Coq10-containing soft capsule

Abstract

To provide a CoQ10-containing soft capsule filling composition that is less prone to aggregation and precipitation of CoQ10 during storage, and a CoQ10-containing soft capsule made using the same.SOLUTION: A coenzyme Q10-containing soft capsule filling composition contains coenzyme Q10 and a polyglyceryl fatty acid ester mixture, where the polyglyceryl fatty acid ester mixture has an average polymerization degree of polyglycerol of 2-20, with an average esterification ratio of 40% or more. In the total of the constituent fatty acids, the saturated fatty acid content is 95-100 mass%, comprising 6-25 mass% of C16 and C18 saturated fatty acids and 55-85 mass% of C20 or higher saturated fatty acids.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a coenzyme Q10-containing soft capsule having excellent storage stability, and a capsule filling composition used for said capsule. [Background technology]

[0002] Coenzyme Q10 (hereafter referred to as "CoQ10") is a type of coenzyme Q found in plants, bacteria, and animals (humans), and is a fat-soluble vitamin-like substance found in large quantities in mitochondria. The main functions of CoQ10 are energy metabolism and antioxidant action, and in energy metabolism, it is an essential component in the production of energy (ATP) in mitochondria. In addition, with regard to its antioxidant action, it is thought to eliminate reactive oxygen species, reduce the vitamin E radicals produced, and regenerate vitamin E.

[0003] There are two types of CoQ10: oxidized (ubiquinone) and reduced (ubiquinol). Reduced CoQ10 is considered to be the active form of CoQ10, and most CoQ10 exists in the reduced form in the body. As we age, the amount of CoQ10 produced in the body and its ability to be converted to the reduced form decrease, so in recent years, it has been recommended to consume oily fish, meat, and vegetables that contain a lot of CoQ10, and it has also been suggested to supplement CoQ10 with supplements.

[0004] On the other hand, since CoQ10 is a fat-soluble substance, when it is filled into capsules to prepare a formulation, it is filled by dissolving or suspending it in fats or oils. However, since the melting point of CoQ10 is 47°C to 52°C, when it is cooled below room temperature, CoQ10 aggregates and precipitates, resulting in a decrease in its absorption rate in the body and a significant decrease in its commercial value due to the appearance of the aggregates and precipitates.

[0005] Conventionally, methods for improving the storage stability of CoQ10 have been reported, such as blending specific (poly)glycerol fatty acid esters such as decaglycerol myristic acid ester and decaglycerol behenic acid ester, or sorbitan fatty acid esters such as sorbitan tribehenic acid ester (Patent Document 1), blending polyglycerol fatty acid esters in which a polyglycerol having a hydroxyl value of 1,200 or less and in which 50% or more of all hydroxyl groups are primary hydroxyl groups and a fatty acid are esterified (Patent Document 2), and blending decaglyceryl pentastearate and decaglyceryl pentaoleate (Patent Document 3). However, the aggregation-inhibiting effect of CoQ10 is still not sufficient. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] JP 2017-214335 A [Patent Document 2] JP 2007-209251 A [Patent Document 3] JP 2019-26600 A Summary of the Invention [Problem to be solved by the invention]

[0007] An object of the present invention is to provide a composition for filling a CoQ10-containing soft capsule, which is less likely to cause aggregation or precipitation of CoQ10 during storage, and a CoQ10-containing soft capsule preparation using the same. [Means for solving the problem]

[0008] As a result of extensive research aimed at solving the above problems, the present inventors have found that by adding a polyglycerol fatty acid ester mixture having a specific fatty acid composition to CoQ10, the aggregation and precipitation of CoQ10 during storage can be significantly suppressed, and a CoQ10-containing soft capsule formulation having excellent storage stability and high commercial value can be obtained.

[0009] That is, the present invention relates to the following 1) to 6). 1) A composition for filling coenzyme Q10-containing soft capsules, which contains coenzyme Q10 and a polyglycerol fatty acid ester mixture, the polyglycerol having an average degree of polymerization of 2 to 20 and an average esterification rate of 40% or more, and which contains 95 to 100% by mass of saturated fatty acids in all of the constituent fatty acids, 6 to 25% by mass of saturated fatty acids having 16 and 18 carbon atoms, and 55 to 85% by mass of saturated fatty acids having 20 or more carbon atoms. 2) The composition according to claim 1, wherein the mass ratio of coenzyme Q10 to the polyglycerol fatty acid ester mixture in the composition is 1:0.05 to 1:1. 3) The composition according to 1) or 2), which contains 1 to 50% by mass of coenzyme Q10. 4) The composition according to 1), wherein the HLB of the polyglycerol fatty acid ester mixture is 2.5 to 3.0. 5) A soft capsule containing coenzyme Q10, which is filled with the composition according to any one of 1) to 4). 6) A method for inhibiting aggregation or precipitation of coenzyme Q10 in a composition for filling coenzyme Q10-containing soft capsules, comprising blending a polyglycerol fatty acid ester mixture, wherein the polyglycerol has an average degree of polymerization of 2 to 20, an average esterification rate of 40% or more, and contains 95 to 100% by mass of saturated fatty acids in all of the constituent fatty acids, 6 to 25% by mass of saturated fatty acids having 16 and 18 carbon atoms, and 55 to 85% by mass of saturated fatty acids having 20 or more carbon atoms. Effect of the Invention

[0010] According to the present invention, it is possible to provide a CoQ10-containing soft capsule having excellent storage stability and high commercial value, in which aggregation and precipitation of CoQ10 during storage is suppressed and deterioration of the capsule's appearance and decrease in absorbency are suppressed. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The CoQ10-containing soft capsule filling composition of the present invention contains CoQ10 and a polyglycerol fatty acid ester mixture, in which the polyglycerol has an average degree of polymerization of 2 to 20, an average esterification rate of 40% or more, and a saturated fatty acid content of 95 to 100% by mass of all the constituent fatty acids, including 6 to 25% by mass of saturated fatty acids having 16 and 18 carbon atoms and 55 to 85% by mass of saturated fatty acids having 20 or more carbon atoms. By incorporating such a polyglycerol fatty acid ester mixture into a CoQ10-containing soft capsule filling composition, aggregation or precipitation of CoQ10 in the composition can be suppressed.

[0012] In the present invention, coenzyme Q10 (CoQ10) may be either oxidized ubiquinone or reduced ubiquinol, and includes cases in which oxidized CoQ10 or reduced CoQ10 is contained alone, as well as cases in which a mixture of oxidized CoQ10 and reduced CoQ10 is contained.

[0013] In the soft capsule filling composition of the present invention, the content of CoQ10 is not particularly limited, but taking into consideration the stability of CoQ10 and ease of administration when formulated into a soft capsule, the content can be, for example, 1 to 50% by mass, preferably 2 to 40% by mass, more preferably 3 to 30% by mass, even more preferably 4 to 25% by mass, and even more preferably 5 to 15% by mass.

[0014] A polyglycerol fatty acid ester is a fatty acid ester of a glycerol condensate, and the polyglycerol fatty acid ester mixture used in the present invention refers to a mixture of esters of polyglycerol (glycerol condensate) and multiple types of fatty acids. The average polymerization degree of the polyglycerol in the polyglycerol fatty acid ester mixture of the present invention is preferably 2-20. In the present invention, the average degree of polymerization of polyglycerol is the average degree of polymerization (n) of polyglycerol calculated from the hydroxyl value by terminal group analysis, and the average degree of polymerization is calculated from the following formulas (Formula 1) and (Formula 2). (Formula 1) Molecular weight=74n+18 (Equation 2) Hydroxyl value = 56110 (n + 2) / molecular weight The hydroxyl value in the above formula (2) is a numerical value that indicates the number of hydroxyl groups contained in polyglycerin, and refers to the number of milligrams of potassium hydroxide required to neutralize the acetic acid required to acetylate the free hydroxyl groups contained in 1 g of polyglycerin. The number of milligrams of potassium hydroxide is calculated in accordance with the "Standard Test Methods for the Analysis of Fats, Oils and Related Materials, 2013 Edition, Published by the Japan Oil Chemists' Society" compiled by the Japan Oil Chemists' Society.

[0015] In addition, the esterification rate of the polyglycerol fatty acid ester is 40% or more, preferably 50% or more, and more preferably 60% or more, from the viewpoint of suppressing aggregation of CoQ10. There is no particular upper limit, and it may be 100%. In the present invention, the esterification rate of a polyglycerol fatty acid ester is a value calculated by (Equation 3) where n is the average degree of polymerization of a polyglycerol calculated from a hydroxyl value obtained by terminal group analysis, n+2 is the number of hydroxyl groups possessed by the polyglycerol, and M is the number of moles of fatty acid added to the polyglycerol. (Equation 3) Esterification rate (%) = (M / (n+2)) x 100

[0016] Examples of fatty acids that form esters with such polyglycerol include fatty acids having 16, 18, 20, 22, etc. carbon atoms, and may be unsaturated or saturated fatty acids. The content of saturated fatty acids in all the constituent fatty acids is 95 to 100% by mass, preferably 97 to 100% by mass, and more preferably 98 to 100% by mass. The content of saturated fatty acids having 16 and 18 carbon atoms is 6 to 25 mass%, preferably 7 to 23 mass%, and more preferably 8 to 20 mass%, and the content of saturated fatty acids having 20 or more carbon atoms is 55 to 85 mass%, preferably 60 to 85 mass%, and more preferably 70 to 85 mass%.

[0017] The polyglycerol fatty acid ester mixture of the present invention preferably has an HLB value of 1.0 to 5.0, more preferably 2.5 to 3.0. HLB is an abbreviation for Hydrophile Lipophile Balance, and is an index for knowing whether an emulsifier is hydrophilic or lipophilic, and takes a value of 0 to 20. The smaller the HLB value, the stronger the lipophilicity. In the present invention, the HLB value is calculated using the Atlas method. The Atlas method is a method of calculating the HLB value from the following formula (Formula 4). In this calculation method, the HLB value is calculated as an arithmetic mean. (Formula 4) HLB = 20 × (1-S / A) (wherein S is the saponification value, and A is the neutralization value of the fatty acid in the ester).

[0018] Examples of commercially available products of such polyglycerol fatty acid ester mixtures include "SY Glystar CV-23" (manufactured by Sakamoto Yakuhin Kogyo Co., Ltd.) and "SY Glystar CV-1L" (manufactured by Sakamoto Yakuhin Kogyo Co., Ltd.). "SY Glystar CV-23" has a total fatty acid composition of 99.9% by mass saturated fatty acids, 8.8% by mass saturated fatty acids with 16 and 18 carbon atoms, and 80.3% by mass saturated fatty acids with 20 or more carbon atoms. The average degree of polymerization of polyglycerin is 10, and the esterification rate is 50% or more. "SY Glystar CV-1L" contains 99.9% by mass of saturated fatty acids, 19.9% ​​by mass of saturated fatty acids with 16 and 18 carbon atoms, and 63.9% by mass of saturated fatty acids with 20 or more carbon atoms, with an average degree of polymerization of polyglycerol of 10 and an esterification rate of 50% or more.

[0019] In the soft capsule filling composition of the present invention, the mass ratio of CoQ10 to the polyglycerol fatty acid ester mixture is not particularly limited as long as it is within a range that can suppress precipitation of CoQ10 crystals in the composition. From the viewpoint of increasing the dispersibility of CoQ10 and suppressing crystal precipitation, however, it is preferably 1:0.05 to 1:1, more preferably 1:0.09 to 1:0.75, and even more preferably 1:0.1 to 1:0.5.

[0020] In the soft capsule filling composition of the present invention, in addition to CoQ10, other oils and fats may be added as necessary, such as vegetable oils and fats such as soybean oil, rapeseed oil, safflower oil, rice oil, corn oil, sunflower oil, cottonseed oil, olive oil, sesame oil, peanut oil, pearl barley oil, wheat germ oil, perilla oil, linseed oil, perilla oil, Sacha Inchi oil, walnut oil, kiwi seed oil, salvia seed oil, parsley seed oil, grape seed oil, macadamia nut oil, hazelnut oil, almond oil, pumpkin seed oil, camellia oil, tea seed oil, borage oil, palm oil, palm olein, palm stearin, coconut oil, palm kernel oil, cacao butter, monkey fat, shea oil, algae oil, seaberry fruit oil, and rose oil; animal oils and fats such as fish oil, lard, beef tallow, and butter fat; or interesterified oils, hydrogenated oils, and fractionated oils thereof; Polyhydric alcohols such as polyethylene glycol, propylene glycol, glycerin, and sorbitol; Surfactants such as sorbitan fatty acid esters, sucrose fatty acid esters, and polyoxyethylene hydrogenated castor oil; Ginkgo leaf extract, phosphatidylserine, GABA, chicken-derived plasmalogen, bilberry extract and blackcurrant extract containing anthocyanins, marigold pigment containing lutein and zeaxanthin, Haematococcus algae pigment containing astaxanthin, gardenia pigment containing crocetin; Carotenoids such as α-carotene, β-carotene, lycopene, and β-cryptoxan; quinones such as vitamin K and PQQ; Polyphenols such as flavonols, isoflavones, tannins, catechins, quercetin, anthocyanins, flavangenols, and flavonoids; Cannabidiol, a cannabinoid, propolis, and xylitol; Vitamins such as vitamin B1, B2, niacin, pantothenic acid, vitamin B6, biotin, vitamin B12, vitamin C, vitamin D3, vitamin E, vitamin P; Minerals such as calcium, phosphorus, sodium, potassium, magnesium, zinc, selenium, chromium, molybdenum, iron and copper; Lactic acid bacteria such as L-92 lactic acid bacteria, Lactobacillus casei plasma, Lactobacillus casei strain Shirota, Lactobacillus gasseri SP strain, and Lactobacillus casei LG-21, and bifidobacteria such as BB-536 strain and B-3 strain can be added as appropriate.

[0021] In addition, the composition of the present invention may further contain other pharma- ceutically acceptable ingredients within the range that does not impair the effects of the present invention. Examples of such ingredients include, but are not limited to, antioxidants (e.g., tocopherol, vitamin A, β-carotene, sodium hydrogen sulfite, sodium thiosulfate, sodium pyrosulfite, citric acid, ascorbic acid, etc.), colorants (natural dyes, tar-based dyes, etc.), absorption promoters (higher alcohols, higher fatty acids, surfactants, etc.), stabilizers (benzoic acid, sodium benzoate, ethyl paraoxybenzoate, etc.), viscosity adjusters (beeswax, candelilla wax, Japan wax, carnauba wax, rice bran wax, sugarcane wax, shellac wax, jojoba wax, etc.), etc.

[0022] The CoQ10-containing soft capsule of the present invention may be any of a rotary die type soft capsule formulation, a flat plate type soft capsule formulation, and a seamless type soft capsule formulation, depending on the manufacturing method. 1) The rotary die type soft capsule formulation is a formulation in which a capsule shell composition is stretched on a pair of rotating drums on the left and right sides using a rotary die type soft capsule molding machine to form a coating sheet, and then an appropriate temperature is applied to the surface of the coating sheet with a segment, and the coating sheet is molded into a predetermined shape using a rotating die roll, and at the same time, the contents are filled while the coating sheet is adhered. 2) The flat plate type soft capsule formulation is a formulation in which a coating sheet is placed on one of a pair of flat plate dies, the contents are placed on top of that, the coating sheet is further covered, and finally the other die is placed on top, and then pressed to form into a predetermined shape. 3) The seamless type soft capsule formulation is a formulation formed by dropping a capsule shell composition and a content liquid simultaneously discharged from a double nozzle existing on a concentric circle into a cooling liquid flowing at a constant speed.

[0023] Among these, the rotary die type soft capsule formulation is preferred from the viewpoints of a wide range of content liquids that can be produced, a high degree of freedom in selecting shapes and sizes, and productivity. A suitable example of a rotary die type soft capsule formulation is one in which the soft capsule filling composition of the present invention is injected between capsule shell sheets formed into a sheet shape, and compression molded from both sides. The capsule shell sheet can be manufactured according to a conventional method. For example, a base material mainly composed of gelatin and a plasticizer such as sorbitol, maltitol, or glycerin are each stirred and dispersed in water, stirred and dissolved at 60 to 98°C, degassed, and then spread on a rotating drum using a casting device.

[0024] The filled and molded soft capsule preparation is dried and then, if necessary, finished by surface treatment using a tumbler or the like.

[0025] Thus, soft capsules filled with the composition for filling soft capsules of the present invention do not show any aggregation or precipitation of CoQ10 even when stored for 4 months under conditions of 40° C. and 75% humidity. The determination of the aggregation or precipitation of CoQ10 during storage can be performed by known crystal observation methods such as visual inspection, stereomicroscopy, and X-ray CT photography. For example, after storage in an environment of 40°C and 75% humidity for 2 weeks or more, 1 month or more, 2 months or more, 3 months or more, or 4 months or more, it can be evaluated by whether there is no aggregation or precipitation, or whether there are aggregations or precipitates with a major axis of 0.25 mm or more. EXAMPLES

[0026] The present invention will be described in more detail below with reference to examples and comparative examples. However, the present invention is not limited to these examples as long as it does not depart from the gist of the present invention.

[0027] 1. Manufacturing Example (1) Raw materials for soft capsule formulations

[0028] [Table 1]

[0029] (2) Preparation of soft capsule formulation contents The emulsifiers, Poem S-100, beeswax FP, and safflower oil shown in the Examples and Comparative Examples in Tables 3 and 4 below were dissolved by heating at about 70°C, cooled to 60°C or less, lecithin was added and mixed, and then cooled further to 30°C, CoQ10 was added and stirred. The contents were then adjusted by wet grinding (homogenizer), sieving, and defoaming.

[0030] (3) Raw material for the coating solution of soft capsule formulations

[0031] [Table 2]

[0032] (4) Preparation of coating solution for soft capsule formulation 100 parts by mass of gelatin, 40 parts by mass of glycerin, and an appropriate amount of water were weighed out, dissolved at 80° C., and degassed to obtain a coating solution.

[0033] (5) Capsule molding using a rotary die type soft capsule filling machine The coating solution was filled into the sprayer box of a rotary die type soft capsule filling machine, spread onto a rotating drum to form a thin film of about 0.9 mm, and cooled to obtain a coating sheet. Sheet evaluation was carried out using the coating sheet obtained at this stage. Next, the film sheet was heated and bonded with the segments, and the content liquid was filled just before punching out, and the punched and molded product was dried to produce a soft capsule.

[0034] (6) Drying The molded soft capsules were sent to a tumbler dryer connected to a filling machine and dried at a temperature of 20 to 30° C. and a relative humidity of 5 to 70% for 8 to 60 hours to obtain the desired soft capsules.

[0035] 2. Test Example: Evaluation of CoQ10's Inhibition of Aggregation (1) Method The aggregation inhibitory effect of CoQ10 was evaluated by storing the obtained soft capsules at a temperature of 40°C and a humidity of 75% for 3 days, 1 month, 2 months, and 4 months, then transferring them to 25°C and visually observing the presence or absence of aggregation or precipitation after 5 days, and evaluating them according to the following criteria. The contents were removed from the soft capsules to observe the presence or absence of aggregation or precipitation. <Evaluation criteria> ◯: No aggregation or precipitation was observed even after storage for 4 months △: No aggregation or precipitation was observed after 3 days of storage, but aggregation or precipitation of 0.25 mm or more was observed after 1 month and 2 months of storage. ×: Aggregation or precipitation of 0.25 mm or more is observed after storage for 3 days.

[0036] (2) Results The results are shown in Tables 3 and 4. As is clear from Table 3, the aggregation and precipitation of CoQ10 was suppressed in the soft capsules filled with the soft capsule filling composition of the present invention (Examples 1 to 12). On the other hand, as shown in Table 4, the aggregation and precipitation of CoQ10 was confirmed in Comparative Examples 1 to 4, suggesting that the effect of suppressing the aggregation of CoQ10 may be insufficient. From the above results, it was found that the coexistence of the polyglycerol fatty acid ester mixture used in the present invention is effective in inhibiting the aggregation of CoQ10 in CoQ10-containing soft capsules.

[0037] [Table 3]

[0038] [Table 4]

Claims

1. A composition for filling coenzyme Q10-containing soft capsules, comprising coenzyme Q10 and a polyglycerin fatty acid ester mixture, wherein the polyglycerin fatty acid ester mixture has an average degree of polymerization of 2 to 20 of polyglycerin, an average esterification rate of 40% or more, a saturated fatty acid content of 95 to 100% by mass of the total constituent fatty acids, and contains 6 to 25% by mass of saturated fatty acids having 16 and 18 carbon atoms, and 55 to 85% by mass of saturated fatty acids having 20 or more carbon atoms.

2. The composition according to claim 1, wherein the mass ratio of coenzyme Q10 to polyglycerin fatty acid ester mixture in the composition is 1:0.05 to 1:

1.

3. The composition according to claim 1, wherein the composition contains 1 to 50% by mass of coenzyme Q10.

4. The composition according to claim 1, wherein the HLB of the polyglycerin fatty acid ester mixture is 1.0 to 5.

0.

5. A coenzyme Q10-containing soft capsule, filled with the composition described in any one of claims 1 to 4.

6. A method for suppressing aggregation or precipitation of coenzyme Q10 in a composition for filling soft capsules containing coenzyme Q10, wherein the composition contains a polyglycerin fatty acid ester mixture, the polyglycerin fatty acid ester mixture having an average degree of polymerization of 2 to 20 of polyglycerin, an average esterification rate of 40% or more, a saturated fatty acid content of 95 to 100% by mass of the total constituent fatty acids, and containing 6 to 25% by mass of saturated fatty acids having 16 or 18 carbon atoms and 55 to 85% by mass of saturated fatty acids having 20 or more carbon atoms.