KR101057623B1 - Coenzyme Q10-containing self-emulsifying drug delivery system composition and method of manufacturing the same - Google Patents

Abstract

The present invention relates to a coenzyme Q10-containing self-emulsifying drug delivery system composition for improving the poor solubility and increasing the bioavailability of coenzyme Q10, also known as ubide carenone, and to a method for preparing the same. Coenzyme Q10-based self-emulsifying drug delivery system that contains co-surfactant, and is particularly suitable for high concentrations of coenzyme Q10-containing liquid beverages, soft capsules and injections because it is stable, transparent and long-term storage / maintenance when dispersed in water. (Self-microemulsifying Drug Delivery System, SMEDDS) composition and a method for producing the same.

Coenzyme Q10, self-emulsifying drug delivery system, composition, manufacturing method

Description

Self-microemulsifying drug delivery system composition containing coenzyme Q10 and method for preparing the same}

The present invention relates to a coenzyme Q10-containing self-emulsifying drug delivery system composition for improving the poor solubility and increasing the bioavailability of coenzyme Q10, also known as ubide carenone, and to a method for preparing the same. Coenzyme Q10 self-emulsifying drug delivery system that contains surfactants and is particularly suitable for high concentrations of coenzyme Q10 containing liquid beverages, soft capsules and injectables, as it is stable, transparent and prolonged storage / maintenance when dispersed in water. (Self-microemulsifying Drug Delivery System, SMEDDS) composition and a method for producing the same.

Coenzyme Q10 (Chemical Formula 1) is a fat-soluble substance belonging to ubiquinones (Formula C ₅₉ H ₉₀ O ₄ , molecular weight 863.4, yellow crystal, melting point about 49 ° C).

Coenzyme Q10 is located in the cell's mitochondrial electron transport system and is effective in promoting energy production and improving metabolism.It plays an important role such as antioxidant activity in the body through the action similar to vitamins. It turned out to be a substance with stability that can be expected to prevent the effects of heart disease, diabetes, anti-cancer drugs, and fatigue recovery. In addition, coenzyme Q10 is present in the living body, and as it is known to improve the immune function of the living body through high biological activity, it is recently used for not only pharmaceuticals, but also cosmetics, health drinks, functional foods and nutritional supplements.

Accordingly, there is a continuing need for coenzyme Q10 in chemical combinations that are combined with coenzyme Q10 to increase the solubility of coenzyme Q10 and improve absorption and uptake.

However, coenzyme Q10 is a lipophilic substance that is difficult to be soluble at room temperature, and has a disadvantage in that it is not easily absorbed in the body because it is unstable to light or heat and is very poorly soluble. Solubilization is required to overcome these problems, but there is considerable difficulty in solubilization because coenzyme Q10 is also highly crystalline. In addition, coenzyme Q10 has poor storage stability and transparency at low temperatures, precipitation, crystallization, and shape change, resulting in a decrease in content during long-term storage, and when added to formulations containing large amounts of other ingredients, It has problems such as recrystallization (precipitation), color, viscosity, pH, and so on.

Accordingly, in recent years, as a formulation containing coenzyme Q10, solids such as tablets and capsules have been mainly developed.

Japanese Patent Laid-Open No. 2006-0082791 proposes a chemical compound, especially a chemical compound which is combined with coenzyme Q10 to increase the stable solubility, absorption efficiency, and intake of coenzyme Q10, but is strong due to the use of a large amount of essential oils. Due to its volatility, it is too irritating for oral use and can only be used externally. Cetyl myristoleate wax is also an excipient for external use.

Japanese Patent Application Laid-Open No. 2006-182770 discloses a grouped formulation in a solid preparation containing ubide carenone, vitamin B1 and acid, and a group containing ubide carenone and acid and a group containing vitamin B1. Although it is proposed a solid preparation characterized in that there is a disadvantage that the solid preparation requires a number of manufacturing processes, the stability is poor, and the absorption rate when ingested with the solid preparation.

Japanese Patent Laid-Open Publication No. 2003-095932 discloses a capsule coating of gelatin containing calcium lactate and vegetable pigment obtained by adding calcium lactate and pigment to gelatin, and then filling the capsule with ubidecarenone. Ubide carenone is proposed to improve the light stability of ubide carenone capsule formulation, but when water and glycerin, etc. coexist, the effect of stability is very bad.

Japanese Patent Application Laid-Open No. 2001-354553 proposes stabilization by incorporating organic acid into a composition containing ubidecarenone and water-soluble vitamins coexisting with gelatin, but when it is actually dispersed in water, it is not transparently dissolved. There are disadvantages.

In addition to the above-mentioned prior arts, various documents explain that the solubility of coenzyme Q10 (ie, ubidecarenone) is poorly available. However, this is a case where coenzyme Q10 is low in content and an excessive amount of surfactant is used, and the stability thereof is large. It is also insufficient.

An object of the present invention is to solve the problems of the prior art as described above, finely dispersed in water through self-emulsification to maintain a stable state for a long time, excellent transparency, high bioavailability, low manufacturing cost and manufacturing process This simple and easy to manufacture without other special conditions, and can have a wide range of applications, such as pharmaceuticals, health functional foods to provide a coenzyme Q10-containing composition and a method for producing the same particularly suitable for soft capsules, liquid drinks and injections.

According to the present invention, there is provided a coenzyme Q10-containing self-emulsifying drug delivery system composition comprising the active ingredient coenzyme Q10, a surfactant and a co-surfactant.

According to another aspect of the present invention, there is provided a method for preparing a coenzyme Q10-containing self-emulsifying drug delivery system composition characterized in that the coenzyme Q10, surfactant and cosurfactant is eutectic-mixed at 40 ℃ to 70 ℃.

According to another aspect of the present invention, there is provided an aqueous coenzyme Q10-containing composition comprising an aqueous medium and a coenzyme Q10-containing self-emulsifying drug delivery system composition of the present invention emulsified in the aqueous medium.

According to another aspect of the present invention, there is provided a method for preparing a coenzyme Q10-containing aqueous composition, characterized in that the coenzyme Q10-containing self-emulsifying drug delivery system composition of the present invention is mixed with an aqueous medium of 40 ℃ to 70 ℃.

According to the present invention, long-term storage does not occur precipitation, aggregation, recrystallization, shape change and content change, excellent stability and transparency, excellent thermal stability, and significantly improved the coenzyme Q10 absorption rate in vivo administration compared to conventional formulations The bioavailability can be greatly improved to obtain a coenzyme Q10-containing composition which is particularly suitable for liquid beverages, soft capsules and injections. In addition, the coenzyme Q10-containing composition of the present invention has an economical advantage in that its production does not require a physically strong force and can be easily produced without using a device such as a high speed stirrer.

Hereinafter, the present invention will be described in more detail.

Coenzyme Q10 (Chemical Structural Formula 1), which is included as an active ingredient in the composition according to the present invention, is also called ubidecarenone, and is used in ubiquinones (C ₅₉ H ₉₀ O ₄ , molecular weight 863.4, yellow crystals, melting point of about 49 ° C.). It belongs to fat-soluble substances.

Coenzyme Q10 is warmed near the melting point and can be used as a liquid oil.

The surfactant included in the composition according to the present invention is not particularly limited, and stable microemulsion of 0.005 to 0.2 μm is obtained by stably emulsifying oil components such as coenzyme Q10 and hydrophilic components such as co-surfactants in water. If it is a surfactant which can be formed, Especially preferably, if it is a surfactant suitable for food additives, it can be used individually or in mixture.

Representative surfactants include polyglycerin fatty acid esters, and the fatty acids constituting this type of surfactant include, for example, myristic acid, palmitic acid, stearic acid, behenic acid, and oleic acid. Saturated or unsaturated, preferably saturated fatty acids having 14 to 22 carbon atoms, preferably 14 to 18 carbon atoms, and the like, and the like are particularly preferred as the main component of decaglycerin myristic acid.

The degree of polymerization of the polyglycerol constituting the polyglycerol fatty acid ester is usually 2-20, preferably 4-12, more preferably 6-10.

In the present invention, for example, the HLB value of the surfactant such as polyglycerol fatty acid ester is preferably 6 to 20, more preferably 12 to 18. If the HLB value is outside this range, problems may occur in terms of transparency, stability, and solubility of the microemulsion.

Specific examples of the polyglycerol fatty acid esters include decaglycerol lauric acid ester, decaglycerin myristic acid ester, deca glycerine palmitic acid ester, deca glycerine stearic acid ester, deca glycerol oleic acid ester, deca glycerine behenic acid ester, and deca glycerin erca acid. Ester, decaglycerol mixed fatty acid ester, polyglycerol stearic acid ester, polyglycerol lauric acid ester, polyglycerol oleic acid ester and the like.

In the composition of the present invention, the content of the surfactant is not particularly limited, but preferably 0.1 to 20 parts by weight, and more preferably 0.2 to 10 parts by weight, may be used based on 1 part by weight of coenzyme Q10. If the amount of the surfactant is less than 0.1 part by weight with respect to 1 part by weight of coenzyme Q10, the amount of the surfactant is too small relative to the amount of oil to form an opaque microemulsion, and thus it cannot serve as a surfactant. Saturation may occur due to the addition of excess surfactant, and may cause significant difficulties in taste improvement in future doses.

There is no particular limitation on the co-surfactant included in the composition according to the present invention, and it is possible to form a stable microemulsion by stably emulsifying coenzyme Q10, which is highly crystalline as poorly soluble in water, with such a surfactant. If it is a co-surfactant, Especially preferably, if it is a co-surfactant suitable for food additive, it can be used individually or in mixture.

Cosurfactants usable in the present invention include the following:

① polyoxyethylene-sorbitan-fatty acid esters, for example, polyoxyethylene-sorbitan-mono, trilauryl, palmityl, stearyl, oleyl ester (product name: polysorbate 80, Tween, ICI));

Polyoxyethylene fatty acid esters such as polyoxyethylene stearic acid ester (trade name: Myrj, ICI);

③ polyoxyethylene-polyoxypropylene block copolymer (trade name: Poloxamer, Pluronic, Lutrol; BASF);

④ mono-, di- or mono / di-glycerides, for example capryl / capric acid mono- or di-glycerides (trade name: Imwitor, Huls);

⑤ sorbitan fatty acid esters such as sorbitan monolauryl, sorbitan monopalmityl or sorbitan monostearyl (product name: Span);

⑥ trans-esterification products of natural vegetable oil triglycerides and polyalkylene polyols (trade name: Labrafil, Gattefosse).

Generally, sorbitan fatty acid ester means a mixture of sorbitol, sorbitan, sorbide mono, di, tri ester and free sorbitol, sorbitan, sorbide and fatty acid salts.

In the present invention, the HLB value of the cosurfactant is preferably 7 or more, more preferably 12 to 18. In one embodiment of the present invention, a polyoxyethylene-sorbitan-fatty acid ester of HLB 7 or more having a high monoester content is preferably used. For example, polysorbate 80, which is a polyoxyethylene-sorbitan-fatty acid ester having an HLB of 15, More preferably used. If the HLB of the polyoxyethylene-sorbitan-fatty acid ester is lower than 7, the emulsion stability may be deteriorated.

Such cosurfactants may be used alone or as a mixture of two or more thereof. According to one embodiment of the present invention, Labrafil, which is a trans-esterification reaction product of the polyoxyethylene-sorbitan-fatty acid esters of tween and vegetable oil triglycerides and polyalkylene polyols, may be used alone or in combination. .

In the composition of the present invention, the content of the co-surfactant is not particularly limited, but preferably 0.1 to 20 parts by weight, and more preferably 0.2 to 10 parts by weight, may be used based on 1 part by weight of coenzyme Q10. If the content of the cosurfactant is less than 0.1 part by weight based on 1 part by weight of coenzyme Q10 If it exceeds 20 parts by weight, the reversal phenomenon occurs due to the addition of an excessive amount of cosurfactant, and the self-emulsifying system composed of the surfactant and the cosurfactant is broken. Oversaturation can cause problems such as precipitation during long-term preservation.

The coenzyme Q10-containing self-emulsifying drug delivery system composition and / or the coenzyme Q10-containing aqueous composition of the present invention may further contain the following food additives to improve the stability and taste and aroma of the composition, in addition to the above components:

1) Stabilizer

For example, tocopherol, tocopherol acetate, vitamin derivatives, Butylated Hydroxy Anisole (BHA), Butylated Hydroxy Toluene (BHT), DL-Sodium Tartrate, L-Sodium Tartrate, Potassium Hydrogen Tartrate, L-Potassium Hydrogenate, Curdlan, Guar Gum, sodium caseate, sodium polyacrylate, lecithin (liquid or powder), hydroxypropylmethylcellulose and the like.

2) flavoring agents

For example, formic acid keranyl, formic citronellyl, formic acid isoamyl, geraniol, cinnamon acid, methyl cinnamon, ethyl cinnamon, cinnamon aldehyde, cinnamon alcohol, ketones, butyric acid, butyl butyrate, ethyl butyrate, isoamyl amyl acid, deca Day, ethyl decanoate, decanol, lactones, linalol, maltol, methyl β-naphthyl ketone, methyl N-methyl anthranilate, DL-menthol, L-menthol, vanillin, aromatic aldehydes, aromatic alcohols, benzaldehyde, Benzyl alcohol, methyl salicylate, allyl cyclohexane propionate, citral, citronellal, citronellol, anisealdehyde, α-amylcinnamaldehyde, ethyl acetoacetate, methyl anthranilate, esters, ethyl vanillin, ethers, oxanoic acid Ethyl, Eugenol, γ-Undecaractone, Eucalyptol, Isoyl Acetate, Isoyl Acetate, Isoyl Cyanate Allyl, Isothiocyanates, Iso Eugenol, α-Ionone, β- Ionone, fatty acids, aliphatic aldehydes, li Aliphatic alcohols, aliphatic hydrocarbons, geranyl acetate, linalyl acetate, benzyl acetate, butyl acetate, citronelyl acetate, cinnamic acetate, allyl carbonate, terpene hydrocarbons, paramethylacetophenone, phenols, phenol ethers, Ethyl phenyl acetate, isobutyl phenyl acetate, ethyl propionate, isoamyl propionate, benzyl propionate, piperonal, ethyl hexanoate, hydroxycitronellal, hydroxycitronellal dimethylacetal, modified hop extract, formic acid and the like.

3) sweetener

end. Synthetic additives: for example, trisodium glycylate, disodium glycylate, D-maltinol, sodium saccharin, D-sorbitol solution, D-sorbitol, aspartame, xylitol, isomalt, lactitol, maltinol syrup, mannitol , Acecelpam potassium, sucralose, theanine and the like.

I. Natural additives such as licorice extract, stevioside, D-xylose, yeast extract, D-ribose, tomate, L-sorbose, erythritol, enzyme treatment stevia and the like.

4) defoamer

For example, silicon resins.

5) pH (pH) regulator

For example, citric acid, potassium citrate, glucono-delta-lactone, trisodium citrate, calcium citrate, calcium gluconate, DL-peracid, DL-sodium peroxide, potassium hydroxide, sodium hydroxide, calcium hydroxide, sodium hydroxide solution, adipic acid, hydrochloric acid , Calcium lactate, lactic acid, sodium triphosphate, potassium triphosphate, tricalcium phosphate, sodium diphosphate, ammonium diphosphate, potassium diphosphate, calcium diphosphate, sodium phosphate, ammonium phosphate, potassium phosphate, potassium phosphate, DL-tartrate, L-tartrate, acetic acid, sodium acetate, magnesium carbonate, sodium bicarbonate, ammonium bicarbonate, ammonium carbonate, potassium carbonate (anhydrous), sodium fumarate, succinic acid, sulfuric acid, sodium sulfate, potassium aluminum sulfate, gluconic acid, Calcium oxide, sodium sesquicarbonate, ammonium hydroxide, magnesium triphosphate, magnesium diphosphate, potassium hydrogencarbonate, potassium sulfate and the like.

6) antioxidant

end. Synthetic Additives: Dibutylhydroxytoluene, Butylhydroxyanisole, Vitamin E, Vitamin E Acetate, Erythorbic Acid, Sodium Erythorbate, EDTA Disodium, EDTA Disodium Sodium, Calcium Ascorbate, L-As Corville stearate, oxystearin and the like.

I. Natural additives: D-tocopherol (mixed type), D-α-tocopherol, degreasing rice bran extract, tea extract, moles, enzymatically treated rutin, sesame oil uncompounded, balsam extract, quercetin, ferulic acid and the like.

According to one embodiment of the present invention, in order to solve the stability problem for coenzyme Q10 in formulating a microemulsion as a CoQ10-containing liquid beverage, such as D-α-tocopherol, DL-α-tocopherol, vitamin E, etc. Stabilizer is added to the composition. In addition, inorganic and organic acids such as citric acid, malic acid, tartaric acid, lactic acid, phosphoric acid, succinic acid, acetic acid, gluconic acid, glutamic acid, hydrochloric acid, polyphosphoric acid, fumaric acid, aspartic acid, malonic acid, maleic acid, and the like may be further added as acidity regulators. These may be used alone or in combination of two or more thereof, preferably, D-α-tocopherol, DL-α-tocopherol, vitamin E or citric acid may be used alone or in combination.

In the composition of the present invention, there is no particular limitation on the content of the food additive as described above. For example, in the case of D-α-tocopherol, 0.02 to 0.05 parts by weight may be used for 1 part by weight of coenzyme Q10, and in the case of an antifoaming agent, 0.01 to 0.05 parts by weight may be used per 1 part by weight of coenzyme Q10, but is not limited thereto.

The self-emulsifying drug delivery system (SMEDDS) composition of the present invention is prepared by eutectic-mixing a coenzyme Q10 component with a surfactant and a co-surfactant at 40 ° C. to 70 ° C., preferably at 45 ° C. to 65 ° C., while homogeneous by stirring. And additives, including stabilizers, may be added if necessary. If the temperature condition is less than 40 ℃ coenzyme Q10 component is not easily dissolved problem occurs, if it exceeds 70 ℃ coenzyme may cause some flexible material is not preferable.

There are no particular limitations on the eutectic-mixing means in preparing the self-emulsifying drug delivery system (SMEDDS) compositions of the present invention, and conventional eutectic-mixing equipment such as a warming reactor such as a waterbath, an agitator and a homogenizer can be used. In addition, there are no particular limitations on the mixing conditions other than the temperature conditions, but mixing is preferably performed for 10 to 20 minutes in terms of improving process productivity and preventing deactivation of coenzyme Q10.

According to one preferred embodiment of the present invention, the coenzyme Q10-containing self-emulsifying drug delivery system composition prepared as described above is emulsified in an aqueous medium such as purified water or aqueous solution at 40 ° C to 70 ° C, preferably 45 ° C to 65 ° C. For example, a coenzyme Q10-containing aqueous composition containing fine emulsified particles having an average diameter of 200 nm or less can be prepared.

There are no particular restrictions on the emulsification means in the preparation of the coenzyme Q10-containing aqueous composition of the present invention, and conventional emulsifying equipment such as Homogenizers, stirrers can be used. In addition, the emulsification conditions other than the temperature conditions are not particularly limited, but in terms of improving process productivity and preventing deactivation of coenzyme Q10, emulsification is preferably performed for 10 to 20 minutes.

The prepared coenzyme Q10-containing aqueous composition is excellent in stability and transparency, and maintains its state even after being left at room temperature for a long time or cooled. The aqueous composition thus prepared may be a liquid beverage per se or may be used as an intermediate raw material in a conventional liquid beverage manufacturing process.

Hereinafter, the present invention will be described in more detail with reference to Examples, but these Examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Example  One

According to the composition shown in Table 1, coenzyme Q10 as a surfactant decaglycerol monomylistate, Mitsubishi-Kagaku Foods Corporation, Japan and a co-surfactant polyoxyethylene- sorbitan fatty acid ester (Polyoxyethylene Sorbitan Monooleate , Kao Corporation, Japan) was dissolved at 55 ± 10 ℃ to obtain a SMEDDS composition.

A suitable amount (about 100 mg) of purified water at 55 ± 10 ° C. was added to the prepared SMEDDS composition to prepare a microemulsion aqueous composition showing stability and transparency.

Example  2-9

According to the compositions shown in Tables 2 to 9, respectively, the microemulsion aqueous compositions of Examples 2 to 9 were prepared in the same manner as in Example 1.

Comparative example  1-2

According to the compositions shown in Tables 10 to 11, respectively, the microemulsion aqueous compositions of Comparative Examples 1-2 were prepared in the same manner as in Example 1.

Test Example  1: emulsified particles Particle size distribution  analysis

The particle size distribution of the microemulsion aqueous compositions prepared in Examples and Comparative Examples was measured using a particle size analyzer (Shimadzu, SALD-2001 model, Japan), and the results are shown in Table 12 below.

As can be seen in Table 12, the coenzyme Q10 SMEDDS composition prepared in the embodiment of the present invention formed microemulsion particles having an average particle diameter of about 0.09㎛. It is a transparent liquid microemulsion composition, which is a significantly smaller emulsified particle than the particles of the comparative example composition which is an opaquely dispersed liquid phase.

Test Example  2: precipitation formation test

It was observed visually whether or not the precipitate produced and the transparency of the microemulsion aqueous composition prepared in the Examples and Comparative Examples, the results are shown in Table 13.

Test Example  3: Stability and Content Test

Samples of SMEDDS compositions prepared in Examples 1 and 7 and Comparative Examples 1 and 2 over time after extended storage at accelerated (40 ° C., 75% RH), room temperature (25 ° C.) and refrigerated (1-4 ° C.) The content of internal coenzyme Q10 was analyzed by HPLC, and the results are shown in Table 14 below.

-Analysis of Coenzyme Q10

A sample of SMEDDS composition (0.5 g to 1 g weighing) was added to 4 ml of water, and warmed at 50 ° C for 10 minutes, which was cooled to room temperature. After adding 10 ml of n-hexane and 5 ml of 2-propanol containing 0.1% ferric chloride, 50 ml were adjusted using pure 2-propanol, and this solution was separated by HPLC under the following conditions. Moreover, it quantified using the analytical curve previously prepared using the standard solution.

Column: L-column ODS 4.6mm 250mm

Column temperature: 40 ℃

Mobile phase: 60% methanol + 40% ethanol

Flow rate: 1.0ml / min

Detector: UV

Wavelength: 275nm

As can be seen in Table 14, in the case of the comparative example, it was difficult to proceed with the test any more because of the settling and discoloration of the properties from 2 weeks. However, in Examples 1 and 7 it was confirmed that excellent stability and transparency at room temperature, accelerated and refrigerated conditions, the content is also not nearly reduced.

Test Example  4: Pharmacokinetics  exam

The pharmacokinetic test on the microemulsion aqueous composition prepared in Example 1 was carried out as follows.

Test Methods

(1) Test system: SD rat (Orient Bio Co., Ltd.), male 7 weeks old, 7 days of acclimatization period, feed, free water intake, (n = 4)

(2) Test drug (group):

Coenzyme Q10 (CoQ10) SMEDDS composition prepared in Example 1

Example 1 Raw Material CoQ10 (Control) Used to Prepare the Composition

(3) Dosage: 60mg / kg oral administration

(4) Blood collection time: 0, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 12, 24 hours

(5) Collection area: Orbital sinus capillary

(6) Analysis method: LC / MS / MS

sampling

The blood sample obtained at each time was immediately centrifuged at 3,000 rpm for 10 minutes, and 100 µl of the upper plasma was transferred to a clean EP tube. Plasma samples were stored frozen at −20 ° C. until analysis.

LC / MS / MS Analysis Conditions

Analytical Method: LC / MS / MS Method

Detector: MS / MS detector (positive ion mode, MRM mode)

Coenzyme Q10: m / z 863.9 → 197.2 (Positive)

Coenzyme Q9 (internal standard): m / z 795.9 → 197.0 (Positive)

Desolvation temp .: 350 ° C

Source temp .: 120 ° C

Ion spray capillary voltage: 3.0 kV

Desolvation gas flow: 800 L / hour

Collision gas flow: 0.2 L / hour

Collision gas: argon

Nebulizing gas: nitrogen

Column: Shiseido Capcell PAK ™ C18 MG Column (2.0ⅹ250 mm, 5 mm)

Data Processing Unit: MassLynx 4.1

Mobile phase:

0.5% formic acid in isopropanol: 0.5% formic acid in acetonitrile = 60: 40

Flow rate: 0.25 mL / min

Injection volume: 7 μl

Preparation of Standard Solution and Preparation of Calibration Chart

10 mg of coenzyme Q10 was precisely weighed, dissolved in isopropanol to make a concentration of 1 mg / mL, and then refrigerated, and the solution was sequentially diluted to a concentration of 1000, 500, 100, 50, 20, 10 ng / mL. The internal standard coenzyme Q9 was dissolved in acetonitrile to prepare a concentration of 0.5 μg / mL.

 Next, 100 μl of co-plasma of rat, 100 μl of standard solution of each drug concentration, 100 μl of internal standard solution (in 0.5 μg / mL acetonitrile of coenzyme Q9) and 200 μl of MeOH were added to the clean EP tube and vortexed. 2.5 mL of Hexane was added thereto, shaken for 10 minutes, and centrifuged at 2000 rpm for 10 minutes. The supernatant was transferred to a clean test tube and then evaporated with nitrogen gas. After evaporation the residue was taken up in 100 μl isopropanol, of which 7 μl were injected into LC / MS / MS.

A calibration curve was created with the peak area ratio of coenzyme Q10 to the peak area of the internal standard. Since coenzyme Q10 exists as an endogenous substance, the background concentration was corrected by subtracting the concentration peak of coenzyme Q10 for coplasm from the peak of each concentration.

Analysis of Plasma Samples

100 μl of the plasma sample stored after the collection was treated in the same manner as the sample processing method when preparing the calibration curve, and then the coenzyme Q10 in each plasma sample was extrapolated to the obtained calibration curve by obtaining the peak area ratio of coenzyme Q10 to the peak area of the internal standard. The concentration of was calculated.

The pharmacokinetic profile of the CoQ10 SMEDDS composition prepared in Example 1 of the present invention was obtained using the calculated concentration of coenzyme Q10 for each plasma sample, which is shown in FIG. 2. The profiles of raw material CoQ10 and endogenous CoQ10 are shown as a control.

The area under curve (AUC) and the maximum concentration (Cmax) calculated from the results obtained in this test are as follows.

As can be seen from Table 15 and FIG. 2, the coenzyme Q10-containing self-emulsifying drug delivery system composition according to the present invention can significantly increase the coenzyme Q10 absorption rate within a short time upon in vivo administration, thereby greatly improving the bioavailability.

1 is a pharmacokinetic profile of the CoQ10 SMEDDS composition prepared in Example 1 of the present invention.

Claims (8)

A coenzyme Q10-containing self-emulsifying drug delivery system composition comprising an active ingredient coenzyme Q10, a polyglycerin fatty acid ester and a polyoxyethylene-sorbitan-fatty acid ester. delete delete The composition of claim 1 wherein the HLB value of the polyglycerol fatty acid ester is 6-20. The composition according to claim 1, wherein the HLB value of the polyoxyethylene-sorbitan-fatty acid ester is 7 or more. A method for producing a coenzyme Q10-containing self-emulsifying drug delivery system composition characterized by eutectic-mixing coenzyme Q10, polyglycerin fatty acid ester and polyoxyethylene-sorbitan-fatty acid ester at 40 ° C to 70 ° C. A coenzyme Q10-containing aqueous composition comprising an aqueous medium and the coenzyme Q10-containing self-emulsifying drug delivery system composition of claim 1 emulsified in the aqueous medium. A method for producing a coenzyme Q10-containing aqueous composition, characterized in that the coenzyme Q10-containing self-emulsifying drug delivery system composition of claim 1 is mixed with an aqueous medium of 40 ℃ to 70 ℃.

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