JP2886672B2 - A non-medical aqueous flowable with good aging stability and dilutability - 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, an aqueous flowable non-medical drug which is stable over time and has good dilutability, characterized by containing one or more selected from liquid lanolin and lanolin derivatives having a surfactant activity. Agent.

(Prior art) Non-medical drugs such as pesticides, epidemic preventive drugs, animal drugs, slime control agents, fungicides, wood preservatives, etc. are formulated into various dosage forms for their convenience. 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 may have insufficient controlling effect 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 intentionally soft agglomerate the formulation to prevent hard caking, increase the viscosity of the formulation, and prevent separation. According to this method, hard caking and layer separation can be substantially reduced.
On the other hand, the water dilutability is poor, and particularly when the preparation is heavier than water, there is a drawback that strong stirring is required in order to disperse the flowable settled at the bottom of the dilution tank. 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 chemicals are pesticides, many Japanese farmers do not have a dilution tank with a stirrer, because many farmers are small. For such a farmer, stirring the diluting solution to disperse the flowable that has settled in the bottom of the container is a troublesome operation, and may involve danger 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. Since a separate container is required, there is a problem that the concentrated dilute solution may adhere to the operator at the time of 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 investigations, when combined with a small amount of liquid lanolin and a lanolin derivative having a surfactant activity in the formulation of the flowable agent, the respective stabilizing actions act synergistically, and extremely The present inventors have found that the object can be easily achieved without causing sedimentation or layer separation with time with low viscosity, and the present invention has been completed.

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 alkylaryl ethers, polyoxyalkylene arylaryl 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, as an essential component, liquid lanolin and a lanolin derivative having a surfactant activity.
Lanolin, which is a raw material of these, is wool fat by-produced when wool is obtained from raw wool of sheep, and is a kind of animal wax. The chemical composition is not always constant depending on the type of sheep, the place of production, weather conditions, etc., but the alcohol part is mainly composed of aliphatic alcohols, cholesterols and triterpene alcohols, and the acid part is normal fatty acid, iso fatty acid,
It is said that anti-iso fatty acids and hydroxy fatty acids make up the majority. Since lanolin is a mixture of many compounds, it usually has the property of forming a paste at normal temperature and melting at several tens of degrees when heated. Such lanolin can be purified or chemically modified to obtain various derivatives. For example, those obtained by fractionating and purifying an alcohol or acid moiety obtained by hydrolyzing lanolin by solvent fractionation and the like are examples of derivatives.These hydrolysates or lanolin itself include acetylation, alkoxylation, sulfonation, Those to which chemical actions such as hydrogenation, transesterification, reduction and the like are added are also lanolin derivatives.

The liquid lanolin used in the present application is obtained by separating only a low melting point portion from lanolin by a method such as solvent separation, and exhibits a liquid state at normal temperature. Further, lanolin derivatives having a surfactant activity include, for example, lanolin and its derivatives into which alkylene oxides such as ethylene oxide and propylene oxide have been introduced, those having introduced a hydrophilic group such as a sulfate group or a phosphate group, and salts thereof, And alkali metal and ammonium salts of lanolin fatty acids. In the present application, both are used in combination.

In the present invention, these liquid lanolin and the lanolin derivative having a surface-active action can be added in any step before or after emulsification or pulverization, but many of the lanolin derivatives having a surface-active action are themselves emulsified. Since it has a dispersing action, other dispersants and emulsifiers may not be required depending on the formulation. In such a case, it is necessary to add it in a pre-step of emulsification or pulverization. Of course, it is also possible to add these lanolin derivatives to concentrated products emulsified or pulverized using other dispersants or emulsifiers.

The compounding amount of the liquid lanolin and the lanolin derivative having a surfactant effect used in the flowable formulation is about 0.1 to 20%, and a good result is obtained when the compound is added in an amount of usually 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 so different from each other, the obtained flowable tends to undergo two-layer separation 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-speed 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 a liquid lanolin and a lanolin derivative having a surfactant activity are blended and formulated appropriately, a stable preparation which does not cause phase separation, oil, cream separation, hard caking, etc. over time even at such a viscosity can be obtained. In some cases, it is often necessary to incorporate small amounts of thickeners. However, since the flowable blended with the liquid lanolin of the present invention and a lanolin derivative having a surface-active action has extremely good stability even at a low viscosity, the viscosity of the preparation is 400 m.
Pa · sec or less, usually about 200 mPa · sec or less, enables stable flow over time. Even if such a low-viscosity flowable is put into a large amount of water at once,
Very simple stirring can be used to prepare a uniform dilution.

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, dripping or pouring.

(Operation) The present invention will be described in more detail below with reference to Examples and Test Examples, but the present invention is not limited only 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 No. 1 rotors below and No. 2 rotors above, and measure at 30 rpm for each.

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.

Examples 1 to 4 Solutions of Solvesso # 100 (aromatic hydrocarbon-based high boiling point solvent, manufactured by Exxon Chemical Co., Ltd.) containing 30% of the following compound A were 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
Part, the following compounding surfactant 2.0 parts, liquid lanolin (manufactured by Yoshikawa Oil Co., Ltd.) α part, lanoster-S-LPA (softened part separated from isopropyl ester of lanolin fatty acid and sulfonated, Yoshikawa Oil Co., Ltd.) The mixture of β part was added, and 45
The mixture was stirred and emulsified for minutes. The total amount of water is 65.0
Part. 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: A mixture of the following surfactants: Hytenol N-17 (Daiichi Kogyo Seiyaku Co., Ltd. 50 parts (ammonium sulfate ammonium salt of polyoxyethylene nonylphenol ether)) Newcol 714 (Nippon Emulsifier) 25 parts (polyoxyethylene distyryl cresyl ether) Newcol 562 (manufactured by Nippon Emulsifier Co., Ltd.) 25 parts (polyoxyethylene nonylphenyl ether) Comparative Examples 1 to 7 Liquid lanolin and ( Or) Aqueous flowables containing 1.5% Compound A were prepared without the addition of Lanosta-S-LPA and the other components being identical.

Test Example 1 Flowable samples of Examples 1 to 4 and Comparative Examples 1 to 7 were heated to 50 ° C.
Were subjected to an accelerated aging test and a cycle aging test. As shown in Table 1 below, the results showed that the addition of liquid lanolin or Lanosta-S-LPA improved the stability over time of the flowable, but these alone could not prevent slight layer separation. However, no layer separation was observed in any of the flowables using both of them. In addition, the viscosity of each flowable was low at 30 mPa · sec or less, and the dilutability and dispersibility were good.

Example 5 Neochol SWCE (sodium salt of diethylhexylsulfosuccinic acid, manufactured by Daiichi Kogyo Seiyaku Co., Ltd.) in 35.8 parts of water 0.2
Parts, Labelin FAN (sodium salt of naphthalenesulfonic acid condensate) 3.0 parts, liquid lanolin 2.0 parts, Lanosta-S-
4.0 parts of LPA was dissolved and dispersed. Diclomedin drug substance is added to this solution
30 parts were added and suspended, and pulverized for 2 hours with an Attritor 30S (manufactured by Mitsui Miike Seisakusho Co., Ltd.) to obtain 75 parts of a concentrated pulverized product. Separately, 0.1 part of Road Pole 23 (xanthan gum, manufactured by Rohm & Haas Co., Ltd.) was dissolved in 9.9 parts of water, and then a solution was prepared by adding 15.0 parts of propylene glycol.
The mixture was added to the thick pulverized product and mixed to obtain a flowable containing 30% of diclomedin.

Comparative Examples 8 to 13 In Example 5, liquid lanolin, Lanoster-S-LPA,
The amounts of the load pole 23 are α, β, and γ, respectively.
The other components were exactly the same to obtain a flowable containing 30% of diclomedin.

Test Example 2 The flowables of Example 5 and Comparative Examples 8 to 13 were subjected to a 50 ° C. accelerated aging test and a cycle aging test. As shown in Table 2 below, when no stabilizer was added, the stability of the preparation with time was poor, and hard caking occurred. When the viscosity was increased by adding a thickener to this, the layer separation after aging decreased, but the dilution / dispersibility deteriorated, and hard caking could not be prevented. When liquid lanolin or Lanost-S-LPA was added to the preparation, the stability of the flowable over time was improved, but these alone could not completely prevent phase separation. When a thickener was added thereto, layer separation over time could be prevented, but dilutability and dispersibility deteriorated. Compared with these, the composition of Example 5 was able to prevent layer separation, and had good dilutability and dispersibility.

Example 6 3.0 parts of the following compound B, 12.0 parts of Solvesso # 100, 1.5 parts of the following compounded emulsifier, 2.0 parts of liquid lanolin, Lamigen ET-90
4.0 parts 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 29.9 parts of water and mixing them. Add the emulsified stock solution of the compound B, and use TK Mycolloider (manufactured by Tokushu Kikai Co., Ltd.)
The solution was passed three times under the conditions of a rotation speed of 5000 rpm and an interval between grinding wheels of 100 μm to obtain a concentrated product. To 65 parts of this concentrated product, 35 parts of water was added and stirred and mixed to obtain an emulsion type flowable containing 3% of compound B.

This flowable had a specific gravity of 1.00, a viscosity of 12 mPa · sec, and a dilutability of 0 seconds, indicating self-dispersibility. 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.

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] pentacosa
−10,14,16,22-tetraene-6-spiro-2 ′-(6′-
ethyl-5'-methyltetrahydropyran) a mixture of (milbemycin A _4).

Formulated emulsifier: Formulation 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 (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 7 Compound B of Example 6 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, Newcalgen BXC (sodium salt of diisobutylnaphthalenesulfonic acid, manufactured by Takemoto Yushi Co., Ltd.) 3.0 Parts, liquid lanolin 5.0 parts, Bellpol L-
30 parts (polyoxyethylene lanolin ether, manufactured by Yoshikawa Oil Co., Ltd.) were added to 48 parts of water, and glass beads (1.0 mmφ) were used with Dynomill (manufactured by Shinmaru Enterprises Co., Ltd.) at 3000 rpm. Milled for 40 minutes. The resulting flowable has a specific gravity of 1.05, a viscosity of 282 mPasec and a dilutability of 1.
It showed self-dispersion for 5 seconds. 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] 1. A non-medical drug which is stable over time and has good dilutability, characterized by comprising one or more selected from liquid lanolin and a lanolin derivative having a surfactant effect. , Except chlorhexidine salt.)
Aqueous flowable agent. 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.