KR100943652B1 - Composition comprising coenzyme Q10 with enhanced bioavailability - Google Patents

Abstract

The present invention provides a method for improving the bioavailability of poorly soluble materials, particularly coenzyme Q10. In another aspect, the present invention provides a composition with improved bioavailability of coenzyme Q10 and a formulation containing the same as an active ingredient. The composition of the present invention is characterized in that it comprises coenzyme Q10, conjugated linoleic acid and vitamin E.

Coenzyme Q10, conjugated linoleic acid, vitamin E, bioavailability

Description

Composition comprising coenzyme Q10 with enhanced bioavailability}

The present invention relates to a method for improving the bioavailability of poorly soluble materials. More specifically, it relates to methods of improving the bioavailability of coenzyme Q10 and compositions and formulations prepared thereby.

Coenzyme Q10, also called CoQ10, Ubiquinone (UQ), is a vitamin-like substance of benzoquinones having the formula 2,3-dimethoxy-5-methyl-6-decaprenyl-1,4 benzoquinone . Coenzyme Q10 is found in endoplasmic reticulum, peroxisomes, lysosomes, and mitochondrial linings in cells. Electron transport systems of mitochondrial membranes include complex I, complex II, complex III, complex IV and two molecules, coenzyme Q10 and cytochrome c.

Coenzyme Q10 plays an important role in the production of ATP-type energy in the body by contributing to the transport of electrons and proton transport by delivering reducing equivalents to receptors such as coenzyme Q: cytochrome c oxidoreductase in mitochondrial and bacterial respiration. In charge of. Thus, coenzyme Q10 is highest in organs that require large amounts of energy, such as the heart, lungs, liver and the like.

Coenzyme Q10 is known to play a variety of roles in maintaining homeostasis in the body. Coenzyme Q10 also acts as an important antioxidant in mitochondria and lipid membranes in the form of ubiquinol in addition to its role as coenzyme of electron transport system in mitochondria, preventing damage of biofilm by free radicals and minimizing DNA oxidation (Alleva R, Tomasetti M, Battino M, Curatola G, Littarru GP, Folkers K: The roles of coenzyme Q10 and vitamin E on peroxidation of human low density subfractions.Proc Nat Acad Sci. USA, 92: 9388-9391, 1995), function by aging It is known to prevent deterioration and to serve as a supplemental vitamin for the prevention and treatment of many diseases.

Coenzyme Q10 is synthesized from lower ubiquinones such as Q6 or Q8 in younger people, but older and unhealthy people are not able to synthesize it sufficiently, so they need to be administered externally like vitamins. widely used as a dietary supplement). Pharmaceuticals or nutritional supplements containing coenzyme Q10 may be used for mitochondrial related diseases or metabolic diseases (Berbel-Garcia, A .; et al. (July 2004). "Coenzyme Q 10 improves lactic acidosis, stroke like episodes) , and epilepsy in a patient with MELAS ". Clinical Neuropharmacology 27: 187-191). Coenzyme Q10 has also been reported to be effective for migraine (Rozen T, Oshinsky M, Gebeline C, Bradley K, Young W, Shechter A, Silberstein S (2002). "Open label trial of coenzyme Q10 as a migraine preventive". Cephalalgia 22 (2): 137-41). Recent studies have shown that Coenzyme Q increases survival after cardiac arrest (Damian, MS; et al. (July 2004). "Coenzyme Q10 Combined With Mild Hypothermia After Cardiac Arrest" .Circulation, American Heart Foundation 110 : 3011-3016) Maintaining a healthy heart or effective in heart disease, preventing neurodegenerative diseases such as Parkinson's disease (Biol Signals Recept. 2001 May-Aug; 10 (3-4): 224-53) (Rosenfeldt FL, Haas SJ, Krum H, Hadj A, Ng K, Leong JY, Watts GF. Coenzyme Q10 in the treatment of hypertension: a meta-analysis of the clinical trials.J Human Hypertension 21: 297-306, 2007). U.S. Patent No. 5,011,858 also describes that coenzyme Q10 is effective in the treatment of diseases caused by retroviruses such as AIDS. Coenzyme Q10 is also effective in maintaining healthy gums and teeth.

Therefore, the demand for coenzyme Q10 in the body has increased. However, coenzyme Q10 is classified as fat-soluble due to isoprenoid chains, but has a very low solubility in lipid solution as well as aqueous solution, and very low absorption and skin absorption. In general, the fat-soluble compound is in the form of an oil solution, or water and / or oil suspensions or emulsions in the body when the bioabsorption rate is low, low blood concentration and effective concentration takes a long time. The same is true for coenzyme Q10, so it is very important to develop a method to stably increase the solubility of coenzyme Q10 and increase bioavailability.

In an attempt to solve this problem, Japanese Patent Application Laid-Open No. 54-92616 describes a method for improving absorbency by dissolving coenzyme Q10 in liquid edible natural fats or triglycerides of medium-chain fatty acids at room temperature and formulating them in liquid form. Japanese Patent Application Laid-Open No. 64-10494 describes the use of a hydrophilic surfactant such as bile salt or HCO-60 in order to increase solubility. However, since the solubility of coenzyme Q10 in the solvent is still low, the size of the capsule containing the dissolved coenzyme Q10 is large, or when encapsulated in a capsule having a normal size, a plurality of capsules must be taken in order to consume the required amount. This is accompanied by great inconvenience. In addition, when dissolving coenzyme Q10 in a lipid containing a plurality of double bonds, there is a problem that the solubility of the coenzyme Q10 may be lowered because the double bond is oxidized and epoxidized to lower the stability.

Representative coenzyme Q10 formulations currently commercially available include NovaSOL® Q and NovySOL® Nanosome technology from AquaNova German Solubilisatea Technologies (AGT), registered under US Pat. No. 6,774,247, and Biosytes USA, Inc., registered under US Pat. No. 6,056,971. Q-GEL® with BioSolv® technology. NovaSOL® Nanosome technology increases the solubility and bioavailability of poorly soluble materials by forming nano-sized micelles that cover the active ingredient using an excess emulsifier with a HLB value of about 9-18, such as polysorbate 80. . NovaSOL® Q treated with coenzyme Q10 with NovaSOL® has been reported to have four times higher bioavailability than conventional coenzyme Q10 formulations (2006 Frost & Sullivan data). Q-GEL®, a coenzyme Q10 formulation with BioSolv® technology, is formulated with Span®80, Tween® 80, and propylene glycol in combination with coenzyme Q10, compared to coenzyme Q10 dissolved in vegetable oils. Concentrations were reported to be 2.7 times higher on the Q-GEL® side (US Pat. No. 6,056,971). However, these formulations have a problem in that they are harmful to the human body because they use a large amount of emulsifiers or surfactants. Therefore, it is necessary to develop a formulation having improved bioavailability of coenzyme Q10 without using such an emulsifier or a surfactant.

The problem to be solved in the present invention is to develop a pharmaceutical or food delivery system of coenzyme Q10 improved bioavailability than the prior art without using an additive such as an emulsifier or surfactant.

As a result of various studies to solve the above problems, the inventors of the present invention surprisingly do not use other additives such as emulsifiers or surfactants when preparing compositions containing coenzyme Q10, conjugated linoleic acid and vitamin E. The present invention was completed by discovering that the bioabsorption rate of coenzyme Q10 is improved compared to coenzyme Q10 preparations according to the prior art.

Therefore, the present invention provides a composition comprising coenzyme Q10, conjugated linoleic acid and vitamin E, an agent containing the same, and a method of preparing the same, wherein the bioabsorption rate of coenzyme Q10 is improved.

The composition comprising coenzyme Q10, conjugated linoleic acid and vitamin E of the present invention can not only increase the solubility of coenzyme Q10 and maintain it stably, but also have higher bioavailability than the preparations according to the prior art. Therefore, when manufacturing a soft capsule with the composition of the present invention can reduce the size of the capsule or can be filled in one capsule all the amount to be ingested in one capsule manufacturing process, transportation process, taking process will be more economical and convenient Can be. In addition, there is an advantage that can be prepared without containing an emulsifier or a surfactant.

The composition of the present invention can be used in various ways to prepare a pharmaceutical or food preparation comprising coenzyme Q10. The composition of the present invention requires the prevention, treatment and improvement of disease, metabolic disease, migraine, heart disease, Parkinson's disease, hypertension, acquired immune deficiency disease, retrovirus disease, gum disease, etc. You can use it anywhere you need Coenzyme Q10.

Moreover, conjugated linoleic acid contained in the composition of the present invention has a body fat decomposition effect and is widely used as a diet food for obesity management, and vitamin E has an effect of antioxidant, anti-aging, blood circulation improvement, and so on, the composition of the present invention. Provides the effects of conjugated linoleic acid and vitamin E as well as the effects of coenzyme Q10.

The present invention provides a composition comprising coenzyme Q10, conjugated linoleic acid, vitamin E having improved bioabsorption of coenzyme Q10, and a pharmaceutical or nutritional supplement comprising the same, and a method of preparing the same. In addition, the present invention is caused by diseases related to the disorders of the mitochondria of the composition or pharmaceutical or nutritional supplements, metabolic diseases, migraine, heart disease, Parkinson's disease, hypertension, acquired immune deficiency disease, retrovirus disease, excessive free radicals It provides a use for the prevention, treatment or improvement of diseases, gum disease and obesity.

Hereinafter, the present invention will be described in detail.

The present invention surprisingly when preparing a composition comprising coenzyme Q10, conjugated linoleic acid and vitamin E is dissolved in a high concentration of coenzyme Q10 without other additives, the dissolved state is maintained for a long time stable, bioabsorption rate It is based on the finding of improvement.

NovaSOL®, a capsule Mito Q according to the invention (II; hereafter referred to as MITO), a coenzyme Q10 formulation employing AQUA NOVA® technology, filled with a composition comprising coenzyme Q10 powder (I), coenzyme Q10, conjugated linoleic acid, vitamin E Q (III; referred to as NOVA below) and CARNI Q-GEL® (IV; referred to as CARNI), a coenzyme Q10 formulation employing BioSolv® technology, were orally administered to rats and beagle dogs in an amount of 60 mg / kg. Blood concentrations were measured and analyzed by obtaining pharmacokinetic parameters.

In rats, the administration of MITO improved the plasma concentration-curved area (AUC) by 3.8 times and the bioavailability by 4.4 times compared with the administration of coenzyme Q10 powder. Plasma concentrations after oral administration of MITO showed higher plasma concentrations at a faster time than NOVA or CARNI, which were the control preparations. Plasma concentration-curved area (AUC) was about 1.6 times higher than that of the control preparations, and Cmax Were 2 and 3 times, respectively, and bioavailability was about 1.6 times. Since MITO shows higher plasma concentrations at a faster time than other formulations, the relative bioavailability of MITO for other agents is calculated by time zone, up to 8.4 times for coenzyme Q10 powder and up to 2.5 times for NOVA. For CARNI, it is up to four times better.

In beagle dogs, MITO administration was 1.9 times higher in plasma concentration-curved area (AUC) and 1.9 times higher bioavailability compared to administration of coenzyme Q10 powder. Oral administration of MITO was 1.5 and 1.2 times the plasma concentration-curved area (AUC) and 1 and 1.3 times the Cmax, respectively, compared to NOVA and CARNI, which were the control agents. It was improved by about 1.5 times and about 1.2 times. Since MITO shows higher plasma concentrations at a faster time than other formulations, the relative bioavailability of MITO for other agents is calculated by time zone, up to 2.3 times for coenzyme Q10 powder, up to 1.4 times for NOVA, It was up to 1.7 times higher for CARNI.

As described above, the MITO formulation containing the composition of the present invention was evaluated as an excellent formulation having increased bioavailability after oral administration compared to other formulations.

Based on the above experimental results, the present invention provides the following.

[1] An improved bioavailability composition of coenzyme Q10, comprising a therapeutically and nutritionally effective amount of coenzyme Q10, conjugated linoleic acid and vitamin E.

[2] The composition of [1], wherein the weight ratio of coenzyme Q10: conjugated linoleic acid is 0.01: 1 to 1: 1.

[3] The composition of [1], wherein the content of vitamin E is 5 IU to 500 IU.

[4] A soft capsule for oral administration containing the composition of any of [1] to [3] as an active ingredient.

[5] The soft capsule according to [4], wherein the content of coenzyme Q10 contained in the capsule is 5 mg to 2000 mg.

[6] A method for preparing a composition having improved bioavailability of coenzyme Q10, the method comprising heating conjugated linoleic acid and mixing coenzyme Q10 and vitamin E in a solution state.

[7] preparing a soft capsule containing a composition having improved bioavailability of coenzyme Q10, comprising heating the conjugated linoleic acid, preparing coenzyme Q10 and vitamin E in a solution state, and then filling the soft capsule. How to.

[8] The disease of [1], which is related to disorders of mitochondria, metabolic diseases, migraine, heart disease, Parkinson's disease, hypertension, acquired immunodeficiency disease, retrovirus disease, disease caused by excessive free radicals, gum disease And a composition for the prevention, treatment or amelioration of a disease selected from the group consisting of obesity.

Coenzyme Q10 is divided into ubiquinol, semiquinone radical, ubiquinone, and the like according to tautomerization or radical form, and the term "coenzyme Q10" is used herein. In both forms and mixtures thereof.

Conjugated linoleic acid contained in the composition of the present invention, like linoleic acid, is a fatty acid having two double bonds of 18 carbon atoms, but with linoleic acid, the position of the double bond and the cis (c) and trans (t) The positional relationship is different and it 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, and the main isomers are (9c, 11t-C _{18 : 2} ) and (10t, 12c-C _{18 : 2} ). As used herein, the term "conjugated linoleic acid" includes all of the above forms and mixtures thereof.

The term "vitamin E" herein includes all three-dimensional forms of α-, β- and γ-tocopherol and their racemates and physiologically acceptable esters thereof, including synthetic and natural vitamin E.

As used herein, "therapeutically / nutritively effective amount" refers to a desired effect such as degenerative neurological disease, tumor, cardiovascular disease, diabetes and aging, Alzheimer's disease, acquired immunodeficiency syndrome, excessive free radicals. As the amount of a medicament or nutritional supplement necessary for the prevention, treatment or amelioration of a disease or the like, it can be easily determined by those skilled in the art from known documents for each purpose.

The weight ratio of coenzyme Q10 and conjugated lenoleic acid contained in the composition of the present invention may be 0.01: 1 to 1: 1, preferably 0.01: 1 to 0.8: 1. Vitamin E contained in the composition of the present invention may be 5 IU to 500 IU, preferably 10 IU to 100 IU.

Compositions of the present invention formulated in unit dosage form may contain, but are not limited to, coenzyme Q10, for example in an amount of 5 mg to 2 g per formulation.

The composition of the present invention may be prepared in the form of tablets, solutions, suspensions, capsules and the like, with the form of soft capsules being preferred. The soft capsule agent uses components that can form a skin such as various gelatin and various plasticizers, and may be added an additive thereto. As various gelatin, gelatin derived from animals, such as a cow and a pig, can be used, for example. The various gelatin herein includes alkali treated gelatin, acid treated gelatin, chemical formula gelatin and the like, and can be used as various gelatin alone or as a mixture. Alkaline treated gelatin is gelatin obtained by hydrolyzing collagen and acein, which is a raw material of gelatin, with an alkaline substance such as coal liquid, and acid treated gelatin is hydrolyzed by collagen and aceine with acidic substances such as dilute hydrochloric acid and dilute sulfuric acid. Gelatin. Chemical chemical gelatin is generally prepared by reacting a gelatin amino acid with a substance such as succinic acid, phthalic acid, acetic acid, but is not limited thereto. The gelatin used for the chemical formula gelatin may be an alkali treated gelatin or an acid treated gelatin. Examples of the various plasticizers include glycerin, sorbitol, maltose, glucose, maltose, sucrose, xylitol, mannitol, erythritol, and polyethylene glycols (molecular weights 400 to 8000). Examples of the various additives include ethyl paraoxybenzoate, propyl paraoxybenzoate, potassium sorbate white pigment, yellow iron oxide and red iron oxide. As a white pigment, titanium oxide, calcium carbonate, alumina, etc. are mentioned, for example. In order to adjust a hue, you may add further dyes, such as caramel. Caramel used in the present invention is a heat treatment of edible carbohydrates such as glucose, white sugar, invert sugar, starch syrup, starch hydrolyzate and molasses.

Hereinafter, the present invention will be described in detail through examples. However, this is intended to illustrate the present invention and should not be construed as limiting the present invention.

Example

Experimental material

Coenzyme Q10 was purchased from Mitsubish, and conjugated linoleic acid used Tonalin CLA from Cognis. NovaSOL® Q and CARNI Q-GEL® used in pharmacokinetic experiments were purchased commercially. All other reagents were either Express or HPLC.

The experimental animals were purchased from Samtako (Anseong, Gyeonggi-do, Korea) with a weight of 220-250g male Sprague Dawley rats and 10-11 kg male beagle dogs. Beagle dog feed (Samyang maintenance) per animal at a rate of ± 2 ℃, relative humidity 50 ± 10%, ventilation frequency 10-15 times / hr, lighting cycle 12 hr lighting / 12 hr off, illuminance 150-300 Lux Feed (Co., Ltd., Wonju-si, Gangwon-do, Korea) and the purified water filtered using a filter after a period of about 1 week of free ingestion, was used in the experiment.

HPLC  Analysis condition

HPLC analysis conditions of coenzyme Q10 are as follows.

Model: Jasco Co. Model PI-980 pump, LC-Net II control borwin integrater, AS-950-10 autoinjector)

Detector: UV / VIS detector Jasco Co.

Luna C18 Column (4.6 mm x 250 mm x 5um)

Mobile phase: Methanol: Ethanol: 2-propanol = 55: 20: 25 v / v%

Flow rate: 1.0 mL / min

Detection wavelength: 275 nm

Internal Standard: Coenzyme Q9

< Example 1 > Coenzyme Q10 Preparation of the composition containing

Coenzyme Q10-containing compositions were prepared with the ingredients and contents in Table 1 below. Conjugated linoleic acid was warmed to 37 ^° C. with stirring, coenzyme Q10 was slowly added and stirred, followed by addition of vitamin E and stirring until completely clear.

Coenzyme Q10 (mg) Conjugated linoleic acid (mg) Vitamin E (IU) One 100 200 25 2 50 250 25 3 30 220 10 4 60 200 50

< Example 2 > Coenzyme Q10  Production of capsules containing the composition as an active ingredient

The composition prepared in Example 1 was filled in a soft capsule. The soft capsule film used was prepared by the conventional manufacturing method using the manufacturing component of the general soft capsule containing gelatin. Gelatin 68.4%, glycerin 30.16%. Titanium dioxide 0.661%, ethylvanillin 0.2%, red 40 No. 0.232%, blue No. 1 0.004%, yellow No. 5 0.343% was included.

< Example 3 > In rats  In Vivo Dynamics Test After Intravenous Administration

Rats were lightly anesthetized with ether, followed by intubation of polyethylene tubes (PE-50, Intramedic, Clay Adams, U.S.A) to the left femoral artery and vein. After rats recover from anesthesia, coenzyme Q10 is administered intravenously (6 mg / kg) and blood is drawn from the left femoral artery at 0, blank, 1, 5, 10, 15, 30, 60, 90, 120, 180 minutes. It was. Coenzyme Q10 was quantified by analyzing 250 μl of blood in a microtube and centrifuging 100 μl of plasma obtained by high performance liquid chromatography (HPCL).

Plasma concentrations after intravenous administration of coenzyme Q10 (6 mg / kg) rapidly disappeared at a rapid time of up to 60 minutes, and then slowly disappeared . Was concentration is detected in plasma up to six hours after administration, half life (t _{1/2, β)} of the distribution phase inversion (α-phase) half-life (t _{1/2, α)} and the distribution upper rear (β-phase) at about each 3.3 minutes and 52 minutes. AUC was 4378 ugmin / ml and AUCt was 3793 ugmin / ml.

< Example 4 > In rats  In Vivo Dynamics Test After Oral Administration

Coenzyme Q10 Powder, Coenzyme Q10: Conjugated Linoleic Acid: Vitamin E = 30 mg: 220 mg: 10 IU soft capsule formulation Mito Q (hereinafter referred to as 'MITO'), CARNI Q- The contents of GEL® (hereinafter referred to as 'CARNI') and NovaSOL® Q (hereinafter referred to as 'NOVA') soft capsule formulations were orally administered (60 mg / kg) for 4 days at 24 hour intervals, respectively, followed by 5 days Immediately before, rats were lightly anesthetized with ether and polyethylene tubes (PE-50, Intramedic, Clay Adams, USA) were inserted into the left femoral artery. After the rats recovered from anesthesia, oral administration of coenzyme Q10 (60 mg / kg) followed by 0 (blank), 0.5, 1, 1.5, 2, 3 4, 6, 8, 12, 18, 24, Blood was collected at 48 hours. 250 μl of blood was received in a microtube and 100 μl of plasma obtained after centrifugation was used for quantification.

The pharmacokinetic parameters calculated from plasma concentration-time data after oral administration of the powder are shown in Table 2. Maximum plasma concentration (C _max ) is 0.665 μg / mL, C _max Is the time T _max appears Was 4.67 hours. In addition, the bioavailability (BA) calculated by adjusting AUC and dose after intravenous administration was 3.19%. This is presumably because coenzyme Q10 is very poorly soluble, so its absorption rate is not high.

The pharmacokinetic parameters calculated from the plasma concentration-time profile after oral administration of the MITO, NOVA and CARNI formulations are shown in Table 3. Plasma concentrations after oral administration of MITO showed higher plasma concentrations at a faster time than the control agents CARNI and NOVA. In contrast, CARNI of the three formulations showed a maximum plasma concentration (C)._max) Appeared last.

Plasma concentration-curved area (AUC) after oral administration of MITO was about 1.6 times higher than CARNI and NOVA. In addition, C _max after oral administration of MITO was 3 and 2 times higher than CARNI and NOVA, respectively. On the other hand, T _max after oral administration of MITO did not show a significant difference compared to NOVA, but showed a value of about 1/2 (2 times faster value) than CARNI (Fig. 1).

Plasma concentrations after oral administration of MITO were similar to those of NOVA, showing no significant difference in T _max , but high C _max . In addition, bioavailability (BA) was 1.6 times higher than that of NOVA.

On the other hand, the plasma concentration in the case of oral administration of MITO showed about 3 times higher C _max and faster absorption (2 times faster T _max ) than CARNI. In addition, bioavailability (BA) was 1.6 times higher than that of NOVA.

In the case of MITO, relative plasma utilization rate (RBA) of other preparations was calculated for different preparations in different time zones because of higher plasma concentrations at different time points than in other preparations (Table 4). It was up to 8.4 times higher than powder, up to 4 times higher than CARNI, and up to 2.5 times higher for NOVA, and higher than time 0 to infinity.

In conclusion, the MITO was evaluated as an agent having improved bioavailability (absorption rate) after oral administration compared to other preparations CARNI and NOVA.

< Example 5 > In beagle dogs  In Vivo Dynamics Test After Intravenous Administration

Intravenous administration of coenzyme Q10 to beagle dogs (6 mg / 10 kg) followed by 0, blank, 1, 3, 5, 10, 15, 30, 60, 120, 180, 240, 360 , Blood was collected at 480 minutes. After receiving 3 mL of blood into each blood collection tube and centrifuging, 1 mL of the obtained plasma was used for HPLC analysis. Plasma concentrations after intravenous administration of coenzyme Q10 (6 mg) rapidly disappeared at a rapid time of up to 60 minutes, and then slowly disappeared. Plasma concentrations were detected up to 8 hours post-dose, and pharmacokinetic parameters calculated from plasma concentration-time data. Distribution half-life in the phase-inversion (α-phase) half-life of (t _{1/2, α)} and the distribution upper rear _{(β-phase) (t 1/2, β} ) was approximately 1.17 min and 403 min, respectively, AUC was 1628 ug · min / ml.

< Example  6> In beagle dogs   In Vivo Dynamics Test After Oral Administration

Beagle dogs were orally administered coenzyme Q10 powder (POWDER), MITO, CARNI, and NOVA at 12 hour intervals for 4 days each day (60 mg / kg) and then orally administered coenzyme Q10 preparation on day 5 (9th day) (60 mg / kg). The blood samples were collected at 0, blank, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, and 72 hours from the basal vein of the beagle dog. After receiving 3 mL of blood into each blood collection tube and centrifuging, 1 mL of the obtained plasma was used for HPLC analysis.

A calibration curve was established in which a good linear relationship (R = 0.999) was established in the concentration range of 0.01 μg / mL to 10 μg / mL with respect to coenzyme Q10. In sample treatment, 50 μL of 50 μM Coenzyme Q9 was added to 1 mL of the collected plasma sample as an internal standard (IS), followed by extraction of 1 mL of trichloro acetic acid (10%) and 4 mL of hexane. That is, the mixture was shaken sufficiently for 20 minutes and then centrifuged (2000 g, 10 minutes). 2 mL of the organic solvent layer was taken, transferred to a new test tube, all evaporated with N ₂ gas, and redissolved in 200 μL of 1-propanol. 100 μL of this was taken and quantified by the HPLC assay described above.

The pharmacokinetic parameters were calculated from the plasma-time data after oral administration of coenzyme Q10 powder, the AUC was 6.63 hr · ug / ml, the maximum plasma concentration (C _max ) was 0.18 μg / mL, and C _max. Is the time T _max appears Was 7.5 hours. In addition, the bioavailability (BA) calculated by adjusting AUC and dose after intravenous administration was 2.44%. This is presumably because coenzyme Q10 is very poorly soluble, so its absorption rate is not high.

Plasma concentrations after oral administration of MITO showed higher plasma concentrations at a faster time than the control agents CARNI and NOVA. On the other hand, CARNI showed the lowest peak plasma concentration (C _max ) among the three preparations. Plasma concentration-curved area (AUC) after oral administration of MITO was about 15% higher than NOVA and CARNI. In addition, C _max after oral administration is a MITO did not show a significant difference compared to NOVA about 40% compared to CARNI showed a high value. On the other hand, T _max after oral administration of MITO showed no significant difference compared to NOVA, but was about 0.5 times faster than CARNI. Plasma concentrations after oral administration of MITO were similar to those of NOVA, with no significant differences between C _max and T _max , and higher C _max and faster absorption than CARNI.

Since MITO shows higher plasma concentrations at a faster time than other preparations, the relative bioavailability (RBA) of MITO for other preparations was calculated for each time zone. It was up to 2.3 times higher than coenzyme Q10 powder, up to 1.7 times higher than CARNI, and up to 1.4 times higher than NOVA, and higher than the values from time 0 to infinity.

Figure 1 shows coenzyme Q10 preparations in rats 60 mg / kg once daily for 5 days after plasma concentration curve area (AUC) of coenzyme Q10.

Figure 2 shows the area under the plasma concentration curve (AUC) of coenzyme Q10 after coenzyme Q10 formulations were administered once daily for 5 days at 60 mg / kg in beagle dogs.

Claims (8)

A composition having improved bioavailability of coenzyme Q10, comprising a therapeutically / nutritively effective amount of coenzyme Q10, conjugated linoleic acid and vitamin E. The composition of claim 1, wherein the weight ratio of coenzyme Q10: conjugated linoleic acid is 0.01: 1 to 1: 1. The composition of claim 1, wherein the content of vitamin E is 5 IU to 500 IU. A soft capsule for oral administration containing the composition of any one of claims 1 to 3 as an active ingredient. The soft capsule according to claim 4, wherein the content of coenzyme Q10 contained in the capsule is 5 mg to 2000 mg. Method for preparing a composition consisting of a therapeutically and nutritionally effective amount of coenzyme Q10, conjugated linoleic acid and vitamin E, comprising the step of warming conjugated linoleic acid and mixing the coenzyme Q10 and vitamin E in solution. . Coenzyme Q10, conjugated linoleic acid and vitamin E are prepared by heating the conjugated linoleic acid and mixing the coenzyme Q10 and vitamin E to form a solution and then filling the soft capsule. A method for producing a soft capsule containing a composed composition. The method according to claim 1, wherein the disease is related to disorders of mitochondria, metabolic diseases, migraine, heart disease, Parkinson's disease, hypertension, acquired immunodeficiency disease, retrovirus disease, disease caused by excessive free radicals, gum disease and obesity. A composition for the prevention, treatment or amelioration of a disease selected from the group consisting of.

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