JP2885508B2 - Aqueous flowable - Google Patents

Description

Description: FIELD OF THE INVENTION The present invention relates to an aqueous flowable non-medical drug having good stability over time and dilutability. More specifically, it is stable over time, characterized by incorporating liquid lanolin,
The present invention relates to an aqueous flowable non-medicinal agent having good dilutability.

(Prior Art) Non-medical drugs such as pesticides, epidemics, animal drugs, slime control agents, fungicides, wood preservatives, etc. are formulated into various dosage forms for the convenience of use. For example, agricultural chemicals and epidemics are mainly formulated into powders, wettable powders, emulsions, granules and the like, but dusts and wettable powders have a problem of health of users and producers due to dusting. In particular, dust has a large drift and may have a negative effect on nearby residents and the environment. In addition, wettable powders have poor fluidity and often cause troubles in the manufacturing process. In the case of emulsions, there is a risk of toxicity and fire hazard due to organic solvents. Granules have few such disadvantages, but in many cases, a sufficient control effect cannot be obtained depending on the active ingredient.

For these reasons, new dosage forms called flowable and dry flowable have recently been developed. Dry flowable is also referred to as a water dispersible granule, and has fluidity and low dusting, easily disperses in water, and becomes an aqueous solution or suspension. For this reason, it can be said that the dosage form solves the above-mentioned drawbacks of the wettable powder, but there is a drawback that it is difficult to apply to a low melting point compound or a highly volatile compound and the production cost is high.

On the other hand, flowables include those using water as a continuous phase and those using an organic solvent. These are roughly classified into a case where the dispersoid is a liquid (emulsion type) and a case where the dispersoid is a solid (suspension type). However, the use of an organic solvent for the continuous phase has disadvantages such as economical and environmental pollution, and the scatter of the spray liquid may have an adverse effect on car coating. Will be

Since aqueous flowables use water as a medium, they easily rot,
Although some compounds have drawbacks such as hydrolysis and particle growth, they are less prone to toxicity and environmental pollution and have less risk of fire.

(Problems to be Solved by the Present Invention) Since a flowable agent is a heterogeneous system, hard caking and layer separation often occur over time. In order to prevent this, various attempts have been made to deliberately soft-aggregate the formulation to prevent hard caking, or to increase the viscosity or increase of the formulation and prevent separation. According to this method, hard caking and layer separation can be substantially reduced.
On the other hand, there is a drawback that the water dilutability is poor, especially when the preparation is better than water, in order to disperse the flowable sinking to the bottom of the dilution tank, strong stirring is required. In addition, when applying or spraying the raw solution as it is, there are inconveniences such as that the applied surface becomes too thick or that the spray of the nozzle of the atomizer cannot be carried out for spraying.

When the chemical is pesticide, many Japanese farmers do not have a dilution tank with a stirrer because many farmers are small. For such a farmer, stirring the diluting liquid to disperse the flowable sinking into the bottom of the vessel is a troublesome task, and may involve dangers such as damage to the eyes due to splashing of the droplets. For this reason, in the case of a flowable with a high viscosity, a two-stage dilution method of diluting with a small amount of water in advance and re-diluting with a large amount of water is adopted, but such a work is not only troublesome but also requires another step. There is a problem that a separate container is required, and there is a risk that the concentrated diluent may adhere to the operator during re-dilution. In addition, due to the high viscosity, the efficiency of subdivision is reduced in the manufacturing process, and from the viewpoint of use, there is also a problem in treating containers in which a chemical solution remains at the bottom of the vessel.

From the above, there has been a strong demand for the development of a flowable that has good dilutability and is stable over time.

(Means for Solving the Problems) Under such circumstances, the present inventors have developed a flowable which has a low viscosity and good dispersibility, and which does not cause sedimentation, layer separation, hard caking, etc. due to long-term storage. As a result of intensive studies, the present inventors have found that the object can be achieved only by adding a small amount of liquid lanolin to the formulation of the flowable agent, and completed the present invention.

The flowable in the present invention means the above-mentioned emulsion or suspension type aqueous flowable. In the case of a compounding agent, when one of the active ingredients is a solid and the other is a liquid (or a solution of an organic solvent incompatible with water), a so-called suspoemulsion type which is a hybrid system of an emulsion and a suspension is used. Includes flowables. In the case of a solid active ingredient that is readily soluble in an organic solvent that is incompatible with water, it can be dissolved in an appropriate organic solvent and emulsified in water to form an emulsion type flowable. When one of the active ingredients is a compound which is easily soluble in water, first, an aqueous solution of a water-soluble ingredient is prepared, and a solid or liquid hardly soluble active ingredient is added thereto, and dispersed or emulsified. It is also possible to form suspensions or emulsions of the solid active ingredient therein.

At least one kind of the active ingredient which can be prepared into the flowable of the present invention must be hardly soluble in liquid or solid water. If the active ingredient is water-soluble, particle growth and coalescence of emulsified particles are likely to occur, so the water solubility at 20 ° C is 100p
pm or less, preferably 10 ppm or less is desirable.

In preparing the flowable, a suitable surfactant is used as a wetting or dispersing agent or emulsifying agent. The surfactant to be used may be appropriately selected from nonionic, anionic, cationic and amphoteric surfactants. Those having a strong solubilizing power with respect to the solid active ingredient may cause particle growth over time, and thus it is desirable to avoid them if possible.

The amount of the surfactant to be blended is sufficient as long as there is an amount necessary for emulsifying or dispersing the active ingredient. Although it depends on the type and content of the active ingredient, generally, 0.1 to 2
It is about 0% by weight.

Representative surfactants include polyoxyalkylene alkyl aryl ethers, polyoxyalkylene aryl aryl ethers, polyoxyalkylene alkyl ethers, polyoxyalkylene alkyl esters, sorbitan alkyl esters, polyoxyalkylene sorbitan alkyl esters, ethylene oxide and propylene oxide Nonionic surfactants such as polyoxyethylene castor oil ether, sulfates and phosphates of polyoxyalkylene-based nonionic surfactants and phosphates and salts thereof, alkylbenzene sulfonates, sulfates of higher alcohols, and lignin sulfone Acid salts, salts of (alkyl) naphthalenesulfonic acids and condensates thereof, dialkylsulfosuccinates, soaps, salts of sulfated olefins, α- Lefin sulfonate, alkyl tauride, carboxylic acid type polysoap, anionic surfactant such as sulfonic acid type polysoap, amino acid type and betaine type amphoteric surfactant, higher alkylamine salt, polyoxyalkylene higher alkylamine, imidazoline type, Cationic surfactants such as quaternary ammonium salts can be mentioned.

During flowable, besides this, deicing agents, preservatives,
Those generally used as auxiliaries, such as various stabilizers, dyes, and thickeners, can be blended.

As the antifreezing agent, ethylene glycol, propylene glycol, and derivatives thereof are usually used.

As the preservative, generally used preservatives such as alkylparaben, sorbic acid and its salts, benzoic acid and its salts, dehydroacetic acid and its salts are used.

The stabilizer is appropriately selected from commonly used antioxidants, light stabilizers, pH adjusters and the like, if necessary.

Dyes are added for the purpose of identification, stabilization of the active ingredient, or prevention of particle growth. What is necessary is just to select suitably from various dyes, and to use it.

Thickeners include, if necessary, synthetic polymers such as polyacrylates, polyvinyl alcohols, sodium salts of carboxymethyl cellulose, natural gums such as gum arabic, guar gum, xanthan gum, and lanthanum, magnesium aluminosilicate, acidic It may be used by appropriately selecting from inorganic mineral fine powders such as clay, bentonite, smectite, white carbon, etc., but the flowable of the present invention can be used for layer separation or hardening over time even if the viscosity is much lower than before. Since caking or the like hardly occurs, it can be kept sufficiently stable with a small amount of addition as compared with the conventional case.

In the process of emulsifying or pulverizing a flowable, it is economically advantageous to have as high an active ingredient concentration as possible. Therefore, it is more advantageous to carry out emulsification or pulverization at a concentration as high as possible, excluding those unnecessary for the emulsification and pulverization steps, and to blend other auxiliary substances into the obtained emulsion or suspension. In particular, emulsification and pulverization become difficult to proceed when the viscosity is increased. Therefore, it is preferable to add a thickener to the emulsified or pulverized low-viscosity, high-concentration product.

The flowable of the present invention contains liquid lanolin as an essential component. The liquid lanolin used in the present invention is obtained by separating only a low melting point component from wool fat (lanolin) by-produced when wool is obtained from raw wool of a sheep by solvent separation or the like, and exhibits a liquid state at normal temperature.

JP-A-1-151935 proposes to incorporate a wax for the purpose of stabilizing an aqueous dispersion. The wax described in the publication is a solid wax such as an animal wax including wool wax, a vegetable wax, and a petroleum wax, and differs in physical state and chemical composition from the liquid lanolin of the present invention.
In addition, in the aqueous flowable preparation of the present invention, a solid wax cannot sufficiently achieve the object.

In the present invention, liquid lanolin is added in any of the steps before and after emulsification and pulverization. However, since it is hardly soluble in water, it is difficult to finely disperse it in water by simple stirring even if it is added later. For this reason, before emulsification or pulverization, it is often better to mix the active ingredient, surfactant and the like and to emulsify in water by heating in some cases.

The amount of liquid lanolin used in the flowable formulation is 0.
It is about 1 to 20%, and a good result is usually obtained when it is blended in an amount of 0.5 to 10%.

In the case of preparing an emulsion type flowable, if the specific gravity of the emulsified substance and the specific gravity of the aqueous phase are too different, the obtained flowable tends to separate into two layers with time. Therefore, it is desirable that the specific gravity of both is as equal as possible, and when the ratio of the specific gravity of both is about 0.90 to 1.10, preferably about 0.95 to 1.05, the physical temporal stability of the composition of the present invention is particularly remarkable. is there. It is also important to select the type of emulsifier for the product to be emulsified and to optimally adjust HLB.From these viewpoints, select a combination of a solvent and a surfactant that exhibit fine and stable emulsification. It is desirable.

The machine for preparing the flowables of the present application is a conventional emulsifier or wet mill. It is also possible to finely pulverize the active ingredient together with a small amount of pulverizing aid if necessary, using a dry pulverizer such as a jet pulverizer, and to suspend the obtained pulverized product in water together with other auxiliary agents. .

An emulsifier is used when preparing an emulsion type flowable. For example, a propeller stirrer, a turbine-type stirrer, a high-speed shear mixer, a vacuum emulsifier, a pipeline mixer, a spiral pin mixer, a high-pressure emulsifier, and the like can be used.

Wet mills used to prepare suspension-type flowables are usually high-speed rotary shock-shear mills such as wet hammer mills, medium-agitation mills such as sand mills and attritors, and wet high-speed rotary mills such as colloid mills. Crusher and the like.

When emulsifying (or crushing) using these machines, the degree of emulsification (or crushing) depends on the type of stirring blade, disk, hammer, grinding wheel, etc., number of rotations and gaps, crushing time, pressure and number of times, supply speed. The particle size can be adjusted by the amount and type of the medium, so that the active ingredient is adjusted to a desired particle size.

The viscosity of the emulsified (or pulverized) liquid thus obtained is usually several mPa · sec to several tens mPa · sec when no thickener is added.
It is about. When liquid lanolin is blended and formulated appropriately, a stable formulation that does not cause layer separation, oil, separation of cream, hard caking, etc. over time can be obtained even with such a viscosity, but usually a small amount. It is often necessary to compound a thickener. However, the flowable containing the liquid lanolin of the present invention has extremely good stability even at a low viscosity, so that the viscosity of the preparation is 400 mPasec or less, usually 2 mPa.sec.
At about 00 mPa · sec or less, a stable flowable over time can be obtained. Even if such a low-viscosity flowable is poured into a large amount of water at a time, it can be stirred very simply to prepare a uniform diluent.

The thus obtained flowable agent may be used as it is, such as a cockroach control agent, a wood preservative, or a fungicide, or may be used by spraying or dipping, or may be diluted with water, such as an agricultural chemical or an epidemic control agent. After that, it may be used by spraying, transferring as it is into a paddy field or pool water, dropping or pouring.

(Operation) The present invention will be described in more detail with reference to examples and test examples below, but the present invention is not limited to these. The test method is as follows.

Viscosity: Using a B-type rotational viscometer, measure the viscosity at 20 ° C to 200 mPa
c Use a No. 1 rotor for the following and a No. 2 rotor for the following, and measure each at 30 rpm.

Specific gravity: The specific gravity at 20 ° C. is determined by the floating measurement method.

Dispersibility: Close the bottom of a glass tube with an inner diameter of 3 cm and a length of 1 m with a rubber tube and stand upright. Fill the tube with hard water three times and add a drop of the flowable agent from above. The state of dispersion of the flowable agent in water is visually observed.

Dilution: Add 1L of hard water 3 times into a 1L beaker. Set a rotating blade made of wire (3mmφ) that rotates at a height of 2cm from the bottom at 120rpm and a rotating diameter of 8.5cm, and put a mirror so that the bottom can be seen. Add 1 ml of flowable agent into the beaker,
The time until the flowable agent in the beaker is completely dispersed is measured by rotating the rotating blades.

Accelerated aging test: Put 100 ml of flowable into a 100 ml capacity graduated measuring cylinder, accelerated aging test at 50 ° C for 30 days, and 50 ° C (3 days) → 20 ° C (3 days) → -10 ° C (3 days) → 20 ° C
(3 days) Cycle test (12 days per cycle for a total of 36 days for 3 cycles). After a lapse of time, the flowable layer separation state is visually observed, and the number of ml of the separation layer is determined.

Example 1 A solution of Solvesso # 100 (aromatic hydrocarbon-based high boiling point solvent, manufactured by Exxon Chemical Co., Ltd.) containing 30% of the following compound A was prepared. Separately, 1.0 part of Aerosil # 200 (silicon dioxide by vapor phase method, manufactured by Nippon Aerosil Co., Ltd.) and 1.0 part of Aerosil MOX80 (silicon dioxide by vapor phase method containing 1% of aluminum oxide, manufactured by Nippon Aerosil Co., Ltd.) are dissolved in water. Propyl paraben 0.1 part, citric acid 0.05 part, the above solution 5.14 parts, propylene glycol 15.5
, Silicon KM-6-1F (Shin-Etsu Chemical Co., Ltd.) 0.5
Of lanolin (available from Yoshikawa Oil Co., Ltd.) and TK homomixer (manufactured by Tokushu Kikai Co., Ltd.) for 45 minutes to emulsify. Was. The amount of water was such that all these amounts were 65.0 parts. The resulting emulsion was diluted with 35.0 parts of water to obtain an aqueous flowable containing 1.5% of compound A.

Compound A: {3- (4-Chlorophenoxy) phenylcyanometh
yl (2,2-dimethyl-3-trans-2-chloro-1-prop
Surfactant containing enylcyclo-propane) carboxylate: mixture of the following surfactants: Hytenol N-17 (manufactured by Daiichi Kogyo Seiyaku Co., Ltd.) 50 parts (sulfuric acid ester ammonium salt of polyoxyethylene nonylphenyl ether) Newcol 714 ( 25 parts (polyoxyethylene distyryl cresyl ether) Newcol 562 (manufactured by Nippon Emulsifier Co.) 25 parts (polyoxyethylene nonylphenyl ether) Comparative Example 1 In Example 1, liquid lanolin was used. Industrial lanolin A
An aqueous flowable containing 1.5% of compound A was obtained in exactly the same manner as above except that it was replaced by (Yoshikawa Oil Co., Ltd.).

Test Example 1 The flowable obtained in Example 1 was subjected to an accelerated aging test at 50 ° C. and a cycle aging test. Table 1 shows the results
As shown in Table 2, when liquid lanolin was added, the stability of the flowable over time was significantly improved. Especially liquid lanolin
The effect when 0.5 part or more was blended was remarkable. Also,
Each of the flowables had a low viscosity and good dilutability and dispersibility.

On the other hand, in the case of the comparative example in which industrial lanolin A, which is ordinary paste-like lanolin, was blended, the stability of the flowable with time was insufficient, and the separation after the time test was large.

Further, in comparison with liquid lanolin, the flowable in which industrial lanolin A was blended had a high viscosity of the formulation, and the dispersibility became worse as the blending amount increased.

Example 2 Emulsion 6 of Example 1 obtained by blending 2 parts of liquid lanolin
To 5.0 parts, 35.0 parts of an aqueous solution of Road Pole 23 (xanthan gum, manufactured by Rohm & Haas Co., Ltd.) having different concentrations was added and diluted to obtain aqueous flowable agents having different viscosities.

Comparative Example 2 Using the emulsion of Comparative Example 1 obtained by blending 2 parts of industrial lanolin A, the same operation as in Example 2 was performed to obtain an aqueous flowable agent.

Test Example 2 The flowable obtained in Example 2 was subjected to a aging test under the same conditions as in Test Example 1. As shown in Table 2 below, the results showed that slight layer separation observed only with liquid lanolin was not observed when the viscosity of the flowable was 70 mPa · sec or more. When the flowable viscosity was 400 mPa · sec or less, the dilutability and dispersibility were extremely good.

On the other hand, in the case of the comparative example containing industrial lanolin A,
Even when the viscosity was increased, the stability over time of the flowable was insufficient, and layer separation was observed with the passage of the test time.

In addition, the viscosity was significantly increased by the addition of the thickener, and the dispersibility was extremely deteriorated.

Example 3 3.0 parts of the following compound B, 12.0 parts of Solvesso # 100, 1.5 parts of the following emulsifier, and 2.0 parts of liquid lanolin were uniformly dissolved.
Separately, a dispersion was prepared by adding 1.0 part of Aerosil # 200 and 1.0 part of Aerosil MOX80, 10.0 parts of propylene glycol, 0.1 part of propylparaben, and 0.5 part of silicon KM-68-1F to 33.9 parts of water and mixing them. TK Mycolloider (Special Machine Processing Co., Ltd.)
), Whetstone # 120, rotation speed 5000rpm, whetstone interval 100
The mixture was passed three times under the condition of μm to obtain a concentrated product. To 65 parts of this concentrated product, 23 parts of a 0.5% solution of load pole 23 and 12 parts of water were added and stirred and mixed to obtain an emulsion type flowable containing 3% of compound B.

This flowable had a specific gravity of 1.01, a viscosity of 126 mPa · sec, and a dilutability of 0 seconds, indicating self-dispersibility.

Compound B: (1R, 4S, 5'S, 6R ', 8R, 13R, 20R, 21R, 24S)-
(10E, 14E, 16E, 22Z) -21,24-dihydroxy-11,13,22-t
rimethyl-2-oxo-3,7,19-trioxatetracyclo [15,6,
^{1,1 4.8, 0 20.24] pentacosa-} 10,14,16,22-tetraene-
6-spiro-2 '-(6'-methyl-5'-methyltetra
hydropyran) (milbemycin A ₃ ) and (1R, 4S, 5'S, 6
R ', 8R, 13R, 20R, 21R, 24S)-(10E, 14E, 16E, 22Z) -21,
24-dihydroxy-11,13,22-trimethyl-2-oxo-3,7,1
^{9-trioxatetracyclo [15,6,1,1 4.8, 0} 20.24] pentacos
a-10,14,16,22-tetraene-6-spiro-2 '-(6'
-Ethyl-5'-methyltetrahydropyran) (milbemycin A ₄ ).

Compounded emulsifier: mixture of the following surfactants: calcium salt of dodecylbenzenesulfonic acid 26.1 parts Newcol 704 (manufactured by Nippon Emulsifier Co., Ltd.) 11.7 parts (polyoxyethylene distyryl cresyl ether) Newcol 710F (manufactured by Nippon Emulsifier Co., Ltd.) 27.7 parts (polyoxyethylene distyryl cresyl ether) Newcol 565 (manufactured by Nippon Emulsifier Co., Ltd.) 34.5 parts (polyoxyethylene nonylphenyl ether) Example 4 Compound B of Example 3 30.0 parts, propylene glycol 10.
0 parts, Hytenol NO8 (sulfuric acid ester ammonium salt of polyoxyethylene nonylphenyl ether, manufactured by Daiichi Kogyo Co., Ltd.) 1.0 part, Newcargen BXC (sodium salt of diisobutylnaphthalenesulfonic acid, Takemoto Yushi Co., Ltd.)
3.0 parts) and 5.0 parts of liquid lanolin were added to 35.9 parts of water, and the mixture was pulverized using Dynomill (manufactured by Shinmaru Enterprises Co., Ltd.) for 40 minutes at 3000 rpm with glass beads (1.0 mmφ). A solution obtained by dissolving 0.1 part of DK Ramzan (Lanzan gum, manufactured by Daiichi Kogyo Seiyaku Co., Ltd.) in 15 parts of water is added to the obtained concentrated suspension, and the mixture is uniformly stirred and mixed to contain 30% of compound B. An aqueous flowable was obtained. This flowable has a specific gravity of 1.
05, viscosity: 342 mPa · sec, dilutability: 23 seconds, dispersibility: One part was self-dispersed while settling. In addition, no deterioration in physical properties such as layer separation and hard caking was observed in a reciprocating aging test at 50 ° C. for 30 days and three cycles.

(Effects of the Invention) As described above, the present invention provides a means for stably dispersing a water-insoluble substance of a non-medical drug in an aqueous medium without increasing the viscosity of the dispersion. This makes it possible to produce an aqueous flowable that is easy to use and easy to handle because of its good water dilutability. This can contribute to various manufacturing and utilization industries that produce these aqueous flowables.

Claims (6)

(57) [Claims] An aqueous flowable non-medical drug which is stable over time and has good dilutability, characterized by containing liquid lanolin. 2. The aqueous flowable according to claim 1, wherein the non-medical drug is a pesticide or an epidemiological drug. 3. The aqueous flowable according to claim 1, wherein the aqueous flowable is a suspension type aqueous flowable. 4. The aqueous flowable according to claim 1, wherein the aqueous flowable is an emulsion type aqueous flowable. 5. The aqueous flowable according to claim 1, wherein the aqueous flowable is a suspoemulsion type aqueous flowable. 6. The aqueous flowable according to claim 1, which has a viscosity of 400 mPa · sec or less.