JPH0312932B2 - - Google Patents

Description

[Detailed description of the invention]

<Industrial Application Field> The present invention relates to a W/O/W composite emulsion that can be used, for example, as a pharmaceutical product. More specifically, the present invention relates to a W/O/W composite emulsion that can be used as a pharmaceutical product. The present invention relates to a W/O/W composite emulsion that can dissolve anticancer drugs and induce the anticancer drugs locally using a magnetic field. <Prior Art> Most of the anticancer drugs currently manufactured and sold are water-soluble substances. However, when the above-mentioned water-soluble anticancer drugs are used in the human body, the reaction speed and leakage are large, and they can significantly destroy not only cancer cells but also normal cells.
There is a risk of danger to life. Therefore, for the purpose of injecting anticancer drugs into the body (in blood vessels), a technique was developed in which the anticancer drugs are contained in a magnetic fluid and the anticancer drugs are guided locally using a magnetic field (Japanese Patent Laid-Open No. 56-9000). and Japanese Patent Application No. 55-185101 (see Japanese Unexamined Patent Publication No. 57-109714). As mentioned above, most anticancer drugs are water-soluble, while the magnetic fluid used as a carrier is oil-soluble. , (1) containing an anticancer agent in an oil-soluble magnetic fluid (in this case, the anticancer agent is dispersed in the magnetic fluid as a fine powder);
(2) Wrap a water-soluble anticancer drug in a magnetic fluid to form a W/O emulsion so that it can be administered into the body. /O/W composite emulsion, etc. <Problems to be Solved by the Invention> The above-mentioned method (2) using a W/O/W composite emulsion does not allow the interposition of an oil phase based on an oil component that is not toxic to the human body between the aqueous phase. However, in reality, W/O/W emulsions based on oil components that are not toxic to the human body are unstable and cannot be microencapsulated. <Means for Solving the Problems> The present invention was proposed in view of the above, and the base oil is a vegetable oil, a higher fatty acid, a higher fatty acid ester,
1 to 20% oil-soluble emulsifier with HLB 2 to 10 to a magnetic fluid consisting of animal oil and one or more fluorocarbons,
and a W/O/W composite emulsion obtained by emulsifying a W/O emulsion consisting of an oil component and water in which 0.1 to 10% of an oil-soluble stabilizer is dissolved into water containing a water-soluble emulsifier of 0.1 to 1.0%. It is. Therefore, the W/O/W composite emulsion of the present invention has, for example, a water-soluble anticancer drug dissolved in the innermost aqueous phase,
The magnetic field allows anticancer drugs to be guided to areas other than the affected area without leaking out. Regarding the manufacturing method of the magnetic fluid used in the above-mentioned present invention, Japanese Patent Publication No. 53-17118 and Japanese Patent Publication No. 54-
As detailed in Publication No. 40069, it is necessary to consider toxicity to the human body when including anticancer agents, etc., and high-grade substances such as oleic acid, linoleic acid, and stearic acid are recommended as substances to be adsorbed to magnetic particles. Fatty acids can be used, and the base liquid is usually vegetable oils such as cottonseed oil, rapeseed oil, olive oil, safflower oil, soybean oil, higher fatty acids such as oleic acid, linoleic acid, or ester compounds of higher fatty acids such as oleic acid. , squalene,
Animal oils such as squalane or synthetic oils such as fluorocarbons can be used. In addition, anticancer agents that can be dissolved in the innermost aqueous phase of the W/O/W emulsion in the present invention include alkylating agents, antimetabolites, antibiotics, hormones, alkaloids, etc. For example, nitrogen mustard-N-
oxide, chloroamptyl, triethylene melamine, dibromomannitol, CCNU (1-3
-cyclohexyl-1-nitrosourea), 6-
MP (6-mercaptopurine), 6-TG (6-thioguanine), FT-207 ( _N1-5 -fluorouradyl)), cytosine arapinoside (1-β-D-arapinofuranosilysin), 5-FU (5-fluorouradil), adreamycin, matomycin,
Examples include pleomycin. Furthermore, in the present invention, in order to enable and strengthen microencapsulation, an oil-soluble emulsifier and an oil-soluble stabilizer are added and dissolved in the magnetic fluid to form an oil phase. As the oil-soluble emulsifier that dissolves in the above-mentioned magnetic fluid, a low-toxicity surfactant that forms a W/O emulsion can be used, and HL
B.2.0 to 10.0 is good; if the HLB is 2.0 or less, the action as an oil-soluble emulsifier is significantly reduced, and if the HLB is 10.0 or more, the solubility in oil decreases and it cannot be said to be good. HLB2.0 like this
An example of an oil-soluble emulsifier with ~10.0 is Nitsukor
CO-3, CO-10 (manufactured by Nippon Surf Actant Co., Ltd.)
Polyoxyethylene castor oil derivatives such as HLB3.0, HLB6.5, polyoxyethylene hydrogenated castor oil derivatives such as Nikkor HCO-40, or Nikkor MYA-2, MYS-2, MYO-
Polyethylene glycol fatty acid esters such as No. 6 can be mentioned, and the amount is 1 to 20% based on the oil phase.
It is preferable to use the amount within the range of 1% or less, the emulsifying power will be weak and there will be problems with the stability of W/O emulsion, and if it is added in a large amount of 20% or more, it will have an adverse effect on the use of the water-soluble emulsifier described later. give,
Makes the O/W emulsion unstable. In addition, examples of oil-soluble stabilizers that dissolve in the magnetic fluid together with the above-mentioned oil-soluble emulsifiers include batyl monostearate such as Nikkor GM-18S,
Sorbit, beeswax, polyoxyethylene sorbitan beeswax derivatives such as Nikkol GBW-25, cetanol, stearic acid, aluminum stearate, aluminum octylate, ethyl cellulose, sorbitan fatty acid esters such as Nikkol SS-12, Nikkol MGS-F-75 ,
Glycerin fatty acid esters such as MGS-F-50 are good, and it is preferable to use them in the range of 0.1 to 10% based on the oil phase.If it is less than 0.1%, it will not work as a stabilizer, so add less than 10%. This increases the viscosity of the oil phase, which becomes a factor that makes the subsequent O/W emulsion unstable. Next, a method for preparing a W/O emulsion consisting of water and an oil phase consisting of a magnetic fluid in which the above-mentioned oil-soluble emulsifier and oil-soluble stabilizer are dissolved will be explained. First, as the oil phase, ethyl oleate-based
To 100 g of 15% magnetic fluid, add 10% of Nitsukor CO-10 as an oil-soluble emulsifier and 5% of cetanol, beeswax, stearic acid, etc. as an oil-soluble stabilizer, and heat and stir to dissolve uniformly. Next, by gradually adding an amount of water equivalent to the above solution while stirring at high speed, a uniform W/O
Emulsions can be created. Furthermore, in order to microcapsule the above-mentioned W/O emulsion, an ALM homogenizer type O (AUGUSTE & MOUTIS PARIS.
FRANCE) for 10-15 minutes.
A uniform W/O emulsion of 0.1-1.0μ can be obtained. In addition, the ALM homogenizer type O mentioned above is
A homogenizer that circulates and homogenizes the material by passing it through a closed-type emulsifier (optulator). Specifically, the base material to be emulsified is introduced from a tank into a cylinder, pressure is applied by a pump, and the material is attached to the cylinder. This is a method in which the emulsion is passed through an optulator with special cuts.When the emulsion passes through the optulator, the complex cuts apply rolling and impact, resulting in extremely large diffusion and homogenization. It is. Then, by using fine opticulators (006, 012) as described above, the average particle size is
A 0.6μ W/O emulsion can be obtained. In order to uniformly disperse the W/O emulsion obtained as described above in water to form a W/O/W composite emulsion, it is necessary to add an appropriate water-soluble emulsifier. However, if the dispersion of the W/O emulsion is too good due to the addition of the above-mentioned water-soluble emulsifier, the W/O
The emulsion will coalesce, and if dispersion is insufficient, the particles will become coarse. The water-soluble emulsifier used in the present invention does not cause the above-mentioned problems and creates a stable W/O/W composite emulsion. Sarcosinate, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene higher fatty acid ester, gelatin, casein, etc. are effective, but especially polyoxyethylene hydrogenated castor oil such as Nitsukor HCO-60, Nitsukor
Particularly good are polyoxyethylene higher fatty acid esters such as MYS-55, polyoxyethylene sorbitan fatty acid esters such as Nikkor TL-10, and gelatin. In addition, the amount of the above-mentioned water-soluble emulsifier added is preferably in the range of 0.1 to 1.0% relative to water;
If it is less than 0.1%, the dispersion will become unstable, and if it is more than 1.0%, the emulsion will coalesce, and a composite emulsion may not be obtained. <Examples> Examples 1 to 8, Comparative Examples 1 to 5 (A) Innermost aqueous phase: Blend composition shown in Table 1 (B) Oil phase: Blend composition shown in Table 2 (C) Outermost aqueous phase: Table Compound composition shown in 2

【table】

【table】

【table】

[Table] As mentioned above, the innermost aqueous phase, oil phase,
A solution of the outermost aqueous phase was prepared according to the compositions shown in Tables 1 and 2. Next, 100g of the oil phase was uniformly dissolved at 70℃, and while stirring at high speed, 100g of the water phase was heated to 70℃.
was gradually added and stirred for 10 minutes to prepare a W/O emulsion. Furthermore, the particles were recycled for 15 minutes using an ALM homogenizer to adjust the particle size to 1.0μ or less. 50g of the obtained W/O emulsion was collected in a 200ml beaker, and 50ml of the outermost aqueous phase was gradually added to the W/O emulsion that was being stirred at high speed for 30 seconds to 1 hour.
A W/O/W composite emulsion was prepared by stirring for a minute. (Stability test) Each of the W/O/W composite emulsions of Examples 1 to 8 and Comparative Example prepared as above 100
ml was placed in a colorimetric tube, left to stand at 25°C, and the state of separation was measured in [ml]. The results are shown in Table 3.

[Table] <Effects of the Invention> As explained above, the W/O/W composite emulsion of the present invention has high separation stability, and since the oil phase is composed of magnetic fluid, it can be guided locally by a magnetic field. It is something that can be done. Therefore, dissolving pharmaceuticals such as anticancer drugs in the innermost aqueous phase has extremely high practical value as a carrier that can be applied only to the affected area.

Claims (1)

[Claims] 1 The base oil is one or more of vegetable oil, higher fatty acid, higher fatty acid ester, animal oil, and fluorocarbon.The magnetic fluid is selected from polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, and polyoxyethylene higher fatty acid ester with an HLB of 2 to 10. 1 to 20% of one or more oil-soluble emulsifiers, and batyl monostearate, sorbitan, beeswax, polyoxyethylene sorbitan beeswax derivatives, cetanol, stearic acid, aluminum stearate, aluminum octylate, ethyl cellulose, sorbitan fatty acid ester, glycerin fatty acid ester A W/O emulsion consisting of an oil component and water in which 0.1 to 10% of one or more oil-soluble stabilizers selected from the following are dissolved is further mixed with sodium alkyl sulfate, N-acyl sarcosinate, polyoxyethylene hydrogenated castor oil, A W/O/W composite emulsion obtained by emulsifying water containing 0.1 to 1.0% of one or more water-soluble emulsifiers selected from polyoxyethylene higher fatty acid ester, polyoxyethylene sorbitan fatty acid ester, gelatin, and casein.