WO1997036576A1

WO1997036576A1 - Preparation method of emulsion for chemoembolization

Info

Publication number: WO1997036576A1
Application number: PCT/KR1997/000054
Authority: WO
Inventors: Seo Young Jeong; Ick Chan Kwon; Yong-Hee Kim
Original assignee: Korea Institute Of Science And Technology
Priority date: 1996-04-01
Filing date: 1997-03-31
Publication date: 1997-10-09
Also published as: AU2308597A; KR970069028A

Abstract

A preparation method of an emulsion to be used in a chemoembolization which comprises the steps of mixing an aqueous contrast medium containing an anti-cancer agent as an inner aqueous phase and an oily contrast medium containing a surface active agent as an oil phase and then severely agitating the same. The thus obtained emulsion has an effect that the anti-cancer agent is released therefrom continuously and in a sustained manner due to its reduced difference in the viscosity between aqueous phase and oil phase.

Description

PREPARATION METHOD OF EMULSION FOR CHEMOEMBOLIZATION

TECHNICAL FIELD

The present invention relates to a preparation method of an emulsion for

a chemoembolization, and in particular to a preparation method of an emulsion

for a chemoembolization, which is capable of preparing a stable emulsion by

using a water-soluble anti-cancer agent and an oily contrast medium used for diagnosing a cancer.

BACKGROUND ART

The chemoembolization is related to a technique for attacking cancer cells

by blocking an artery or other blood vessel through which nutrition is

transferred to a growing cancer cell and at the same time, by delivering an

anti-cancer agent.

However, this technique has problems in that even though major blood vessels through which nutrition is transferred to cancer cells are blocked, other

blood vessels around the blocked blood vessels become activated, resulting

in that the cancer cells receive nutrition. In addition, when an anti-cancer agent

is delivered, the anti-cancer agent is quickly spread into all blood vessels

because the anti-cancer agent is separated from the chemical embolus-

causing material at the time when the anti-cancer agent is delivered into the

human body afflicted with cancer, thus significantly reducing the therapeutic

effects with respect to the cancers, whereby it may inflict critical damage to the human body because side effects may occur throughout the human body.

Lipiodol which is an oily contrast medium among the embolus causing materials remains in the blood vessels around the cancer cells and selectively causes an embolus with respect to only the cancer cells. Therefore, the therapy method of using lipiodol has been widely used in the medical field.

However, due to the oily properties of lipiodol, there is a predetermined limit for spreading the oily lipiodol when using a water-soluble anti-cancer agent such as doxorubicin which has a good therapeutic effect against cancer cells.

In addition, after the oily lipiodol is spread throughout the blood vessels, since the anti-cancer agent is quickly separated therefrom, it is impossible to cause the anti-cancer agent to effectively spread over the cancer cells with a

therapeutically desired level for a long time.

In addition, a liver cancer therapy method which has been generally used in the diagnostic radiation field is implemented by using three ampules respectively containing adriamicin, which is an anti-cancer agent, iopamiro,

which is an aqueous contrast medium, and lipiodol, which is an oily contrast

medium. Namely, before the anti-cancer agent is provided to a cancer patient, the anti-cancer agent is dissolved in an aqueous contrast medium and then is mixed with the oily contrast medium by using a three-way stopcock based on

a simple pumping method. At this time, since a surface active agent is not

provided, a very heterogeneous emulsion is temporarily formed.

DISCLOSURE OF THE INVENTION Accordingly, it is an object of the present invention to provide a chemical

embolus emulsion preparation method which overcomes the aforementioned

problems encountered in the conventional art.

It is another object of the present invention to provide an improved

preparation method of an emulsion for a chemoembolization which is capable

of reducing the conventional three ampules to one ampule by stabilizing an

aqueous contrast medium phase and an oily contrast medium phase which

contain an anti-cancer agent by adding a surface active agent.

It is another object of the present invention to provide an improved preparation method of an emulsion for a chemoembolization which is capable

of achieving a sustained release effect of an anti-cancer agent by providing a

stable emulsion containing a water-soluble anti-cancer agent, selectively

delivering the anti-cancer agent to cancer cells, by effectively forming a

chemical embolus.

It is another object of the present invention to provide an improved

preparation method of an emulsion for a chemoembolization which is capable

of forming a stable emulsion by using an inner aqueous phase and obtaining

a sustained release of an anti-cancer medicine, whereby it is possible to

provide an effective chemical embolus medicine.

To achieve the above objects, there is provided a method of forming a

stable emulsion for a long time by mixing and agitating an oily phase

containing a surface active agent and an aqueous phase wherein an anti¬

cancer agent is dissolved. To achieve the above objects, in the chemical embolus emulsion

preparation method according to the present invention, as an inner aqueous phase in which is dissolved a water-soluble anti-cancer agent, a solvent which has a viscosity similar to an oily phase is used, and as a surface active agent, an injection agent which has a desired stability is used.

To achieve the above objects, there is provided a chemical embolus emulsion preparation method which includes the steps of mixing an aqueous contrast medium containing an anti-cancer agent as an inner aqueous phase and an oily contrast medium containing a surface active agent as an oil phase and then severely agitating the same.

Additional advantages, objects and features of the invention will become more apparent from the description which follows.

BRIEF DESCRIPTION OF THE DRAWINGS The present invention will become more fully understood from the detailed description given hereinbelow and the accompanying drawing, which is given

by way of illustration only, and thus is not limitative of the present invention, and wherein:

Figure 1 is a graph comparing a releasing profile of doxorubicin

hydrochloride of an emulsion according to Example 1 of the present invention

(-D-) and an emulsion according to Comparative Example 2 (--O~).

MODES FOR CARRYING OUT THE INVENTION In the present invention, as an inner aqueous phase, iopamiro (lopamiro:

Bracco Industria Chimica s.p.a., Italy) (Component: lopamidol) which is an

aqueous contrast medium having a specific gravity of 1.334 at 20° C, or hexabrix (Hexabrix: Laboratories Guebet, France) having a specific gravity of

1.343 may be used, for thus reducing the density difference between the same

and lipiodol ultra fluide (Laborities Guebet, France) having a specific gravity

of 1.282, and well spreading the inner aqueous inner phase. In order to reduce

the density difference, an aqueous solution of glycerin, a monosaccharide, and

a disaccharide may be used. In the present invention, water-soluble anti-

cancer agent such as doxorubicin, epirubicin, daunorubicin, etc. may be used.

In the present invention, the volume ratio of the inner aqueous phase to

the oil phase is 1:2 ~ 1:6.

In addition, as the surface active agent contained in the oil phase, fatty

acids, aliphatic alcohol sulfates, sulfated fat and oils, phosphoric esters, polyoxyethylenes, phosphatides, etc. may be used. Among these,

polyoxyethylene Hydrogenated Castor Oil (HCO) is preferably used. The

concentration of the polyoxyethylene HCO is 0.01 - 10 w/v% based on the oily

phase used. Preferably, the concentration thereof is 1 ~ 5 w/v%.

In addition, in the emulsion preparation method according to the present

invention, when mixing the inner aqueous phase and the oily phase, a

homogenizer, an ultrasonic apparatus, a microfluidizer, etc. may be used.

The preferred embodiments according to the present invention will now be

explained. The embodiments are not limited to their description. In other words, the examples below are provided for those skilled in the present field to more easily understand.

Example 1 2 w/v % of a doxorubicin hydrochloride is dissolved in an inner aqueous phase comprising iopamiro, and 1 w/v % of HCO 60 is dissolved in a lipiodol to make an oil phase, and then they are mixed at a volume ratio of the inner

aqueous phase to the oil phase of 1:4, and then the mixture is severely agitated for one minute at 8000 rpm by using a homogenizer at room temperature, for thus obtaining a stable emulsion.

Example 2

Example 2 is identical to Example 1 except that HCO derivatives such as HCO 10, HCO 20, HCO 40 or HCO 50 are used as a surface active material

instead of using the HCO 60.

Comparative Example 1

As a surface active agent, 5 w/v% of a Pluronic™ L 92, Pluronic™ L101

is used in the poloxamer(polyoxyethylene-polyoxypropilene-polyoxyethylene), or each of the poloxamer is mixed with a bovine serum albumin of 0.2 w/v%,

or a recitin of 5 w/v% is used. The remaining methods are identical to Example

1. Comparative Example 2

Instead of the iopamiro in Example 1 , distilled water is used, and the

surface active agent HCO 60 of 5 w/v% is used. The remaining steps are

identical to Example 1.

Stability test based on surface active agent selection

As a method for measuring the stability of the prepared emulsion, the time

when the emulsion is separated at around 50° C which is a hard condition is

measured. In accordance with Comparative example 1, the emulsion obtained

by using the poloxamer, the mixture of the poloxamer and bovine serum

albumin or the recitin as the surface active agent become separated in 24

hours. However, the emulsion of Example 1 obtained by using the HCO 60

was not separated for more than 900 hours. Other emulsions of Example 2

except the one wherein HCO 10 was used show the same result as that of the cases wherein HCO 60 was used.

Drug release test based on the selection of inner aqueous phase

In order to continuously maintain a therapeutic effect, the anti-cancer

agent must be released continuously. In addition, for safety aspect, the surface

active agent should be employed as small amount as possible. In the drug

release test, an emulsion of 1ml is prepared, and is introduced into a dialysis

membrane bag, and both ends thereof sealed by using a closure, and the bag

is flooded into a PBS of 100ml, and then the emulsion is released in a water shaking bath at a temperature of 37° C.

As a result of the release test compared to the emulsion of Example 1

which is directed to adjusting the viscosity of the inner aqueous phase and the

emulsion of Comparative example 2, in the emulsion of Example 1 , it is

possible to continuously release by using the surface active agent of 1%, but

in the emulsion of Comparative example 2, a greater amount of surface active

agents as much as 5 w/v % was requested in order to obtain the same effect

as Example 1 as shown in Figure 1.

Example 3

In this example, in order to prevent the oxidation of the HCO 60, alpha

tocopherol of 0.05% was added to the inner aqueous phase. The remaining steps were performed identically to Example 1 of the present invention.

Although the preferred embodiments of the present invention have been

disclosed for illustrative purposes, those skilled in the art will appreciate that

various modifications, additions and substitutions are possible, without

departing from the scope and spirit of the invention as recited in the

accompanying claims.

Claims

1. A preparation method of an emulsion to be used in chemoembolization, comprising: mixing an aqueous contrast medium containing an anti-cancer agent as

an inner aqueous phase and an oily contrast medium containing a surface

active agent as an oily phase and then severely agitating the mixture to form an emulsion.

2. The method of claim 1, wherein said oily contrast medium is

lipiodol, and an aqueous contrast medium is one of iopamiro and a hexabrix.

3. The method of claim 1 , wherein a surface active agent is added

by 0.01 ~ 10 w/v% based on the oily phase.

4. The method of claim 3, wherein a surface active agent is added

by 1 ~ 5 w/v% based on the oily phase.

5. The method of claim 3, wherein said surface active agent is selected from the group comprising fatty acids, aliphatic alcohol sulfates, sulfated fat and oils, phosphoric esters, polyoxyethylenes, phosphatides, and

polyoxyethylene hydrogenated castor oil (HCO).

6. The method of claim 1, wherein a volume ratio between the aqueous phase to oily phase is 1:2 to 1:6.

7. The method of claim 1 , wherein an anti-oxidation agent is added

to the inner aqueous phase.