 100 g.

[0083] The solid Coenzyme Q10-containing composition according to this embodiment can be produced by conventional processes depending on the form, such as powder, granules, tablets, or hard capsules. Powdered Coenzyme Q10-containing compositions can be produced, for example, by mixing coenzyme Q10 and emulsifying starch as powder raw materials, and, if necessary, substances other than the Coenzyme Q10 and emulsifying starch, such as antioxidants, emulsifiers, binders, and excipients. Granular Coenzyme Q10-containing compositions can be produced, for example, by mixing coenzyme Q10 and emulsifying starch, binders, and, if necessary, substances other than the Coenzyme Q10 and emulsifying starch as powder raw materials, adding water to the mixture, granulating, drying, and classifying and pulverizing. Tablet Coenzyme Q10-containing compositions can be produced by compressing the powdered or granular Coenzyme Q10-containing composition into tablets using conventional methods. The hard capsule of the Coenzyme Q10-containing composition can be produced by filling the powder or granule of the Coenzyme Q10-containing composition into a hard capsule by a conventional method.

[0084] In the above-mentioned production method, after coenzyme Q10 such as reduced coenzyme Q10 and a substance other than emulsifying starch such as an emulsifier are granulated, emulsifying starch or other substances may be further added.

[0085] The granulation method is not particularly limited, and can be appropriately selected from, for example, extrusion granulation, stirring granulation, tumbling granulation (rotational granulation), dry granulation, compression granulation, powder bonding, fluidized bed granulation, coacervation, spray drying, cold spray, evaporation, and liquid hardening. The granulation method is preferably a granulation method that applies pressure (for example, extrusion granulation, stirring granulation, tumbling granulation, dry granulation, compression granulation, powder bonding, etc.) or fluidized bed granulation, more preferably extrusion granulation, stirring granulation, or fluidized bed granulation, and particularly preferably extrusion granulation or stirring granulation.

[0086] In this embodiment, when the composition contains reduced coenzyme Q10 crystals, the reduced coenzyme Q10 crystals are not completely dissolved or melted during the granulation process, but are mixed and granulated while basically remaining in a crystalline state.

[0087] Reduced coenzyme Q10 crystals are preferably subjected to a micronization treatment before mixing with other ingredients. Micronization can enhance the bioabsorbability of coenzyme Q10. In particular, when an emulsifier other than emulsifying starch is used in addition to the micronization treatment, bioabsorbability can be significantly improved. The degree of micronization is not particularly limited, but it is preferable to micronize the reduced coenzyme Q10 so that the median diameter (D50) of the crystal particles is 60 μm or less, preferably 55 μm or less, more preferably 40 μm or less, and most preferably 35 μm or less. Furthermore, since extremely micronized reduced coenzyme Q10 has poor powder properties such as fluidity and is difficult to handle, it is preferable to micronize the reduced coenzyme Q10 so that the median diameter (D50) of the crystal particles is, for example, 0.1 μm or more, usually 1 μm or more, preferably 3 μm or more, more preferably 5 μm or more, particularly preferably 10 μm or more, and most preferably 20 μm or more. It is preferable to refine the reduced coenzyme Q10 crystals so that the median diameter (D50) of the crystal particles is within the range of 20 to 60 μm, preferably within the range of 30 to 50 μm. Various conventionally known means can be appropriately employed for the refinement, and mechanical refinement using a homogenizer, high-pressure homogenizer, grinder, ball mill, jet mill, hammer mill, pin mill, etc. can be carried out. Furthermore, fine crystals can also be obtained by adjusting the conditions for precipitating reduced coenzyme Q10 crystals. Furthermore, fine reduced coenzyme Q10 crystals can also be obtained by classification using a sieve and / or airflow, etc. These methods can be used alone or in combination of two or more.

[0088] The components of the mixture to be granulated other than the liquid binder may be in the form of a powder. The characteristics of each component of the mixture other than the liquid binder are as described above.

[0089] Examples of the liquid binder include water, ethanol, etc. Alternatively, the liquid binder may be prepared by dissolving the above-mentioned binder in a liquid such as water or ethanol. Water is particularly preferred as the liquid binder.

[0090] Granulation can be carried out under appropriate conditions so as to obtain a solid composition having dimensions appropriate for the intended use.

[0091] It is preferable to further include a drying step in which the solid composition after granulation is dried to dry and remove volatile components derived from each raw material component and the liquid binder. If necessary, the solid composition having the desired particle size can be separated and recovered by sieving or the like.

[0092] The tablet-type coenzyme Q10-containing composition can be produced by tableting a powder composition or a granular composition obtained through processes such as granulation and drying, but the tableting method is not particularly limited. For example, it can be appropriately selected from methods such as direct compression, semi-direct compression, dry granule compression, and wet granule compression. The tableting method is preferably performed by direct compression or semi-direct compression, and more preferably by direct compression.

[0093] The coenzyme Q10-containing composition of the present invention can also be added to common food and drink.The food and drink to which the coenzyme Q10-containing composition of the present invention is added is not particularly limited, but can be suitably added to, for example, milk drink, soft drink, sports drink, nutritional drink, beauty drink, liquid nutritional supplement and other drinks; chewing gum, chocolate, candy, jelly, cake, biscuit, cracker and other confectionery; ice cream, frozen dessert and other frozen dessert; udon, Chinese noodles, spaghetti, instant noodles and other noodles; kamaboko, chikuwa, half-piece and other paste products; dressing, mayonnaise, sauce and other seasonings; bread, ham, porridge, rice, soup, various retort food, various frozen food and so on. Foods and beverages containing the coenzyme Q10-containing composition according to the present invention can be used for applications such as so-called health foods, supplements, functional foods, functional foods, nutritional supplements, foods for specified health uses, nutritionally functional foods, nursing care foods, smile care foods, chewing and swallowing aids, thick liquid foods, and foods for the sick. Needless to say, they can also be used in other food forms. Furthermore, the coenzyme Q10-containing composition according to one embodiment of the present invention can be added to general pharmaceuticals. It can also be used in pet foods, livestock feed, and the like.

[0094] Next, the coenzyme Q10 absorption enhancer according to the present invention will be described. The coenzyme Q10 absorption enhancer according to one embodiment of the present invention contains starch sodium octenyl succinate as an active ingredient. When ingested by humans or the like in combination with a composition containing coenzyme Q10, the absorption enhancer of this embodiment can enhance the absorption of coenzyme Q10 into the body. In particular, when combined with a composition containing reduced coenzyme Q10 as coenzyme Q10, the absorption-enhancing effect can be further enhanced. Here, "combination" includes both the case where the absorption enhancer and the composition containing coenzyme Q10 are mixed together to prepare a single composition and then ingested, or the case where the absorption enhancer and the composition containing coenzyme Q10 are ingested separately.

[0095] In the present invention, the "coenzyme Q10 absorption-enhancing effect" refers to the effect of increasing the amount of coenzyme Q10 absorbed into the body compared to when coenzyme Q10 is ingested alone. A specific example of this effect is the effect of increasing the AUC (area under the blood concentration-time curve) of coenzyme Q10. Furthermore, the absorption enhancer of this embodiment has the effect of extending the time that coenzyme Q10 can exist in the body without being decomposed or metabolized compared to when coenzyme Q10 is ingested alone. A specific example of this effect is the effect of maintaining the coenzyme Q10 concentration in the blood. The effect of increasing the AUC and the effect of maintaining the coenzyme Q10 concentration in the blood can be evaluated by measuring the coenzyme Q10 blood concentration using means known to those skilled in the art.

[0096] In the absorption enhancer according to this embodiment, the content of starch sodium octenyl succinate in the absorption enhancer (starch sodium octenyl succinate weight / total absorption enhancer weight) is not particularly limited, but is usually about 0.1% by weight or more, preferably about 0.5% by weight or more, more preferably about 1% by weight or more, particularly preferably about 5% by weight or more, particularly preferably 10% by weight or more, and particularly preferably 20% by weight or more. The upper limit is not particularly limited, but is usually about 99.9% by weight or less, preferably about 99% by weight or less, more preferably about 95% by weight or less, and particularly preferably about 90% by weight or less.

[0097] When the absorption enhancer according to this embodiment is combined with a composition containing coenzyme Q10, the weight ratio of starch sodium octenyl succinate to coenzyme Q10 in the combined state (starch sodium octenyl succinate weight / coenzyme Q10 weight) is preferably within the range of 0.4 to 5.0, and more preferably within the range of 1.0 to 5.0. If the weight ratio is less than 0.4, the effect of improving the absorbability of coenzyme Q10 may not be sufficiently achieved compared to when coenzyme Q10 is taken alone.

[0098] In the coenzyme Q10 absorption enhancer of this embodiment, the components other than starch sodium octenyl succinate are not particularly limited. For example, it can be formulated with various conventionally known base materials and carriers that are acceptable for food or pharmaceutical use, and any additives acceptable for food or pharmaceutical use, such as binders, disintegrants, buffers, preservatives, humectants, antibacterial agents, antiseptics, flavorings, surfactants, stabilizers, and solubilizers, may be added as needed. Furthermore, the dosage form of the absorption enhancer is not particularly limited, and it can be a parenteral dosage form such as an injection, or an oral dosage form. For example, formulations suitable for oral intake include, but are not limited to, tablets, capsules, powders, granules, solubilizers, suspensions, syrups, and the like.

[0099] The composition of the starch sodium octenyl succinate is similar to that of the starch sodium octenyl succinate described above in relation to the invention of the coenzyme Q10-containing composition.Furthermore, the composition of the coenzyme Q10-containing composition combined with the absorption enhancer is similar to that described above in relation to the coenzyme Q10-containing composition, except that it does not contain emulsifying starch such as starch sodium octenyl succinate.

[0100] Next, the sustained-release enhancer for coenzyme Q10 according to the present invention will be described. The sustained-release enhancer for coenzyme Q10 according to one embodiment of the present invention contains starch sodium octenyl succinate as an active ingredient. When the sustained-release enhancer of this embodiment is ingested by humans or the like in combination with a composition containing coenzyme Q10, it can improve the sustained-release of coenzyme Q10 when administered to a living body. In particular, when combined with a composition containing reduced coenzyme Q10 as coenzyme Q10, the sustained-release can be further improved. Here, "combination" includes both the case where the sustained-release enhancer and the composition containing coenzyme Q10 are mixed together to prepare a single composition and then ingested, or the case where the sustained-release enhancer and the composition containing coenzyme Q10 are ingested separately.

[0101] In the present invention, the sustained-release improving effect of coenzyme Q10 refers to the effect of extending the time that coenzyme Q10 can exist in the body without being decomposed or metabolized compared to when coenzyme Q10 is ingested alone. Specific examples of this effect include an increase in the relative value of the AUC (area under the blood concentration-time curve) of coenzyme Q10 after a certain time has elapsed since administration compared to the AUC of coenzyme Q10 immediately after administration, an extension of the time required to reach a certain relative AUC value compared to the AUC after a certain time has elapsed since administration, and an increase in the relative value of the blood concentration of coenzyme Q10 after a certain time has elapsed since administration compared to the blood concentration of coenzyme Q10 after a certain time has elapsed since administration. Note that, in this specification, if any one of these effects is observed, it is considered to have a sustained-release improving effect, but it is not necessarily required that all effects be observed. The AUC and blood concentration of coenzyme Q10 can be evaluated by measuring them using means known to those skilled in the art. The specific evaluation of the above-mentioned effect can be performed using the method explained in relation to the invention of the coenzyme Q10-containing composition mentioned above.

[0102] In the sustained-release enhancer according to this embodiment, the content of starch sodium octenyl succinate in the sustained-release enhancer (starch sodium octenyl succinate weight / total weight of sustained-release enhancer) is not particularly limited, but is usually about 0.1% by weight or more, preferably about 0.5% by weight or more, more preferably about 1% by weight or more, particularly preferably about 5% by weight or more, particularly preferably 10% by weight or more, and particularly preferably 20% by weight or more. The upper limit is not particularly limited, but is usually about 99.9% by weight or less, preferably about 99% by weight or less, more preferably about 95% by weight or less, and particularly preferably about 90% by weight or less.

[0103] When the sustained-release enhancer according to this embodiment is combined with a composition containing coenzyme Q10, the weight ratio of starch sodium octenyl succinate to coenzyme Q10 in the combined state (starch sodium octenyl succinate weight / coenzyme Q10 weight) is preferably within the range of 0.4 to 5.0. Preferably, it is within the range of 1.0 to 5.0. If the weight ratio is less than 0.4, the sustained-release enhancing effect of coenzyme Q10 may not be sufficiently achieved compared to when coenzyme Q10 is taken alone.

[0104] In the sustained-release enhancer for coenzyme Q10 of this embodiment, the components other than starch sodium octenyl succinate are not particularly limited. For example, it can be formulated with various conventionally known base materials and carriers that are acceptable for food or pharmaceutical use, and any additives acceptable for food or pharmaceutical use, such as binders, disintegrants, buffers, preservatives, humectants, antibacterial agents, antiseptics, flavorings, surfactants, stabilizers, and solubilizers, may be added as needed. Furthermore, the dosage form of the sustained-release enhancer is not particularly limited, and it can be a parenteral dosage form such as an injection, or an oral dosage form. For example, formulations suitable for oral intake include, but are not limited to, tablets, capsules, powders, granules, solubilizers, suspensions, syrups, and the like.

[0105] The composition of the starch sodium octenyl succinate is similar to that of the starch sodium octenyl succinate described above in relation to the invention of the coenzyme Q10-containing composition.Furthermore, the composition of the coenzyme Q10-containing composition combined with the sustained-release enhancer is similar to that described above for the coenzyme Q10-containing composition, except that it does not contain emulsifying starch such as starch sodium octenyl succinate.

[0106] Next, a method for enhancing absorption of Coenzyme Q10 according to the present invention will be described. The method for enhancing absorption of Coenzyme Q10 according to one embodiment of the present invention is characterized by including a step of coexisting Coenzyme Q10 and emulsifying starch. The term "coexistence" refers to the simultaneous presence of Coenzyme Q10 and emulsifying starch within a specific region. The specific region is not particularly limited, but may include, for example, a liquid, an emulsion, a solid, or a suspension containing a liquid and a solid. Furthermore, when coexisting, the emulsifying starch or a composition containing Coenzyme Q10 may be added to Coenzyme Q10 or a composition containing Coenzyme Q10, or vice versa. The absorption-enhancing method of this embodiment can improve the absorbability of Coenzyme Q10 when ingested by humans, etc., compared to when emulsifying starch is not coexistent. The coexistence of reduced Coenzyme Q10 as Coenzyme Q10 can further enhance the body's absorption-enhancing effect.

[0107] In the absorption-enhancing method according to this embodiment, it is preferable that coenzyme Q10 and emulsifying starch be present together such that the weight ratio of emulsifying starch to coenzyme Q10 (emulsifying starch weight / coenzyme Q10 weight) is within the range of 0.4 to 5.0. Preferably, it is within the range of 1.0 to 5.0. If the weight ratio is less than 0.4, the effect of improving the absorbability of coenzyme Q10 may not be as sufficient as when coenzyme Q10 is taken alone.

[0108] The other components of the coenzyme Q10 and emulsifying starch are similar to those described above for the invention of the coenzyme Q10-containing composition. The evaluation method and evaluation criteria for the absorption-enhancing effect of this method are similar to those described above for the coenzyme Q10-containing composition and the coenzyme Q10 absorption enhancer. Similarly, the configuration of the composition obtained by coexisting coenzyme Q10 and emulsifying starch is similar to those described above for the invention of the coenzyme Q10-containing composition and the coenzyme Q10 absorption enhancer.

[0109] Next, a method for improving the sustained-release of coenzyme Q10 according to the present invention will be described. The method for improving the sustained-release of coenzyme Q10 according to one embodiment of the present invention is characterized by including a step of coexisting coenzyme Q10 with emulsifying starch. The term "coexistence" refers to the simultaneous presence of coenzyme Q10 and emulsifying starch within a specific region. The specific region is not particularly limited, but may include, for example, a liquid, an emulsion, a solid, or a suspension containing a liquid and a solid. Furthermore, when coexisting, emulsifying starch or a composition containing it may be added to coenzyme Q10 or a composition containing it, or vice versa. The sustained-release improving method of this embodiment can improve the sustained-release of coenzyme Q10 when ingested by humans, etc., compared to when emulsifying starch is not coexistent. The coexistence of reduced coenzyme Q10 as coenzyme Q10 can further enhance the sustained-release improving effect.

[0110] In the sustained-release improving method according to this embodiment, it is preferable that coenzyme Q10 and emulsifying starch are present together so that the weight ratio of emulsifying starch to coenzyme Q10 (emulsifying starch weight / coenzyme Q10 weight) is within the range of 0.4 to 5.0. Preferably, it is within the range of 1.0 to 5.0. If the weight ratio is less than 0.4, the sustained-release improving effect of coenzyme Q10 may not be sufficiently obtained compared to when coenzyme Q10 is taken alone.

[0111] The other components of the coenzyme Q10 and emulsifying starch are similar to those described above for the invention of the coenzyme Q10-containing composition. The evaluation method and evaluation criteria for the sustained-release improving effect of this method are similar to those described above for the coenzyme Q10-containing composition and the sustained-release enhancer for coenzyme Q10. Similarly, the configuration of the composition obtained by coexisting coenzyme Q10 and emulsifying starch is similar to those described above for the invention of the coenzyme Q10-containing composition and the sustained-release enhancer for coenzyme Q10.

[0112] The present invention will be described in more detail below with reference to examples and comparative examples, but the present invention is not limited to these examples.

[0113] (Preparation of Composition A) First, the formulation of the composition that forms the basis for the formulation of the compositions prepared in each Example and Comparative Example will be described. This base composition (hereinafter referred to as "Composition A") was prepared by mixing 55 wt% of Form II crystals of reduced coenzyme Q10 (QH Form II) as a base material with a glycerin fatty acid ester as an emulsifier, sodium L-ascorbate as an antioxidant, and hydroxypropyl cellulose (HPC) as a binder, as shown in Table 1.

[0114]

[0115] (Example 1 and Comparative Examples 1 to 5) Pregelatinized starch sodium octenyl succinate was mixed with composition A at a weight ratio of 1:1 as an emulsifying starch to prepare the coenzyme Q10-containing composition of Example 1. Here, Amycol Nyuka D (product name, derived from waxy corn, manufactured by Nippon Starch Chemical Co., Ltd.) was used as the pregelatinized starch sodium octenyl succinate. The content of octenyl succinic acid groups in this pregelatinized starch sodium octenyl succinate was 3.0% or less.

[0116] Instead of the pregelatinized starch sodium octenylsuccinate used in Example 1, predetermined amounts of lysolecithin, glycerin monostearate succinate, and sorbitan monostearate, which are emulsifying agents similar to those used in Example 1, were used and mixed with Composition A to prepare the compositions of Comparative Examples 3 to 5. The weight ratio of the emulsifier to Composition A used in each Comparative Example is shown in Table 2. Comparative Example 2 consisted of Composition A alone, and Comparative Example 1 was a composition with a conventional QH soft capsule formulation. Here, the composition with the conventional QH soft capsule formulation contained edible oils and fats, reduced coenzyme Q10, an emulsifier, and beeswax (thickener).

[0117] Each of the compositions of Example 1 and Comparative Examples 1 to 5 was filled into a gelatin capsule for administration to rats (manufactured by TORPAC, size 9 eL, filling volume 0.08 ml) to prepare capsules for testing. In Example 1 and Comparative Example 5, a mixture of Composition A and the other ingredients was filled into the capsule in advance, while in Comparative Examples 3 and 4, Composition A and the other ingredients were filled separately during capsule filling.

[0118]

[0119] Next, each capsule of Example 1 and Comparative Examples 1 to 5 was administered to SD rats (male, 8 weeks old). The administration method was forced oral administration (satiated condition) using a capsule administration device for rats, and the dose was 30 mg / kg / capsule. After administration, the rats were allowed to ingest 0.5 ml of distilled water.

[0120] Approximately 0.5 ml of blood was then collected from the rats' carotid arteries 1, 2, 4, 8, and 24 hours later, and the coenzyme Q10 concentration in plasma was measured by HPLC. The time to maximum blood concentration (Tmax), maximum blood concentration (Cmax), AUC from 0 to 24 hours, and AUC from 0 to 8 hours for each composition are summarized in Table 3. The AUC (area under the blood concentration-time curve) of total coenzyme Q10 over 24 hours for each composition is also shown in Figure 1. Furthermore, Figure 2 shows the change in total coenzyme Q10 blood concentration over 24 hours. It is assumed that the coenzyme Q10 blood concentration at 0 hours after administration is 0.

[0121]

[0122] As shown in Figure 1, the solid coenzyme-containing composition of Example 1 containing pregelatinized starch sodium octenyl succinate exhibited an AUC value equivalent to that of the conventional QH soft capsule formulation, demonstrating high bioabsorbability of coenzyme Q10. In contrast, the compositions of Comparative Examples 3 to 5 showed no difference in absorbability from Composition A alone (Comparative Example 2). Furthermore, the results of Figure 2 reveal that the composition of Example 1 maintained the coenzyme Q10 concentration in plasma for a long period of time and exhibited a slow absorption rate.

[0123] Next, to evaluate the sustained-release properties of each capsule of Example 1 and Comparative Examples 1 to 5, the following values ​​were calculated: (AUC 8-24 hours after administration) / (AUC 0-4 hours after administration), the time required to reach 40% of the AUC (area under the blood concentration-time curve) of coenzyme Q10 24 hours after administration (AUC 40% time), and the relative value of the coenzyme Q10 blood concentration 8 hours after administration relative to the coenzyme Q10 blood concentration 1 hour after administration (concentration ratio (8h / 1h)). If the decrease in blood concentration after a certain time after administration is gradual compared to the increase in blood concentration immediately after administration, the above values ​​will be high, and the capsule can be evaluated as having excellent sustained-release properties. The calculated results are summarized in Table 4.

[0124]

[0125] As shown in Table 4, the solid coenzyme-containing composition of Example 1 containing pregelatinized starch sodium octenyl succinate had higher values ​​for (AUC 8 to 24 hours after administration) / (AUC 0 to 4 hours after administration), time to AUC 40%, and concentration ratio (8h / 1h) than the other compositions of Comparative Examples 1 to 5, demonstrating superior sustained release of coenzyme Q10.

[0126] (Examples 2-3 and Comparative Examples 6-8) Pregelatinized starch sodium octenylsuccinate (N-CREAMER 46, derived from waxy corn, manufactured by Ingredion) was used as the emulsifying starch. The viscosity of this pregelatinized starch sodium octenylsuccinate at 30°C was 150 mPa·s, and the content of octenylsuccinic acid groups in the pregelatinized starch sodium octenylsuccinate was 3.0% or less. The pregelatinized starch sodium octenylsuccinate was mixed with Composition A at various weight ratios to prepare the compositions of Examples 2-3 and Comparative Example 8. Comparative Example 7 consisted of Composition A alone, and Comparative Example 6 was a composition with a conventional QH soft capsule formulation. The compositions of Examples 2-3 and Comparative Examples 6-8 are shown in Table 5.

[0127]

[0128] Each of the compositions of Examples 2 to 3 and Comparative Examples 6 to 8 was filled into a capsule and administered to rats, and the plasma total coenzyme Q10 concentration was measured 1, 2, 4, 8, and 24 hours after administration. The animals used, administration method, dosage, blood sampling method, and analytical method were the same as those in Example 1. The results are shown in Table 6. The AUC (area under the blood concentration-time curve) of total coenzyme Q10 over 24 hours for each composition is also shown in Figure 3. Furthermore, the change in blood concentration of total coenzyme Q10 over 24 hours is shown in Figure 4.

[0129]

[0130] As shown in Figure 3, the solid coenzyme-containing compositions of Examples 2 and 3 (the weight ratio of Example 2 was 1.82, and the weight ratio of Example 3 was 2.73), which contained a weight ratio of pregelatinized starch sodium octenyl succinate to coenzyme Q10 (55 wt% in Composition A) of more than 0.4, exhibited AUC values ​​equivalent to those of the conventional QH soft capsule formulation, demonstrating high bioabsorbability of coenzyme Q10. In contrast, the composition of Comparative Example 8 (the weight ratio of Comparative Example 8 was 0.36), in which the weight ratio of pregelatinized starch sodium octenyl succinate to coenzyme Q10 was less than 0.4, showed no difference in absorbability from Composition A alone (Comparative Example 7). Furthermore, the results of Figure 4 reveal that the compositions of Examples 2 and 3 maintained plasma coenzyme Q10 concentrations for a relatively long period of time and exhibited a slow absorption rate.

[0131] Next, to evaluate the sustained release properties of each of the capsules in Examples 2 and 3 and Comparative Examples 6 to 8, the values ​​of (AUC 8 to 24 hours after administration) / (AUC 0 to 4 hours after administration), time to AUC 40%, and concentration ratio (8 h / 1 h) were calculated. The results are summarized in Table 7.

[0132]

[0133] As shown in Table 7, the solid coenzyme-containing compositions of Examples 2 and 3, which contained starch pregelatinized octenyl succinate in a weight ratio of more than 0.4 to coenzyme Q10, had a value of (AUC 8 to 24 hours after administration) / (AUC 0 to 4 hours after administration) of 2.1 or more compared to the other compositions of Comparative Examples 6 to 8, and also showed high values ​​for the AUC 40% time and the concentration ratio (8h / 1h), demonstrating excellent sustained-release properties of coenzyme Q10.

[0134] (Example 4 and Comparative Examples 9 to 13) The pregelatinized starch sodium octenyl succinate used in Example 2 as the emulsifying starch was mixed with Composition A in a weight ratio of 1:1 to prepare the composition of Example 4. Furthermore, instead of the pregelatinized starch sodium octenyl succinate of Example 4, hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), xanthan gum, carboxymethyl cellulose (CMC), and alginic acid, which are conventionally known as thickeners and absorption enhancers, were mixed with Composition A in the same weight ratio to prepare the compositions of Comparative Examples 9 to 13. The compositions of Example 4 and Comparative Examples 9 to 13 are shown in Table 8.

[0135]

[0136] Each composition of Example 4 and Comparative Examples 9 to 13 was filled into a capsule. In Example 4 and Comparative Examples 9 to 12, Composition A and the other ingredients were mixed together and filled into the capsule. In Comparative Example 13, Composition A and the other ingredients were filled separately during capsule filling. The prepared capsules were then administered to rats, and plasma total coenzyme Q10 concentrations were measured 1, 2, 4, 8, and 24 hours after administration. The animals used, administration method, dosage, blood sampling method, and analytical method were the same as in Example 1. The results are shown in Table 9. The 24-hour AUC (area under the blood concentration-time curve) of total coenzyme Q10 for each composition is shown in Figure 5. Furthermore, Figure 6 shows the change in blood concentration of total coenzyme Q10 over 24 hours.

[0137]

[0138] As shown in Figure 5, the solid coenzyme-containing composition of Example 4 containing pregelatinized starch sodium octenyl succinate exhibited a higher AUC value than the compositions of Comparative Examples 9 to 13, which combined other thickeners and absorption enhancers, demonstrating superior bioabsorbability of coenzyme Q10. Furthermore, the results of Figure 6 reveal that the composition of Example 4 maintained the plasma coenzyme Q10 concentration for the longest period of time compared to Comparative Examples 9 to 13, and exhibited a sufficiently slow absorption rate.

[0139] Examples 5-6 and Comparative Examples 14-17 Compositions were prepared by mixing Composition A with either pregelatinized starch sodium octenylsuccinate (Example 5) used as the emulsifying starch in Example 2 or non-gelatinized starch sodium octenylsuccinate (NATIONAL 912, derived from waxy corn, manufactured by Ingredion) (Example 6) in a 1:1 weight ratio. Furthermore, instead of pregelatinized starch sodium octenylsuccinate in Example 5, ingredients expected to promote the absorption of coenzyme Q10 (Bioperine, capsaicin, gingerol, and lysolecithin + hydroxypropyl cellulose (HPC)) were mixed with Composition A in various weight ratios to prepare the compositions of Comparative Examples 14-17. The compositions of Examples 5-6 and Comparative Examples 14-17 are shown in Table 10.

[0140]

[0141] Each of the compositions of Examples 5 to 6 and Comparative Examples 14 to 17 was filled into a capsule. In Examples 5 to 6 and Comparative Example 14, Composition A and the other ingredients were mixed together and filled into the capsule. In Comparative Examples 15 to 17, Composition A and the other ingredients were filled separately during capsule filling. The prepared capsules were then administered to rats, and plasma total coenzyme Q10 concentrations were measured 1, 2, 4, 8, and 24 hours after administration. The animals, administration method, dosage, blood sampling method, and analytical method used were the same as in Example 1. The results are shown in Table 11. The 24-hour AUC (area under the blood concentration-time curve) of total coenzyme Q10 for each composition is shown in Figure 7. Furthermore, Figure 8 shows the change in blood concentration of total coenzyme Q10 over 24 hours.

[0142]

[0143] As shown in Figure 7, the solid coenzyme-containing compositions of Examples 5 and 6, which contained pregelatinized starch sodium octenylsuccinate or starch sodium octenylsuccinate that had not been pregelatinized, exhibited higher AUC values ​​than the compositions of Comparative Examples 14 to 17, which combined other ingredients that were expected to promote absorption to some extent, demonstrating superior bioabsorbability of Coenzyme Q10. Furthermore, the results of Figure 8 reveal that the compositions of Examples 5 and 6 maintained plasma Coenzyme Q10 concentrations for longer periods of time than the compositions of Comparative Examples 14 to 17, allowing Coenzyme Q10 to be absorbed at a slower rate.

[0144] Example 7 A composition was prepared and an absorbability test was conducted using rats in the same manner as in Example 2, except that PURITY GUM 2000 (derived from waxy corn, manufactured by Ingredion, viscosity at 30°C: 30 mPa·s) was used as the pregelatinized starch sodium octenyl succinate. As a result, the AUC (0-24 h) was 6.9 μg / mL×hr, demonstrating an improved absorbability compared to Composition A alone (Comparative Example 7). However, compared to N-CREAMER 46 (viscosity at 30°C: 150 mPa·s), the pregelatinized starch sodium octenyl succinate used in Example 2, the contribution to sustained release and improved absorbability was small.

[0145] Example 8 A composition was prepared and an absorbability test was carried out using rats in the same manner as in Example 2, except that CAPSUL (derived from waxy corn, manufactured by Ingredion, viscosity at 30°C: 30 mPa·s) was used as the pregelatinized starch sodium octenyl succinate. The results showed that CAPSUL's contribution to improving sustained release was smaller than that of N-CREAMER 46 (viscosity at 30°C: 150 mPa·s), the pregelatinized starch sodium octenyl succinate used in Example 2.

[0146] Example 9 In Example 9, a composition (the weight ratio of starch sodium octenyl succinate to coenzyme Q10 was 0.64) was prepared by mixing Composition A with Poem M-300P (NA) (components: a mixture of starch sodium octenyl succinate and lauric acid monoglyceride (starch sodium octenyl succinate content: approximately 35%), manufactured by Riken Vitamin Co., Ltd.) at a weight ratio of 1:1. An absorbability test was conducted using rats in the same manner as in Example 2 for each of the composition of Example 9 and the composition of Example 2. As a result, the composition of Example 9 mixed with Poem M-300P (NA) showed an AUC (0-24 h) of 100% relative to the composition of Example 2. The composition of Example 9, which had a smaller weight ratio of starch sodium octenyl succinate to coenzyme Q10, exhibited an absorbability-enhancing effect equivalent to that of Example 2, suggesting that lauric acid monoglyceride enhances the absorbability-enhancing effect of starch sodium octenyl succinate.

[0147] (Examples 10 to 12) The composition of Example 2 was mixed with RYOTO Sugar Ester S-470 (ingredient: sucrose stearate, manufactured by Mitsubishi Chemical Corporation), Classic CM201 (ingredient: pectin, manufactured by MP Gokyo Food & Chemical Co., Ltd.), or YM-150-LJ (ingredient: pectin, manufactured by CP Kelco) at a weight ratio of 2:0.5 to prepare the compositions of Examples 10 to 12. For each of the compositions of Examples 10 to 12 and the composition of Example 2, an absorbability test was conducted using rats in the same manner as in Example 2. The relative values ​​of AUC (0-24 h) when using each of the compositions of Examples 10 to 12 compared to when using the composition of Example 2 are shown in Table 12.

[0148]

[0149] The results in Table 12 show that sucrose stearate and pectin enhance the absorbability-enhancing effect of starch sodium octenyl succinate.

[0150] (Preparation of fine QH-containing composition (homomixer)) 5.5 g of QH Form II crystals and 50 g of 20 wt% ethanol aqueous solution were placed in a beaker and treated with a homomixer (model number: T.K. HOMOMIXER MARK II Model 2.5, manufactured by PRIMIX) for 3 minutes. Thereafter, the QH Form II crystals were recovered by filtration, and 3.3 g of sodium ascorbate, 0.7 g of HPC, and 0.5 g of diglyceryl monooleate were added. After stirring and granulation while adding water, the resulting granules were vacuum dried to obtain a fine QH-containing composition (homomixer). The obtained composition was suspended in water, and wet particle size distribution measurement was carried out using a laser diffraction / scattering particle size distribution analyzer (Partica LA-960, manufactured by Horiba, Ltd.). As a result, the median diameter of the QH Form II crystals contained in the composition was 51.4 μm.

[0151] (Preparation of Fine QH-Containing Composition (Dry Milling)) QH Form II crystals were pulverized using a small mill and passed through a sieve with a mesh size of 75 μm. 3.6 g of sodium ascorbate and 0.3 g of diglycerol monooleate were added to 6.0 g of the obtained pulverized QH Form II crystals, and the mixture was mixed and granulated to obtain a fine QH-containing composition (dry milling). The obtained composition was suspended in water, and wet particle size distribution measurement was performed using a laser diffraction / scattering particle size distribution analyzer (Partica LA-960, manufactured by Horiba, Ltd.). The median diameter of the QH Form II crystals contained in the composition was 30.6 μm.

[0152] Examples 13-15: N-CREAMER 46 (ingredient: starch pregelatinized octenyl succinate sodium) was mixed with the above-mentioned fine QH-containing composition (homomixer) or fine QH-containing composition (dry-milled) at a weight ratio of 1:1 to prepare the coenzyme Q10-containing compositions of Examples 13 and 14. Furthermore, N-CREAMER 46 and Classic CM201 (ingredient: pectin) were mixed with the fine QH-containing composition (dry-milled) at a weight ratio of 1:1:0.5 to prepare the coenzyme Q10-containing composition of Example 15. For each of the prepared compositions of Examples 13-15 and the composition of Example 2, an absorbability test was conducted using rats in the same manner as in Example 2. The relative AUC (0-24 h) values ​​for the compositions of Examples 13-15 compared to the composition of Example 2 are shown in Table 13.

[0153]

[0154] The results in Table 13 show that absorbability can be improved by using micronized QH Form II crystals in combination with starch sodium octenyl succinate. The results in Table 13 also show that the combined use of micronized QH Form II crystals, starch sodium octenyl succinate, and pectin can significantly improve absorbability due to a synergistic effect that was not anticipated from the results of using each alone.

[0155] (Example 16 and Comparative Example 18) An absorption test was conducted on six male subjects aged 30 to 39 (average age 34.33±4.08 years). Each subject was administered 100 mg of QH. As a comparative example, each subject orally ingested one conventional QH-containing soft capsule (each capsule containing 100 mg of QH; manufactured by Kaneka) (Comparative Example 18). The composition of the conventional QH-containing soft capsule contained edible oils and fats, reduced coenzyme Q10, modified starch, glycerin, an emulsifier, carrageenan (a gelling agent), beeswax (a thickener), and a pH adjuster. As an example, a hard capsule formulation (each capsule containing 50 mg of QH) was prepared by filling 200 mg of a coenzyme Q10-containing composition, which was a 1:1 mixture of Composition A and sodium starch octenyl succinate, into a hard capsule (Lonza, size 2), and two capsules of this formulation were orally ingested by a subject (Example 16). N-CREAMER 46 (product name, derived from waxy corn, manufactured by Ingredion) was used as the starch octenyl succinate.

[0156] Blood samples were collected from a peripheral vein at 0, 2, 4, 6, 8, 10, 12, 24, 30, 36, 48, 60, and 72 hours after ingestion, and plasma coenzyme Q10 concentrations were measured by LC / MS / MS. Figure 9 shows the changes in total coenzyme Q10 blood concentrations up to 72 hours after ingestion. Because coenzyme Q10 is naturally present in the human body, the blood concentration at 0 hours after ingestion was set to 0, and the blood concentration up to 72 hours was base-corrected.

[0157] For each test, the time to reach maximum blood concentration (Tmax), maximum blood concentration (Cmax), AUC from 0 to 72 hours, and as an index of sustained release (AUC 24 to 72 hours after administration) / (AUC 0 to 12 hours after administration), the time to reach 40% of the AUC relative value (AUC 40% time) for the AUC (area under the blood concentration-time curve) of coenzyme Q10 72 hours after administration, and the relative value of the blood concentration of coenzyme Q10 60 hours after administration to the blood concentration of coenzyme Q10 4 hours after administration (concentration ratio (60h / 4h)) were calculated. The results are shown in Tables 14 and 15.

[0158]

[0159] As shown in Tables 14 and 15, the coenzyme Q10-containing composition containing starch sodium octenyl succinate also showed higher AUC values ​​than conventional QH soft capsules in human studies, demonstrating high bioavailability of coenzyme Q10. Furthermore, the results of Figure 9 reveal that the composition of Example 16 maintained plasma coenzyme Q10 concentrations for extended periods. The sustained-release properties of the composition of Example 16 were evaluated using the values ​​of (AUC 24-72 hours after administration) / (AUC 0-12 hours after administration), the time to AUC 40%, and the concentration ratio (60 h / 4 h). These values ​​were higher than those of Comparative Example 18, suggesting that the coenzyme Q10-containing composition containing starch sodium octenyl succinate also exhibits superior sustained-release properties in humans.

[0160] (Disintegration Test) Tablets containing no starch sodium octenyl succinate relative to coenzyme Q10 (Reference Example 1) and tablets containing two different types of starch sodium octenyl succinate relative to coenzyme Q10 (Reference Examples 2 and 3) were prepared using a tablet press according to a conventional method. The tablets had a thickness of approximately 6 mm and a hardness of 8 to 13 kgf. The prepared tablets were placed on a mesh with an opening of approximately 2 mm in a disintegration tester (NT-20HS, manufactured by Toyama Sangyo Co., Ltd., with an auxiliary plate), and a disintegration test was performed under the conditions shown below. The disintegration time was measured as the time when the tablet placed on the mesh disintegrated to the extent that it passed through the mesh. The tablets sank on the mesh in water both before the disintegration test (without the auxiliary plate) and during the disintegration test. <Disintegration test conditions> Testing machine: NT-20HS (manufactured by Toyama Sangyo Co., Ltd.), with auxiliary plate Test liquid: distilled water Temperature: 37°C Vibration frequency: 30 times / min

[0161] The results of disintegration time are shown in Table 16. The tablets of Reference Examples 2 and 3 containing starch sodium octenyl succinate had long disintegration times, and it was found that the tablet (Reference Example 2) containing the high-viscosity N-CREAMER 46 (viscosity at 30°C: 150 mPa s) had a significantly longer disintegration time than the tablet (Reference Example 3) containing the lower-viscosity CAPSUL (viscosity at 30°C: 30 mPa s). This suggests that starch sodium octenyl succinate may delay the disintegration time of the tablet and contribute to improving the absorbability of active ingredients such as coenzyme Q10, and it was revealed that starch sodium octenyl succinate, which has a high viscosity, was particularly effective.

[0162]

[0163] All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety.

Claims

1. A coenzyme Q10-containing composition comprising coenzyme Q10 and emulsifying starch, wherein the weight ratio of the emulsifying starch to the coenzyme Q10 is 0.4 to 5.

0.

2. The coenzyme Q10-containing composition according to claim 1, wherein the weight ratio is 1.0 to 5.

0.

3. A coenzyme Q10-containing composition according to claim 1 or 2, wherein the emulsifying starch is starch sodium octenyl succinate.

4. A coenzyme Q10-containing composition according to claim 1 or 2, wherein the coenzyme Q10 is reduced coenzyme Q10.

5. A coenzyme Q10-containing composition according to claim 1 or 2, which is in solid form.

6. A coenzyme Q10-containing composition according to claim 1 or 2, wherein the viscosity of the emulsifying starch at 30°C is 10 to 200,000 mPa·s.

7. The coenzyme Q10-containing composition according to claim 3, wherein the octenylsuccinic acid group in the starch sodium octenylsuccinate is greater than 0 to 5.0%.

8. The coenzyme Q10-containing composition according to claim 5, further comprising one or more emulsifiers selected from the group consisting of glycerin fatty acid esters, sucrose fatty acid esters, water-soluble polysaccharides, retinol fatty acid esters, propylene glycol fatty acid esters, sorbitan fatty acid esters, and polysorbates.

9. A coenzyme Q10-containing composition according to claim 1 or 2, in which the relative value of the AUC (area under the blood concentration-time curve) of coenzyme Q10 from 0 to 4 hours after administration to rats is 2.1 or more.

10. A coenzyme Q10-containing composition according to claim 1 or 2, in which the relative value of the AUC (area under the blood concentration-time curve) of coenzyme Q10 24 to 72 hours after administration to the AUC of coenzyme Q10 0 to 12 hours after administration when orally administered to humans is 3.5 or more.

11. A coenzyme Q10 absorption enhancer containing starch sodium octenyl succinate as an active ingredient.

12. The absorption enhancer according to claim 11, wherein the coenzyme Q10 is reduced coenzyme 10.

13. A sustained-release enhancer for coenzyme Q10 containing starch sodium octenyl succinate as an active ingredient.

14. A method for promoting absorption of coenzyme Q10, comprising the step of allowing coenzyme Q10 and emulsifying starch to coexist, wherein the weight ratio of the emulsifying starch to the coenzyme Q10 in the coexisting state is 0.4 to 5.

0.

15. A method for improving the sustained release of coenzyme Q10, comprising the step of allowing coenzyme Q10 and emulsifying starch to coexist, wherein the weight ratio of the emulsifying starch to the coenzyme Q10 in the coexisting state is 0.4 to 5.0.

Images