WO2009022798A2 - Self-microemulsifying drug delivery system composition containing coenzyme q10 and method for preparing the same - Google Patents

Self-microemulsifying drug delivery system composition containing coenzyme q10 and method for preparing the same Download PDF

Info

Publication number
WO2009022798A2
WO2009022798A2 PCT/KR2008/004373 KR2008004373W WO2009022798A2 WO 2009022798 A2 WO2009022798 A2 WO 2009022798A2 KR 2008004373 W KR2008004373 W KR 2008004373W WO 2009022798 A2 WO2009022798 A2 WO 2009022798A2
Authority
WO
WIPO (PCT)
Prior art keywords
coenzyme qlo
composition containing
self
acid
delivery system
Prior art date
Application number
PCT/KR2008/004373
Other languages
French (fr)
Other versions
WO2009022798A3 (en
Inventor
Min Suk Lee
Hee Chul Chang
Young Ho Jo
Original Assignee
Daewoong Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Daewoong Pharmaceutical Co., Ltd. filed Critical Daewoong Pharmaceutical Co., Ltd.
Publication of WO2009022798A2 publication Critical patent/WO2009022798A2/en
Publication of WO2009022798A3 publication Critical patent/WO2009022798A3/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof

Definitions

  • the present invention relates to a self-microemulsifying drug delivery system (SMEDDS) composition containing coenzyme QlO for improving solubility and increasing bioavailability of coenzyme QlO which is also known as ubidecarenone; and method for preparing the same. More specifically, the present invention relates to a self-microemulsifying drug delivery system composition containing coenzyme QlO, which comprises coenzyme QlO as active component, a surfactant and a cosurfactant, and is suitable for applying to coenzyme QlO- containing liquid drinks, soft capsules, injections, etc. because of its stability, transparency and long-term preservability when dispersed in water; and method for preparing the same.
  • SMEDDS self-microemulsifying drug delivery system
  • Coenzyme QlO (Formula 1) is an oil-soluble substance belonging to ubiquinones (Chemical formula C 59 H 90 O 4 , Mw. 863.4, Yellow crystal, mp. ⁇ 49 ° C). [Formula 1 ]
  • Coenzyme QlO is present in the mitochondrial electron transport system of cell and it is known to be effective to promote the energy generation and to improve metabolism. It plays an important role such as in vivo anti-oxidation through the similar function with vitamins. Recently, it is known that coenzyme QlO is stable and promising significant effects against aging, heart diseases, diabetes, side effects of anti-cancer drugs, fatigue or the like. Further, as coenzyme QlO existing in living body has been known to improve the immune function of living body through its high bioactivity, it is being used recently for cosmetics, health drinks, functional foods, nutrition supplements and the like, as well as medicaments.
  • coenzyme QlO is a lipophilic substance which is poorly soluble in water at normal temperature, unstable in light or heat, and has poor absorption in living body due to its poor solubility.
  • Coenzyme QlO needs solubilization to overcome such defects, but the solubilization is very difficult because of its high crystal lattice energy.
  • the preservation stability and transparency of coenzyme QlO become deteriorated at low temperature, and so the precipitation, crystallization and deformation occur, resulting in the potency reduction during long-term storage.
  • the formulations containing coenzyme QlO developed recently are mainly in forms of solid such as tablet, capsule or the like.
  • Japanese patent laid-open publication No. 2006-0082791 suggests a chemical formulation which combines with coenzyme QlO specifically and increases solubility, JS.U/JSJK. zo. ⁇ y. z ⁇ o
  • Japanese patent laid-open publication No. 2006-182770 suggests a solid formulation containing ubidecarenone, vitamin Bl group and acid, characterized in the formulation of a group containing ubidecarenone and acid with the other group containing vitamin Bl.
  • this solid formulation disadvantageously requires many sub-processes for production, has low stability, and shows lowered absorption rate when it is taken in solid form.
  • Japanese patent laid-open publication No. 2003-095932 suggests a capsule formulation with an improved stability of ubidecarenone to light, prepared by filling ubidecarenone into a capsule with a gelatin coating containing calcium lactate and phytopigment, which is obtained by adding calcium lactate and pigment to gelatin.
  • the stabilization effect of this capsule formulation becomes too bad in the co-existence of water or glycerin.
  • Japanese patent laid-open publication No. 2001-354553 suggests a composition stabilized by combining organic acid with a mixture containing gelatin, co-existing ubidecarenone, and water-soluble vitamins. However, when this composition is dispersed in water actually, it does not provide a clear solution.
  • the object of the present invention is to provide a composition containing coenzyme QlO with wide application as medicament, functional food for health, etc., particularly suitable for soft capsule, liquid drink, injection and the like, which maintains a stable state of fine dispersion in water by self-microemulsification for a long time, has an excellent transparency and high bioavailability, and can be easily prepared with reasonable cost by simple process requiring no special conditions; and a method for preparing the same.
  • a self-microemulsifying drug delivery system composition containing coenzyme QlO which comprises coenzyme QlO as active component, a surfactant and a cosurfactant, is provided.
  • a method for preparing a self- microemulsifying drug delivery system composition containing coenzyme QlO which is characterized in comprising comelting and mixing coenzyme QlO, surfactant and cosurfactant at the temperature of 40 ° C to 70 ° C, is provided.
  • an aqueous composition containing coenzyme QlO which comprises an aqueous medium and the self-microemulsifying drug delivery system composition containing coenzyme QlO of the present invention emulsified in the aqueous medium.
  • a method for preparing an aqueous composition containing coenzyme QlO which is characterized in comprising admixing the self-microemulsifying drug delivery system composition containing coenzyme QlO according to anyone of claims 1 to 5 with an aqueous medium at 40 ° C to 70 ° C, is provided.
  • composition containing coenzyme QlO which has excellent stability, transparency and thermal stability, and increased bioavailability due to remarkably improved absorption of coenzyme QlO when administered as compared with conventional formulations, showing no precipitation, aggregation, recrystallization, deformation and content change even in a long-term storage, and so is particularly suitable for applications such as liquid drink, soft capsule, injection and the like.
  • the composition containing coenzyme QlO of the present invention can be easily prepared needless to apply large physical force and use special device such as a high speed agitator, and thus has economical advantages.
  • Figure 1 is a pharmacokinetic profile of the CoQlO SMEDDS composition prepared in
  • Example 1 of the present invention is a diagrammatic representation of Example 1 of the present invention.
  • Coenzyme QlO (Formula 1), which is contained in the composition according to the present invention as active component and also referred as ubidecarenone, is an oil- soluble substance belonging to ubiquinones (Chemical formula C 59 H 9 QO 4 , Mw. 863.4,
  • Coenzyme QlO is used in a liquid oil form obtained by heating it to around melting point.
  • surfactant contained in the composition according to the present invention. Any surfactant can be used alone or in combination as long as it can emulsify oil components such as coenzyme QlO and hydrophilic components such as cosurfactant stably in water and thus form a stable microemulsion in 0.005 to 0.2 ⁇ m size.
  • surfactants suitable for food additives are preferably used.
  • Polyglycerin fatty acid ester is a representative example of the surfactant.
  • Fatty acids constituting this surfactant type include saturated or unsaturated, preferably saturated fatty acids with 14 to 22, preferably 14 to 18 carbon atoms such as myristic acid, palmitic acid, stearic acid, behenic acid, oleic acid, and the like. Particularly preferred one is that mainly contains decaglycerin myristic acid.
  • the conventional polymerization degree of polyglycerin constituting the polyglycerin fatty acid ester is 2 to 20, preferably 4 to 12, and more preferably 6 to 10, in average.
  • a surfactant such as the polyglycerin fatty acid ester has preferably a HLB value of 6 to 20, and more preferably 12 to 18. If the HLB value is out of this range, problems in transparency, stability and/or solubility of the microemulsion may occur.
  • the concrete examples of the polyglycerin fatty acids ester include decaglycerin lauric acid ester, decaglycerin myristic acid ester, decaglycerin palmitic acid ester, decaglycerin stearic acid ester, decaglycerin oleic acid ester, decaglycerin behenic acid ester, decaglycerin erucic acid ester, mixed fatty acid ester of decaglycerin, polyglycerin stearic acid ester, polyglycerin lauric acid ester, polyglycerin oleic acid ester, and the like.
  • the content of the surfactant may be, but not limited thereto, preferably 0.1 to 20 parts by weight, and more preferably 0.2 to 10 parts by weight, based on 1 part by weight of Coenzyme QlO. If the content of the surfactant is lower than 0.1 parts by weight based on 1 part by weight of coenzyme QlO, an opaque microemulsion may be formed since the content of the surfactant is too little relative to the content of oil component and so it may not act as surfactant, whereas if the content of the surfactant exceeds 20 parts by weight, the system may be saturated with the excessive surfactant and so precipitation may occur, and taste improvement for oral application in the future may be very hard.
  • cosurfactant contained in the composition according to the present invention. Any cosurfactant can be used alone or in combination as long as it can emulsify the highly crystalline and poorly water-soluble coenzyme QlO together with the above mentioned surfactant stably in water and thus form a stable microemulsion.
  • T Polyoxyethylene-sorbitan-fatty acid esters.
  • esters of polyoxyethylene- sorbitan-mono, tri lauric acid, palmitic acid, stearic acid, oleic acid product name:
  • Polyoxyethylene fatty acid esters For example, polyoxyethylene stearic acid ester
  • Mono-, di- or mono/di-glyceride For example, caprylic/capric acid mono- or di- glyceride (product name: Imwitor (HuIs)); (ED Sorbitan fatty acid esters. For example, esters of sorbitan monolauric acid, sorbitan monopalmitic acid or sorbitan monostearic acid (product name: Span) ⁇ Trans-esterif ⁇ cation product of natural vegetable oil triglyceride and polyalkylene polyol (product name: Labrafil (Gattefosse)).
  • the sorbitan fatty acid ester refers to a mixture of mono, di, tri esters of sorbitol, sorbitan, sorbide; and free sorbitol, sorbitan, sorbide; and fatty acid salt.
  • cosurfactant has preferably a HLB value of 7 or higher, more preferably 12 to 18.
  • polyoxyethylene- sorbitan-fatty acid ester having a HLB value of 7 or higher with high contents of monoester is preferably used. More preferably, for example, Polysorbate 80, polyoxyethylene-sorbitan- fatty acid ester having a HLB value of 15, is used.
  • polyoxyethylene-sorbitan-fatty acid ester having a HLB value of lower than 7 is used, the stability of emulsion may be deteriorated.
  • Labrafil which is a trans- esterif ⁇ cation product of Tween (polyoxyethylene-sorbitan-fatty acid ester), vegetable oil triglyceride, and polyalkylene polyol, can be used alone or in combination.
  • the content of the cosurfactant may be, but not limited thereto, preferably 0.1 to 20 parts by weight, and more preferably 0.2 to 10 parts by weight, based on 1 part by weight of coenzyme QlO. If the content of the cosurfactant is lower than 0.1 parts by weight based on 1 part by weight of coenzyme
  • the self-microemulsifying system consisting of surfactant and cosurfactant may be destroyed by reversion due to the excessive cosurfactant, and the precipitation problem may arise from supersaturation of the cosurfactant.
  • the self-microemulsifying drug delivery system composition containing coenzyme QlO and/or the aqueous composition containing coenzyme QlO of the present invention may further comprise the following food additives to improve stability, taste and flavor of the composition.
  • tocopherol for example, tocopherol, tocopherol acetate, vitamin derivatives, BHA (Butylated Hydroxy Anisole), BHT (Butylated Hydroxy Toluene), DL-sodium tartrate, L-sodium tartrate, DL-potassium bitartrate, L- potassium bitartrate, curdlan, guar gum, sodium caseinate, sodium polyacrylate, lecithin (liquid or powder), hydroxypropyl methylcellulose, and the like.
  • BHA butylated Hydroxy Anisole
  • BHT Butylated Hydroxy Toluene
  • DL-sodium tartrate L-sodium tartrate
  • DL-potassium bitartrate L-potassium bitartrate
  • L- potassium bitartrate for example, curdlan, guar gum, sodium caseinate, sodium polyacrylate, lecithin (liquid or powder), hydroxypropyl methylcellulose, and the like.
  • A. Synthetic additives For example, trisodium glycyrrhizinate, disodium glycyrrhizinate, D-maltitol, sodium saccharin, D-sorbitol solution, D-sorbitol, aspartame, xylitol, isomalt, lactitol, maltitol syrup, mannitol, acesulfame potassium, sucralose, theanine, and the like.
  • Natural additives For example, licorice extract, stevioside, D-xylose, yeast extract, D-ribose, thaumatin, L-sorbose, erythritol, enzymatically modified stevia, and the like.
  • D-tocopherol (mixed), D- ⁇ -tocopherol, defatted ricebran extract, tea extract, gallic acid, enzymatically modified rutin, sesame seed oil unasponified matter, garden balsam extract, quercetin, ferulic acid, and the like.
  • a food-acceptable additive such as D-otocopherol, DL- ⁇ -tocopherol, vitamin E or the like may be added to the composition.
  • a food-acceptable additive such as D-otocopherol, DL- ⁇ -tocopherol, vitamin E or the like may be added to the composition.
  • an organic and/or inorganic acid 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 or the like may be further added.
  • the above additive can be used alone or in combination.
  • D- ⁇ -tocopherol, DL- ⁇ -tocopherol, vitamin E and/or citric acid can be used alone or in combination.
  • composition of the present invention there is no special limitation to the content of the food additive as mentioned above.
  • D- ⁇ -tocopherol can be used 0.02 to 0.05 parts by weight per 1 part by weight of coenzyme QlO
  • an antifoaming agent can be used 0.01 to 0.05 parts by weight per 1 part by weight of coenzyme QlO, but not limited thereto.
  • the self-microemulsifying drug delivery system (SMEDDS) composition of the present invention can be prepared by comelting and mixing coenzyme QlO, surfactant and cosurfactant at the temperature of 40 ° C to 70 ° C , preferably 45 ° C to 65 ° C , with agitation and homogenization. If necessary, additives such as stabilizers can be added further. If the temperature of comelting and mixing is lower than 40 ° C, coenzyme QlO may not melt well. If the temperature is higher than 70 ° C , some related compounds may be generated from coenzyme QlO, which is not desirable.
  • SMEDDS self-microemulsifying drug delivery system
  • comelting and mixing means in preparing the self- microemulsifying drug delivery system (SMEDDS) composition of the present invention.
  • conventional comelting and mixing devices including heating reactor such as waterbath, agitator and homogenizer can be used.
  • mixing conditions other than temperature it is preferable that the mixing is performed for 10 minutes to 20 minutes in terms of the process productivity and the prevention of the lowering of coenzyme QlO's activity.
  • an aqueous composition containing coenzyme QlO which comprises microemulsified particles having average particle diameter, for example, 200 nm or less, can be prepared by emulsifying the self- microemulsifying drug delivery system composition containing coenzyme QlO as prepared above in an aqueous medium such as purified water or aqueous solution at 40 ° C to 70 ° C , preferably 45 ° C to 65 ° C .
  • emulsifying means in preparing the aqueous composition containing coenzyme QlO of the present invention.
  • conventional emulsifying devices including homogenizer and agitator can be used.
  • emulsifying conditions other than temperature it is preferable that the emulsification is performed for 10 minutes to 20 minutes in terms of the process productivity and the prevention of the lowering of coenzyme QlO's activity.
  • the aqueous composition containing coenzyme QlO as prepared above has excellent stability and transparency, and maintains its state even though it is kept at normal temperature for a long time or cooled.
  • the aqueous composition containing coenzyme QlO as prepared above can be a liquid drink by itself, or can be used as an intermediate material in conventional production process for liquid drink.
  • a SMEDDS composition was obtained by dissolving coenzyme QlO with decaglycerin myristic acid ester (Decaglycerol Monomylistate; Mitsubishi-Kagaku Foods Corporation, Japan) as surfactant and polyoxyethylene sorbitan fatty acid ester (Polyoxyethylene Sorbitan Monooleate; Kao Corporation, Japan) as cosurfactant at 55 ⁇ 10 ° C .
  • decaglycerin myristic acid ester Decaglycerol Monomylistate; Mitsubishi-Kagaku Foods Corporation, Japan
  • polyoxyethylene sorbitan fatty acid ester Polyoxyethylene Sorbitan Monooleate; Kao Corporation, Japan
  • microemulsion aqueous compositions of Examples 2 to 9 were prepared respectively in the same method as in Example 1.
  • microemulsion aqueous compositions of Comparative Examples 1 and 2 were prepared respectively in the same method as in Example 1.
  • Test Example 1 Analysis of particle size distribution of emulsified particle
  • the microemulsified particles having an average particle size of about 0.09 jtM were formed in the coenzyme QlO SMEDDS compositions prepared in the examples of the present invention. These compositions were transparent liquid microemulsion compositions and had remarkably small emulsified particles, as compared to the compositions of the comparative examples which were opaquely dispersed liquid phase.
  • Test Example 2 Test to precipitation formation
  • Test Example 3 Test to stability and content
  • Comparative Examples 1 and 2 were stored at high temperature (40 ° C, 75% RH), room temperature (25 ° C), and cold temperature (1 to 4 " C) for a long time. The content of coenzyme QlO in the samples according to the storage time was then analyzed by HPLC.
  • a pharmacokinetic test for the microemulsion aqueous composition prepared in Example 1 was performed as follows.
  • Coenzyme QlO (CoQlO) SMEDDS composition prepared in Example 1 CoQlO raw material used for preparing the composition in Example 1 (Control)
  • Plasma samples obtained from the respective times were centrifuged at 3,000 rpm for 10 min, and then 100 [d of supernatant plasma was moved to clean EP tube.
  • the plasma samples were stored at a temperature of -20 ° C (refrigerated) before analysis.
  • Coenzyme Q9 (internal standard substance): m/z 795.9 ⁇ 197.0 (Positive)
  • Source temp. 120 ° C
  • the calibration curve was plotted with the ratio of peak area of coenzyme QlO versus peak area of the internal standard substance. Since endogenic coenzyme QlO also exists, background concentration was adjusted by subtracting the concentration peak of coenzyme QlO in free-plasma from that of the respective concentration.
  • AUC Area under curves (AUC) and maximum concentrations (Cmax) calculated from the results of this test are shown in the following Table 15.
  • the self-microemulsifying drug delivery system composition containing coenzyme QlO according to the present invention when administered into the body, can remarkably improve the absorption of coenzyme QlO in a short time and thus increase the bioavailability greatly.
  • composition containing coenzyme QlO which has excellent stability, transparency and thermal stability, and increased bioavailability due to remarkably improved absorption of coenzyme QlO when administered as compared with conventional formulations, showing no precipitation, aggregation, recrystallization, deformation and content change even in a long-term storage, and so is particularly suitable for applications such as liquid drink, soft capsule, injection and the like.
  • the composition containing coenzyme QlO of the present invention can be easily prepared needless to apply large physical force and use special device such as a high speed agitator, and thus has economical advantages.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Dispersion Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

The present invention relates to a self-microemulsifying drug delivery system (SMEDDS) composition containing coenzyme QlO for improving solubility and increasing bioavailability of coenzyme QlO which is also known as ubidecarenone; and method for preparing the same. More specifically, the present invention relates to a self-microemulsifying drug delivery system composition containing coenzyme QlO, which comprises coenzyme QlO as oily active component, a surfactant and a cosurfactant, and is suitable for applying to coenzyme QlO- containing liquid drinks, soft capsules, injections, etc. because of its stability, transparency and long-term preservability when dispersed in water; and method for preparing the same.

Description

SELF-MICROEMULSIFYING DRUG DELIVERY SYSTEM COMPOSITION CONTAINING COENZYME QlO AND METHOD FOR PREPARING THE
SAME
TECHNICAL FIELD
The present invention relates to a self-microemulsifying drug delivery system (SMEDDS) composition containing coenzyme QlO for improving solubility and increasing bioavailability of coenzyme QlO which is also known as ubidecarenone; and method for preparing the same. More specifically, the present invention relates to a self-microemulsifying drug delivery system composition containing coenzyme QlO, which comprises coenzyme QlO as active component, a surfactant and a cosurfactant, and is suitable for applying to coenzyme QlO- containing liquid drinks, soft capsules, injections, etc. because of its stability, transparency and long-term preservability when dispersed in water; and method for preparing the same.
BACKGROUND ART
Coenzyme QlO (Formula 1) is an oil-soluble substance belonging to ubiquinones (Chemical formula C59H90O4, Mw. 863.4, Yellow crystal, mp. ~ 49 °C). [Formula 1 ]
Figure imgf000003_0001
Coenzyme QlO is present in the mitochondrial electron transport system of cell and it is known to be effective to promote the energy generation and to improve metabolism. It plays an important role such as in vivo anti-oxidation through the similar function with vitamins. Recently, it is known that coenzyme QlO is stable and promising significant effects against aging, heart diseases, diabetes, side effects of anti-cancer drugs, fatigue or the like. Further, as coenzyme QlO existing in living body has been known to improve the immune function of living body through its high bioactivity, it is being used recently for cosmetics, health drinks, functional foods, nutrition supplements and the like, as well as medicaments.
Accordingly, there has been a continuous demand for chemical formulations in combination with coenzyme QlO which can increase the solubility of coenzyme QlO and improve absorption and ingestion thereof. However, coenzyme QlO is a lipophilic substance which is poorly soluble in water at normal temperature, unstable in light or heat, and has poor absorption in living body due to its poor solubility. Coenzyme QlO needs solubilization to overcome such defects, but the solubilization is very difficult because of its high crystal lattice energy. Also, the preservation stability and transparency of coenzyme QlO become deteriorated at low temperature, and so the precipitation, crystallization and deformation occur, resulting in the potency reduction during long-term storage. Further, when it is added to a formulation which contains other ingredients in large amounts, according to the time development and storage temperature, it causes some problems such as recrystallization (precipitation), time-dependent changes of product properties such as color, viscosity, pH, etc. and excessive variation in threshold value.
Accordingly, the formulations containing coenzyme QlO developed recently are mainly in forms of solid such as tablet, capsule or the like.
Japanese patent laid-open publication No. 2006-0082791 suggests a chemical formulation which combines with coenzyme QlO specifically and increases solubility, JS.U/JSJK. zo. υy. zυυo
absoption and ingestion of coenzyme QlO. However, this formulation can be used only for external application because it contains excessive essential oil and so is too volatile and irritating to be used for oral application. It also can be said that cetyl myristoleate wax is an excipient for external application.
Japanese patent laid-open publication No. 2006-182770 suggests a solid formulation containing ubidecarenone, vitamin Bl group and acid, characterized in the formulation of a group containing ubidecarenone and acid with the other group containing vitamin Bl. However, this solid formulation disadvantageously requires many sub-processes for production, has low stability, and shows lowered absorption rate when it is taken in solid form.
Japanese patent laid-open publication No. 2003-095932 suggests a capsule formulation with an improved stability of ubidecarenone to light, prepared by filling ubidecarenone into a capsule with a gelatin coating containing calcium lactate and phytopigment, which is obtained by adding calcium lactate and pigment to gelatin. However, the stabilization effect of this capsule formulation becomes too bad in the co-existence of water or glycerin. Japanese patent laid-open publication No. 2001-354553 suggests a composition stabilized by combining organic acid with a mixture containing gelatin, co-existing ubidecarenone, and water-soluble vitamins. However, when this composition is dispersed in water actually, it does not provide a clear solution.
In addition to the above, many publications explain that the poor soluble coenzyme QlO (i.e. ubidecarenone) can be solubilized in water. However, most of such cases are those of low-content of coenzyme QlO in use of excessive surfactants, with insufficient stability.
DETAILED DESCRIPTION OF THE INVENTION
TECHNICAL PURPOSE As a solution to the above-mentioned problems of prior arts, the object of the present invention is to provide a composition containing coenzyme QlO with wide application as medicament, functional food for health, etc., particularly suitable for soft capsule, liquid drink, injection and the like, which maintains a stable state of fine dispersion in water by self-microemulsification for a long time, has an excellent transparency and high bioavailability, and can be easily prepared with reasonable cost by simple process requiring no special conditions; and a method for preparing the same.
TECHNICAL SOLUTION
According to the present invention, a self-microemulsifying drug delivery system composition containing coenzyme QlO, which comprises coenzyme QlO as active component, a surfactant and a cosurfactant, is provided.
According to the other aspect of the present invention, a method for preparing a self- microemulsifying drug delivery system composition containing coenzyme QlO, which is characterized in comprising comelting and mixing coenzyme QlO, surfactant and cosurfactant at the temperature of 40 °C to 70 °C, is provided.
According to another aspect of the present invention, an aqueous composition containing coenzyme QlO, which comprises an aqueous medium and the self-microemulsifying drug delivery system composition containing coenzyme QlO of the present invention emulsified in the aqueous medium, is provided. According to another aspect of the present invention, a method for preparing an aqueous composition containing coenzyme QlO, which is characterized in comprising admixing the self-microemulsifying drug delivery system composition containing coenzyme QlO according to anyone of claims 1 to 5 with an aqueous medium at 40 °C to 70 °C, is provided.
ADVANTAGEOUS EFFECTS
According to the present invention, it is possible to obtain a composition containing coenzyme QlO, which has excellent stability, transparency and thermal stability, and increased bioavailability due to remarkably improved absorption of coenzyme QlO when administered as compared with conventional formulations, showing no precipitation, aggregation, recrystallization, deformation and content change even in a long-term storage, and so is particularly suitable for applications such as liquid drink, soft capsule, injection and the like. Further, the composition containing coenzyme QlO of the present invention can be easily prepared needless to apply large physical force and use special device such as a high speed agitator, and thus has economical advantages. BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a pharmacokinetic profile of the CoQlO SMEDDS composition prepared in
Example 1 of the present invention.
BEST MODE FOR CARRYING OUT THE INVENTION
Hereinafter, the present invention will be described in more detail.
Coenzyme QlO (Formula 1), which is contained in the composition according to the present invention as active component and also referred as ubidecarenone, is an oil- soluble substance belonging to ubiquinones (Chemical formula C59H9QO4, Mw. 863.4,
Yellow crystal, mp. ~ 49 "C).
[Formula 1 ]
Figure imgf000009_0001
Coenzyme QlO is used in a liquid oil form obtained by heating it to around melting point. There is no special limitation to the surfactant contained in the composition according to the present invention. Any surfactant can be used alone or in combination as long as it can emulsify oil components such as coenzyme QlO and hydrophilic components such as cosurfactant stably in water and thus form a stable microemulsion in 0.005 to 0.2μm size. Surfactants suitable for food additives are preferably used.
Polyglycerin fatty acid ester is a representative example of the surfactant. Fatty acids constituting this surfactant type include saturated or unsaturated, preferably saturated fatty acids with 14 to 22, preferably 14 to 18 carbon atoms such as myristic acid, palmitic acid, stearic acid, behenic acid, oleic acid, and the like. Particularly preferred one is that mainly contains decaglycerin myristic acid.
The conventional polymerization degree of polyglycerin constituting the polyglycerin fatty acid ester is 2 to 20, preferably 4 to 12, and more preferably 6 to 10, in average.
In the present invention, a surfactant such as the polyglycerin fatty acid ester has preferably a HLB value of 6 to 20, and more preferably 12 to 18. If the HLB value is out of this range, problems in transparency, stability and/or solubility of the microemulsion may occur.
The concrete examples of the polyglycerin fatty acids ester include decaglycerin lauric acid ester, decaglycerin myristic acid ester, decaglycerin palmitic acid ester, decaglycerin stearic acid ester, decaglycerin oleic acid ester, decaglycerin behenic acid ester, decaglycerin erucic acid ester, mixed fatty acid ester of decaglycerin, polyglycerin stearic acid ester, polyglycerin lauric acid ester, polyglycerin oleic acid ester, and the like.
In the composition of the present invention, the content of the surfactant may be, but not limited thereto, preferably 0.1 to 20 parts by weight, and more preferably 0.2 to 10 parts by weight, based on 1 part by weight of Coenzyme QlO. If the content of the surfactant is lower than 0.1 parts by weight based on 1 part by weight of coenzyme QlO, an opaque microemulsion may be formed since the content of the surfactant is too little relative to the content of oil component and so it may not act as surfactant, whereas if the content of the surfactant exceeds 20 parts by weight, the system may be saturated with the excessive surfactant and so precipitation may occur, and taste improvement for oral application in the future may be very hard. There is no special limitation to the cosurfactant contained in the composition according to the present invention. Any cosurfactant can be used alone or in combination as long as it can emulsify the highly crystalline and poorly water-soluble coenzyme QlO together with the above mentioned surfactant stably in water and thus form a stable microemulsion.
Examples of the cosurfactant that can be used in the present invention are as follows:
(T) Polyoxyethylene-sorbitan-fatty acid esters. For example, esters of polyoxyethylene- sorbitan-mono, tri lauric acid, palmitic acid, stearic acid, oleic acid (product name:
Polysorbate 80, Tween (ICI));
(2) Polyoxyethylene fatty acid esters. For example, polyoxyethylene stearic acid ester
(product name: Myrj (ICI)); (S) Polyoxyethylene-polyoxypropylene block copolymer (product name: Poloxamer,
Pluronic, Lutrol (BASF));
© Mono-, di- or mono/di-glyceride. For example, caprylic/capric acid mono- or di- glyceride (product name: Imwitor (HuIs)); (ED Sorbitan fatty acid esters. For example, esters of sorbitan monolauric acid, sorbitan monopalmitic acid or sorbitan monostearic acid (product name: Span) © Trans-esterifϊcation product of natural vegetable oil triglyceride and polyalkylene polyol (product name: Labrafil (Gattefosse)).
Generally, the sorbitan fatty acid ester refers to a mixture of mono, di, tri esters of sorbitol, sorbitan, sorbide; and free sorbitol, sorbitan, sorbide; and fatty acid salt.
In the present invention, cosurfactant has preferably a HLB value of 7 or higher, more preferably 12 to 18. In one embodiment of the present invention, polyoxyethylene- sorbitan-fatty acid ester having a HLB value of 7 or higher with high contents of monoester is preferably used. More preferably, for example, Polysorbate 80, polyoxyethylene-sorbitan- fatty acid ester having a HLB value of 15, is used. When a polyoxyethylene-sorbitan-fatty acid ester having a HLB value of lower than 7 is used, the stability of emulsion may be deteriorated.
The cosurfactants described above can be used alone or as mixtures of two or more. According to one embodiment of the present invention, Labrafil, which is a trans- esterifϊcation product of Tween (polyoxyethylene-sorbitan-fatty acid ester), vegetable oil triglyceride, and polyalkylene polyol, can be used alone or in combination.
In the composition of the present invention, the content of the cosurfactant may be, but not limited thereto, preferably 0.1 to 20 parts by weight, and more preferably 0.2 to 10 parts by weight, based on 1 part by weight of coenzyme QlO. If the content of the cosurfactant is lower than 0.1 parts by weight based on 1 part by weight of coenzyme
QlO, it may not act to aid the function of the surfactant, whereas if the content of the surfactant exceeds 20 parts by weight, the self-microemulsifying system consisting of surfactant and cosurfactant may be destroyed by reversion due to the excessive cosurfactant, and the precipitation problem may arise from supersaturation of the cosurfactant.
In addition to the above-mentioned components, the self-microemulsifying drug delivery system composition containing coenzyme QlO and/or the aqueous composition containing coenzyme QlO of the present invention may further comprise the following food additives to improve stability, taste and flavor of the composition. 1) Stabilizers
For example, tocopherol, tocopherol acetate, vitamin derivatives, BHA (Butylated Hydroxy Anisole), BHT (Butylated Hydroxy Toluene), DL-sodium tartrate, L-sodium tartrate, DL-potassium bitartrate, L- potassium bitartrate, curdlan, guar gum, sodium caseinate, sodium polyacrylate, lecithin (liquid or powder), hydroxypropyl methylcellulose, and the like.
2) Flavoring agents
For example, geranyl formate, citronellyl formate, isoamyl formate, geraniol, cinnamic acid, methyl cinnamate, ethyl cinnamate, cinnamaldehyde, cinnamyl alcohol, ketones, butyric acid, butyl butyrate, ethyl butyrate, isoamyl butyrate, decanal, ethyl decanoate, decanol, lactones, linalool, maltol, methyl /3-naphthyl ketone, methyl N- methylanthranilate, DL-menthol, L-menthol, vanillin, aromatic aldehydes, aromatic alcohols, benzaldehyde, benzyl alcohol, methyl salicylate, allyl cyclohexanepropionate, citral, citronellal, citronellol, anisaldehyde, α-amyl cinnamaldehyde, ethyl acetoacetate, methyl anthranilate, esters, ethyl vanillin, ethers, ethyl octanoate, eugenol, γ- undecalactone, eucalyptol, ethyl isovalerate, isoamyl isovalerate, allyl isothiocyanate, isothiocyanates, isoeugenol, α-ionone, β-ionone, fatty acids, aliphatic aldehydes, aliphatic alcohols, aliphatic hydrocarbons, geranyl acetate, linalyl acetate, benzyl acetate, butyl acetate, citronellyl acetate, cinnamyl acetate, allyl caproate, terpenic hydrocarbons, p-methyl acetophenone, phenols, phenol ethers, ethyl phenylacetate, isobutyl phenylacetate, ethyl propionate, isoamyl propionate, benzyl propionate, piperonal, ethyl hexanoate, hydroxycitronellal, hydroxycitronellal dimethylacetal, modified Hop extract, formic acid, and the like.
3) Sweeteners
A. Synthetic additives: For example, trisodium glycyrrhizinate, disodium glycyrrhizinate, D-maltitol, sodium saccharin, D-sorbitol solution, D-sorbitol, aspartame, xylitol, isomalt, lactitol, maltitol syrup, mannitol, acesulfame potassium, sucralose, theanine, and the like.
B. Natural additives: For example, licorice extract, stevioside, D-xylose, yeast extract, D-ribose, thaumatin, L-sorbose, erythritol, enzymatically modified stevia, and the like.
4) Antifoaming agents
For example, silicone resin and the like. 5) pH modifiers
For example, citric acid, potassium citrate, glucono-delta-lactone, trisodium citrate, calcium citrate, calcium gluconate, DL-malic acid, sodium DL-malate, potassium hydroxide, sodium hydroxide, calcium hydroxide, sodium hydroxide solution, adipic acid, hydrochloric acid, calcium lactate, lactic acid, tribasic sodium phosphate, tribasic potassium phosphate, tribasic calcium phosphate, dibasic sodium phosphate, dibasic ammonium phophate, dibasic potassium phosphate, dibasic calcium phosphate, monobasic sodium phosphate, monobasic ammonium phopshate, monobasic potassium phosphate, monobasic calcium phosphate, DL-tartaric acid, L-tartaric acid, acetic acid, sodium acetate, magnesium carbonate, sodium bicarbonate, ammonium bicarbonate, ammonium carbonate, anhydrous potassium carbonate, monosodium fumarate, succinic acid, sulfuric acid, sodium sulfate, aluminium potassium sulfate, gluconic acid, calcium oxide, sodium sesquicarbonate, ammonium hydroxide, tribasic magnesium phosphate, dibasic magnesium phosphate, potassium bicarbonate, potassium sulfate, and the like.
6) Antioxidants
A. Synthetic additives: Dibutyl hydroxytoluene, butyl hydroxyanisole, vitamin E, vitamin E acetate, erythorbic acid, sodium erithorbate, disodium ethylenediaminetetraacetate, calcium disodium ethylenediaminetetraacetate, calcium ascorbate, L-ascorbyl stearate, oxystearin, and the like.
B. Natural additives: D-tocopherol (mixed), D-α-tocopherol, defatted ricebran extract, tea extract, gallic acid, enzymatically modified rutin, sesame seed oil unasponified matter, garden balsam extract, quercetin, ferulic acid, and the like.
According to one embodiment of the present invention, when the present composition is formulated to a microemulsion as a CoQIO-containing liquid drink, in order to solve the problem of stability to CoQlO, a food-acceptable additive such as D-otocopherol, DL- α-tocopherol, vitamin E or the like may be added to the composition. Also, as a pH modifier, an organic and/or inorganic acid 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 or the like may be further added. The above additive can be used alone or in combination. Preferably, D-α-tocopherol, DL-α-tocopherol, vitamin E and/or citric acid can be used alone or in combination.
m the composition of the present invention, there is no special limitation to the content of the food additive as mentioned above. For example, D-α-tocopherol can be used 0.02 to 0.05 parts by weight per 1 part by weight of coenzyme QlO, and an antifoaming agent can be used 0.01 to 0.05 parts by weight per 1 part by weight of coenzyme QlO, but not limited thereto.
The self-microemulsifying drug delivery system (SMEDDS) composition of the present invention can be prepared by comelting and mixing coenzyme QlO, surfactant and cosurfactant at the temperature of 40 °C to 70 °C , preferably 45 °C to 65 °C , with agitation and homogenization. If necessary, additives such as stabilizers can be added further. If the temperature of comelting and mixing is lower than 40 °C, coenzyme QlO may not melt well. If the temperature is higher than 70 °C , some related compounds may be generated from coenzyme QlO, which is not desirable.
There is no special limitation to the comelting and mixing means in preparing the self- microemulsifying drug delivery system (SMEDDS) composition of the present invention. For example, conventional comelting and mixing devices including heating reactor such as waterbath, agitator and homogenizer can be used. Also, though there is no special limitation to mixing conditions other than temperature, it is preferable that the mixing is performed for 10 minutes to 20 minutes in terms of the process productivity and the prevention of the lowering of coenzyme QlO's activity.
According to a preferred embodiment of the present invention, an aqueous composition containing coenzyme QlO, which comprises microemulsified particles having average particle diameter, for example, 200 nm or less, can be prepared by emulsifying the self- microemulsifying drug delivery system composition containing coenzyme QlO as prepared above in an aqueous medium such as purified water or aqueous solution at 40 °C to 70 °C , preferably 45 °C to 65 °C .
There is no special limitation to the emulsifying means in preparing the aqueous composition containing coenzyme QlO of the present invention. For example, conventional emulsifying devices including homogenizer and agitator can be used. Also, though there is no special limitation to emulsifying conditions other than temperature, it is preferable that the emulsification is performed for 10 minutes to 20 minutes in terms of the process productivity and the prevention of the lowering of coenzyme QlO's activity. The aqueous composition containing coenzyme QlO as prepared above has excellent stability and transparency, and maintains its state even though it is kept at normal temperature for a long time or cooled. The aqueous composition containing coenzyme QlO as prepared above can be a liquid drink by itself, or can be used as an intermediate material in conventional production process for liquid drink.
< EXAMPLES >
The present invention will be described in more detail with reference to the following examples. These examples are provided only for illustrating the present invention and should not be construed as limiting the scope and spirit of the present invention.
Example 1
According to the composition given in the following Table 1, a SMEDDS composition was obtained by dissolving coenzyme QlO with decaglycerin myristic acid ester (Decaglycerol Monomylistate; Mitsubishi-Kagaku Foods Corporation, Japan) as surfactant and polyoxyethylene sorbitan fatty acid ester (Polyoxyethylene Sorbitan Monooleate; Kao Corporation, Japan) as cosurfactant at 55±10°C . The appropriate amount (about 100 mg) of purified water having the temperature of 55±10°C was then added to the obtained SMEDDS composition to prepare a microemulsion aqueous composition showing stability and transparency.
[Table 1] Composition of Example 1
Figure imgf000022_0001
Examples 2 to 9
According to the compositions given in the following Tables 2 to 9, microemulsion aqueous compositions of Examples 2 to 9 were prepared respectively in the same method as in Example 1.
[Table 2]
Composition of Example 2
Figure imgf000022_0002
Figure imgf000023_0001
[Table 3]
Composition of Example 3
Figure imgf000023_0002
[Table 4]
Composition of Example 4
Figure imgf000023_0003
[Table 5]
Composition of Example 5
Figure imgf000024_0001
[Table 6] Composition of Example 6
Figure imgf000024_0002
[Table 7]
Composition of Example 7
Figure imgf000024_0003
Figure imgf000025_0001
[Table 8]
Composition of Example 8
Figure imgf000025_0002
[Table 9]
Composition of Example 9
Figure imgf000025_0003
Comparative Examples 1 and 2
According to the compositions given in the following Tables 10 and 11, microemulsion aqueous compositions of Comparative Examples 1 and 2 were prepared respectively in the same method as in Example 1.
[Table 10] Composition of Comparative Example 1
Figure imgf000026_0001
[Table 11]
Composition of Comparative Example 2
Figure imgf000026_0002
Test Example 1: Analysis of particle size distribution of emulsified particle
The particle size distribution of the aqueous compositions prepared in the above examples and comparative examples were measured by a particle size analyzer (Shimadzu, SALD-2001 model, Japan). The results are shown in the following Table
12.
[Table 12] The measurement results of particle size distribution
Figure imgf000027_0001
As can be seen in the above Table 12, the microemulsified particles having an average particle size of about 0.09 jtM were formed in the coenzyme QlO SMEDDS compositions prepared in the examples of the present invention. These compositions were transparent liquid microemulsion compositions and had remarkably small emulsified particles, as compared to the compositions of the comparative examples which were opaquely dispersed liquid phase.
Test Example 2 : Test to precipitation formation
The precipitation formation and transparency of the microemulsion aqueous compositions prepared in the above examples and comparative examples were observed by the naked eyes. The results are shown in the following Table 13.
[ Table 13 ]
The observation results for precipitation formation and transparency
Figure imgf000028_0001
Figure imgf000029_0001
Test Example 3 : Test to stability and content
The SMEDDS compositions prepared in Examples 1 and 7 and the compositions of
Comparative Examples 1 and 2 were stored at high temperature (40 °C, 75% RH), room temperature (25 °C), and cold temperature (1 to 4 "C) for a long time. The content of coenzyme QlO in the samples according to the storage time was then analyzed by HPLC.
The results are shown in the following Table 14.
Analysis of coenzyme QlO
The samples of SMEDDS compositions (0.5 g to 1 g weighing) were added to 4 mL of water, and the mixtures were warmed at 50°C for 10 min and then cooled to room temperature. 10 mL of n-hexane and 5 mL of 2-propanol containing 0.1% ferric chloride were added thereto, and pure 2-propanol was added to prepare 50 mL solution. The resulting solution was separated by HPLC under the following conditions, and quantified with using a calibration curve plotted by using standard solutions in advance.
Column: L-column ODS 4.6mm 250mm
Column Temperature: 40 °C Mobile Phase: 60% methanol + 40% ethanol
Flow rate: l.O mL/min
Detector: UV
Wavelength: 275nm
[ Table 14 ]
The anlaysis of coenzyme QlO content
Figure imgf000030_0001
* Note Prcpt = Precipitation was formed, Color = Color was changed 0
As can be seen in the above Table 14, it was not possible to continue the tests for the
samples of comparative examples after 2 weeks since the precipitation was formed and
the color was changed. However, the samples of examples 1 and 7 exhibited significantly improved stability and transparency, and also the contents of coenzyme QlO were not substantially reduced under any condition of room temperature, high temperature, and cold temperature.
Test Example 4: Pharmacokinetic Test
A pharmacokinetic test for the microemulsion aqueous composition prepared in Example 1 was performed as follows.
Method of test (1) Test system: SD rats (Orient Bio corporation), male 7-week-old, acclimated for 7 days, supplied chow and water ad libitum, (n=4)
(2) Test drug (group):
Coenzyme QlO (CoQlO) SMEDDS composition prepared in Example 1 CoQlO raw material used for preparing the composition in Example 1 (Control)
(3) Dosage : 60 mg/kg via oral administration
(4) Blood sampling time : 0, 15 min, 30 min, 1, 2, 4, 6, 8, 12, and 24 hr
(5) Blood sampling site : capillary of orbital cavity (6) Method for analysis : LC/MS/MS
Sampling
Blood samples obtained from the respective times were centrifuged at 3,000 rpm for 10 min, and then 100 [d of supernatant plasma was moved to clean EP tube. The plasma samples were stored at a temperature of -20 °C (refrigerated) before analysis.
Conditions of LC/MS/MS analysis
Method for analysis: LC/MS/MS method Detector: MS/MS detector (Positive ion mode, MRM mode)
Coenzyme QlO: m/z 863.9 → 197.2 (Positive)
Coenzyme Q9 (internal standard substance): 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/hr
Collision gas flow: 0.2 L/hr
Collision gas: Argon Nebulizing gas: Nitrogen
Column: Shiseido Capcell PAK™ Cl 8 MG column (2.0 x 250 mm, 5 mm)
Data processor: MassLynx 4.1 Mobile phase: 0.5% formic acid (in isopropanol):0.5% formic acid (in acetonitrile) = 60:40
Flow rate: 0.25 niL/min
Injection volume: 7 μJL
Preparation of the standard solutions and plotting of the calibration curve
10 mg of coenzyme QlO was weighed precisely, diluted with isopropanol to make a solution of 1 mg/niL, and stored in refrigerator. Then, the solution was successively diluted to the concentrations of 1000, 500, 100, 50, 20, and 10 ng/niL. Coenzyme Q9 as an internal standard substance was added to acetonitrile to make a concentration of 0.5 βglmL.
Next, 100 μJt of rat's free-plasma, 100 μi of the standard solutions of respective drug concentration, 100 μi of internal standard solution (0.5 //g/mL of coenzyme Q9 in acetonitrile) and 200 jΛ of MeOH were added to a clean EP tube, and then vortexed. 2.5 niL of hexane was added thereto, shaken for 10 min, and then centrifuged at 2,000 rpm for 10 min. The supernatant layer of the solution was transferred to a clean test tube, and then evaporated by nitrogen gas. Then, the residue after evaporation was dissolved in 100 μi of isopropanol, from which the volume oi l μi was injected into LC/MS/MS.
The calibration curve was plotted with the ratio of peak area of coenzyme QlO versus peak area of the internal standard substance. Since endogenic coenzyme QlO also exists, background concentration was adjusted by subtracting the concentration peak of coenzyme QlO in free-plasma from that of the respective concentration.
Analysis of plasma sample
100 μi of plasma sample stored after the sampling was treated by the same method as described in the above section for the plotting of the calibration curve. Then, the concentrations of coenzyme QlO in the samples were calculated by extrapolating the ratio of peak area of coenzyme QlO versus peak area of the internal standard substance from the calibration curve. Pharmacokinetic profile of the CoQlO SMEDDS composition prepared in Example 1 of the present invention was made by using the calculated coenzyme QlO concentrations of the respective plasma samples. The result is shown in Figure 1. The profiles of raw material CoQlO and endogenic CoQlO are also shown as control groups.
Area under curves (AUC) and maximum concentrations (Cmax) calculated from the results of this test are shown in the following Table 15.
[ Table 15 ]
The result of pharmacokinetic test
Figure imgf000035_0001
As can be seen from the above Table 15 and Figure 1, the self-microemulsifying drug delivery system composition containing coenzyme QlO according to the present invention, when administered into the body, can remarkably improve the absorption of coenzyme QlO in a short time and thus increase the bioavailability greatly. INDUSTRIAL APPLICABILITY
According to the present invention, it is possible to obtain a composition containing coenzyme QlO, which has excellent stability, transparency and thermal stability, and increased bioavailability due to remarkably improved absorption of coenzyme QlO when administered as compared with conventional formulations, showing no precipitation, aggregation, recrystallization, deformation and content change even in a long-term storage, and so is particularly suitable for applications such as liquid drink, soft capsule, injection and the like. Further, the composition containing coenzyme QlO of the present invention can be easily prepared needless to apply large physical force and use special device such as a high speed agitator, and thus has economical advantages.

Claims

1. A self-microemulsifying drug delivery system composition containing coenzyme QlO, which comprises coenzyme QlO as active component, a surfactant and a cosurfactant.
2. The composition according to claim 1, wherein the surfactant is polyglycerin fatty acid ester.
3. The composition according to claim 1, wherein the cosurfactant is polyoxyethylene- sorbitan-fatty acid ester.
4. The composition according to claim 2, wherein the surfactant has a HLB value of 6 to 20.
5. The composition according to claim 1, wherein the cosurfactant has a HLB value of 7 or higher.
6. A method for preparing a self-microemulsifying drug delivery system composition containing coenzyme QlO, which is characterized in comprising comelting and mixing coenzyme QlO, surfactant and cosurfactant at the temperature of 40 °C to 70 °C .
7. An aqueous composition containing coenzyme QlO, which comprises an aqueous medium and the self-microemulsifying drug delivery system composition containing coenzyme QlO according to anyone of claims 1 to 5 emulsified in the aqueous medium.
8. A method for preparing an aqueous composition containing coenzyme QlO, which is characterized in comprising admixing the self-microemulsifying drug delivery system composition containing coenzyme QlO according to anyone of claims 1 to 5 with an aqueous medium at 40 "C to 70 °C .
PCT/KR2008/004373 2007-07-26 2008-07-25 Self-microemulsifying drug delivery system composition containing coenzyme q10 and method for preparing the same WO2009022798A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR20070075304 2007-07-26
KR10-2007-0075304 2007-07-26

Publications (2)

Publication Number Publication Date
WO2009022798A2 true WO2009022798A2 (en) 2009-02-19
WO2009022798A3 WO2009022798A3 (en) 2009-04-09

Family

ID=40351271

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2008/004373 WO2009022798A2 (en) 2007-07-26 2008-07-25 Self-microemulsifying drug delivery system composition containing coenzyme q10 and method for preparing the same

Country Status (2)

Country Link
KR (1) KR101057623B1 (en)
WO (1) WO2009022798A2 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102846544A (en) * 2011-08-29 2013-01-02 华北制药集团新药研究开发有限责任公司 Self-microemulsion composition of insoluble medicine
CN114869904A (en) * 2022-05-09 2022-08-09 广州汉光药业股份有限公司 Compound vitamin self-emulsifying drug delivery system and preparation method thereof
WO2022222683A1 (en) * 2021-04-23 2022-10-27 浙江新和成股份有限公司 Coenzyme q10 microemulsion, preparation method therefor and use thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000212066A (en) * 1998-11-16 2000-08-02 Eisai Co Ltd Aqueous liquid preparation of fat-soluble material
US20030147927A1 (en) * 2001-11-14 2003-08-07 Khan Mansoor A. Eutectic-based self-nanoemulsified drug delivery system
WO2004050072A1 (en) * 2002-12-04 2004-06-17 Nisshin Pharma Inc. Water-soluble composition containing coenzyme q10
KR100712823B1 (en) * 2006-02-23 2007-05-02 한국유나이티드제약 주식회사 The solubilized coenzyme q10 soft capsules composition and the producing method thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000212066A (en) * 1998-11-16 2000-08-02 Eisai Co Ltd Aqueous liquid preparation of fat-soluble material
US20030147927A1 (en) * 2001-11-14 2003-08-07 Khan Mansoor A. Eutectic-based self-nanoemulsified drug delivery system
WO2004050072A1 (en) * 2002-12-04 2004-06-17 Nisshin Pharma Inc. Water-soluble composition containing coenzyme q10
KR100712823B1 (en) * 2006-02-23 2007-05-02 한국유나이티드제약 주식회사 The solubilized coenzyme q10 soft capsules composition and the producing method thereof

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102846544A (en) * 2011-08-29 2013-01-02 华北制药集团新药研究开发有限责任公司 Self-microemulsion composition of insoluble medicine
WO2022222683A1 (en) * 2021-04-23 2022-10-27 浙江新和成股份有限公司 Coenzyme q10 microemulsion, preparation method therefor and use thereof
CN114869904A (en) * 2022-05-09 2022-08-09 广州汉光药业股份有限公司 Compound vitamin self-emulsifying drug delivery system and preparation method thereof
CN114869904B (en) * 2022-05-09 2023-10-20 广州汉光药业股份有限公司 Compound vitamin self-emulsifying drug delivery system and preparation method thereof

Also Published As

Publication number Publication date
KR101057623B1 (en) 2011-08-19
WO2009022798A3 (en) 2009-04-09
KR20090012185A (en) 2009-02-02

Similar Documents

Publication Publication Date Title
US9981899B2 (en) Composition containing reduced coenzyme Q10 and production method thereof
JP5343002B2 (en) Bioactive substance-containing composition
JP5256041B2 (en) Biologically active substance-containing particulate composition and method for producing the same
US20190365667A1 (en) Oral cannabinoid formulations
ZA200402692B (en) Composition comprising paracetamol and a bitterness masking component.
JP2004196781A (en) Water-soluble composition containing coenzyme q10
WO2009022798A2 (en) Self-microemulsifying drug delivery system composition containing coenzyme q10 and method for preparing the same
JP3195360B2 (en) Pharmaceutical composition containing tiagabine hydrochloride and method for producing the same
US20100092560A1 (en) Reduced coenzyme q10-containing particulate composition and method for producing the same
KR100712823B1 (en) The solubilized coenzyme q10 soft capsules composition and the producing method thereof
JP5028885B2 (en) Ubidecalenone-containing self-emulsifying composition
CN116209437B (en) Butylphthalide composition delivered through oral mucosa and application thereof
JP2009149584A (en) Reduced coenzyme q10-containing particulate composition and its manufacturing method
CN114681432A (en) Butylphthalide composition and application thereof
KR100786884B1 (en) Water soluble composition containing coenzyme q10
JP2007051115A (en) Liposoluble medicament composition
EP3644967A1 (en) A stable aqueous hydroxycarbamide solution
KR20190098638A (en) A pharmaceutical composition comprising bisphosphonate and cholecalciferol, and its manufacturing method
CN116370442A (en) Pharmaceutical composition, method for stabilizing pharmaceutical composition, and method for evaluating storage stability of pharmaceutical composition
EP4101442A1 (en) Process for preparing compacted coenzyme q10 particles of high density and improved flowability
EP4289417A1 (en) Process for preparing high-density quercetin
JP4747534B2 (en) W / O / W type composite emulsion
JP5181497B2 (en) Ubidecarenone-containing composition for solid preparations
JP6499970B2 (en) Easy to take jelly-like pharmaceutical composition
WO2022187295A1 (en) Poloxamer compositions and beverages

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08778942

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08778942

Country of ref document: EP

Kind code of ref document: A2