KR100859781B1 - Ubidecarenone-containing pharmaceutical composition - Google Patents

Abstract

A pharmaceutical composition is provided to increase bio-availability of ubidecarenone by formulating the ubidecarenone into a microemulsion pre-concentrate through dissolving the ubidecarenone in a carrier including a conjugated linolenic acid, a non-ionic surfactant and a co-surfactant. A ubidecarenone-containing pharmaceutical comprises a carrier including: (a) a conjugated linolenic acid; (b) at least one non-ionic surfactant selected from the group consisting of polyoxyethylene sorbitan fatty acid ester, caprylocaproyl macroglyceride, and polyoxyethylene glycolated natural or hydrogenated castor oil; and (c) at least one co-surfactant selected from the group consisting of sorbitan fatty acid ester, propylene glycol laurate, hydroxylated lecithin, propylene carbonate, polyethylene glycol, triglyceride of caprylic acid and capric acid, ethanol, transcutol, glycofurol, dimethyl isosorbide, and triacetin, and a therapeutically effective amount of ubidecarenone. Regarding a total weight of the carrier, 25-30 wt.% of the conjugated linolenic acid and 35-65 wt.% of the non-ionic surfactant are contained.

Description

Ubidecarenone-containing pharmaceutical composition

The present invention relates to a ubidecarenone-containing pharmaceutical composition.

Ubidecarenone is called coenzyme Q10, or CoQ10, and has the structure of Formula 1.

In addition, ubidecarenone may be divided into ubiquinol, semiquinone radical, ubiquinone, and the like according to tautomerization or radical form, as represented by the following structural formula. And the term "ubide carenone" includes all of the above forms.

Ubidecarenone is a vitamin-like substance that is also synthesized in the body. Ubidecarenone has two biphasic properties, due to the hydrophilic benzoquinone ring and lipid-compatible poly-isoprenoid side-chain. Ubidecarenone contributes to the transport of electrons and the transport of protons in mitochondria and bacteria, while also acting as an antioxidant as an oxidized form of ubiquinol. Uvide carenone acts as an antioxidant that regulates the fluidity of cell membranes, contributes to the circulation of vitamins C and E, and protects the phospholipids of cell membranes from peroxidation. Ubiquinone and ubiquinol concentrations have been reported to be low in several diseases, particularly neurodegenerative diseases, tumors, cardiovascular diseases, diabetes and aging, and Alzheimer's disease. Imply an important role.

On the other hand, since ubide carenone has poor water solubility property, the body absorption and skin absorption are very low. In an attempt to solve this problem, Japanese Patent Application Laid-Open No. 54-92616 discloses improving absorbency by dissolving ubidecarenone in a liquid phase at room temperature by dissolving ubidecarenone in liquid edible natural fat or triglycerides of medium-chain fatty acids. However, since the solubility of ubide carenone in the solvent is still low, when a solvent in which ubide carenone is dissolved is encapsulated in a capsule having a normal size, a plurality of capsules may be used to ingest a required amount of ubide carenone. You have to take it, so it is inconvenient. Japanese Patent Application Laid-Open No. 64-10494 discloses the use of a hydrophilic surfactant such as bile salt or HCO-60 in order to increase the solubility. However, the hydrophilic surfactant may cause disorders in the gastric or gastrointestinal mucosa. have.

In addition, Korean Patent Registration No. 553,160 discloses a nano-sized phospholipid liposome composition and a method for preparing the same, and International Patent Publication No. WO 2002/90304 (Korean Patent Registration Nos. 617,928 and 617,929) is Ubide-Carenone. In order to keep it stable against oxidation, ubidecarenone was emulsified or solubilized with a surfactant, and a solution having a concentration of the surfactant of 0.01% by weight or more was disclosed.

Further, Japanese Patent Laid-Open No. 2004-238373 discloses a composition in which ubidecarenone is dissolved in free fatty acid such as conjugated linoleic acid and a capsule containing the same. However, when ubide carenone is dissolved in conjugated linoleic acid, the double bonds of conjugated linoleic acid in the resulting solution are oxidized to epoxidize, thereby lowering stability and thus lowering solubility of ubide carenone. In addition, the drug delivery system consisting of only ubide carenone and conjugated linoleic acid is affected by drug absorption by interaction with bile acids secreted in vivo. Therefore, the amount of bile acid secreted in the living body is greatly changed according to food intake, drug delivery system consisting of only ubide carenone and conjugated linoleic acid may significantly change the drug absorption behavior by food. In particular, drug delivery systems consisting only of ubidecarenone and conjugated linoleic acid still do not show satisfactory levels of bioavailability.

The present inventors conducted various studies to develop a drug delivery system that can effectively increase the bioavailability of ubide carenone when administered orally and in vivo. As a result, when ubidecarenone is dissolved in a carrier containing a conjugated linoleic acid, a nonionic surfactant, and a co-surfactant and formulated as a microemulsion preconcentrate, the bioavailability can be increased, and the microemulsion stable in the body It was found that

Accordingly, it is an object of the present invention to provide a pharmaceutical composition comprising ubidecarenone and a carrier comprising an oil, a nonionic surfactant, and a co-surfactant.

In addition, an object of the present invention is to provide a method for producing the pharmaceutical composition.

According to one aspect of the invention, there is provided a pharmaceutical composition comprising: (a) conjugated linoleic acid; (b) a nonionic surfactant selected from the group consisting of polyoxyethylene sorbitan fatty acid esters, caprylocaproyl macroglycerides and polyoxyethylene glycolated natural or hydrogenated castor oils; And (c) sorbitan fatty acid esters, propylene glycol laurate, hydroxylated lecithin, propylene carbonate, polyethylene glycol, triglycerides of caprylic acid and capric acid, ethanol, transcutol, glycofurol, dimethylisosorbide And a ubidecarenone-containing pharmaceutical composition comprising a therapeutically effective amount of ubide carenone and a carrier comprising at least one co-surfactant selected from the group consisting of: and triacetin.

Hereinafter, the present invention will be described in detail.

The ubidecarenone-containing pharmaceutical composition of the present invention is prepared by dissolving the soluble drug ubidecarenone in a carrier containing a conjugated linoleic acid, a nonionic surfactant, and a co-surfactant, and formulating it as a microemulsion preconcentrate. The bioavailability of ubide carrenone can be increased. Therefore, not only the content of the active ingredient per unit formulation can be reduced, but also the content of the additive used for solubilization of the active ingredient can be reduced, so that it is easy to formulate with a conventional soft capsule. In particular, the pharmaceutical composition according to the present invention can form a microemulsion in an aqueous medium, as well as to ensure physicochemical stability by configuring the carrier system with a specific component and content. In addition, oral administration can maintain uniform in vivo behavior.

Ubidecarenone (or coenzyme Q10, CoQ10, etc.) used as an active ingredient in the pharmaceutical composition of the present invention includes all forms such as ubiquinol, semiquinone radical, ubiquinone and the like. In addition, the "therapeutically effective amount" of the ubide carenone is the amount required for treatment of the desired therapeutic effect, for example, degenerative neurological disease, tumor, cardiovascular disease, diabetes and aging, Alzheimer's disease, etc. As can be readily determined by one skilled in the art from known documents for each purpose. Pharmaceutical compositions of the invention formulated in unit dosage form may contain, but are not limited to, ubidecarenone, for example in an amount of 20 mg or 30 mg per formulation.

Conjugated linoleic acid contained as an oil in the pharmaceutical composition of the present invention is a fatty acid having two C18 double bonds like linoleic acid, but the position of the double bond with linoleic acid and the cis type (c), trans form ( The positional relationship of t) is different and is a mixture of the regioisomers and geometric isomers of linoleic acid. To date, (9c, 11t-C _{18: 2} ), (8t, 10c-C _{18 : 2} ), (9t, 11c-C _{18 : 2} ), (11c, 13t-C _{18 : 2} ), (10t, 12c-C _{18 : 2} ), (8c, 10c-C _{18 : 2} ), (9c, 11c-C _{18 : 2} ), (10c, 12c-C _{18 : 2} ), (11c, 13c-C _{18 : 2} ), (11t, 13t-C _{18: 2} ), (10t, 12t-C _{18 : 2} ), (9t, 11t-C _{18 : 2} ), (8t, 10t-C _{18 : 2} ), (7t, 9c -C _{18 : 2} ) and the like are known, but the main isomers are (9c, 11t-C _{18 : 2} ), (10t, 12c-C _{18 : 2} ), and the like. The content of the conjugated linoleic acid is preferably 25 to 30% by weight based on the total weight of the carrier.

The nonionic surfactant contained as a carrier in the pharmaceutical composition of the present invention is a polyoxyethylene sorbitan fatty acid ester (for example, Tween 80 ^TM , Tween 20 ^TM , etc.), caprylocaproyl macrogolglycerides (e. g., La bra Sol ^TM (Labrasol ^TM), etc.), and polyoxyethylene glycol screen natural or hydrogenated castor oil and one or more selected from the group consisting of (e. g., Crescent mode pore ^TM (Cremophor ^TM), etc.) Can be. Preferably the nonionic surfactant may be a mixture of polyoxyethylene sorbitan fatty acid ester and polyoxyethylene glycolated natural or hydrogenated castor oil, wherein the polyoxyethylene sorbitan fatty acid ester and polyoxyethylene glycolated natural or The weight ratio of the hydrogenated castor oil may be 3-5: 1, more preferably 4: 1.

The content of the nonionic surfactant contained in the pharmaceutical composition of the present invention is preferably 35 to 65% by weight based on the total weight of the carrier.

The ball to be contained as a carrier in pharmaceutical compositions of the present invention the surfactant is sorbitan (for example, Span 80 ^TM (Span 80 ^TM), etc.) tan fatty acid ester, propylene glycol laurate (propylene glycol laurate) (e.g., lauroyl glycol ^TM (Lauroglycol ^TM), etc.), hydroxylated lecithin (hydroxylated lecithin) (e.g. Lecinol SH50 ^TM (Lecinol SH50 ^TM), etc.), propylene carbonate, polyethylene glycols (e.g., polyethylene glycol 200 and the like), and South triglycerides of ruffles acid and capric acid (triglyceride of caprylic acid and capric acid) (for example, La bra Park lipoic field 1349 ^TM (Labrafac lipophil 1349 ^TM) and the like), ethanol, trans kyutol (transcutol ), Glycofurol dimethylisosorbide, and triacetin. Among them, propylene carbonate or triglyceride of caprylic acid and capric acid can be preferably used. In particular, propylene carbonate is a non-volatile non-hydrophilic component having a boiling point of about 242 ° C., and because it is a non-alcoholic component containing no hydroxy group, the propylene carbonate is less hygroscopic, and thus propylene carbonate can be more preferably used.

The content of the co-surfactant contained in the pharmaceutical composition of the present invention is preferably 10 to 40% by weight based on the total weight of the carrier.

According to one embodiment of the present invention, the pharmaceutical composition of the present invention comprises (a) conjugated linoleic acid; (b) a mixture of 1 part by weight of polyoxyethylene glycolated natural or hydrogenated castor oil and 4 parts by weight of polyoxyethylene sorbitan fatty acid ester; And (c) a carrier comprising propylene carbonate and a therapeutically effective amount of ubidecarenone.

According to another embodiment of the present invention, the pharmaceutical composition of the present invention comprises (a) 25 to 30% by weight of conjugated linoleic acid; (b) 35 to 65% by weight of a mixture of 1 part by weight of polyoxyethylene glycolated natural or hydrogenated castor oil and 4 parts by weight of polyoxyethylene sorbitan fatty acid ester; And (c) a carrier comprising 10-40% by weight of propylene carbonate and a therapeutically effective amount of ubidecarenone.

According to another embodiment of the present invention, the pharmaceutical composition of the present invention comprises (a) 30% by weight of conjugated linoleic acid; (b) 30% by weight of a mixture of 1 part by weight of polyoxyethylene glycolated natural or hydrogenated castor oil and 4 parts by weight of polyoxyethylene sorbitan fatty acid ester; And (c) a carrier comprising 40% by weight propylene carbonate and a therapeutically effective amount of ubidecarenone.

The pharmaceutical composition of the present invention is a preparation in the form of a microemulsion preconcentrate as described above, and when dispersed in an aqueous medium, having a particle size of about 100 nm to 1000 nm forms a stable microemulsion in the body. It is preferable in that.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, these examples are intended to illustrate the invention and should not be construed as limiting the invention.

Example 1-19

To prepare a microemulsion preconcentrate with the components and contents of Table 1. That is, a 4: 1 mixture of conjugated linoleic acid, Tween 20 and Cremophor ELP, propylene carbonate and ubidecarenone were added to a 20 ml vial, then warmed to about 60 ° C. and shaken. To prepare a microemulsion preconcentrate.

After leaving the obtained microemulsion preconcentrate at room temperature for about 12 hours, about 200 ul was added to 300 ml of purified water warmed to about 37 ℃ and stirred for 5 minutes, and then observed the formation of emulsion visually. . The criteria for emulsion formation were determined to form an emulsion when the product obtained was a translucent homogeneous liquid, and it was determined that an emulsion was not formed when the droplets were not dispersed and agglomerated. When the emulsion was formed, the particle size of the emulsion was measured using a Zeta meter ELS 8000 (Otasuka Electronics Co., Japan). In addition, the microemulsion preconcentration prepared above was allowed to stand at room temperature for 3 days to observe the precipitation of drug (ubide carenone).

Table 1 shows the results of the emulsion formation, the particle size of the emulsion, and the stability (precipitation).

Example Conjugated linoleic acid Tween 20: Cremophor ELP = 4: 1 Propylene carbonate Ubidecharenon Emulsion Formation / Precipitation Particle Size (nm) One 40% (200mg) 60% (300mg) 0% (0mg) 30mg NO 2 40% (200mg) 50% (250mg) 10% (50 mg) 30mg NO 3 40% (200mg) 40% (200mg) 20% (100mg) 30mg NO 4 40% (200mg) 30% (150mg) 30% (150mg) 30mg NO 5 40% (200mg) 20% (100mg) 40% (200mg) 30mg NO 6 40% (200mg) 10% (50 mg) 50% (250mg) 30mg NO 7 30% (150mg) 70% (350mg) 0% (0mg) 30mg NO 8 30% (150mg) 60% (300mg) 10% (50 mg) 30mg YES 622 9 30% (150mg) 50% (250mg) 20% (100mg) 30mg YES 516.5 10 30% (150mg) 40% (200mg) 30% (150mg) 30mg YES 930.7 11 30% (150mg) 30% (150mg) 40% (200mg) 30mg YES 257.2 12 30% (150mg) 20% (100mg) 50% (250mg) 30mg NO 13 25% (125mg) 65% (325 mg) 10% (50 mg) 30mg YES 492 14 25% (125mg) 25% (125mg) 50% (250mg) 30mg Precipitation 532 15 20% (100mg) 80% (400mg) 0% (0mg) 30mg Precipitation 16 20% (100mg) 70% (350mg) 10% (50 mg) 30mg Precipitation 17 20% (100mg) 60% (300mg) 20% (100mg) 30mg Precipitation 18 20% (100mg) 50% (250mg) 30% (150mg) 30mg Precipitation 19 20% (100mg) 40% (200mg) 40% (200mg) 30mg Precipitation

NO: no emulsion formed

YES: emulsion formed

As can be seen in Table 1, when the oil component is 40% or more or 20% or less, no emulsion is formed, or ubidecarenone is precipitated from the formed emulsion. In addition, even when there is no co-surfactant or 50% or more, no emulsion is formed, or ubidecarenone is precipitated from the formed emulsion.

Example 20-39

To prepare a microemulsion pre-concentrate in the same manner as in Example 1-19 with the components and contents of Table 2, and whether the emulsion was formed, the particle size of the emulsion, and the stability (precipitation) was measured.

Example Conjugated linoleic acid Twin 80 Span 80 Ubidecharenon Emulsion Formation / Precipitation Particle Size (nm) 20 40% (200mg) 60% (300mg) 0% (0mg) 30mg NO 21 40% (200mg) 50% (250mg) 10% (50 mg) 30mg NO 22 40% (200mg) 40% (200mg) 20% (100mg) 30mg NO 23 40% (200mg) 30% (150mg) 30% (150mg) 30mg NO 24 40% (200mg) 20% (100mg) 40% (200mg) 30mg NO 25 40% (200mg) 10% (50 mg) 50% (250mg) 30mg NO 26 30% (150mg) 60% (300mg) 10% (50 mg) 30mg YES 366.4 27 30% (150mg) 50% (250mg) 20% (100mg) 30mg YES 429.6 28 30% (150mg) 40% (200mg) 30% (150mg) 30mg YES 1052.1 29 30% (150mg) 30% (150mg) 40% (200mg) 30mg YES 829 30 30% (150mg) 20% (100mg) 50% (250mg) 30mg NO 31 25% (125mg) 65% (325 mg) 10% (50 mg) 30mg YES 396 32 25% (125mg) 55% (275mg) 20% (100mg) 30mg YES 403 33 25% (125mg) 45% (220mg) 30% (150mg) 30mg YES 449 34 25% (125mg) 25% (125mg) 50% (250mg) 30mg NO 35 20% (100mg) 80% (400mg) 0% (0mg) 30mg Precipitation 36 20% (100mg) 70% (350mg) 10% (50 mg) 30mg Precipitation 37 20% (100mg) 60% (300mg) 20% (100mg) 30mg Precipitation 38 20% (100mg) 50% (250mg) 30% (150mg) 30mg Precipitation 39 20% (100mg) 40% (200mg) 40% (200mg) 30mg Precipitation

NO: no emulsion formed

YES: emulsion formed

Example 40-53

The microemulsion preconcentrate was prepared in the same manner as in Example 1-19 using the ingredients and contents shown in Table 3 below, and whether the emulsion was formed, the particle size of the emulsion, and the stability (precipitation) were measured.

Example Conjugated linoleic acid Twin 80 Lauroglycol Ubidecharenon Emulsion Formation / Precipitation Particle Size (nm) 40 40% (200mg) 30% (150mg) 30% (150mg) 30mg NO 41 40% (200mg) 20% (100mg) 40% (200mg) 30mg NO 42 40% (200mg) 10% (50 mg) 50% (250mg) 30mg NO 43 30% (150mg) 60% (300mg) 10% (50 mg) 30mg YES 540 44 30% (150mg) 50% (250mg) 20% (100mg) 30mg YES 544 45 30% (150mg) 20% (100mg) 50% (250mg) 30mg NO 46 25% (125mg) 75% (375mg) 0% (0mg) 30mg Precipitation 405.4 47 25% (125mg) 65% (325 mg) 10% (50 mg) 30mg YES 527.4 48 25% (125mg) 55% (275mg) 20% (100mg) 30mg YES 454.7 49 25% (125mg) 45% (220mg) 30% (150mg) 30mg YES 583.3 50 25% (125mg) 25% (125mg) 50% (250mg) 30mg NO 51 20% (100mg) 80% (400mg) 0% (0mg) 30mg Precipitation 52 20% (100mg) 70% (350mg) 10% (50 mg) 30mg Precipitation 53 20% (100mg) 60% (300mg) 20% (100mg) 30mg Precipitation

NO: no emulsion formed

YES: emulsion formed

Example 54-66

To prepare a microemulsion pre-concentrate in the same manner as in Example 1-19 with the components and contents of Table 4, and whether the emulsion was formed, the particle size of the emulsion, and the stability (precipitation) was measured.

Example Conjugated linoleic acid Labrasol Lauroglycol Ubidecharenon Emulsion Formation / Precipitation Particle Size (nm) 54 40% (200mg) 60% (300mg) 0% (0mg) 30mg NO 55 40% (200mg) 50% (250mg) 10% (50 mg) 30mg NO 56 40% (200mg) 40% (200mg) 20% (100mg) 30mg NO 57 40% (200mg) 30% (150mg) 30% (150mg) 30mg NO 58 40% (200mg) 20% (100mg) 40% (200mg) 30mg NO 59 40% (200mg) 10% (50 mg) 50% (250mg) 30mg NO 60 30% (150mg) 70% (350mg) 0% (0mg) 30mg NO 61 30% (150mg) 20% (100mg) 50% (250mg) 30mg NO 62 25% (125mg) 65% (325 mg) 10% (50 mg) 30mg YES 320.4 63 25% (125mg) 25% (125mg) 50% (250mg) 30mg NO 64 20% (100mg) 80% (400mg) 0% (0mg) 30mg Precipitation 65 20% (100mg) 70% (350mg) 10% (50 mg) 30mg Precipitation 66 20% (100mg) 40% (200mg) 40% (200mg) 30mg NO

NO: no emulsion formed

YES: emulsion formed

Examples 67-80

The microemulsion preconcentrate was prepared in the same manner as in Example 1-19 using the ingredients and contents of Table 5 below, and the emulsion formation, the particle size of the emulsion, and the stability (precipitation) were measured.

Example Conjugated linoleic acid Labrasol Span 80 Ubidecharenon Emulsion Formation / Precipitation Particle Size (nm) 67 40% (200mg) 60% (300mg) 0% (0mg) 30mg NO 68 40% (200mg) 50% (250mg) 10% (50 mg) 30mg NO 69 40% (200mg) 40% (200mg) 20% (100mg) 30mg NO 70 40% (200mg) 30% (150mg) 30% (150mg) 30mg NO 71 40% (200mg) 20% (100mg) 40% (200mg) 30mg NO 72 40% (200mg) 10% (50 mg) 50% (250mg) 30mg NO 73 30% (150mg) 70% (350mg) 0% (0mg) 30mg NO 74 30% (150mg) 20% (100mg) 50% (250mg) 30mg NO 75 25% (125mg) 65% (325 mg) 10% (50 mg) 30mg YES 563 76 25% (125mg) 55% (275mg) 20% (100mg) 30mg YES 590 77 25% (125mg) 45% (220mg) 30% (150mg) 30mg YES 670 78 25% (125mg) 25% (125mg) 50% (250mg) 30mg NO 79 20% (100mg) 50% (250mg) 30% (150mg) 30mg Precipitation 80 20% (100mg) 40% (200mg) 40% (200mg) 30mg NO

NO: no emulsion formed

YES: emulsion formed

Example 81-92

To prepare a microemulsion pre-concentrate in the same manner as in Example 1-19 with the components and contents of Table 6, and whether the emulsion was formed, the particle size of the emulsion, and the stability (precipitation) was measured.

Example Conjugated linoleic acid Twin 80 Hydroxylated lecithin Ubidecharenon Emulsion Formation / Precipitation Particle Size (nm) 81 40% (200mg) 60% (300mg) 0% (0mg) 30mg NO 82 40% (200mg) 50% (250mg) 10% (50 mg) 30mg NO 83 40% (200mg) 40% (200mg) 20% (100mg) 30mg NO 84 40% (200mg) 30% (150mg) 30% (150mg) 30mg NO 85 40% (200mg) 20% (100mg) 40% (200mg) 30mg NO 86 40% (200mg) 10% (50 mg) 50% (250mg) 30mg NO 87 30% (150mg) 70% (350mg) 0% (0mg) 30mg NO 88 30% (150mg) 20% (100mg) 50% (250mg) 30mg NO 89 25% (125mg) 65% (325 mg) 10% (50 mg) 30mg YES 332 90 25% (125mg) 55% (275mg) 20% (100mg) 30mg YES 346.2 91 25% (125mg) 45% (220mg) 30% (150mg) 30mg YES 379.4 92 25% (125mg) 25% (125mg) 50% (250mg) 30mg NO

NO: no emulsion formed

YES: emulsion formed

Example 93-108

To prepare a microemulsion pre-concentrate in the same manner as in Example 1-19 with the components and contents of Table 7, and whether the emulsion was formed, the particle size of the emulsion, and the stability (precipitation) was measured.

Example Conjugated linoleic acid Twin 20 Labrapak Lipofill 1349 Ubidecharenon Emulsion Formation / Precipitation Particle Size (nm) 93 40% (200mg) 60% (300mg) 0% (0mg) 30mg NO 94 40% (200mg) 50% (250mg) 10% (50 mg) 30mg NO 95 40% (200mg) 20% (100mg) 40% (200mg) 30mg NO 96 40% (200mg) 10% (50 mg) 50% (250mg) 30mg NO 97 30% (150mg) 70% (350mg) 0% (0mg) 30mg Precipitation 98 30% (150mg) 60% (300mg) 10% (50 mg) 30mg YES 530.5 99 30% (150mg) 50% (250mg) 20% (100mg) 30mg YES 340.7 100 30% (150mg) 40% (200mg) 30% (150mg) 30mg YES 210.2 101 30% (150mg) 30% (150mg) 40% (200mg) 30mg YES 182.4 102 25% (125mg) 75% (375mg) 0% (0mg) 30mg Precipitation 103 25% (125mg) 25% (125mg) 50% (250mg) 30mg Precipitation 104 20% (100mg) 80% (400mg) 0% (0mg) 30mg Precipitation 105 20% (100mg) 70% (350mg) 10% (50 mg) 30mg Precipitation 106 20% (100mg) 60% (300mg) 20% (100mg) 30mg Precipitation 107 20% (100mg) 50% (250mg) 30% (150mg) 30mg Precipitation 108 20% (100mg) 40% (200mg) 40% (200mg) 30mg Precipitation

NO: no emulsion formed

YES: emulsion formed

Test Example 1 Pharmacokinetic Analysis

20 male rats weighing 300-330 g were divided into 5 groups of 4 rats each. The first group orally administered a commercial product Mega CoQ10 (Country-Life, USA), and the second group had a concentration of 20 w / w% of ubidecarenone in conjugated linoleic acid according to Japanese Patent Publication No. 2004-238373. The solution prepared by dissolution was orally administered, and the third group was orally administered a suspension prepared by suspending ubidecarenone at a concentration of 10% in methyl cellulose, and the fourth group was a microemulsion preconcentration prepared in Example 11. Was orally administered, and the fifth group was orally administered a solution prepared by dissolving ubidecarenone at a concentration of 20 w / w% in soybean oil. Each oral administration was performed at a concentration of 100 mg / kg using a gagage needle and a syringe, and heparinized at 0.25, 0.5, 1, 2, 4, 6, 10 hours after administration. Blood was drawn into the tube. The collected blood samples were centrifuged at 3000 rpm for 10 minutes to separate plasma. 600 ul of 2-propanol was added to 250 ul of separated plasma, followed by sonication for 10 minutes and shaking for 6 minutes, followed by centrifugation at 3000 rpm for 10 minutes. The supernatant obtained by centrifugation was placed in an Eppendorf tube, centrifuged at 13000 rpm for 15 minutes, and the supernatant was taken and analyzed by high performance liquid chromatography (HPLC). HPLC conditions are as follows.

Model: Simazu LC-10AD

Detector: Simazu SPD-10A UV -Vis detector (275 nm)

Column: Xterra C18 Column (5 um, 4.5X150 cm)

Mobile phase: MeOH: n-hexane = 9: 1

Injection volume: 50 ul

Flow rate: 1 ml / min

The pharmacokinetic parameters measured and calculated as above are shown in Table 8 below. The results in Table 8 represent the mean values of each group.

First group 2nd group 3rd group 4th group Fifth group AUC 2956.6 ± 751.8 2790.9 ± 63.5 190.3 ± 27.6 4076.4 ± 265.0 1654.7 ± 548.5 Cmax 539.2 ± 225.0 648.1 ± 41.2 49.7 ± 13.1 991.4 ± 174.0 388 ± 195.2

As can be seen in Table 8, when the composition of the present invention is administered, it can be seen that the AUC and Cmax increased significantly. In particular, the composition of the present invention has a high bioavailability because it exhibits a high AUC value of about 2-3 times as compared to the formulations (groups 2 and 5) dissolved in oils such as conjugated linoleic acid or soybean oil.

The ubidecarenone-containing pharmaceutical composition of the present invention is prepared by dissolving the soluble drug ubidecarenone in a carrier containing a conjugated linoleic acid, a nonionic surfactant, and a co-surfactant, and formulating it as a microemulsion preconcentrate. The bioavailability of ubide carrenone can be increased. Therefore, not only the content of the active ingredient per unit formulation can be reduced, but also the content of the additive used for solubilization of the active ingredient can be reduced, so that it is easy to formulate with a conventional soft capsule. In particular, the pharmaceutical composition according to the present invention can form a microemulsion in an aqueous medium, as well as to ensure physicochemical stability by configuring the carrier system with a specific component and content. In addition, oral administration can maintain uniform in vivo behavior.

Claims (12)

(a) conjugated linoleic acid; (b) a nonionic surfactant selected from the group consisting of polyoxyethylene sorbitan fatty acid esters, caprylocaproyl macroglycerides and polyoxyethylene glycolated natural or hydrogenated castor oils; And (c) sorbitan fatty acid esters, propylene glycol laurate, hydroxylated lecithin, propylene carbonate, polyethylene glycol, triglycerides of caprylic acid and capric acid, ethanol, transcutol, glycofurol, dimethylisosorbide And a carrier comprising at least one co-surfactant selected from the group consisting of triacetin and A ubidecarenone-containing pharmaceutical composition comprising a therapeutically effective amount of ubidecarenone. The pharmaceutical composition according to claim 1, wherein the content of the conjugated linoleic acid is 25 to 30% by weight based on the total weight of the carrier. The pharmaceutical composition according to claim 1, wherein the content of the nonionic surfactant is 35 to 65% by weight based on the total weight of the carrier. 4. A pharmaceutical composition according to claim 1 or 3, wherein the nonionic surfactant is a mixture of polyoxyethylene sorbitan fatty acid ester and polyoxyethylene glycolated natural or hydrogenated castor oil. The pharmaceutical composition according to claim 4, wherein the weight ratio of the polyoxyethylene sorbitan fatty acid ester and polyoxyethylene glycolated natural or hydrogenated castor oil is 3 to 5: 1. 6. The pharmaceutical composition according to claim 5, wherein the weight ratio of polyoxyethylene sorbitan fatty acid ester and polyoxyethylene glycolated natural or hydrogenated castor oil is 4: 1. The pharmaceutical composition according to claim 1, wherein the content of the co-surfactant is 10 to 40% by weight based on the total weight of the carrier. 8. A pharmaceutical composition according to claim 1 or 7, wherein said co-surfactant is propylene carbonate or triglyceride of caprylic acid and capric acid. The compound of claim 1, further comprising: (a) conjugated linoleic acid; (b) a mixture of 1 part by weight of polyoxyethylene glycolated natural or hydrogenated castor oil and 4 parts by weight of polyoxyethylene sorbitan fatty acid ester; And (c) a carrier comprising propylene carbonate and A pharmaceutical composition comprising a therapeutically effective amount of ubidecarenone. The method of claim 9, wherein the total weight of the carrier comprises: (a) from 25 to 30% by weight of conjugated linoleic acid; (b) 35 to 65% by weight of a mixture of 1 part by weight of polyoxyethylene glycolated natural or hydrogenated castor oil and 4 parts by weight of polyoxyethylene sorbitan fatty acid ester; And (c) 10 to 40% by weight of propylene carbonate and A pharmaceutical composition comprising a therapeutically effective amount of ubidecarenone. 10. The method of claim 9, wherein the total weight of the carrier comprises: (a) 30% by weight of conjugated linoleic acid; (b) 30% by weight of a mixture of 1 part by weight of polyoxyethylene glycolated natural or hydrogenated castor oil and 4 parts by weight of polyoxyethylene sorbitan fatty acid ester; And (c) 40% by weight of propylene carbonate and A pharmaceutical composition comprising a therapeutically effective amount of ubidecarenone. The pharmaceutical composition according to any one of claims 1 to 9, which forms a microemulsion having a particle size of 100 nm to 1000 nm when dispersed in an aqueous medium.