WO2007086689A1

WO2007086689A1 - A solid dispersion comprising ubidecarenone, a process for preparing the same and a pharmaceutical composition comprising the same

Info

Publication number: WO2007086689A1
Application number: PCT/KR2007/000436
Authority: WO
Inventors: Ji Sun Kim; Se Jong Lee; Hee Chul Chang; Min Suk Lee
Original assignee: Daewoong Pharmaceutical Co., Ltd.
Priority date: 2006-01-26
Filing date: 2007-01-25
Publication date: 2007-08-02
Also published as: KR100956583B1; KR20070078272A

Abstract

The present invention relates to a solid dispersion of ubidecarenone, a process for preparing the same, and a pharmaceutical composition comprising the same. The present invention provides a solid form of ubidecarenone which has improved solubility and bioavailability, and is easy to handle.

Description

A SOLID DISPERSION COMPRISING UBIDECARENONE, A PROCESS FOR

PREPARING THE SAME AND A PHARMACEUTICAL COMPOSITION

COMPRISING THE SAME

TECHNICAL FIELD

The present invention relates to a solid dispersion of ubidecarenone, a process for

preparing the same, and a pharmaceutical composition comprising the same.

BACKGROUND ART

In using insoluble and/or non- absorbable materials as medicament, many studies have

been made to improve their solubility and absorbability. As one physicochemical

method disclosed in those studies, amorphization has been known. Amorphization is a

method to disrupt and micronize the crystal structure of a material to molecular level.

One form of amorphization is solid dispersion. Solid dispersion comprises materials

which are dispersed at molecular level in solid, i.e., wherein solid is dissolved in solid.

In solid dispersion, dispersed materials do not contact with each other. Therefore,

crystallization is difficult to occur, and thus the stability of a material is usually improved

in amorphization state. As processes for preparing solid dispersion, there have been known solvent method

wherein solvent is removed by dissolving material and hydrophilic polymer in suitable

solvent [See, Chem. Pharm. Bull., 34(8), 3408 (1986)]; melting method wherein material

and hydrophilic polymer are dissolved, followed by cooling and solidification [See, J.

Pharm. ScL, 59, 937 (1970)]; mixing and crushing method wherein material and

hydrophilic polymer are mixed and crushed by using ball mill and the like [See,

pharmacology, 45(4), 291 (1985)]; spray drying method wherein drug and hydrophilic

polymer are spray-dried [See, Chem. Pharm. Bull., 44(3); 568(1996)], etc.

One of representative insoluble drugs is ubidecarenone (hereinafter referred as ¹¹CoQlO").

CoQlO exists in the electron transfer system of myocardial mitochondria, and conducts

principal biochemical function in energy generation. CoQlO is clinically efficacious

against diseases comprising chronic hypertension, ischemic heart disease, congestion due

to heart failure, angina pectoris, hypomyotonia, periodontal disease, drug-induced

deficiency, and disorder of the immune system (or autoimmune disease) (AIDS, allergy).

In addition, CoQlO has strong anti-oxidation activity, and so may prevent aging and

various diseases. CoQlO is included mainly in fish and meat, but food intake only is not sufficient to satisfy a required amount. Further, as human beings get older, the amount

of CoQlO in the body decreases. Thus, it is desirable to complement additional CoQlO

to the body for preserving physical vitality and preventing arteriosclerosis.

Necessity for CoQlO has been increased for the above reasons, but its usage has been

limited due to its physico-chemical properties. That is, CoQlO is a yellow insoluble

powder at room temperature (the melting point of CoQlO: 48 ^°C-52^°C), has poor

absorbability and bioavailability due to its high molecular weight and crystallinity. In

addition, CoQlO is unstable to light, heat or alkali, and has low meting point. Thus,

CoQlO is difficult to be developed as various formulations.

The processes for preparing liquid formulation by solubilizing CoQlO were disclosed in

Korean Patent Application No. 1992-12250, Korean Patent No. 27307, etc. CoQlO

aqueous solution prepared by these processes has low content of CoQlO and high content

of surfactant. Also, since it is liquid, the stability is decreased and the handling is

difficult. Thus, CoQlO solution is difficult to apply to most solid formulations.

Korean Patent Application No. 2005-0084126 also disclosed an aqueous composition containing CoQlO whose average particle size is l lOnm or less, by using polyglycerine

having 10 of average polymerization degree, and monoester of fatty acid having 18 of

carbon atom number; or polyglycerine having 3-6 of average polymerization degree,

mono-, di-, tri- or penta-ester of fatty acid having 18 of carbon atom number, and water.

However, this process uses homogenizing treatment to make the particle size small by

using homogenizer, and so the particle size becomes larger in time. Thus, the prepared

aqueous solution has a stability problem, and is suitable only for liquid formulation having

low content of CoQlO. To overcome these problems of aqueous formulation of CoQlO,

a study for powder to solubilize CoQlO has been an alternative.

Regarding the powder to solubilize CoQlO, US Patent No. 5,989,583 disclosed a process

for preparing solid powder containing 10-15% of CoQlO, by using solid lipid,

phospholipids, and other saccharide, with a freeze drying or spray drying method.

However, the above process has such problems as having a relatively low content of

CoQlO, requiring high-cost apparatus in using a freeze-drying method, and increasing the

manufacturing cost since the preparation time is very long. Thus, this process is

disadvantageous to mass production. Korean Patent No. 28370 disclosed a process for dissolving fat-soluble active vitamin or

CoQlO by using hydrogenated lecithin. However, this process also has problems of

requiring other dissolving solubilizing agent, and having low solubility and stability.

US Patent Application No. 2003-0147927 disclosed a process for preparing solid powder

of CoQlO by mixing self-nanoemulsified drug delivery system (SNEDDS) to use oil,

surfactant and medium chain mono-and diglyceride, with Kollidone VA 64, maltodextrin,

non-crystalline cellulose, etc. However, this process requires a large amount of other

excipient to solidify liquid SNEDDS, and also has problems that the content of CoQlO is

low, and the handling is difficult due to a large amount of liquid excipient.

US Patent Application No. 2005-0142123 disclosed a process of granulating

polysaccharide or gelatin solution, comprising the steps of mixing melted polysaccharide

or gelatin solution by heat with CoQlO melted solution, homogenizing the mixture under

high pressure, spraying it with fluidized bed granulator, and granulating it with corn starch.

However, this process requires a long time, and is not simple since the emulsion's particle

size is reduced by using homogenization under high pressure. DISCLOSURE OF THE INVENTION

The present inventors have searched a solid dispersion of CoQlO which overcomes the

above problems and can improve solubility and bioavailability of CoQlO, and discovered

that a solid CoQlO whose solubility and stability are improved, and whose handling is

easy can be prepared by combining emulsifier and hydrophilic polymer, to complete the

present invention.

One object of the present invention is to provide a solid dispersion of CoQlO which has

increased solubility and bioavailability, and improved stability and physical properties.

The solid dispersion contains an increased amount of CoQlO.

Another objection of the present invention is to provide a process for preparing the solid

dispersion of CoQlO.

Still, another object of the present invention is to provide a pharmaceutical composition

comprising the solid dispersion of CoQlO. DETAILED DESCRIPTION OF THE INVENTION

As one embodiment, the present invention relates to a solid dispersion of CoQlO

comprising CoQlO, emulsifier, and hydrophillic polymer.

CoQlO is an insoluble material having the following formula I, which comprises, but not

limited to, crystalline CoQlO.

[Formula I]

An emulsifier included in the solid dispersion of the present invention is a material to

improve the dissolution rate of hydrophobic CoQlO, and any emulsifier may be used as

long as the emulsifier exists as solid or semi-solid at room temperature. For example, the

emulsifier include polyglycerine fatty acid ester; sucrose fatty acid ester; polyoxyethylene-

polyoxypropylene block copolymer; sorbitan fatty acid ester; mixture of polyethylene

glycol fatty acid ester and mono-, di- or tri- glyceride; mono-, di- or mono/di-glyceride

such as caprylic/capric acid mono- or di-glyceride; polyoxyethylene glycolated natural or hydrogenated castor oil; polyoxyethylene fatty acid ester; propylene glycol mono- or di-

fatty acid ester; organic acid, etc., preferably polyglycerine fatty acid ester or

polyoxyethylene-polyoxypropylene block copolymer, more preferably polyglycerine fatty

acid ester including decaglycerine monostearate, decaglycerine monooleate, decaglycerine

monolinolate and the like.

The amount of the emulsifier used in the present invention may be 0.1-20 parts by weight,

preferably 0.2-10 parts by weight, per 1 part by weight of CoQlO. If the amount of the

emulsifier is less than 0.1 part by weight, the dissolution of the active ingredient is little

improved, and if the amount is more than 20 parts by weight, it is difficult to prepare the

active ingredient as tablet or capsule which is easy to use and handle.

A hydrophillic polymer of the present invention is a material used for dispersing CoQlO

and improving stability and physical properties of CoQlO. The kind of the hydrophillic

polymer is not specifically limited, and so any kind can be used as long as the hydrophilic

polymer is pharmaceutically acceptable or acceptable as food. For example, the

hydrophilic polymer includes alkylcellulose such as methylcellulose;

hydroxyalkylcellulose such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxybutylcellulose; hydroxyalkyl alkylcellulose such as

hydroxyethyl methylcellulose or hydroxypropyl methylcellulose; carboxyalkylcellulose

such as carboxymethylcellulose; alkali metal salt of carboxyalkylcellulose such as sodium

carboxyalkylcellulose; carboxyalkylalkylcellulose such as carboxymethylethylcellulose;

carboxyalkylcellulose ester; starch; pectin such as sodium carboxymethylamylopectin;

chitin derivative such as chitosan; alginic acid, alkali metal and ammonium salt thereof;

polysacharride such as caraginan, galactomannan, tragacanth, agar-agar, gum arabic, guar

gum, xanthan gum, dextrin, cyclodextrin(CyD) or maltodextrin; polyacrylic acid and salt

thereof; polymethacrylic acid and salt thereof, methacrylate copolymer, aminoalkyl

methacrylate copolymer; polyvinylacetaldiethylaminoacetate; sacharride -based surfactant

such as sucrose distearate, sucrose monostearate, sucrose monopalmitate, etc.;

polyvinylalcohol; polyvinylpyrrolidone; copolymer of vinyl acetate and

polyvinylpyrrolidone; polyalkylene oxide such as polyethylene oxide and polypropylene

oxide; polyethylene glycol polyvinylalcoholester; and copolymer of ethylene oxide and

propylene oxide; and the like; preferably hydroxypropylcellulose,

hydroxypropylmethylcellulose, polyvinylalcohol, polyvinylpyrrolidone, polyethylene

glycol polyvinylalcoholester, dextrin, cyclodextrin, maltodextrin, and the like. The

hydrophillic polymer may be used alone, or in a mixture form thereof. The amount of the hydrophillic polymer used in the present invention may be 0.1-20 parts

by weight, preferably 0.2-10 parts by weight, per 1 part by weight of CoQlO.

In the present invention, the physical properties of the solid dispersion may be more

improved when the emulsifier and the hydrophilic polymer are used together, than when

the emulsifier is used alone. Also, in the solubility, when the solid dispersion is prepared

by using the emulsifier and the hydrophilic polymer together, the physical properties may

be improved, the particle size may become smaller, and the dispersion may work well, and

so superior improvement in the dissolution rate is observed. Thus, by preparing soluble

CoQlO solid dispersion with using semi-solid or solid emulsifier at room temperature and

the hydrophillic polymer as carriers of the solid dispersion, the solid's powderizing

becomes possible, wherein the dissolution rate and stability are improved, and the

handling is easy.

CoQlO solid dispersion of the present invention may further comprise an antioxidant. The

antioxidant may decrease oxidative degradation of CoQlO, and prevent oxidation of the

emulsifier that is a kind of lipid, and thus improve stability of the solid dispersion. The examples of the antioxidant include tocopherol and its analogues (e.g., tocopherol acetate),

butylate hydroxytoluene, and the like. The amount of the antioxidant used in the present

invention may be 0.0001-0.1 part by weight, preferably 0.001-0.05 part by weight, per 1

part by weight of CoQlO.

To make CoQlO solid dispersion of the present invention more easily manageable and to

improve fluidity of the solid dispersion, an inorganic carrier such as silicon dioxide, talc,

hydrotalcite, aluminum magnesium silicate, titanium dioxide, stearic acid, magnesium

stearate or combination thereof, preferably silicon dioxide, may be additionally used.

The amount of the inorganic carrier may be 0.001-2 parts by weight, preferably 0.01-1

part by weight, per 1 part by weight of CoQlO.

In another embodiment, the present invention provides a process for preparing the solid

dispersion of CoQlO.

For example, the present invention provides a process for preparing the solid dispersion of

CoQlO comprising the steps of: (A) dissolving or dispersing CoQlO, an emulsifier and a

hydrophillic polymer in a suitable solvent to form a dissolved or dispersed material; and (B) removing the solvent from the dissolved or dispersed material. In the above process,

to dissolve or disperse CoQlO, the emulsifier and the hydrophilic polymer in solvent more

easily, the step (A) may be carried out under heating, wherein the heating range is not

limited to, but preferably, 40-70 ^°C . Preferably, the process may further comprise

dissolving or dispersing an antioxidant or an emulsifier, in the step (A).

The solvent used in preparing CoQlO solid dispersion of the present invention may be any

one which is pharmaceutically acceptable or acceptable as food, and which can dissolve or

disperse CoQlO, emulsifier and hydrophillic polymer. As the solvent, methanol, ethanol,

isopropylalcohol, dichloromethane, acetone, hexane and the like may be used alone or in

mixture of two or more. Preferably, ethanol, dichloromethane or acetone may be used.

When used in mixture, the ratio of ethanol to dichloromethane or acetone can be 1 : 1 to

2 : 1. The amount of the solvent is preferably l~50 parts by weight, more preferably

5-20 parts by weight, per 1 part by weight of the total weight of CoQlO, the emulsifier

and the hydrophillic polymer.

In the preparation of CoQlO solid dispersion of the present invention, the solvent may be

removed by using any conventional method known in the art. For example, the solvent may be removed by spray-drying in spray-dryer or fluidized bed granulator.

dispersion of CoQlO comprising the steps of: heating CoQlO, an emulsifier and a

hydrophillic polymer to a temperature of 180-260 ^°C , preferably 200-240 ^°C , to melt the

mixture homogeneously; and cooling rapidly and pulverizing the resulted mixture.

The CoQlO solid dispersion prepared by the present invention has very superior

dissolution property and stability. And, the present solid dispersion may be easily

prepared, and has very good absorbance and superior oral absorbance.

In another embodiment, the present invention provides a pharmaceutical composition

comprising the CoQlO solid dispersion.

The solid dispersion of the present invention may be used as medicament, but it is usually

preferable to be administered in the forms of formulation such as fine granule, granule,

tablet, capsule, dry syrup, etc. Such forms of formulation may be prepared from the

present solid dispersion through conventional formulating processes such as mixing, granulating, tabletting, coating, and capsule-filling by using formulating apparatus. Also,

if necessary, pharmaceutical composition may be prepared by using suitable formulating

additive, and thus prepared pharmaceutical composition may be formulated into the above

forms of formulation.

The formulating additive may include, but is not limited to, excipient (e.g., lactose,

mannitol, crystalline cellulose, corn starch, potato starch, etc.), disintegrant (e.g., sodium

carboxymethylstarch, calcium carboxymethylcellulose, sodium crosscameros,

polyvinylpolypyrrolidone, low-substituted hydroxypropylcellulose,

carboxymethylcellulose, etc.), rheology enhancer (e.g., hard anhydrous silicic acid,

hydrous silica, etc.), colorant (e.g., titanium oxide, yellow iron sesquioxide, etc.),

condiment (e.g., tartaric acid, ascorbic acid, citric acid, etc.), surfactant (e.g., sodium

lauryl sulfate, polysorbate 80, polyoxyethylene hydrogenated castor oil, etc.), dispersing

agent (e.g., crystalline cellulose, carboxyvinyl polymer, etc.), and lubricant (e.g.,

magnesium stearate, etc.). And, the amount of these additives may be selected suitably

by a skilled artisan. These additives may be added suitably in one or more processes, for

example, in the process of preparing the solid dispersion or a formulation from the solid

dispersion. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 represents data showing the dissolution test results on CoQlO capsules prepared

by the methods of Formulation Examples 1 and 2; and Comparative Examples 1 and 2.

Figure 2 is a graph comparing by time, (i) CoQlO concentration in the serum of rat

administered with CoQlO formulation prepared by the method of Comparative Example 1

(■); (ii) CoQlO concentration in the serum of rat administered with CoQlO formulation

prepared by the method of Formulation Example 1 (o); and (iii) as negative control, serum

concentration of endogenous CoQlO existing in rat's living body not administered with

anything (A).

Figure 3 represents patterns of X-ray powder diffraction data on CoQlO solid dispersion

prepared by the method of Example 1 according to the present invention; and crystalline

CoQlO raw material.

Figure 4 represents differential scanning calorimeter charts of CoQlO solid dispersion prepared by the method of Examples 1 and 2 according to the present invention; and

crystalline CoQlO raw material.

Figure 5 represents optical microscopic photo of CoQlO solid dispersion prepared by the

method of Example 1 according to the present invention; and crystalline CoQlO raw

material. Photos (a) and (b) show crystalline CoQlO raw material; and photos (c) and (d)

show CoQlO solid dispersion prepared by the method of Example 1 according to the

present invention.

The present invention will be more specifically explained in the following examples.

However, it should be understood that the following examples are intended to illustrate the

present invention, and cannot limit the scope of the present invention in any manner.

Example 1: Preparation of solid dispersion containing 33.3% of CoQlO

With heating 500inf, of ethanol to a temperature of 40-50 ^°C , 2Og (33.3%) of

decaglycerine monostearate was added thereto, stirred and dissolved, to which 18.74g

(31.2%) of hydroxypropylmethylcellulose was added and slowly dispersed. This solution was mixed with 2Og (33.3%) of CoQlO in 500m£ of dichloromethane. Then,

0.06g (0.1%) of DL-α-tocopheryl acetate and 1.2g (2%) of silicon dioxide were further

added to the solution, which was mixed homogeneously. 48.5g of solid dispersion was

prepared from the above mixed solution by using spray dryer (N-DlOl, Dongjin

Technology Institute). The spray-drying conditions were as follows:

Inlet temp.: 80 ^°C , Outlet temp.: 48-53 ^°C, Atomizer speed (disc type): 10,000

rpm, Flow rate (peristaltic pump): 4.0.

Example 2: Preparation of solid dispersion containing 25% of CoQlO

With heating 80OmU of ethanol to a temperature of 40-50 ^°C , 2Og (25.0%) of

decaglycerine monostearate was added thereto, and stirred and dissolved, to which 38.32g

(47.9%) of hydroxypropylmethylcellulose was addted and slowly dispersed. This

solution was mixed with 2Og (25.0%) of CoQlO in 800m£ of dichloromethane. Then,

0.08g (0.1%) of DL-α-tocopheryl acetate and 1.6g (2%) of silicon dioxide were further

added to the solution, which was mixed homogeneously. 62.7g of solid dispersion was

prepared from the above mixed solution by using spray dryer (N-DlOl, Dongjin

Technology Institute). Example 3: Preparation of solid dispersion containing 33.3% of CoQlO

With heating 500m£ of ethanol to a temperature of 40-50 ^°C, 2Og (33.3%) of

decaglycerine monostearate was added thereto, and stirred and dissolved, to which 18.74g

(31.2%) of hydroxypropylmethylcellulose was added and slowly dispersed. This

solution was mixed with 2Og (33.3%) of CoQlO in 50(M of acetone. Then, 0.06g

(0.1%) of DL-otocopheryl acetate and 1.2g (2%) of silicon dioxide were further added to

the solution, which was mixed homogeneously. 48.5 g of solid dispersion was prepared

from the above mixed solution by using spray dryer (N-DlOl, Dongjin Technology

Institute).

Example 4: Preparation of solid dispersion containing 25% of CoQlO

With heating 80OmC, of ethanol to a temperature of 40-50 ^°C , 2Og (25%) of decaglycerine

monostearate was added thereto, and stirred and dissolved, to which 38.32g (47.9%) of

hydroxypropylmethylcellulose was added and slowly dispersed. This solution was

mixed with 2Og (25.0%) of CoQlO in 80OmC, of acetone. Then, 0.08g (0.1%) of DL-α- tocopheryl acetate and 1.6g (2%) of silicon dioxide were further added to the solution,

which was mixed homogeneously. 62.7g of solid dispersion was prepared from the above

mixed solution by using spray dryer (N-DlOl, Dongjin Technology Institute).

Example 5 Preparation of solid dispersion containing 33.3% of CoQlO

With heating 50OmC of ethanol to a temperature of 50-60 ^°C, 2Og (33.3%) of

(31.2%) of hydroxypropylmethylcellulose was added and slowly dispersed. This

solution was mixed with 2Og (33.3%) of CoQlO in 50Om-C of dichloromethane. Then,

added to the solution, which was mixed homogeneously. 48.5 g of solid dispersion was

prepared from the above mixed solution by using spray dryer (N-DlOl, Dongjin

Technology Institute).

Example 6: Preparation of solid dispersion containing 25% of CoQlO

With heating 80OmC. of ethanol to a temperature of 50-60 ^°C , 2Og (25%) of decaglycerine monostearate was added thereto, and stirred and dissolved, to which 38.32g (47.9%) of

hydroxypropylmethylcellulose was added and slowly dispersed. This solution was

mixed with 2Og (25.0%) of CoQlO in 800m£ of dichloromethane. Then, 0.08g (0.1%) of

DL-α-tocopheryl acetate and 1.6g (2%) of silicon dioxide were further added to the

solution, which was mixed homogeneously. 62.7g of solid dispersion was prepared from

the above mixed solution by using spray dryer (N-DlOl, Dongjin Technology Institute).

Example 7: Preparation of solid dispersion containing 33.3% of CoQlO

With heating 500m4 of ethanol to a temperature of 50-60 ^°C, 2Og (33.3%) of

(31.2%) of hydroxypropylmethylcellulose was added and slowly dispersed. This

solution was mixed with 2Og (33.3%) of CoQlO in 500in£ of acetone. Then, 0.06g

(0.1%) of DL-α-tocopheryl acetate and 1.2g (2%) of silicon dioxide were further added to

the solution, which was mixed homogeneously. 48.5g of solid dispersion was prepared

from the above mixed solution by using spray dryer (N-DlOl, Dongjin Technology

Institute). Example 8: Preparation of solid dispersion containing 25% of CoQlO

With heating 800ml of ethanol to a temperature of 50-60 ^°C, 2Og (25%) of decaglycerine

hydroxypropylmethylcellulose was added and slowly dispersed. This solution was

mixed with 20g(25.0%) of CoQlO in 80OmC of acetone. Then, 0.08g (0.1%) of DL-α-

tocopheryl acetate and 1.6g (2%) of silicon dioxide were further added to the solution,

which was mixed homogeneously. 62.7g of solid dispersion was prepared from the

above mixed solution by using spray dryer (N-DlOl, Dongjin Technology Institute).

Example 9: Preparation of solid dispersion containing 33.3% of CoQlO

With heating 500ml of ethanol to a temperature of 60-70 ^°C , 2Og (33.3%) of

(31.2%) of hydroxypropylmethylcellulose was added and slowly dispersed. This

solution was mixed with 2Og (33.3%) of CoQlO in 500inf, of dichloromethane. Then,

added to the solution, which was mixed homogeneously. 48.5 g of solid dispersion was prepared from the above mixed solution by using spray dryer (N-DlOl, Dongjin

Technology Institute).

Example 10: Preparation of solid dispersion containing 25% of CoQlO

With heating 800m£ of ethanol to a temperature of 60-70 ^°C, 2Og (25%) of decaglycerine

hydroxypropylmethylcellulose was added and slowly dispersed. This solution was

mixed with 2Og (25.0%) of CoQlO in 80(M of dichloromethane. Then, 0.08g (0.1%) of

Example 11: Preparation of solid dispersion containing 33.3% of CoQlO

With heating 500m£ of ethanol to a temperature of 60~70^°C , 2Og (33.3%) of

(31.2%) of hydroxypropylmethylcellulose was added and slowly dispersed. This solution was mixed with 2Og (33.3%) of CoQlO in 500ml, of acetone. Then, 0.06g

from the above mixed solution by using spray dryer (N-DlOl, Dongjin Technology

Institute).

Example 12: Preparation of solid dispersion containing 25% of CoQlO

With heating 800ml of ethanol to a temperature of 60-70 ^°C , 2Og (25%) of decaglycerine

hydroxypropylmethylcellulose was added and slowly dispersed. This solution was

mixed with 2Og (25.0%) of CoQlO in 800in£ of acetone. Then, 0.08g (0.1%) of DL-α-

which was mixed homogeneously. 62.7g of solid dispersion was prepared from the

above mixed solution by using spray dryer (N-D 101, Dongj in Technology Institute) .

Example 13: Preparation of solid dispersion containing 33.3% of CoQlO 2Og (33.3%) of CoQlO, 2Og (33.3%) of decaglycerine monostearate and 18.74g (31.2%)

of hydroxypropylmethylcellulose were heated and melted with stirring at the temperature

range of 200-240 ^°C to obtain homogeneously molten material. And, the molten material

was cooled rapidly on ice-water. After cooling sufficiently, thus cooled material was

suitably pulverized and passed through No. 60 sieve to obtain 54.2g of solid dispersion.

Example 14: Preparation of solid dispersion containing 25% of CoQlO

2Og (25.0%) of CoQlO, 2Og (25.0%) of decaglycerine monostearate and 38.32g (47.9%)

range of 200-240 °C to obtain homogeneously molten material. And, the molten

material was cooled rapidly on ice-water. After cooling sufficiently, thus cooled material

was suitably pulverized and passed through No. 60 sieve to obtain 72.6g of solid

dispersion.

Example 15: Preparation of solid dispersion containing 33.3% of CoQlO

With heating 50OmK of ethanol to a temperature of 40-50 ^°C , 2Og (33.3%) of decaglycerine monooleate was added thereto, and stirred and dissolved, to which 18.74g

(31.2%) of hydroxypropylmethylcellulose was added and slowly dispersed. This

prepared from the above mixed solution by using spray dryer (N-DlOl, Dongjin

Technology Institute).

Example 16: Preparation of solid dispersion containing 25% of CoQlO

With heating 800ia£ of ethanol to a temperature of 40-50 ^°C , 2Og (25.0%) of

decaglycerine monooleate was added thereto, and stirred and dissolved, to which 38.32g

(47.9%) of hydroxypropylmethylcellulose was added and slowly dispersed. This

solution was mixed with 2Og (25.0%) of CoQlO in 800ml, of dichloromethane. Then,

prepared from the above mixed solution by using spray dryer (N-DlOl, Dongjin

Technology Institute). Example 17: Preparation of solid dispersion containing 33.3% of CoQlO

2Og (33.3%) of CoQlO, 2Og (33.3%) of decaglycerine monooleate and 18.74g (31.2%) of

hydroxypropylmethylcellulose were heated and melted with stirring at the temperature

suitably pulverized and passed through No. 60 sieve to obtain 53.7g of solid dispersion.

Example 18: Preparation of solid dispersion containing 25% of CoQlO

2Og (25.0%) of CoQlO, 2Og (25.0%) of decaglycerine monooleate and 38.42g (47.9%) of

suitably pulverized and passed through No. 60 sieve to obtain 71.5g of solid dispersion.

Example 19: Preparation of solid dispersion containing 33.3% of CoQlO 18.74g (31.2%) of hydroxypropylmethylcellulose was slowly dispersed in 500m£ of

ethanol, and then 2Og (33.3%) of poloxamer 407 was added thereto and dissolved at room

temperature. This solution was mixed with 2Og (33.3%) of CoQlO in 500ffl# of

dichloromethane. Then, 0.06g (0.1%) of DL-α-tocopheryl acetate and 1.2g (2%) of

silicon dioxide were further added to the solution, which was mixed homogeneously.

48.5 g of solid dispersion was prepared from the above mixed solution by using spray

dryer (N-DlOl, Dongjin Technology Institute).

Example 20: Preparation of solid dispersion containing 25% of CoQlO

38.32g (47.9%) of hydroxypropylmethylcellulose was slowly dispersed in 800in# of

ethanol, and then 2Og (25.0%) of poloxamer 407 was added thereto and dissolved at room

temperature. This solution was mixed with 2Og (25.0%) of CoQlO in 800ml, of

dichloromethane. Then, 0.08g (0.1%) of DL-α-tocopheryl acetate and 1.6g (2%) of

62.7g of solid dispersion was prepared from the above mixed solution by using spray

dryer (N-DlOl, Dongjin Technology Institute). Example 21: Preparation of solid dispersion containing 33.3% of CoQlO

2Og (33.3%) of CoQlO, 2Og (33.3%) of poloxamer 407 and 18.74g (31.2%) of

suitably pulverized and passed through No. 60 sieve to obtain 53.2g of solid dispersion.

Example 22: Preparation of solid dispersion containing 25% of CoQlO

2Og (25.0%) of CoQlO, 2Og (25.0%) of poloxamer 407 and 38.32g (47.9%) of

suitably pulverized and passed through No. 60 sieve to obtain 72.4g of solid dispersion

Example 23: Preparation of solid dispersion containing 33.3% of CoQl O With heating 50(M of ethanol to a temperature of 40-50 ^°C , 2Og (33.3%) of

decaglycerine monostearate was added thereto, and stirred and dissolved, to which 9.37g

(15.6%) of povidone K-30 and 9.37g (15.6%) of hydroxypropylmethylcellulose were

added, and slowly dispersed. This solution was mixed with 2Og (33.3%) of CoQlO in

500ml of dichloromethane. Then, 0.06g (0.1%) of DL-α-tocopheryl acetate and 1.2g

(2%) of silicon dioxide were further added to the solution, which was mixed

homogeneously. 48.5 g of solid dispersion was prepared from the above mixed solution

by using spray dryer (N-DlOl, Dongjin Technology Institute).

Example 24: Preparation of solid dispersion containing 25% of CoQlO

With heating 800in£ of ethanol to a temperature of 40-50 ^°C , 2Og (25.0%) of

decaglycerine monostearate was added thereto, and stirred and dissolved, to which 19.16g

(23.95%) of povidone K-30 and 19.16g (23.95%) of hydroxypropylmethylcellulose were

added, and slowly dispersed. This solution was mixed with 2Og (25.0%) of CoQlO in

80OmC, of dichloromethane. Then, 0.08g (0.1%) of DL-α-tocopheryl acetate and 1.6g

(2%) of silicon dioxide were further added to the solution, which was mixed homogeneously. 62.7g of solid dispersion was prepared from the above mixed solution

by using spray dryer (N-DlOl, Dongjin Technology Institute).

Example 25: Preparation of solid dispersion containing 33.3% of CoQlO

20g(33.3%) of CoQlO, 20g(33.3%) of decaglycerine monostearate, 9.37g(15.6%) of

povidone K-30 and 9.37g(15.6%) of hydroxypropylmethylcellulose were heated and

melted with stirring at the temperature range of 200-240 ^°C to obtain homogeneously

molten material. And, the molten material was cooled rapidly on ice-water. After

cooling sufficiently, thus cooled material was suitably pulverized and passed through No.

60 sieve to obtain 52.5g of solid dispersion.

Example 26: Preparation of solid dispersion containing 25% of CoQlO

2Og (25.0%) of CoQlO, 2Og (25.0%) of decaglycerine monostearate, 19.16g (23.95%) of

povidone K-30 and 19.16g (23.95%) of hydroxypropylmethylcellulose were heated and

molten material. And, the molten material was cooled rapidly on ice-water. After cooling sufficiently, thus cooled material was suitably pulverized and passed through No.

60 sieve to obtain 71.6g of solid dispersion.

Example 27: Preparation of solid dispersion containing 33.3% of CoQlO

18.74g (31.2%) of hydroxypropylmethylcellulose was slowly dispersed in

of

ethanol, and then 2Og (33.3%) of sucrose fatty acid ester (HLB=I 2) was added thereto and

dissolved at room temperature. This solution was mixed with 2Og (33.3%) of CoQlO in

500m# of dichloromethane. Then, 0.06g (0.1%) of DL-α-tocopheryl acetate and 1.2g

(2%) of silicon dioxide were further added to the solution, which was mixed

homogeneously. 48.5g of solid dispersion was prepared from the above mixed solution

by using spray dryer (N-DlOl, Dongjin Technology Institute).

Example 28: Preparation of solid dispersion containing 25% of CoQlO

38.32g (47.9%) of hydroxypropylmethylcellulose was slowly dispersed in 800iiιP, of

ethanol, and then 2Og (25.0%) of sucrose fatty acid ester(HLB=12) was added thereto and

dissolved at room temperature. This solution was mixed with 2Og (25.0%) of CoQlO in 80Om-P, of dichloromethane. Then, 0.08g (0.1%) of DL-α-tocopheryl acetate and 1.6g

(2%) of silicon dioxide were further added to the solution, which was mixed

homogeneously. 62.7g of solid dispersion was prepared from the above mixed solution

by using spray dryer (N-DlOl, Dongjin Technology Institute).

Formulation Example 1: Preparation of solid capsule containing CoQlO

solid dispersion

The solid dispersion containing 33.3% of CoQlO prepared from Example 1 above was

mixed with a mixture of lactose and corn starch (product name: Starlac, Roquette) as

excipient. Then, a solid capsule was filled with 500mg of granule mixture corresponding

to 50mg of CoQlO according to the preparation process for capsule in Korean

Pharmacopeia.

Formulation Example 2: Preparation of solid capsule containing CoQlO solid

dispersion

The solid dispersion containing 25% of CoQlO prepared from Example 2 above was mixed with a mixture of lactose and corn starch (product name: Starlac, Roquette) as

to 50mg of CoQlO according to the preparation process for capsule in Korean

Pharmacopeia.

Formulation Example 3: Preparation of solid capsule containing CoQlO solid

dispersion

The solid dispersion containing 33.3% of CoQlO prepared from Example 3 above was

to 50mg of CoQlO according to the preparation process for capsule in Korean

Pharmacopeia.

Formulation Example 4: Preparation of solid capsule containing CoQlO solid

dispersion

The solid dispersion containing 25% of CoQlO prepared from Example 4 above was mixed with a mixture of lactose and corn starch (product name: Starlac, Roquette) as

to 50mg of CoQlO according to the preparation process for capsule in Korean

Pharmacopeia.

Comparative Example 1: Preparation of solid capsule containing CoQlO raw

material

CoQlO raw material (supplier: Daewoong Chemical) was mixed with a mixture of lactose

and corn starch (product name: Starlac, Roquette) as excipient. Then, a solid capsule

was filled with 500mg of granule mixture corresponding to 50mg of CoQlO according to

the preparation process for capsule in Korean Pharmacopeia.

Comparative Example 2: Preparation of solid capsule containing CoQlO-solubilized

material (Ultrasome-CoQlO)

Commercially available CoQlO-solubilized material (product name: Ultrasome-

CoQlO, Herbamed) was mixed with a mixture of lactose and corn starch (product name:

Starlac, Roquette) as excipient. Then, a solid capsule was filled with 500mg of granule mixture corresponding to 50mg of CoQlO according to the preparation process for capsule

in Korean Pharmacopeia.

Test Example 1 : Dissolution test

Hard capsules containing the CoQlO solid dispersion of Formulation Examples 1 and 2;

and hard capsules of Comparative Examples 1 and 2 were tested for dissolution by using

500ml of pH 1.2 buffer solution containing 1% of polysorbate 80 (Tween80, Sigma),

according to the second method of general test methods described in Korean

Pharmacopeia. That is, the dissolution test was performed at a rate of 50rpm, and

samples were collected 15, 30, 60, 120 min after the test started. Each sample was

analyzed by using HPLC whose conditions were as follows:

Apparatus for testing dissolution: Vankel VK-7020S

Dissolution medium: 50OmL of pH 1.2 buffer solution containing 1% of Tween

80

Temperature of dissolution medium: 37.0±0.5 ^°C

Rotation speed: 50 rpm Analytic method: HPLC

Detector: ultraviolet spectrophotometer (wavelength: 275nm)

Column: Capcell Pak Cl 8 (4.6x150mm, 5um)

Temperature of column: 40 ^°C

Mobile phase: mixture of anhydrous ethanol and methanol (70:30)

Flow rate: l.OmL/min

The analyzed results are shown in Figure 1. As shown in Figure 1, the hard capsules of

Formulation Examples 1 and 2 show higher dissolution rate than those of Comparative

Examples 1 and 2. Thus, it is understood that the soluble CoQlO solid dispersion

according to the present invention is a highly improved formulation, compared to CoQlO

raw material and commercially available CoQlO-solubilized material.

Test Example 2: Bioavailability analysis of CoQlO

Three groups of rats were prepared. CoQl O formulation (containing CoQlO raw

material) prepared by the method of Comparative Example 1 was administered to the first

group (n=6, #1~#6); CoQlO formulation (containing CoQlO solid dispersion) prepared by the method of Formulation Example 1 was administered to the second group (n=6,

#7~#12); nothing was administered to the third group (n=3, #13-15), negative control.

Blood of each rat was collected with appropriate time intervals. Proteins were removed

from the serum by using acetonitrile, the serum was centrifuged (13000 rpm, 10 min, 4^°C),

and then 5/xl of supernatant was inserted into the analyzing apparatus. The results are

shown in Table 1 and Figure 2.

Analytic Conditions

LC-MS/MS: Tandem Mass Spectrometry (API 4000)

Pumb: Bineary Pump (Agilent 1100 series)

CTC-PAL Autosampler

Column: Shiseido Capcell Pak C 18(2.0 X 150mm, 5um)

Mobile phase: methanol and 2-propanol (40:60)

Flow rate: 200 ul/min

Table 1

As shown in Table 1 and Figure 2, in the rat group administered with the hard

capsule of Formulation Example 1 containing CoQlO sold dispersion according to the

present invention, CoQ 10 concentration in the serum increased rapidly at a rate of 200

ng/ml per hour. Also, in the negative control, the maximum concentration of CoQlO

raised by the Formulation Example 1 was about 550 ng/ml. However, in the first rat

group administered with hard capsule of Comparative Example 1, CoQlO concentration in

the serum increased slowly at a rate of 57 ng/ml per hour. And, in the negative control,

the maximum concentration of CoQlO raised by CoQlO raw material was about 180 ng/ml.

Thus, it is understood that the CoQlO solid dispersion according to the present invention

raises CoQlO concentration in the serum to high level in a short period, compared with

CoQlO raw material (Increasing rate: about 3.5 times; Maximum concentration: about 3

times). Also, in the negative control, in case of Formulation Example 1 and Comparative Example

1, CoQlO concentrations in the serum at 8 hour were 205.7 ng/ml and 106.3 ng/ml,

respectively. Thus, it is understood that CoQlO solid dispersing according to the present

invention maintains CoQlO concentration in the serum higher than CoQlO raw material,

for a long time (about 2 times).

Test Example 3: X-ray diffraction analysis

The crystalline properties of CoQlO solid dispersion prepared according to Example 1;

and crystalline CoQlO were compared and evaluated by using X-ray diffraction

spectrophotometer (Mac Science, Japan, Model: M18XHF-SRA). Figure 3 represents X-

ray powder diffraction spectrum data (XRD spectrum data; powder diffraction pattern) of

CoQlO solid dispersion prepared according to Example 1 and crystalline CoQlO. These

data were determined with CuK-α beam under 40 kV of voltage and 300 niA of current,

by using X-ray powder diffraction meter. The pattern of Figure 3 shows that CoQlO solid

dispersion is in non-crystalline form since the relatively strengths of diffraction angle and

peak are very low, differently from crystalline CoQlO. Test Example 4: Differential Scanning Calorimeter (DSC) analysis

The crystalline properties of CoQlO solid dispersion prepared according to Examples 1

and 2; and CoQlO raw material were compared and evaluated by using differential

scanning calorimeter (Mettler-Toledo, DSC822e). Figure 4 represents a chart of

differential scanning calorimeter on CoQlO solid dispersion prepared according to

Examples 1 and 2; and CoQlO raw material. These data were determined with heating

ramp in the range of 25 ^°C~120^°C by using sealable aluminum pan and lid, and heating at a

rate of 10^°C/min. The pattern of Figure 4 shows that enthalpy value of CoQlO solid

dispersion decreased or largely disappeared, differently from crystalline CoQlO. This

pattern seems to show that reduction of a heat required for melting crystalline molecular

mass causes "reduced molecular order." So does decrease or disappearance of the

melting point on DSC.

Test Example 5: Microscopic photo analysis

The appearances of CoQlO solid dispersion prepared according to Example 1, and CoQlO raw material were compared and evaluated by optical microscope (OLYMPUS, BX 51).

Figure 5 represents microscopic photos of CoQlO solid dispersion prepared according to

Example 1, and crystalline CoQlO. In Figure 5, (a)-(b) represent magnified photos of

crystalline CoQlO by 200 times and 500 times, respectively, and (c)-(d) represent

magnified photos of CoQlO solid dispersion prepared according to Example 1 by 200

times and 500 times, respectively. Figure 5 shows that CoQlO solid dispersion is of

round shape which was caused by the disappearance of crystalline shape, differently from

the crystalline CoQlO. Thus, it is understood that CoQlO solid dispersion is in non¬

crystalline form.

INDUSTRIAL APPLICABILITY

Soluble solid dispersion of CoQlO according to the present invention shows increased

solubility and improved bioabsorption and bioavailability, and so can be effectively

prepared in a large scale by using the present process. Also, the present invention

provides solid dispersion of CoQlO which is much more suitable to the preparation of

drug, food and cosmetic material than conventional CoQlO source. Also, the solid

dispersion is very stable and easy to handle.

Claims

1. A solid dispersion of CoQlO comprising CoQlO, an emulsifier and a

hydrophillic polymer.

2. The solid dispersion according to claim 1, further comprising an antioxidant or

an inorganic carrier.

3. The solid dispersion according to claim 1, wherein the emulsifier is semi-solid

or solid at room temperature.

4. The solid dispersion according to claim 3, wherein the emulsifier is

polyglycerine fatty acid ester; sucrose fatty acid ester; polyoxyethylene-polyoxypropylene

block copolymer; sorbitan fatty acid ester; mixture of polyethylene glycol fatty acid ester,

and mono-, di- or tri-glyceride; caprylic/capric acid mono- or di-glyceride;

polyoxyethylene glycolated natural or hydrogenated castor oil; polyoxyethylene fatty acid

ester; propyleneglycol mono- or di-fatty acid ester; or organic acid.

5. The solid dispersion according to claim 4, wherein the emulsifier is polyglycerine fatty acid ester or polyoxyethylene-polyoxypropylene block copolymer.

6. The solid dispersion according to claim 1, wherein the amount of the emulsifier

is 0.1-20 parts by weight per 1 part by weight of CoQlO.

7. The solid dispersion according to claim 1, wherein the hydrophillic polymer is

at least one selected from the group consisting of hydroxypropylmethylcellulose(HPMC),

hydroxypropylcellulose(HPC), polyvinylpyrrolidone^ VP), polyvinylalcohol(PVA),

polyethylene glycol polyvinylalcohol ester, dextrin, cyclodextrin(CyD), maltodextrin and

mixtures thereof.

8. The solid dispersion according to claim 1, wherein the amount of the

hydrophillic polymer is 0.2-10 parts by weight per 1 part by weight of CoQlO.

9. The solid dispersion according to claim 2, wherein the antioxidant is tocopherol,

analogues of tocopherol, or butylate hydroxytoluene.

10. The solid dispersion according to claim 2, wherein the amount of the antioxidant is 0.0001-0.1 part by weight per 1 part by weight of CoQlO.

11. The solid dispersion according to claim 2, wherein the inorganic carrier is

silicon dioxide, talc, hydrotalcite, aluminum magnesium silicate, titanium dioxide, stearic

acid, magnesium stearate, or mixtures thereof.

12. The solid dispersion according to claim 2, wherein the amount of the

inorganic carrier is 0.001-2 parts by weight per 1 part by weight of CoQlO.

13. A process for preparing a solid dispersion of CoQlO comprising the steps of:

(A) dissolving or dispersing CoQlO, an emulsifier and a hydrophillic polymer in a suitable

solvent to form a dissolved or dispersed material; and (B) removing the solvent from the

dissolved or dispersed material.

14. The process according to claim 13, wherein step (B) of removing the solvent

is carried out by using spray dry.

15. The process according to claim 13, wherein an antioxidant or an emulsifier is further dissolved or dispersed in the step (A).

16. The process according to claim 13, wherein step (A) of dissolving or

dispersing CoQlO is carried out by heating to a temperature of 40-70 ^°C .

17. A process for preparing a solid dispersion of CoQlO comprising the steps of:

(A) heating CoQlO, an emulsifier and a hydrophillic polymer to a temperature of

180-260 ^°C to obtain homogeneously molten mixture; and (B) cooling rapidly and

pulverizing the resulted mixture.

18. A pharmaceutical composition of ubidecarenone comprising the CoQlO solid

dispersion as defined in any one of claims 1 to 12.

19. A CoQlO solid dispersion prepared by the process as defined in any one of

claims 13 to 17.