WO2007032643A1

WO2007032643A1 - A solubilized material comprising ubidecarenone, aqueous solution and process for preparation thereof

Info

Publication number: WO2007032643A1
Application number: PCT/KR2006/003649
Authority: WO
Inventors: Ji Sun Kim; Dong Hyun Cho; Hyoung Goo Shin; Tae Wan Kim; Min Suk Lee; Jeong Hwa Park
Original assignee: Daewoong Co Ltd
Current assignee: Daewoong Co Ltd
Priority date: 2005-09-14
Filing date: 2006-09-14
Publication date: 2007-03-22
Anticipated expiration: 2008-03-14
Also published as: KR20070031065A; KR100754953B1

Abstract

The present invention relates to a solubilized material, and an aqueous solution and a process for preparation thereof. Particularly, the present invention relates to an ubidecarenone-containing solubilized material comprising ubidecarenone and Macrogol 15 Hydroxystearate as a solubilizer; an aqueous solution comprising a mixture of said material, and water or aqueous agent; and a process for preparing said material comprising the steps of heating 1 to 20 weight by parts of Macrogol 15 Hydroxystearate to the temperature of 50 'C or more, and forming the solubilized material by adding 1 weight by part of ubidecarenone to Macrogol 15 Hydroxystearate.

Description

A SOLUBILIZED MATERIAL COMPRISING UBIDECARENONE, AQUEOUS

SOLUTION AND PROCESS FOR PREPARATION THEREOF

TECHNICAL FIELD

The present invention relates to insoluble ubidecarenone compound, particularly

an ubidecarenone-containing solubilized material, a solubilized aqueous solution using the

same, and a process for preparing the same.

BACKGROUND ART

Ubidecarenone ("CoQ10,"as referred hereinafter) of the following formula I exists

in the electron transfer system of myocardial mitochondria, and conducts a principal

biochemical function in energy generation. Ubidecarenone 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

immune system recovery (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 only food intake is not sufficient to provide a necessary amount.

Further, as human beings grow 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.

[Formula I]

CoQlO is conventionally marketed as a solid formulation for oral administration.

However, broad applications of CoQlO have been recently demonstrated, and so

development for various formulations of CoQlO has been needed in the art. However,

CoQlO exists in solid state at normal temperature (the melting point of CoQlO: 48 "C-

52 ^°C), and has high lipophilic property. Thus, CoQlO is hardly soluble in water, and so

it was difficult to develop various formulations thereof. A lot of studies have been

performed to apply CoQlO to various liquid formulations by solubilizing CoQlO.

As one method for solubilizing CoQlO, Korean Patent Laid-open Publication No.

1994-0021054 disclosed a method using non-ionic surfactant such as hydrogenated or

non-hydrogenated polyethoxylated castor oil. However, the above method needs a great

amount of surfactants, and so when an aqueous solution prepared by the method is administered via oral route or injection, the surfactants in the solution may cause side

effects such as release of histamine-analogue and diarrhea.

Korean Patent No. 28370 also disclosed a method for solubilizing lipid active

vitamin or ubiquinone by using hydrogenated lecithin. However, this method needs

special apparatuses such as ultrasonic apparatus, and solubilizer.

US Patent No. 6,441,050 disclosed a method for preparing a liquid formulation of

CoQlO by using polysorbate 80 as surfactant, oil and phospholipids. However, when

such liquid formulation is administered to patients via oral route, the taste and taking

feeling are not good.

DISCLOSURE OF THE INVENTION

To overcome the above problems, the present invention provides a solubilized

material comprising the insoluble ubidecarenone, and having high transparency, and good

taste and taking feeling. The present invention also provides an aqueous solution

comprising said material, and an easy process for preparing said material. DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an ubidecarenone-containing solubilized material

comprising ubidecarenone and Macrogol 15 Hydroxystearate (Solutol HS^R 15) as a

solubilizer. Also, the present invention provides a solubilized aqueous solution

comprising a mixture of the solubilized material containing ubidecarenone and Macrogol

15 Hydroxystearate; and purified water or aqueous agent. Also, the present invention

provides a process for preparing the solubilized material comprising the steps of heating 1

to 20 weight by parts of Macrogol 15 Hydroxystearate to 50 ^°C or more; and then forming

the solubilized material by adding 1 weight by part of ubidecarenone to Macrogol 15

Hydroxystearate.

In accordance with the present invention, a transparent solubilized material of

CoQlO is prepared by heating a solubilizer to its melting temperature or more to melt the

solubilizer to a liquid state, adding CoQlO as an active agent to the molten solubilizer, and

completely mixing the molten solubilizer and CoQlO. Solubilizer according to the

present invention is Macrogol 15 Hydroxystearate, non-ionic surfactant. Macrogol 15

Hydroxystearate is preferably molten by heating it to a temperature of 50 ^°C or more, and

then mixed with CoQlO with maintaining the temperature. Macrogol 15 Hydroxystearate can be heated to a melting point or more, and so the upper limit of the

temperature is not restricted. However, heating and mixing are carried out at the

temperature of 50-100 ^°C, more preferably at the temperature of 50-60 ^°C . When the

temperature is lower than 50 ^°C, it is difficult to mix CoQlO with the solubilizer. When

the temperature is over 100^°C, active agent CoQlO may be chemically denatured. The

weight ratio of CoQlO to Macrogol 15 Hydroxystearate is preferably 1:1 ~ 1:20, more

preferably 1:4 - 1:10, and even more preferably 1:4 - 1:5. When the amount of CoQlO

is lager out of a ratio of 1:1 - 1:20, the solubility of CoQlO may decrease. When the

amount of a solubilizer is lager out of the ratio of 1 : 1 - 1 :20, oral administration of a

solubilized aqueous solution may stimulate the gastrointestinal tract and make the taste

and taking feeling worse.

The ubidecarenone-containing solubilized aqueous solution in accordance with

the present invention is prepared by mixing the solubilized material with water or liquid

agent. Liquid agent may comprise additional known additives used for oral liquid

formulation. The additives may comprise solubilizing aids, sweeteners, acidifiers,

preservatives, and the like. The amount of CoQlO used in the solubilized aqueous

solution may be optionally selected within the range of dosage known to be effective for oral administration in the art. The amount of CoQlO may be varied depending on age,

sex or physical state of a patient, administration route, etc. Considering that CoQlO is

administered via oral route in the form of liquid formulation, the amount of CoQlO is

0.0005 to 5w/v%, preferably 0.001 to lw/v%, and more preferably 0.005 to 0.1w/v%,

based on the amount of total aqueous solution.

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 and Comparative Examples 1 to 9

To determine the solubility of CoQlO according to the kinds of solubilizers used

for aqueous solutions, 2g of solubilizer was molten to a liquid form by heating the

solubilizer in water bath of the temperature of 50-60 ^"C . Then, O.lg of CoQlO was

completely mixed with the molten solubilizer, with maintaining the temperature of

50-60 °C , to obtain a transparent CoQIO-containing solubilized material. The resulting

solubilized material was cooled, and then the state was observed (A). Also, to said solubilized material was added IL of water to obtain a solubilized aqueous solution, and

then the state was observed (B). Used solubilizers and test results are described in Table

1 below.

Table 1

Solubility according to the kinds of solubilizer

Prior to adding water to the solubilized material (A), all the solubilized materials

other than those of Comparative Examples 7 and 9 had good solubility to CoQlO.

However, after adding water to the solubilized material (B), only the aqueous solution of

Example 1 and Comparative Examples 3 and 4 showed good transparency and solubility. Example 2 and Comparative Examples 10 and 11

According to formulations in the Table 2 below, Macrogol 15 Hydroxystearate,

propyl 35 castor oil (the solubilizer of Comparative Example 3) and polysorbate 80 (the

solubilizer of Comparative Example 4) were molten to obtain liquid forms by heating

them in water bath of the temperature of 50-60 ^°C . Then, CoQlO was added to the

molten solubilizers, and completely mixed therewith, with maintaining the temperature of

50-60 ^°C, to obtain transparent CoQIO-containing solubilized materials. The above

solubilized materials corresponding to lOmg of CoQlO were mixed with 100ml of

commercially available vitamin C drink (vitamin C content: 700mg/100ml) to obtain

solubilized aqueous solutions. The state and transparent ratio (%) at 640nm of the

solubilized aqueous solutions were determined. The taste and taking feeling of the

solubilized aqueous solutions were evaluated by sensory test after taking them in oral

cavity for 5 seconds, as shown below. The test results are described in Table 2 below.

A: the taste and taking feeling are good

B: the taste and taking feeling are slightly unpleasant C: the taste and taking feeling are unpleasant

Table 2

Examples 3 to 7

According to formulations in Table 3, Macrogol 15 Hydroxystearate was molten

to a liquid form by warming the solubilizer in water bath of the temperature of 50-60 "C,

and then O.lg of CoQlO was completely mixed with the molten solubilizer, with

maintaining the temperature of 50-60 "C , to obtain a transparent CoQIO-containing

solubilized material.

Table 3

Example No.

As shown in the Examples 3 to 7, the solubilized materials, wherein the amount of

CoQlO was O.lg and the amount of Macrogol 15 Hydroxystearate was 0.4g or more,

showed good transparent ratio of 90% or more, immediately after the preparation. In

particular, when the amount of Macrogol 15 Hydroxystearate was 0.4g to Ig, the taste and

taking feeling of the solubilized material were superior.

INDUSTRIAL APPLICABILITY

The present invention provides a solubilized material comprising the insoluble

ubidecarenone which has high transparency, and good taste and taking feeling. Also, the

present invention provides an aqueous solution comprising the same, and a process for

preparing the same.

Claims

1. An ubidecarenone-containing solubilized material comprising ubidecarenone and

Macrogol 15 Hydroxystearate.

2. The solubilized material according to claim 1, wherein the solubilized material

comprises 1 weight by part of ubidecarenone and 1 to 20 weight by parts of Macrogol 15

Hydroxystearate.

3. The solubilized material according to claim 1, wherein the solubilized material

comprises 1 weight by part of ubidecarenone and 4 to 10 weight by parts of Macrogol 15

Hydroxystearate.

4. The solubilized material according to claim 1, wherein the solubilized material

comprises 1 weight by part of ubidecarenone and 4 to 5 weight by parts of Macrogol 15

Hydroxystearate.

5. A solubilized aqueous solution comprising a mixture of solubilized material containing

ubidecarenone and Macrogol 15 Hydroxystearate; and purified water or aqueous agent.

6. The solubilized aqueous solution according to claim 5, wherein the amount of

ubidecarenone is 0.0005 to 5w/v%.

7. The solubilized aqueous solution according to claim 6, wherein the amount of

ubidecarenone is 0.001 to lw/v%.

8. A process for preparing a solubilized material comprising the steps of,

(1) heating 1 to 20 weight by parts of Macro gol 15 Hydroxystearate to the

temperature of 50 ^°C or more; and

(2) forming the solubilized material by adding 1 weight by part of ubidecarenone

to Macrogol 15 Hydroxystearate.