JP5028885B2 - Ubidecalenone-containing self-emulsifying composition - Google Patents

Description

  The present invention relates to a self-emulsifying composition containing ubidecarenone in a high concentration, and belongs to the fields of pharmaceuticals, quasi drugs and foods.

  Ubidecarenone is a coenzyme that is involved in the electron transport system of the mitochondrial inner membrane and plays an important role in the production of ATP, and is used as a therapeutic drug for congestive heart disease in many medical drugs. In recent years, its anti-fatigue action and antioxidant action have attracted attention all over the world, and are widely used as food materials. However, since ubidecarenone is hydrophobic, its solubility in water is low, and its absorbability from the digestive tract is poor (see Non-Patent Document 1).

  Here, as one of the methods for improving the absorption of hydrophobic (lipid-soluble) drugs, a method using a self-emulsified body is known. A method of dissolving ubidecarenone in a fatty acid (see Patent Document 1), fatty acid monoglyceride (See Patent Document 2), a method of dispersing in oil such as soybean oil and filling into small capsules (see Patent Document 3), a method of adding limonene and polyoxyethylene sorbitan ester type emulsifier (Patent Document) 4), a method of dissolving in propylene glycol fatty acid ester (see Non-Patent Document 2), and the like. However, the solubility of ubidecarenone by these methods is small, and it is difficult to dissolve ubidecalenone at a high concentration, for example, 15% by mass or more. Undissolved ubidecarenone not only impairs the appearance of the product, but also has an unfavorable absorbency.

  Further, as a method for improving the absorbability by containing ubidecarenone in a high concentration, a method is known in which an emulsion obtained by emulsifying ubidecalenone with casein, citric acid monoglyceride, and polyglycerol fatty acid ester is spray-dried (see Patent Document 5). ). However, since the manufacturing method is complicated and a special apparatus such as a spray drying apparatus is required, it is not suitable for industrialization.

  Therefore, development of a self-emulsifying composition containing ubidecarenone in a high concentration by a simple method without requiring a special device has been demanded.

Japanese Patent Publication No.63-23965 Japanese Patent Publication No. 64-10494 Japanese Examined Patent Publication No. 63-51122 JP 2005-60252 A JP-A-2005-43 Chem. Pharm. Bull., 20, (12) 2585 (1972) T.R.Kommuru, et.al., Int. J. Pharm., 212, 233-246 (2001)

  An object of the present invention is to provide a self-emulsifying composition that does not require a special apparatus, can be prepared by a simple method, and contains ubidecarenone in a high concentration.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have reduced the melting point of the mixture by mixing ubidecalenone, menthol and camphor, all of which have a melting point of 37 ° C. or higher, and the temperature near body temperature (37 ° C. ), A liquid containing a high concentration of ubidecarenone is obtained, and in this liquid, a hydrophilic surfactant such as polyoxyethylene hydrogenated castor oil 60 having a HLB value of 10 or more, and 12 carbon atoms such as glyceryl monocaprylate are used. It has been found that a self-emulsified product containing ubidecalenone at a high concentration of 15% by mass or more can be easily obtained by adding the following fatty acid monoglyceryl and dissolving by heating.

  One of the embodiments of the present invention obtained based on such findings is that ubidecalenone is 10% by mass or more in the composition, and menthol is 0.2 parts by mass or more and melting point is 37 ° C. with respect to 1 part by mass of the ubidecalenone. Monoglycerides of fatty acids having 0.1 or more parts by mass of the above saturated terpenoids (excluding menthol), 0.05 parts by mass or more of hydrophilic surfactants having an HLB of 10 or more, and 12 or less carbon atoms Is a self-emulsifying composition characterized by containing 0.05 part by mass or more.

  In another aspect of the present invention, 10% by mass or more of ubidecarenone in the composition, and 0.2 parts by mass or more of menthol and 0.6 parts by mass or more of propylene glycol fatty acid ester with respect to 1 part by mass of ubidecalenone. A self-emulsifying composition comprising 0.05 part by mass or more of a hydrophilic surfactant having an HLB of 10 or more and 0.05 part by mass or more of a monoglyceride of a fatty acid having 12 or less carbon atoms. is there.

  According to the present invention, it is possible to provide a self-emulsifying composition which can be prepared by a simple method without requiring a special apparatus such as a spray drying apparatus and contains ubidecarenone in a high concentration.

  “Ubidecarenone” is a kind of coenzyme synthesized in vivo and is also called coenzyme Q10, vitamin Q and ubiquinone. It is hardly soluble in water and has a melting point of about 48 ° C.

  The content (formulation) of ubidecarenone is 10% by mass or more in the composition. From the significance of the present invention that a high-concentration self-emulsified product of ubidecarenone is formed, the content (formulation) of ubidecarenone is preferably 15% by mass or more in the composition. Further, from the viewpoint of maintaining a stable emulsified state of the self-emulsifying composition of the present invention, the upper limit of the content (formulation) of ubidecarenone is 65% by mass in the composition. It is difficult to self-emulsify ubidecarenone in excess of 65% by mass in the composition because the amount of menthol or a saturated terpenoid having a melting point of 37 ° C. or higher is limited.

  “Menthol” includes all of L-form, D-form and DL-form, all of which are extremely insoluble in water. The melting point of the DL form is about 27 to 28 ° C., and the melting point of the L form is about 42 to 43 ° C.

  The content (formulation) of menthol is 0.2 parts by mass or more with respect to 1 part by mass of ubidecarenone, and considering the content of ubidecarenone in the composition, 0.5 to 1.0 parts by mass is preferable. . Moreover, since the digestive tract exercise | movement will be inhibited or irritation | stimulation becomes strong when there are too many compounding quantities of menthol, the upper limit of the compounding quantity is 1.5 mass parts.

  The “terpenoid” is also called a terpene, and in the present invention, a saturated terpenoid having a melting point of 37 ° C. or higher is applicable. However, menthol is not included. Specifically, camphor (including all of D-form, L-form and DL-form, melting point of about 175 to 180 ° C.), borneol (including all of D-form, L-form and DL-form, melting point of about 205 to 210 ° C.) Etc. These may be used alone or in combination of two or more.

  The content (mixture) of saturated terpenoids (excluding menthol) having a melting point of 37 ° C. or higher is 0.1 parts by mass or more with respect to 1 part by mass of ubidecarenone, and the balance between the content of ubidecalenone and solubility. Is considered to be 0.5 to 1.0 part by mass, and the upper limit is 1.5 parts by mass.

  The “propylene glycol fatty acid ester” is preferably a difatty acid ester from the viewpoint of the solubility of ubidecarenone, and a saturated fatty acid from the viewpoint of stability and odor. The carbon chain length is preferably 8-10. If the carbon chain is long, the melting point becomes high and the solubility of ubidecalenone is unfavorable, and if the carbon chain is short, the boiling point becomes low and handling becomes difficult. Specific examples include propylene glycol dicaprylate and propylene glycol dicaprate. Propylene glycol fatty acid esters may be used alone or in combination of several.

  The content (formulation) of propylene glycol fatty acid ester is 0.6 parts by mass or more with respect to 1 part by mass of ubidecarenone, and considering the balance between the content of ubidecalenone and solubility, 0.7 to 1.0 parts by mass The upper limit is 1.5 parts by mass.

  The “hydrophilic surfactant having an HLB of 10 or more” is preferably one having a low melting point and good compatibility with ubidecalenone and terpenoid from the viewpoint of emulsification. For example, it has a branched molecular structure or has a hydrophobic part. Those having an unsaturated bond are preferred. Specific examples of the hydrophilic surfactant having an HLB of 10 or more include polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60, and polysorbate 80. These may be used alone or in combination of two or more.

  The content (formulation) of the hydrophilic surfactant having an HLB of 10 or more is 0.05 parts by weight or more with respect to 1 part by weight of ubidecarenone, and considering the balance between the content of ubidecarenone and the emulsifiability, 3.0 parts by mass is preferred.

  “Monoglycerides of fatty acids having 12 or less carbon atoms” are preferably those having a low melting point and good compatibility with ubidecarenone and terpenoids from the viewpoint of emulsification. Specific examples include caprylic acid monoglyceride, capric acid monoglyceride and lauric acid monoglyceride. These may be used alone or in combination of two or more.

  The content (formulation) amount is 0.05 parts by weight or more with respect to 1 part by weight of ubidecarenone, and considering the balance between the content of ubidecarenone and emulsification, 0.1 to 3.0 parts by weight is preferable.

  The self-emulsifying composition of the present invention includes, for example, a predetermined amount of ubidecalenone, menthol, camphor as a saturated terpenoid having a melting point of 37 ° C. or higher, polyoxyethylene hydrogenated castor oil 60 as a hydrophilic surfactant having an HLB of 10 or higher, carbon atoms Capillic acid monoglyceride is mixed as a monoglyceride of a fatty acid having a number of 12 or less, heated to 50 to 60 ° C. and melted, and then cooled to room temperature (about 25 ° C.).

  Further, the ubidecalenone self-emulsifying composition of the present invention can be blended with other known additives as long as the effects of the present invention are not impaired. Examples of such additives include stabilizers such as preservatives and antioxidants, and flavoring agents such as sugars and fragrances.

  Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples and Test Examples.

Example 1
After mixing 0.4 g of ubidecarenone, 0.2 g of DL-menthol, 0.2 g of DL-camphor, 0.15 g of polyoxyethylene hydrogenated castor oil 60 (Nikkor HCO-60; Nikko Chemicals) and 0.05 g of caprylic acid monoglyceride, 50 It melt | dissolved by heating to -60 degreeC and obtained the self-emulsion.

Example 2
Ubidecarenone 0.4 g, DL-menthol 0.2 g, DL-camphor 0.2 g, 0.1 g of polyoxyethylene hydrogenated castor oil 60 and caprylic acid monoglyceride 0.1 g were mixed and heated to 50-60 ° C. It melt | dissolved and the self-emulsion was obtained.

Example 3
Ubidecarenone 0.4 g, DL-menthol 0.2 g, DL-camphor 0.2 g, 0.05 g of polyoxyethylene hydrogenated castor oil 60 and caprylic acid monoglyceride 0.15 g were mixed and heated to 50-60 ° C. It melt | dissolved and the self-emulsion was obtained.

Example 4
Ubidecarenone 0.39g, DL-menthol 0.18g, DL-camphor 0.18g, 0.15g of polyoxyethylene hydrogenated castor oil 60, and caprylic acid monoglyceride 0.1g were mixed and heated to 50-60 ° C. It melt | dissolved and the self-emulsion was obtained.

Example 5
Ubidecarenone 0.39 g, DL-menthol 0.18 g, DL-camphor 0.18 g, 0.1 g of polyoxyethylene hydrogenated castor oil 60, and caprylic acid monoglyceride 0.15 g were mixed and heated to 50-60 ° C. It melt | dissolved and the self-emulsion was obtained.

Example 6
Ubidecarenone 0.39 g, DL-menthol 0.18 g, DL-camphor 0.18 g, 0.05 g of polyoxyethylene hydrogenated castor oil 60, and caprylic acid monoglyceride 0.2 g were mixed and heated to 50-60 ° C. It melt | dissolved and the self-emulsion was obtained.

Example 7
Ubidecalenone 0.35 g, DL-menthol 0.18 g, DL-camphor 0.18 g, 0.1 g of polyoxyethylene hydrogenated castor oil 60, and caprylic acid monoglyceride 0.14 g were mixed and heated to 50-60 ° C. It melt | dissolved and the self-emulsion was obtained.

Example 8
Ubidecalenone 0.35 g, DL-menthol 0.18 g, DL-camphor 0.18 g, 0.15 g of polyoxyethylene hydrogenated castor oil 60, and caprylic acid monoglyceride 0.14 g were mixed and heated to 50-60 ° C. It melt | dissolved and the self-emulsion was obtained.

Example 9
Ubidecarenone 0.39 g, L-menthol 0.18 g, D-camphor 0.18 g, 0.1 g of polyoxyethylene hydrogenated castor oil 60 and 0.15 g of caprylic acid monoglyceride were mixed and heated to 50-60 ° C. It melt | dissolved and the self-emulsion was obtained.

Example 10
Ubidecarenone 0.3 g, L-menthol 0.18 g, dicaprylic acid propylene glycol 0.26 g, polyoxyethylene hydrogenated castor oil 60 0.14 g and caprylic acid monoglyceride 0.1 g were mixed and heated to 50-60 ° C. And dissolved to obtain a self-emulsified product.

Example 11
Ubidecarenone 0.4 g, DL-menthol 0.2 g, DL-camphor 0.2 g, polyoxyethylene hydrogenated castor oil 60 0.15 g and capric acid monoglyceride 0.05 g were mixed and heated to 50-60 ° C. It melt | dissolved and the self-emulsion was obtained.

Example 12
Ubidecarenone 0.4 g, DL-menthol 0.2 g, DL-camphor 0.2 g, 0.1 g of polyoxyethylene hydrogenated castor oil 60 and 0.15 g of capric acid monoglyceride were mixed and heated to 50-60 ° C. It melt | dissolved and the self-emulsion was obtained.

Example 13
Ubidecalenone 0.42 g, DL-menthol 0.21 g, DL-camphor 0.21 g, 0.11 g of polyoxyethylene hydrogenated castor oil 60 and 0.05 g of capric acid monoglyceride were mixed and heated to 50-60 ° C. It melt | dissolved and the self-emulsion was obtained.

Example 14
Ubidecarenone 0.4 g, L-menthol 0.2 g, D-camphor 0.2 g, 0.15 g polyoxyethylene hydrogenated castor oil 60 and 0.05 g capric acid monoglyceride were mixed and heated to 50-60 ° C. It melt | dissolved and the self-emulsion was obtained.

Example 15
Ubidecalenone 0.42 g, DL-menthol 0.21 g, DL-camphor 0.21 g, 0.11 g of polyoxyethylene hydrogenated castor oil 60 and 0.05 g of lauric acid monoglyceride were mixed and heated to 50-60 ° C. It melt | dissolved and the self-emulsion was obtained.

Example 16
Ubidecarenone 0.35g, DL-menthol 0.175g, DL-camphor 0.175g, polysorbate 80 0.25g, caprylic acid monoglyceride 0.05g were mixed and heated to 50-60 ° C to dissolve and self emulsify Got the body.

Example 17
Ubidecalenone 0.35 g, DL-menthol 0.175 g, DL-camphor 0.175 g, polysorbate 80 0.2 g, caprylic acid monoglyceride 0.1 g were mixed and heated to 50-60 ° C. to dissolve and self-emulsified Got the body.

Example 18
Ubidecalenone 0.17g, DL-menthol 0.165g, DL-camphor 0.165g, polysorbate 80 0.25g, caprylic acid monoglyceride 0.25g was mixed and heated to 50-60 ° C to dissolve and self emulsify Got the body.

Example 19
Ubidecalenone 0.167g, DL-menthol 0.167g, DL-camphor 0.167g, polysorbate 80 0.299g, caprylic monoglyceride 0.2g was mixed and heated to 50-60 ° C to dissolve and self-emulsification Got the body.

Example 20
Ubidecalenone 0.17g, DL-menthol 0.165g, DL-camphor 0.165g, polysorbate 80 0.4g, caprylic acid monoglyceride 0.1g were mixed and heated to 50-60 ° C to dissolve and self-emulsification Got the body.

Example 21
Ubidecarenone 0.33g, DL-menthol 0.16g, DL-camphor 0.16g, polysorbate 80 0.3g, capric acid monoglyceride 0.05g were mixed and heated to 50-60 ° C to dissolve and self-emulsification Got the body.

Example 22
Ubidecalenone 0.38g, DL-menthol 0.19g, DL-camphor 0.19g, polysorbate 80 0.2g, capric acid monoglyceride 0.04g was mixed and heated to 50-60 ° C to dissolve and self-emulsification Got the body.

Example 23
Ubidecarenone 0.4 g, DL-menthol 0.2 g, DL-camphor 0.2 g, polysorbate 80 0.15 g, capric acid monoglyceride 0.05 g were mixed and heated to 50-60 ° C to dissolve and self-emulsification Got the body.

Example 24
Ubidecarenone 0.39 g, L-menthol 0.18 g, D-camphor 0.18 g, polysorbate 80 0.2 g, lauric acid monoglyceride 0.1 g are mixed and heated to 50-60 ° C. to dissolve and self emulsify Got the body.

Example 25
Ubidecalenone 0.17g, L-menthol 0.165g, L-camphor 0.165g, polysorbate 80 0.3g, caprylic acid monoglyceride 0.2g was mixed and heated to 50-60 ° C to dissolve and self-emulsification Got the body.

Comparative Example 1
After mixing 0.37 g of ubidecarenone, 0.38 g of medium-chain fatty acid triglyceride, 0.1 g of polyoxyethylene hydrogenated castor oil 60, and 0.15 g of caprylic acid monoglyceride, the mixture was heated to 50 to 60 ° C. and dissolved to obtain a composition. Obtained.

Comparative Example 2
After mixing 0.4 g of ubidecarenone, 0.2 g of DL-menthol, 0.2 g of DL-camphor and 0.2 g of polyoxyethylene hydrogenated castor oil 60, the mixture was heated to 50 to 60 ° C. and dissolved to obtain a composition. It was.

Comparative Example 3 (Ubidecarenone crystal powder suspension)
0.05 g of ubidecarenone crystal powder was added to 100 mL of a 0.5% by weight aqueous solution of sodium carboxycellulose, irradiated with ultrasonic waves for 1 minute, and then shaken for 10 minutes to obtain a bidecarenone crystal powder suspension.

Test example 1
About 0.3 g of the self-emulsified body obtained in Examples 1 to 25 and the composition obtained in Comparative Examples 1 and 2 were put into purified water (900 mL, 37 ° C.), and a JP dissolution test apparatus (paddle rotation speed 50 rpm). The mixture was gently stirred from 2 minutes to a maximum of 30 minutes, and the emulsified state was visually observed.

  As a result, in the emulsions of Examples 1 to 17 and Examples 21 to 25, the emulsified particles quickly spread in water to form a fine emulsion. Moreover, in the emulsions of Examples 18 to 20, a transparent solution was formed. On the other hand, the composition of Comparative Example 1 was partially emulsified, but most remained on the water surface. Furthermore, the composition of Comparative Example 2 was hardly emulsified and remained in a lump on the water surface.

  From the above, Comparative Example 1 using a medium-chain fatty acid triglyceride which is a general emulsion base and caprylic acid monoglyceride which is a mono fatty acid glyceryl having at least one hydroxyl group in the molecule and having 12 or less carbon atoms In Comparative Example 2 except that, the ubidecalenone self-emulsifier according to the present invention of Examples 1 to 25 was emulsified into fine particles under moderate stirring.

Test example 2
Using SD male rats (11 weeks old, N = 6), the emulsion prepared by emulsifying the bidecarenone crystal powder suspension prepared in Comparative Example 3 and the self-emulsified product prepared in Example 19 was prepared under non-fasting conditions. And 5 mg / kg orally as ubidecarenone. One hour after administration, anesthesia was inhaled with ether, and heparin was collected from the jugular vein. The obtained blood was centrifuged at 4 ° C. to obtain plasma, which was stored at −80 ° C. until measurement. The concentration of ubidecalenone in plasma was determined by Kevin D. et al. Measurement was performed according to the method of Williams et al. (J. Agric. Food. Chem., 1991, 47, 3756-3762) (however, the mobile phase was methanol: isopropanol (6: 4)). The results are shown in FIG.

  From FIG. 1, the plasma concentration of ubidecarenone 1 hour after oral administration was 83.3 ± 28.7 ng / ml (mean ± standard error) in Comparative Example 3 (suspension). The emulsion of 19 was 489.5 ± 91.9 ng / ml, and the emulsion of Example 19 showed significantly higher ubidecalenone absorbability than Comparative Example 3.

  The self-emulsifying composition of the present invention contains ubidecarenone in a high concentration and can be made into a solution even at a temperature around body temperature (about 37 ° C.). Therefore, since it is emulsified into fine particles in the body, absorption of ubidecalenone in the gastrointestinal tract is good, and since it contains ubidecalenone in a high concentration, it is expected to be provided as a small-sized and easy-to-take preparation (liquid capsule etc.). The

4 is a graph showing the concentration (ng / ml) of ubidecarenone in plasma one hour after administration of ubidecarenone in Test Example 2.

Claims (1)

10 parts by mass or more of ubidecarenone in the composition, and 0.2 parts by mass or more of menthol, and 0.6 parts by mass of at least one of propylene glycol dicaprylate and propylene glycol dicaprate relative to 1 part by mass of ubidecalenone above, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60 and polysorbate 80 at least one of 0.05 parts by mass or more, and, caprylic acid monoglyceride, at least one of capric acid monoglyceride and lauric acid monoglyceride Self-emulsifying composition characterized by containing 0.05 mass part or more.

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