JPS58143831A - W/o/w composite emulsion - Google Patents

Abstract

PURPOSE:To obtain the titled emulsion capable of being formed into microcapsules, by emulsifying a W/O emulsion consisting of an oil component dissolving an oil soluble emulsifier with predetermined H.L.B. and an oil soluble stabilizer and water, in water containing a water soluble emulsifier. CONSTITUTION:A W/O emulsion consisting of an oil component having 1-20% oil soluble emulsifier with H.L.B. of 2-10 (e.g., polyoxyethylene derivative of castor oil) and 0.1-10% oil soluble stabilizer (e.g., butyl monostearate) and water is prepared. In the next step, this W/O emulsion is emulsified in water containing 0.1-1.0% water soluble emulsifier (e.g., salt such as sodium lauryl sulfate) to obtain the objective W/O/W composite emulsion. As the representative example of this emulsion, a W/O/W composite emulsion containing water dissolving a drug, especially, a water soluble substance, for example, an anti- cancer agent in the innermost layer thereof can be mentioned.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a W10/W composite emulsion that can be used, for example, as a pharmaceutical, and more specifically, it relates to a W10/W composite emulsion that can be used, for example, as a pharmaceutical. The present invention relates to a W10/W composite emulsion having W10/W as the innermost layer.

Most of the anticancer drugs currently manufactured and sold are water-soluble substances. Therefore, when used in the human body, the reaction speed and leakage are large, and it can significantly destroy not only cancer cells but also other cells, posing a danger to life.As a solution to this problem, anticancer agents are added to the magnetic fluid. developed a technology to induce anticancer drugs locally using a magnetic field (Japanese Patent Application Laid-Open No.
No. 6-9000 and Japanese Patent Application No. 185101/1982).

As mentioned above, most anticancer drugs are water-soluble.
Since the magnetic fluid used as a carrier is oil-soluble,
Methods for containing an anticancer drug in a magnetic fluid and administering it into the body include (1) containing an anticancer drug in an oil-soluble magnetic fluid (in this case, the anticancer drug is contained in a magnetic fluid as a fine powder); (2) an aqueous solution of an anti-cancer drug (most anti-cancer drugs are water-soluble) is wrapped in magnetic fluid to form a W10 emulsion; There are (3) others that have a W10/W ratio so that they can be injected into the body.

Among these, the method using W10/W belly emulsion is as follows:
This is an ideal administration method because it allows an oil phase to be interposed between the aqueous phase and the oil phase by using an oil component that is not toxic to the human body as a base. The emulsion is unstable and will not be microencapsulated.

In view of the above circumstances, this invention proposes a W10/W composite emulsion that can be microencapsulated. In particular, a water-soluble anticancer drug is microencapsulated with a magnetic fluid, and the magnetic fluid is applied to the affected area using a magnetic field. W10/W can induce other anticancer drugs without leaking out.
The present invention proposes a composite emulsion of W1, in which the release of the anticancer drug in the affected area can be adjusted freely by adjusting the strength of the microcapsules.
This paper proposes a 0/W composite emulsion.

Regarding manufacturing methods for magnetic fluids, see 53-17 Japanese Patent Publication.
As detailed in Publication No. 118 and Japanese Patent Publication No. 54-40069, etc., when containing an anticancer agent, etc., the substances to be adsorbed to the magnetic particles due to their toxicity to the human body include oleic acid, linoleic acid, stearic acid, etc. The base liquid is usually a vegetable oil such as cottonseed oil, rapeseed oil, olive oil, safflower oil, or soybean oil, a higher fatty acid such as oleic acid, linoleic acid, or a higher fatty acid such as S-ethyl oleate. Ester compounds can be used, and sometimes animal oils such as squalene, squalane, or synthetic oils such as fluorocarbons can be used.

W10/W emal in this invention? Anticancer agents that can be dissolved in the aqueous phase of the innermost layer include alkylating agents, antimetabolites, antibiotics, hormones, alkaloids, etc. Specific examples include titlodiene mustard-N. - oxide, chloroamptyl, triethylene melamine, sifromomanni)-/l/, CCNTJ
(1-3-cyclohexyl-1-nitrosourea),
6-MP (6-mercaptopurine), 6-TG (6-
thioguanine), FT-207 (N, -5-fluorouracil), cytosine arabinoside (1-β-D-arabinofragirisin), 5-FU (5-fluorouracil), atreamycin, mitomycin, bleomycin, etc. be.

Furthermore, in order to enable microencapsulation in the present invention, in addition to an emulsifier, an emulsifier is added and dissolved in the oil component base to thicken the oil layer, heat it to create an emulsion, and when cooling, an oil film is formed. strengthen the
A stabilizer is added to stabilize the emulsion and make it microencapsulated.As a result of studies, the following can be mentioned as the emulsifier and stabilizer.

In other words, the emulsifier that dissolves in the oil phase to form a W10 emulsion is one with low toxicity among surfactants, and H,
L, B and 2. Those with ON10.0 are good, examples include Niracol C0-3 and CO-10) (
, L, B 3.0, H, L, B 6.5 polyoxyethylene castor oil derivatives, polyoxene ethylene hydrogenated castor oil derivatives such as Niracol HCO-40, Niracol MYO-2, MYS-2, MYO- Examples include polyethylene glycol fatty acid esters such as No. 6. It is preferable to use these emulsifiers in an amount of 1 to 20% based on the oil phase.

On the other hand, as the above-mentioned stabilizer, for example, Niracol GM-1
Bacyl monostearate such as 88, -polyoxyethylene sorbitan beeswax derivatives such as Counillacol GBW-25, Chive: r-A/ 88-12
Sorbitan fatty acid esters such as Nilacol MGS
-F-75, MGS-F-50, glycerin fatty acid esters, cetanol, beeswax, stearic acid, aluminum stearate, aluminum octylate, ethyl cellulose, etc. are good, and these stabilizers are 0. It is preferable to use it in the range of 1 to 10.

An example of creating an emulsion is an oil phase based ioo
r (ethyl oleate alone or ethyl oleate-based 15% magnetic fluid) with Niracol Co-1 as an emulsifier.
010%, and 5 parts of cetanol, beeswax, stearic acid, etc. as stabilizers were mixed and stirred with heating to uniformly dissolve.

Then, an equivalent amount of water is added to the mixture while stirring at high speed to form a uniform W10 emulsion. In order to further microcapsule the emulsion, use A, L, M homogenizer type O (AUGUSTE & MOUTIS PAR).
IS, manufactured by FRANCE) for 10 to 15 minutes, a uniform W10 emulsion of 0.1 μ to 1.0 μ is obtained.

The A, L, and M homogenizers are homogenizers that circulate and homogenize by passing through an optulator under high pressure. Specifically, the base to be emulsified is introduced from a tank into a cylinder and pumped into the cylinder. Pressure is applied to pass it through an obturator, which has a special notch attached to the cylinder. When the emulsion passes through the optulator, rolling and impact are applied by the rough notches, resulting in extremely large diffusion and homogenization.

And in this case fine obturator = (006°01
When using 2), an emulsion with an average particle size of 0.6μ can be obtained.

It is difficult to select an appropriate surfactant in order to uniformly disperse the &crystalline emulsion obtained as described above in water.

This is because if the dispersion is too good, the emulsion will be mixed or the emulsion will coalesce, and if the dispersion is insufficient, the particles will become coarser and cause blockage when administered into the body.

Effective surfactants that meet these conditions include salts such as sodium lauryl sulfate, sarcosinate polyoxine ethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene higher fatty acid ester, gelatin, and casein. , especially Niracol HC
Polyoxyethylene hydrogenated castor oil such as O-60, polyoxyethylene hydrogenated castor oil such as Niracol MYS-55
Particularly good are high R fatty e esters, polyoxyethylene sorbitan fatty acid esters such as Niracol TL-10, and gelatin.

The addition i of the above surfactant is 0.1 to 0.1 to water.
If the range of 1.0- is less than 0.tq'', the dispersion becomes unstable, and if it is more than 1%, the emulsion may coalesce, and a composite emulsion may not be obtained.

Examples of this invention will be described below.

Example 1 IO- Ethyl oleate 85t1 Cetanol 39. Stearin E2F and Nilacol Co-3 (ethylene oxide derivative of castor oil) 10F were dissolved at 70°C to form a homogeneous oil phase, and while stirring at high speed, the dye indicocarmine 0 was dissolved.
．． A spider emulsion was prepared by gradually adding 100 f of water in which 1 f was dissolved and heated to 70°C and stirring for 10 minutes. Furthermore, the particles were recycled for 15 minutes using A, L, and M homogenizers to adjust the particle size to 1.0 μm or less.

5 of the obtained Aya emulsion was placed in a 200-cm beaker.
Niracol To-10 (polyoxyethylene sorbitan monooleate) was dissolved at a total of 0.1%, and 50% of water was gradually added to a high-speed stirring emulsion for 30 minutes.
A W10/W emulsion was prepared by stirring for 1 minute to 1 minute.

Comparative Example 1 Ethyl oleate 901, Nyracol BC-2 (polyoxyethylene cetyl ether) 10 P were heated and dissolved at 70°C to form a homogeneous oil phase, and this was mixed with 0.1 f of the dye idicocarmine while stirring at high speed. Melt /
/ - Gradually add 100 f of water that has been dissolved and heated to 70℃.
The mixture was stirred for 0 minutes to create an emulsion.

The mixture was further stirred with a homogenizer for 15 minutes to create a W10 emulsion. Then the obtained emulsion is 200
-50 in a beaker? 0.3 g of Neogen R (sodium alkylbenzenesulfonate) was collected and dissolved, and 50 rrl of water was gradually added to a high-speed stirring emulsion and stirred for 1 minute to prepare a W10/W emulsion.

As mentioned above, W1 adjusted in Example 1 and Comparative Example 1
Put the 0/W emulsion into a 100-colorimeter tube and heat at 25°C.
The results of observing changes over time were as follows.

The W10/W emulsion prepared in Example 1 was used for 3 days (
Even after 72 hours had passed, the composite emulsion remained stable, with no separation of the emulsion at all.

On the other hand, the Wlo,/W emulsion of Comparative Example 1 was 2
Separation started after 4 hours, and after 72 hours separation was 4
It was 0.

Example 2 FA) Innermost aqueous phase...Demineralized water in which indico carmine of 0.1 r/loo f is dissolved CB) Oil phase...Composition F of Attached Table 1'1 & 11 to Arashi 8
C) Outermost aqueous phase...Compositions of Attached Tables 1 to 8 The method for producing the composite emulsion is the same as in Example 1, and the composition consists of an innermost aqueous phase of 50 f and an oil phase of 50 f to form an emulsion. Created. Of these, so P was collected, and 50% of the outermost aqueous phase was collected.
f was added to obtain a W/ 0 /W emulsion.

Comparative Example 2 A w10/wi emulsion was prepared in the same manner as in Comparative Example 1 except that ethyl oleate-based magnetic fluid 90f was used in place of ethyl oleate in Comparative Example 1.

The table below shows the stability of the W10/W composite emulsion prepared in Example 2 in comparison with Comparative Examples 1 and 2. The stability of the emulsion was determined by putting the composite emulsion 100- in a colorimetric tube, allowing it to stand at 25°C, and measuring the state of separation at -.

Stability of W10/W emulsion Example 3 W10/W emulsions of Iden 4 and Yu 8 made in Example 2 were made, and after confirming that the limb diameter was 1μ or less, they were made into seamless cellulose tubes ( 28 gourds in diameter)
Put 1 ton of demineralized water into a 1 ton glass beaker,
As a result of a dialysis test of the innermost dye indicocarmine by suspending the water in a solution and leaving it at 35℃, the de-melted water remained stable even after one week, and the W10/W emma 7tz John was stable. I confirmed that there is.

On the other hand, when the W10/W emulsion obtained in Comparative Example 1 was subjected to a similar dialysis test, it was found that the water after removal of the water became colored after one day and was unstable.

Patent applicant: Taiho Industries Co., Ltd.

Claims (4)

[Claims] (1) H, L, B2-10 oil-soluble emulsifier 1-2o
A W10 emulsion consisting of an oil component and water in which 0.1 to 10 yen of an oil-soluble stabilizer is dissolved is emulsified in water containing 0.1 to 1.0 yen of a water-soluble emulsifier.
W Composite emulsion. (2) The composite emulsion according to claim 1, wherein the oil-soluble emulsifier is one or more selected from polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, and polyoxyethylene higher fatty acid ester. (3) The oil-soluble stabilizer is one or more selected from patyl monostearate, sorbitol, beeswax, stearic acid, aluminum stearate, aluminum octylate, and ethylceyalose sorbitan fatty acid ester -- Scope 1 Composite emulsion as described in Section. (4) A patent claim in which the water-soluble emulsifier is one or more selected from sodium alkyl sulfate, sarcosinate, polyoxyethylene hydrogenated castor oil, polyoxyethylene higher fatty acid ester, polyoxyethylene sorbitan fatty acid ester, gelatin, and casein.゛゛Composite emulsion according to item 1 of the scope.