JPS6243733B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a new method for controlling the elution of a core substance from a capsule formulation into a dispersion medium. More specifically, in a system consisting of a dispersion medium and a core material coated with a capsule wall film, a surfactant is added in the capsule and/or to the dispersion medium at a concentration of 0.05 to 25%.
This invention relates to a method of controlling and increasing the elution amount of the capsule inner core material to the dispersion medium by adding the surfactant at a concentration of %. Capsules are used in a very wide range of fields, including medicines, agricultural chemicals, fertilizers, veterinary medicines, paints, cosmetics, detergents, photographic chemicals, and many other fields. Conventionally, capsules have been used for the purpose of gradually and gently dissolving the core substance within the capsule into a dispersion medium, particularly water, or in other words, suppressing the elution of the core substance into the dispersion medium. The theory of elution of the core material inside the capsule into the dispersion medium is described in J.
R.Nixon, ed., Microencapsulation, Drugs and
The Pharmaceutical Sciences, Dekker, 3 ,
187, 1976. Formula: dc/dt=3D _n /Vrd(1/δ+ε/h)(C
∞-C) () [Where, C is the concentration of the core substance in the dispersion medium at time t, D is the molecular diffusion constant, m is the capsule mass, V is the amount of solvent, is the average diameter of the capsule, and d is the capsule diameter. Specific gravity, δ is the width of the diffusion layer, ε is a constant representing the properties of the membrane itself, h is the thickness of the capsule membrane, and C∞ represents the solubility of the core substance in the dispersion medium. ] It is expressed as . In this case, factors for suppressing elution include the radius of the capsule (in the formula), the thickness of the capsule membrane (h in the formula), and the properties of the capsule membrane itself (ε in the formula). In other words, conventional capsules can be used in a wide variety of industrial fields by taking advantage of their elution-suppressing effect and selecting the capsule size, membrane thickness, or unique characteristics of the capsule membrane itself. It has been used for various purposes. In using capsule formulations of agricultural pesticides, the present inventors have aimed to reduce the harm to humans and livestock that accompanies the spraying process, and to inactivate the toxicity of the pesticides in the agricultural environment or remove them from the area. reduce the loss of
In order to utilize it more rationally by prolonging its residual effect, we have prepared capsule formulations of agricultural pesticides (hereinafter referred to as pesticide capsules) and investigated the medicinal efficacy of their aqueous dispersions. However, when microencapsulated using an active substance with low solubility in water as the core substance, the expected pesticidal effect is not achieved because a sufficient amount of the active substance to exhibit medicinal efficacy is not released into the agricultural environment. I was faced with the problem of not being able to do it. For core substances with low solubility that did not exhibit sufficient effects, the present inventors applied the conventional method of suppressing the elution rate of the core substance into the dispersion medium. The medicinal efficacy of capsules was tested in comparison with non-capsules by adjusting and/or various capsule membranes, but the efficacy of capsules was unstable and insufficient. Based on the above results, the present inventors found that when a substance with low solubility in a dispersion medium is encapsulated, it is not possible to expect a sufficient amount of elution to exhibit medicinal efficacy by conventional usage methods, so the solubility C∞
Focusing on this, we conducted various studies on increasing the efficacy of micronized formulations by controlling the amount of pesticides eluted into the dispersion medium. As a result, surfactants can be added to the dispersion medium or
Alternatively, it has been found that by adding the pesticide into a capsule, the elution concentration of the pesticide in water can be significantly increased to several tens of times the original C∞ value. Furthermore, it has been discovered that by selecting the type of surfactant and the amount added and utilizing its unique properties, it is possible to control and increase the elution rate to a desired degree. The present invention was completed based on this new knowledge. Surfactants have traditionally been used in a wide variety of fields, but the main principle behind their use is that surfactants adsorb to the interface between two layers. Surfactants reduce interfacial tension. The surfactant itself forms micelles. etc., and, consequentially, surfactants disperse oils with low water solubility uniformly and relatively stably in water. Surfactants relatively stably disperse fine solids with low water solubility in water. Surfactants improve the wettability of solid surfaces with low water solubility. Surfactants promote water penetration into hydrophobic fibers or hydrophobic microporous fibers. Surfactants help substances mixed inside hydrophobic fibrous or hydrophobic microporous tissues to dissolve into water. Surfactants solubilize substances with low water solubility in water. It has been known that the following properties exist. However, the method of the present invention is completely different from the conventional method of using surfactants, namely, the effect of adding a surfactant to control the amount of elution into water separated by a so-called poreless membrane. The knowledge that it has this was completely unknown until now and was surprising. The present invention provides a system in which capsules containing a substance with low solubility in the original dispersion medium (hereinafter referred to as "low original C∞") are dispersed in the dispersion medium, in which the surfactant is added to the dispersion medium. A method in which any desired amount of core material is eluted into a dispersion medium by adding a predetermined amount of a selected composition from among agents or possible mixtures thereof, and By mixing a predetermined amount of the above-mentioned surfactant or a selected composition from among its possible mixtures with a substance having a low original C∞ and encapsulating the mixture, the capsule is made into a dispersion medium. This is a method of increasing the elution amount of the encapsulated core material with a low original C∞ into the dispersion medium to the desired concentration (the former is called the "extracapsule addition method", and the latter is called the "intracapsule addition method"). ). The use of both the extracapsular addition method and the intracapsule addition method is not excluded from the present invention. Furthermore, one of the features of the present invention is to skillfully utilize the unique temperature characteristics (cloud point) of nonionic surfactants. In both the extracapsular and intracapsular dosing methods, intracapsular addition into the dispersion medium of the capsule/dispersion medium system is performed by artificially adjusting the environmental temperature or by taking advantage of natural fluctuations in the environmental temperature. The original C∞ enclosed in
If elution of the core substance with a low concentration is not desired, the amount can be kept at a very small amount, and if desired, it can be freely increased to the desired concentration. Surfactants for use in the present invention may include nonionic, anionic, cationic, zwitterionic surfactants and possible mixtures thereof. For example, specific examples of surfactants include anionic surfactants: alkyl sulfates, [e.g., sodium lauryl sulfate, etc.], arylsulfonic acids, [e.g., alkylarylsulfonates, alkylnaphthalenesulfonic acids, etc.] Sodium, etc.]: Cationic (cationic) surfactants, alkyl amines, [e.g., laurylamine, stearyltrimethylammonium chloride, alkyldimethylbenzylammonium chloride, etc.], polyoxyethylene alkylamines: Nonionic surfactants, poly Oxyethylene glycol ethers, [e.g., polyoxyethylene alkylaryl ether, polyoxyethylene alkyl phenyl ether, etc.], polyoxyethylene glycol esters, [e.g., polyoxyethylene fatty acid esters], polyhydric alcohol esters,
[For example, polyoxyethylene sorbitan monolaurate, etc.]: Amphoteric surfactants, betaines,
[For example, alkyl dimethyl betaine, etc.], amino organic acids, [For example, dialkylaminoethylglycine, etc.], and the like can be mentioned. The concentration of surfactant in the dispersion medium and/or capsule is 0.05-25%. The diameter of the capsule is preferably 10 to 10000μ, more preferably 10 to 200μ, still more preferably 20 to 100μ. A specific example of the dispersion medium is water. As agricultural pesticides, those with a saturation concentration in water of about 1000 ppm or less are preferably used, more preferably about 500 ppm or less, especially about
A content of 100 ppm or less is preferable. Examples of such agents include O-ethyl-S,S-diphenylphosphorodithiolate, O,O-dimethyl-O-
[3-Methyl-4-(methylthio)phenyl]-thiophosphate, O,O-dimethyl-O-4-nitro-m-tolylphosphorothionate, O,O-
Diethyl-O-5-phenyl-3-isoxazolyl phosphorothionate, O,O-dimethyl-S
-[α-(Ethoxycarbonyl)benzyl]phosphorothiorothionate, O,O-dimethyl-S-
(N-Methylcarbamoylmethyl)phosphorothiolothionate, O,O-dimethyl-O-2,2-
Dichlorovinyl phosphate, O,O-dipropyl-O-p-methylthiophenyl phosphate,
O,S-dimethyl-N-acetylphosphoroamidothiolate, O-ethyl-O-p-nitrophenyl-phenylphosphonothionate, O-ethyl-
O-p-cyanophenyl-phenylphosphonothionate, O-ethyl-O-2,4-dichlorophenyl-phenylphosphonothionate, and the like can be mentioned. When the important purpose of encapsulating an agricultural pesticide is to reduce toxicity to humans and livestock, the agricultural pesticide encapsulated in the capsule may be dispersed in a dispersion medium outside the capsule membrane (e.g., in water or air). The smaller the amount released, the better the objective will be achieved. On the other hand, the main purpose of using agricultural pesticides is to control pests and diseases in the agricultural environment.
When pesticide capsules are used for that purpose, the capsules must release a sufficient amount of agricultural pesticide into the agricultural environment to be effective in controlling pests and diseases. The method of using a surfactant to simply increase the concentration of the agricultural pesticide eluted from the capsule in the dispersion system consisting of the pesticide capsule and water is not suitable for the purpose of increasing the pest control effect in the agricultural environment. However, in some cases, significant amounts of the agricultural pesticide have already been leached into the water of the pesticide capsule dispersion to be sprayed, so that during the spraying operation there may be no activity on the sprayer or on the sprayed area. The purpose of encapsulation, which is to reduce the risk of harm to people other than sprayers and/or livestock, is completely contradictory. The present invention solves the above-mentioned contradiction that could not be solved by conventional techniques by controlling the elution amount, and also has a low C∞, making it one of the most promising technologies in recent years. The significance of the present invention is great because it has enabled the encapsulation of a series of agricultural pest control agents that could not be used by encapsulation. Next, the method of the present invention and its effects will be specifically explained. Test example 1 15g of EDDP raw material and nonionic surfactant polyoxyethylene styryl phenyl ether (cloud point 30
5 g of aqueous gelatin treated with an alkali at the same temperature were mixed, and stirring was continued while maintaining the temperature at 50° C.). Thereafter, while stirring, 60 g of a 5% gum arabic aqueous solution and 280 g of water at the same temperature were added. Salt was added thereto, and a 10% acetic acid aqueous solution was gradually added dropwise to lower the pH of the liquid to 4. After stirring for a while, the temperature of the liquid was lowered to 5°C. Next, add 37% formalin solution.
1.5 ml was added dropwise, and then a 10% aqueous sodium hydroxide solution was added dropwise to adjust the pH of the liquid to 9. The liquid temperature is raised to 40°C and stirring is continued for several hours to produce test capsules containing the EDDP raw material containing a surfactant in the capsule as a core material. Test Example 2 Effect of type of surfactant on elution Approximately 10% O-ethyl S,S-diphenylphosphorodithiolate (hereinafter abbreviated as EDDP) manufactured using the complex coacervation method A 50 ml Erlenmeyer flask with a stopper containing 2 ml of a slurry of gelatin gum arabic microcapsules (average particle size of about 40 µm) containing the following was prepared for analysis. To each Erlenmeyer flask, 20 ml of the surfactant aqueous solution described below was added using a measuring pipette, the flasks were stoppered, and after stirring, the flasks were placed in a constant temperature water bath at 20°C. The Erlenmeyer flask was taken out over time, and after stirring,
A 5 ml portion of the solution was taken with a whole pipette, extracted three times with 25 ml of methylene chloride each time, and the active ingredients were quantified using gas liquid chromatography. The surfactant aqueous solution used in this example is as follows. 0.1% aqueous solution of polyoxyalkylene styryl phenyl ether, 0.1% aqueous solution of alkylaryl sulfonate salt, 0.1% aqueous solution of alkylmethyl diethanol ammonium halide, 0.1% aqueous solution of alkyl dimethyl betaine, polyoxyalkylene benzyl phenyl ether and alkylaryl sulfonate 0.1% aqueous solution of salt mixture. As a comparative example, a test using a 0.1% ethyl alcohol aqueous solution of distilled water was also conducted. The results are shown in Table 1 and attached Figure 1.

【table】

[Table] Test Example 3 Effect of surfactant concentration on dissolution A test was conducted using the same EDDP capsule slurry as in Test Example 2 and in the same manner as in Test Example 2. As the surfactant aqueous solution, polyoxyalkylene styryl phenyl ether 1.0%, 0.5%, 0.1%,
The test temperature was 20% using each aqueous solution of 0.05% and 0.01%.
℃. A separate test using distilled water was also conducted as a comparative example. The results are shown in Table 2 and attached Figure 2.

[Table] Test Example 4 Effect of the number of moles of hydrophilic groups added to the surfactant on dissolution A test was conducted using the same EDDP capsule slurry as in Test Example 2 and in the same manner as in Test Example 2. As the surfactant aqueous solutions, 0.1% aqueous solutions of polyoxyalkylene styryl phenyl ether with a hydrophilic group addition mole number of 12, 18, and 32 to 33 were used, and the test temperature was 20°C. The results are shown in Table 3 and attached Figure 3.

[Table] Liquid Test Example 5 Effect of Water Temperature on Dissolution A test was conducted using the same EDDP capsule slurry as in Test Example 2 and the same operating method as in Test Example 2. As the surfactant aqueous solution, a 0.1% aqueous solution of polyoxyalkylene styryl phenyl ether (cloud point: about 90°C), which is a nonionic surfactant, was used at test temperatures of 20°C and 40°C. The results are shown in Table 4 and attached Figure 4.

[Table] Addition moles of renstyrylphenyl ether number 32-33
Cloud point 90℃
Test Example 6 Effect of Water Temperature on Dissolution A test was conducted using the same EDDP capsule slurry as in Test Example 2 and in the same manner as in Test Example 2. As the surfactant aqueous solution, a 0.1% aqueous solution of polyoxyalkylene benzyl phenyl ether (cloud point: about 40°C), which is a nonionic surfactant, was used, and the test temperatures were 10°C, 20°C, and 50°C. The results are shown in Table 5 and attached Figure 5.

[Table] Kylenebenzyl phenyl ether
Cloud point 40℃
Test Example 7 Effect of Surfactant on Dissolution A test was conducted in the same manner as in Test Example 2 using capsules containing toluene as the core material. As the surfactant aqueous solution, a 0.1% aqueous solution of polyoxyethylene alkylphenol having a cloud point of 23°C was used, and the test temperatures were 20°C and 30°C. Separately, as a comparative example, distilled water was used at 20°C. The results are shown in Table 6 and attached Figure 6.

[Table] Alkylphenol
Cloud point 23℃
Test Example 8 Influence of surfactant concentration by external addition method on biological effects (i) Dissolution test A test was conducted using the same EDDP capsule slurry as in Test Example 2 and in the same manner as in Test Example 2. As the surfactant aqueous solution, polyoxyalkylene benzyl phenyl ether (number of moles of hydrophilic group added 12 to 13) 35%, polyoxyalkylene benzyl phenyl ether (number of moles of hydrophilic group added 16) 35%
%, 1.0%, 0.5%, 0.1% and 0.05% of a mixed surfactant consisting of 20% alkylaryl sulfonate
A dissolution test was conducted using an aqueous solution at a test temperature of 20°C, and the results are shown in Table 7 and attached Figure 7. (ii) Biological test (comparative test for efficacy against rice blast fungi) Test method Paddy rice (variety Asahi) was sown in 11 cm vinyl pots, cultivated in a field, and adjusted to seedlings at the 5-6 leaf stage using (i). The same adjustment solution was sprayed. Spraying at pressure 4
Sprayed with a tower sprayer at Kg/cm ² . Two and five days after the spraying, a blast fungus suspension (50 to 100 spores/10 x 10) was inoculated by spraying in a conventional manner. The degree of damage was calculated from the lesion area ratio 8 days after inoculation. The results are shown in Table 8.

【table】

【table】

[Table] Test Example 9 Effect of water temperature on dissolution A slurry of EDDP microcapsules produced by the method of Test Example 2, in which the surfactant accounts for about 25% of the core material, was dispersed in distilled water and the same procedure as in Test Example 2 was carried out. It was tested using the following operations. The test temperatures were 15°C and 35°C. The results are shown in Table 9 and attached Figure 8.

[Table] Test example 10 Water exchange test Contains 25% nonionic surfactant used in Test example 9
Put 2 ml of the EDDP microcapsule slurry into a 50 ml Erlenmeyer flask with a stopper, add 20 ml of distilled water, stir, and leave it in a constant temperature bath at 15°C, changing the water every 10 hours to remove the eluted EDDP. Test example 2
It was analyzed using the same method. The results are shown in Table 10.

[Table] Test Example 10 Test method for biological efficacy test of capsule formulation using internal addition method A biological test was conducted using the same manufacturing method as Test Example 1 and the same procedure as Test Example 8(ii). Ta. The results are shown in Table 11.

[Table] The present invention, which has been explained in detail in the detailed description of the invention, is specifically summarized as follows. (1) In a system consisting of a dispersion medium and a core substance covered with a capsule wall membrane, the amount of elution of the core substance inside the capsule is controlled by the surfactant by adding a surfactant inside/outside the capsule. Method. (2) A method for producing an agricultural capsule formulation comprising an agricultural narcotic agent as the capsule inner core material, the inner core material, a surfactant, and a dispersion medium. (3) A method in which a sufficient amount of surfactant is encapsulated in the capsule to control the amount of elution of the core substance inside the capsule.

[Brief explanation of the drawing]

Figure 1 shows the influence of the type of surfactant on the elution of EDDP. In Figure 1, A is a 0.1% aqueous solution of the nonionic surfactant polyoxyalkylene styryl phenyl ether, B is a 0.1% aqueous solution of the anionic surfactant alkyl sulfonate salt, and C is the cationic surfactant alkylmethyldiethanolammonium. 0.1% aqueous solution of halide, D is 0.1% of zwitterionic surfactant alkyl dimethyl betaine
An aqueous solution, E is a 0.1% aqueous solution of a mixed surfactant of polyoxyalkylene benzyl phenyl ether and an alkylaryl sulfonate salt, F is a 0.1% aqueous solution of ethyl alcohol, and G is distilled water.
Figure 2 shows the effect of surfactant concentration on the elution of EDDP. As the surfactant, a nonionic surfactant polyoxyalkylene styryl phenyl ether (number of moles added with hydrophilic groups: 18) was used. FIG. 3 shows the influence of the number of moles of hydrophilic groups added to the surfactant on the elution of EDDP. As the surfactant, a 0.1% aqueous solution of polyoxyalkylene styryl phenyl ether, a nonionic surfactant, was used. Figure 4 shows the effect of water temperature on the elution of EDDP. Surfactant polyoxyalkylene styryl phenyl ether (number of moles of hydrophilic group added 32 to 33, cloud point 90)
℃) was used. FIG. 5 shows the effect of the cloud point of a nonionic surfactant on the elution of EDDP. As the surfactant, a 0.1% aqueous solution of polyoxyalkylene benzyl phenyl ether (cloud point: 40°C) was used.
Figure 6 shows the effect of surfactants on toluene elution. As the surfactant, a 0.1% aqueous solution of polyoxyethylene alkylphenol (cloud point: 23°C) was used. Figure 7 shows the effect of surfactant concentration on the elution of EDDP. As the surfactant, a mixed surfactant of polyoxyalkylene benzyl phenyl ether and alkylaryl sulfonate was used. FIG. 8 shows the effect of water temperature on the elution of EDDP from EDDP capsules containing nonionic surfactants within the capsules. Polyoxyethylene styryl phenyl ether (number of moles of hydrophilic group added: 14, cloud point: 30°C) was used as the surfactant.

Claims (1)

[Scope of Claims] 1. In a system consisting of a dispersion medium and a core substance covered with a capsule wall film, the inner core of the capsule can be removed by adding a surfactant to the capsule and/or the dispersion medium at a concentration of 0.05 to 25%. A method for controlling and increasing the elution amount of a substance using the surfactant. 2. The method according to claim 1, wherein the capsule has a diameter of 10 to 10,000 μ. 3. A patent claim in which the surfactant is a surfactant selected from the group consisting of nonionic surfactants, anionic surfactants, cationic surfactants, zwitterionic surfactants, and mixtures of at least two thereof. The method described in item 1. 4. The method according to claim 1, wherein the surfactant is a nonionic surfactant and its temperature characteristics are utilized. 5. The method according to claim 1, wherein the core material inside the capsule is an agricultural drug. 6. The method according to claim 1, wherein the dispersion medium is water.