JP2010022973A - Manufacturing method of nanoparticle dispersion of triclosan - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a manufacturing method of nanoparticle dispersion of triclosan which is excellent in storage stability. <P>SOLUTION: The manufacturing method of nanoparticle dispersion of triclosan comprises a liquid contact step of fluidizing each of a first liquid of an aqueous alkaline solution having triclosan dissolved and a second liquid of an acidic aqueous solution and contacting each other so that they are in a mixed state, and a liquid mixing step of obtaining the nanoparticle dispersion of triclosan by circulating the first liquid and the second liquid that have been mixed in the liquid contact step through a micropore 22 for mixing to mix. Polyvinyl pyrrolidone is dissolved and included into the first liquid and/or the second liquid so that the total content of polyvinyl pyrrolidone to triclosan amounts to 0.1-0.5 in terms of mass ratio. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a method for producing a nanoparticle dispersion of triclosan.

  Trichlorosan (5-chloro-2- [2,4-dichlorophenoxyl] phenol) is a kind of phenolic antibacterial agent, and is known as an excellent antibacterial agent, and is blended in many skin care products and household products. Since this triclosan is solid at room temperature and hardly soluble in water, its general usage is almost always used when solubilized using a surfactant, or dissolved in an oily component or an organic solvent. It is. However, many surfactants are known to reduce the antibacterial and bactericidal properties of triclosan in products. In addition, the use of oil components and organic solvents imposes restrictions on the formulation of products.

  For example, Patent Document 1 includes an example in which biofilm growth of an air conditioning facility is suppressed using a bactericidal coating composition containing a water-insoluble bactericidal complex composed of a phenolic bactericidal agent such as triclosan and polyvinylpyrrolidones. It is disclosed. Although this composition is a liquid substance, a film is formed by volatilizing a solvent on the surface of an object, and a bactericidal complex is uniformly distributed in the obtained film. However, it cannot be applied to skin care products and household products from the viewpoint of safety because it uses a large amount of organic solvent.

By the way, Patent Document 2 includes a first liquid containing a solution obtained by dissolving an organic compound having a molecular weight of 1000 or less in a first solvent having a relatively high solubility, and a second solvent containing a second solvent having a relatively low solubility. A method of obtaining a mixed solution in which the fine particles of the organic compound are dispersed and precipitated by causing the two liquids to flow, contacting each other so that they are mixed, and then flowing through the mixing pores and laminar mixing. Is disclosed.
Special table 2007-533781 Japanese Patent Laid-Open No. 2007-8924

  According to the method disclosed in Patent Document 2, it is possible to use a poorly water-soluble organic compound in the form of an aqueous dispersion in which fine particles are dispersed.

  However, when fine particles of triclosan are dispersed, if the particle diameter is reduced to several hundreds of nanometers in order to improve dispersion stability, the particles become physicochemically unstable and crystal growth is likely to be promoted in the dispersion. Problems such as precipitation occur after storage over time.

  An object of the present invention is to provide a method for producing a triclosan nanoparticle dispersion having excellent storage stability.

  In order to achieve the above object, as a result of intensive studies, the present inventors have incorporated polyvinylpyrrolidone, which is a general-purpose dispersion stabilizer, in an amount within a specific range with respect to triclosan, and distributed the triclosan through the pores for mixing. It has been found that if a nanoparticle dispersion is produced, a triclosan nanoparticle dispersion having excellent storage stability, which has not been obtained in the past, can be obtained.

That is, the production method of the triclosan nanoparticle dispersion of the present invention that achieves the above-mentioned object,
A liquid contact step in which the first liquid of the alkaline aqueous solution in which triclosan is dissolved and the second liquid of the acid are caused to flow, and are brought into contact with each other so as to be in a mixed state;
A liquid mixing step of obtaining a triclosan nanoparticle dispersion by flowing and mixing the first liquid and the second liquid mixed in the liquid contact step through the mixing pores;
With
Polyvinylpyrrolidone is dissolved and contained in the first liquid and / or the second liquid so that the total content is 0.1 to 0.5 in terms of a mass ratio with respect to the triclosan content.

  The method for producing a triclosan nanoparticle dispersion of the present invention is a further improvement of the conventional technique, and according to this, the triclosan nanoparticle having excellent storage stability, which has not been conventionally obtained by a simple method. A particle dispersion can be obtained.

  Hereinafter, a method for producing a triclosan nanoparticle dispersion according to this embodiment will be described.

(Liquid mixing system A)
First, the liquid mixing system A used for the production of triclosan nanoparticle dispersion will be described.

  FIG. 1 shows the liquid mixing system A.

  This liquid mixing system A is used for mixing two kinds of liquids, and includes a micromixer 100 having a pair of liquid inflow portions 101 and a single liquid outflow portion 102, and an incidental portion such as a liquid supply system. Has been.

  One liquid inflow portion 101 of the micromixer 100 is connected to a first supply pipe 32a extending from the first storage tank 31a for storing the first liquid. The first supply pipe 32a is provided with a first pump 33a for circulating the first liquid, a first flow meter 34a for detecting the flow rate of the first liquid, and a first filter 35a for removing impurities in the first liquid from the upstream side. A first pressure gauge 36a that detects the pressure of the first liquid is attached to a portion between the first flow meter 34a and the first filter 35a. Each of the first pump 33a, the first flow meter 34a, and the first pressure gauge 36a is electrically connected to the flow controller 37.

  A second supply pipe 32b extending from the second storage tank 31b for storing the second liquid is connected to the other liquid inflow portion 101 of the micromixer 100. The second supply pipe 32b is provided with a second pump 33b for circulating the second liquid, a second flow meter 34b for detecting the flow rate of the second liquid, and a second filter 35b for removing impurities in the second liquid from the upstream side. A second pressure gauge 36b that detects the pressure of the second liquid is attached to a portion between the second flow meter 34b and the second filter 35b. Each of the second pump 33b, the second flow meter 34b, and the second pressure gauge 36b is electrically connected to the flow controller 37.

  The flow rate controller 37 is configured to be able to input the set flow rate and set pressure of the first liquid, and incorporates an arithmetic element. The flow rate detected by the first flow meter 34a, the set flow rate information of the first liquid. The operation of the first pump 33a is controlled based on the information and the pressure information detected by the first pressure gauge 36a. Similarly, the flow rate controller 37 is also configured to be able to input the set flow rate and set pressure of the second liquid, and the set flow rate information of the second liquid, the flow rate information detected by the second flow meter 34b, and the second pressure. The second pump 33b is operated and controlled based on the pressure information detected by the meter 36b.

  A mixed liquid recovery pipe 38 extends from the liquid outflow portion 102 of the micromixer 100 and is connected to a recovery tank 39.

As shown in FIG. 2, the micromixer 100 includes a liquid contact portion 21 and mixing pores 22 provided continuously therewith. The liquid contact part 21 makes the 1st liquid and 2nd liquid supplied from the liquid inflow part 101 contact in the state which each flowed, and they will be in a mixed state. The mixing pores 22 circulate and mix the first liquid and the second liquid in a mixed state. The mixing pore 22 is very small because it mixes the first liquid and the second liquid due to the micro effect of space, and considering the mixing property, the pore diameter D is 0.1 to 1.0 mm, or It is preferable that the pore area S is 0.01 to 1.0 mm 2. Here, when the hole diameter D is 0.1 mm or more or the hole area S is 0.01 mm ² or more, the pressure loss can be reduced. From this viewpoint, the hole diameter D is more preferably 0.2 mm or more, and the hole area S is more preferably 0.04 mm ² or more. On the other hand, the hole diameter D is 1.0 mm or less, or the hole area S is 1.0 mm ² or less, and the mixing property is excellent. From this viewpoint, the pore size D, 0.8 mm or less, more preferably at 0.64 mm ² or less for the hole area S, 0.6Mm below, that for the pore area S is 0.36 mm ² or less Further preferred. The pore diameter D is the diameter of the smallest circle that encloses the cross-sectional outline of the mixing pore 22.

  In the small mixing pores 22 as described above, the ratio of the pore length L to the pore diameter D is preferably 40 or less. If the ratio of the pore length L to the pore diameter D is 40 or less, the development of turbulent flow in the mixing pores 22 can be suppressed, so that uniform mixing can be performed. Considering that the smaller the L / D, the smaller the pressure loss and the smaller the burden on the liquid feeding system, L / D ≦ 40 is preferable, L / D ≦ 20 is more preferable, and L / D ≦ 20 More preferably, D ≦ 10. On the other hand, from the viewpoint of pressure resistance, the hole length L is more than 1/2 of the hole diameter D, that is, L / D ≧ 0.5, and more preferably L / D ≧ 1.

  The cross-sectional outline shape of the mixing pore 22 is not particularly limited, and for example, a circular shape, a semicircular shape, an elliptical shape, a semi-elliptical shape, a square shape, a rectangular shape, a trapezoidal shape, a parallelogram shape, a star shape, and an indefinite shape. Etc. Further, the mixing pores 22 may be formed uniformly along the length direction or may be formed non-uniformly along the length direction.

  The micromixer 100 is not particularly limited as a confluence form of the first liquid and the second liquid, such as an opposed type, a right angle type, a Y shape, a parallel type, a double tube type, and is configured by a tube. Even if the liquid flow path is constituted by the laminated structure of the substrate in which the groove is formed, it may be either.

  In addition, the mixing promotion effect by general space micronization is described in a nonpatent literature (V.Hessel, et al. Chemical Engineering Science 60 (2005) 2479-2501).

  Hereinafter, specific configurations of the three types of micromixers 100 will be described.

<First configuration>
FIG. 3 shows a micromixer 100 having a first configuration.

  This micromixer 100 has a straight tube portion 110 whose both ends are respectively a liquid inflow portion 101 and a branch that is branched from the central portion of the straight tube portion 110 and extends in an orthogonal direction and has a liquid end that is a liquid outflow portion 102. It is constituted by a T-shaped tube composed of a tube portion 120. Such a micromixer 100 using a T-shaped tube has a simple device configuration and is easy to maintain by disassembly and cleaning.

  The straight tube portion 110 has a narrow central channel, and one liquid inflow portion 101 side of the central portion is the first liquid flow channel 11a, and the other liquid inflow portion 101 side is the second liquid. Each of the channels 11b is configured. The branch pipe portion 120 is formed with mixing pores 22 extending along the pipe axis and communicating with the straight pipe portion 110. The central portion of the straight tube portion 110, that is, the inside of the branch portion to the branch tube portion 120 is configured as a liquid contact portion 21 that continues to the mixing pores 22. Each of the first liquid channel 11a and the second liquid channel 11b has a channel cross-sectional area, that is, a hole area that is the same as or similar to that of the mixing pores 22, and can suppress pressure loss to a small level. Further, the flow path length, that is, the hole length is preferably the same as or similar to that of the mixing pore 22.

  The micromixer 100 has a configuration in which the flow directions of the first liquid and the second liquid toward the liquid contact portion 21 and the directions in which the mixing pores 22 extend are different from each other. As described above, when the flow directions of the first liquid and the second liquid toward the liquid contact portion 21 and the extending directions of the mixing pores 22 are different from each other, as shown in FIG. High mixing performance can be obtained as compared with the configuration in which any one of the flow directions toward the two-liquid contact portion 21 is the same as the direction in which the mixing pores 22 extend.

  3 shows a configuration in which the flow path in the central portion of the straight tube portion 110 is narrowed, but the present invention is not particularly limited to this, and as shown in FIG. There may be a configuration having a uniform flow path from one liquid inflow portion 101 to the other liquid inflow portion 101.

  3 shows a configuration in which the mixing pores 22 are formed in the branch pipe portion 120. However, the present invention is not limited to this, and the mixing pores are continuously formed in the branch pipe portion. The structure in which the member formed with is connected separately may be used.

<Second configuration>
FIG. 6 shows a micromixer 100 having a second configuration. Note that portions having the same names as those of the first configuration are denoted by the same reference numerals as those of the first configuration.

  The micromixer 100 is of a substrate laminated type, and each of the first liquid channel 11a and the second liquid channel 11b extending in the substrate surface, and the mixture extending in a direction having an angle with respect to the substrate surface. Each use pore 22 is formed inside. The first liquid channel 11a and the second liquid channel 11b extend so that one ends thereof are joined and open to form a substantially V-shaped locus, and the other end of the former is connected to one of the liquid inflow portions 101. The other end of the latter is formed in the other liquid inflow portion 101. One end of the mixing pore 22 is connected to the coupling portion of the first liquid channel 11 a and the second liquid channel 11 b, and the other end is formed in the liquid outflow portion 102. The liquid contact portion 21 includes a coupling portion of the first liquid passage 11 a and the second liquid passage 11 b and the mixing pores 22.

  Similarly to the first configuration, this micromixer 100 also has a configuration in which the flow directions of the first liquid and the second liquid toward the liquid contact portion 21 and the directions in which the mixing pores 22 extend are different from each other. It has become.

  In addition, what was shown in FIG. 6 is the 1st liquid flow path 11a and the 2nd liquid flow path 11b, respectively, but it is not limited to this in particular, As shown in FIG. There may be a configuration in which there are a plurality of first liquid channels 11a and second liquid channels 11b.

  Further, in the case of the configuration having three or more liquid flow paths as described above, a third liquid different from the first liquid and the second liquid can be circulated through any one of the liquid flow paths.

<Third configuration>
FIGS. 8A to 8C show a micromixer 100 having a third configuration. Note that portions having the same names as those of the first configuration are denoted by the same reference numerals as those of the first configuration.

  The micromixer 100 includes a liquid circulation pipe 10 provided in a piping path and a liquid mixing unit 20 provided continuously on the liquid outflow side.

  The liquid circulation pipe 10 is configured in a double pipe structure by a large diameter pipe 12 and a single small diameter pipe 13 introduced and inserted therethrough. As a result, the liquid flow pipe 10 has two liquid flows, the first liquid flow path 11 a inside the small diameter pipe 13 and the second liquid flow path 11 b inside the large diameter pipe 12 and outside the small diameter pipe 13. The passages extend in parallel to each other inside the pipe and are configured along the length direction. The pipe end of the small diameter pipe is configured as one liquid inflow part 101, and the pipe end of the large diameter pipe 12 exposed to the outside of the liquid circulation pipe 10 is configured as the other liquid inflow part 101. Such a micromixer 100 having the liquid flow pipe 10 having a double-pipe structure has a simple apparatus configuration and is easy to maintain by disassembly and cleaning.

  The liquid mixing unit 20 forms an internal region continuously with the liquid outflow end of the liquid circulation pipe 10. This internal region is configured in the liquid contact portion 21 in contact with the first liquid and the second liquid that have flowed out of the liquid circulation pipe 10. The liquid mixing unit 20 is provided with mixing pores 22 provided continuously to the liquid contact unit 21. The mixing pores 22 are formed to extend in the same direction as the direction in which the first liquid channel 11a and the second liquid channel 11b extend. A recovery pipe connecting portion provided continuously to the mixing pores 22 is formed in the liquid outflow portion 102.

  The micromixer 100 is different from those of the first configuration and the second configuration in the flow directions of the first liquid and the second liquid toward the liquid contact portion 21 and the mixing pores 22. The extending directions have the same configuration.

  By the way, the first liquid and the second liquid that have flowed out of the fluid circulation pipe 10 and contacted by the liquid contact portion 21 are finally mixed by the mixing pores 22. At this time, in order to obtain a faster mixing performance, the mixed state in the liquid contact portion 21 only needs to be composed of minute segments of each liquid. Therefore, it is preferable that the number of the first liquid flow paths 11a is larger, and as shown in FIGS. 8A and 8B, as compared with the case where there is one small diameter tube 13, FIGS. As shown in b), a faster mixing characteristic can be obtained when there are a plurality of small diameter tubes 13.

  Further, in the case of the configuration having three or more liquid flow paths as described above, a third liquid different from the first liquid and the second liquid can be circulated through any one of the liquid flow paths.

  In the third configuration, the inside of the small-diameter pipe 13 can be used as the second liquid passage and the inside of the large-diameter pipe 12, and the portion outside the small-diameter pipe 13 can be used as the first liquid passage.

(Method for producing triclosan nanoparticle dispersion)
Next, a method for producing a triclosan nanoparticle dispersion using this liquid mixing system A will be described.

<First liquid and second liquid>
The first liquid is an alkaline aqueous solution in which triclosan is dissolved.

  The alkaline aqueous solution is, for example, an aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc., and further triclosan is dissolved.

  The concentration of triclosan in the alkaline aqueous solution is preferably 20 to 10000 mg / L, more preferably 50 to 5000 mg / L from the viewpoint of dispersion stability and antibacterial performance.

  The alkaline aqueous solution preferably has a pH of 9 or more, and more preferably 10 or more.

  In addition, the alkaline aqueous solution may contain a surfactant and an organic solvent to such an extent that the antibacterial properties of triclosan are not greatly affected. Examples of the surfactant include anionic ones such as sodium dodecyl sulfate, sodium polyoxyethylene alkyl ether sulfate, and lauryl methyl taurate. Examples of the organic solvent include water-miscible ethanol, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, glycerin, propylene glycol and the like.

  The second liquid is an acid, that is, an acidic aqueous liquid.

  The acid may be an inorganic acid or an organic acid. Specifically, examples of the inorganic acid include hydrochloric acid (dilute hydrochloric acid), sulfuric acid (dilute sulfuric acid), phosphoric acid, and the like, and examples of the organic acid include acetic acid, citric acid, and the like.

  The pH of the acid is preferably 1 to 6, and more preferably 2 to 5.

  The acid may be an acidic buffer. Examples of the acidic buffer include Bis-Tris (Bis (2-hydroxyethyl) iminotris (hydroxymethyl) methane) aqueous solution, HEPES (2- [4- (2-Hydroxyethyl) -1-piperazinyl] ethanesulfonic acid) aqueous solution, Examples include sodium dihydrogen phosphate aqueous solution, citric acid / disodium hydrogen phosphate aqueous solution, and the like.

  As in the case of the alkaline aqueous solution, the acid may contain a surfactant or an organic solvent to the extent that the antibacterial properties of triclosan are not greatly affected.

  Polyvinyl pyrrolidone (PVP) is dissolved and contained in either the first liquid and / or the second liquid, and thus either the first liquid or the second liquid, or both the first liquid and the second liquid.

  Polyvinylpyrrolidone has a weight average molecular weight of preferably 6,000 to 3,000,000, more preferably 30,000 to 2,000,000 from the viewpoint of improving the uniformity of the particle size distribution of the obtained triclosan nanoparticle dispersion and suppressing the increase in viscosity. preferable. The weight average molecular weight of polyvinylpyrrolidone is determined by the K-value calculated from the viscosity measurement based on the Fikentscher formula.

  Polyvinylpyrrolidone is dissolved and contained in the first liquid and / or the second liquid so that the total content is 0.1 to 0.5 in terms of mass ratio to the triclosan content. That is, the amount of polyvinylpyrrolidone contained in the first liquid and the second liquid flowing per unit time is 0.1 to 0.5 by mass ratio with respect to the amount of triclosan contained in the first liquid flowing per unit time. It is. The total content of polyvinyl pyrrolidone means the content of polyvinyl pyrrolidone contained in the liquid flowing per unit time when only one of the first liquid and the second liquid contains polyvinyl pyrrolidone. And when polyvinylpyrrolidone is contained in both the first liquid and the second liquid, it means the total content of polyvinylpyrrolidone contained in both liquids flowing in a unit time.

  This mass ratio may be 0.2 to 0.45 in terms of mass ratio from the viewpoint of reducing the particle size of the resulting triclosan nanoparticles and enhancing the storage stability of the obtained triclosan nanoparticle dispersion. Preferably, it is more preferable to set it as 0.25-0.4.

<Manufacture of triclosan nanoparticle dispersion>
When the liquid mixing system A is operated, the first pump 33a passes the first liquid from the first storage tank 31a through the first supply pipe 32a, sequentially through the first flow meter 34a and the first filter 35a. 100 is continuously supplied to one liquid inflow portion 101. The first flow meter 34 a sends the detected flow rate information of the first liquid to the flow rate controller 37. Further, the first pressure gauge 36 a sends the detected pressure information of the first pressure gauge 36 a to the flow rate controller 37.

  The second pump 33b passes the second liquid from the second storage tank 31b through the second supply pipe 32b to the one liquid inflow portion 101 of the micromixer 100 through the second flow meter 34b and the second filter 35b in order. Supply continuously. The second flow meter 34 b sends the detected flow rate information of the second liquid to the flow rate controller 37. Further, the second pressure gauge 36 b sends the detected pressure information of the second pressure gauge 36 b to the flow rate controller 37.

  Subsequently, the flow controller 37 determines the first flow rate information and the set pressure information of the first liquid, and the flow rate information detected by the first flow meter 34a and the pressure information detected by the first pressure meter 36a. The operation of the first pump 33a is controlled so that the set flow rate and set pressure of one liquid are maintained. At the same time, the flow rate controller 37 sets the second flow rate information and the set pressure information of the second liquid, and the flow rate information detected by the second flow meter 34b and the pressure information detected by the second pressure meter 36b. The second pump 33b is operated and controlled so that the set flow rate and set pressure of the two liquids are maintained. In the micromixer 100, the first liquid and the second liquid are in a mixed state, that is, in a state where small segments of the respective liquids are mixed (liquid contact step), which circulates through the mixing pores 22, In the mixing pore 22, it is stretched by shearing into the mixing pore 22 and shearing in the mixing pore 22 and / or at the outlet of the mixing pore 22 to form fine segments, and molecular diffusion The mixing speed is increased at once, mixing is completed instantaneously, and a dispersion liquid in which triclosan nanoparticles are dispersed and precipitated is obtained (liquid mixing step).

  At this time, each flow rate setting of the first liquid and the second liquid is such that the volume ratio of the first liquid to the second liquid is 5/95 to 95/5, preferably 10 /, from the viewpoint of obtaining highly uniform mixing performance. It is good to make it 90-90 / 10. The flow rate of the first liquid and the second liquid may be set so that the flow rate to the mixing pores 22 combining the first liquid and the second liquid is 0.1 to 1000 mL / min. As will be described later, it is more preferable to operate under conditions where the linear velocity in the mixing pores 22 is a specific value or more.

  The respective pressure settings for the first liquid and the second liquid may be such that the liquid feeding pressure is 0.01 to 3 MPa.

  Each temperature adjustment of the first liquid and the second liquid before mixing may be performed at a temperature from the freezing point to the boiling point of the first liquid and the second liquid, but in consideration of the thermal efficiency and the melting point of triclosan, It is preferable to set it as -50 degreeC, and it is more preferable to set it as 5-40 degreeC.

  Finally, the dispersion liquid in which the nanoparticles of triclosan are dispersed and precipitated is recovered in the recovery tank 39 via the mixed liquid recovery pipe 38.

  According to the method for producing a triclosan nanoparticle dispersion as described above, an average particle size that has not been obtained conventionally by a simple method is 500 nm or less (300 nm or less or 100 nm or less depending on conditions), and A nanoparticle dispersion of triclosan having excellent storage stability can be produced. Here, the average particle diameter is an average particle diameter of fine particles that can be measured by a particle size distribution measuring apparatus using a dynamic light scattering method as a measurement principle.

In addition, in the method for producing the triclosan nanoparticle dispersion, the third power of the in-bore flow velocity of the liquid flowing through the mixing pores 22 is divided by the pore diameter of the mixing pores 22 as will be clarified later in the examples. By manipulating these values, the average particle size of the triclosan nanoparticles can be controlled regardless of the type and size of the micromixer 100. Specifically, if the value obtained by dividing the cube of the in-hole flow velocity of the liquid flowing through the mixing pores 22 by the pore diameter of the mixing pores 22 is set to 1000 (m ² / s ³ ) or more. If sufficient mixing performance is obtained, preferably 10,000 (m ² / s ³ ) or more, more preferably 100,000 (m ² / s ³ ) or more, the average particle size of triclosan having an average particle size of 100 nm or less Nanoparticle dispersions can be produced.

[Test Evaluation 1]
(Nanoparticle dispersion)
Triclosan nanoparticle dispersions of the following Examples 1 to 9 and Comparative Examples 1 to 5 were prepared.

<Example 1>
A 100 mL volumetric flask is charged with 6 mL of 1M aqueous sodium hydroxide (NaOH) (Kishida Chemical), 80 mg of triclosan (Ciba Specialty Chemicals), and 10 mg of polyvinylpyrrolidone (ISP: PVP-K30, weight average molecular weight: 60000). Water was further added to make 100 mL, and an alkaline aqueous solution in which triclosan and polyvinylpyrrolidone were dissolved was used as the first solution. The concentrations of sodium hydroxide, triclosan, and polyvinylpyrrolidone in the first liquid are 60 mM, 800 mg / L, and 100 mg / L, respectively. An aqueous solution in which sodium dihydrogen phosphate (Wako Pure Chemical Industries) was dissolved in water to a concentration of 100 mM was used as the second liquid. Each of the first liquid and the second liquid was adjusted to 20 ° C. The mass ratio of polyvinylpyrrolidone / triclosan is 0.125.

  Using the micromixer 100 having the first configuration shown in FIG. 3, the first liquid and the second liquid are respectively syringe pumps so that the mixing volume ratio is the former / the latter = 1/1 and the total flow rate is 6 ml / min. Then, they were passed through the mixing pores 22 to prepare a triclosan nanoparticle dispersion. The obtained triclosan nanoparticle dispersion was designated as Example 1. The mixing pore 22 of the micromixer 100 was a cylindrical hole, and had a hole diameter of 0.15 mm and a hole length of 1.0 mm.

<Example 2>
A triclosan nanoparticle dispersion obtained in the same manner as in Example 1 except that the content of polyvinylpyrrolidone in the first liquid was 16 mg was defined as Example 2. The concentration of polyvinyl pyrrolidone in the first liquid is 160 mg / L. The mass ratio of polyvinylpyrrolidone / triclosan is 0.2.

<Example 3>
A triclosan nanoparticle dispersion obtained in the same manner as in Example 1 except that the content of polyvinylpyrrolidone in the first liquid was 28 mg was defined as Example 3. The concentration of polyvinyl pyrrolidone in the first liquid is 280 mg / L. The mass ratio of polyvinylpyrrolidone / triclosan is 0.35.

<Example 4>
Example 4 was a nanoparticle dispersion of triclosan obtained in the same manner as in Example 1 except that the content of polyvinylpyrrolidone in the first liquid was 40 mg. The concentration of polyvinyl pyrrolidone in the first liquid is 400 mg / L. The mass ratio of polyvinylpyrrolidone / triclosan is 0.5.

<Example 5>
Triclosan nanoparticle dispersion obtained in the same manner as in Example 1 except that polyvinylpyrrolidone was not dissolved in the first liquid and polyvinylpyrrolidone was dissolved in the second liquid to a concentration of 400 mg / L. Was taken as Example 5. The mass ratio of polyvinylpyrrolidone / triclosan is 0.5.

<Example 6>
A triclosan nanoparticle dispersion obtained in the same manner as in Example 1 except that the content of triclosan in the first liquid was 160 mg and the content of polyvinylpyrrolidone was 56 mg was defined as Example 6. The concentrations of triclosan and polyvinylpyrrolidone in the first liquid are 1600 mg / L and 560 mg / L, respectively. The mass ratio of polyvinylpyrrolidone / triclosan is 0.35.

<Example 7>
A triclosan nanoparticle dispersion obtained in the same manner as in Example 1 except that the content of triclosan in the first liquid was 320 mg and the content of polyvinylpyrrolidone was 112 mg was defined as Example 7. The concentrations of triclosan and polyvinylpyrrolidone in the first liquid are 3200 mg / L and 1120 mg / L, respectively. The mass ratio of polyvinylpyrrolidone / triclosan is 0.35.

<Example 8>
A 100 mL volumetric flask was charged with 12 mL of 1M aqueous sodium hydroxide solution, 160 mg of triclosan and 56 mg of polyvinylpyrrolidone, and water was further added to make 100 mL. The concentrations of sodium hydroxide, triclosan, and polyvinylpyrrolidone in the first liquid are 120 mM, 1600 mg / L, and 560 mg / L, respectively. An aqueous solution in which sodium dihydrogen phosphate (Wako Pure Chemical Industries) was dissolved in water to a concentration of 67 mM was used as the second liquid. Each of the first liquid and the second liquid was adjusted to 20 ° C. The mass ratio of polyvinylpyrrolidone / triclosan is 0.35.

  Using the micromixer 100 used in Example 1, the first liquid and the second liquid were each sent by a syringe pump so that the mixing volume ratio was the former / the latter = 1/3 and the total flow rate was 6 ml / min. Then, they were passed through the mixing pores 22 to prepare a triclosan nanoparticle dispersion. The obtained triclosan nanoparticle dispersion was designated as Example 8.

<Example 9>
A 100 mL volumetric flask is charged with 4 mL of 1M aqueous sodium hydroxide solution, 53.3 mg of triclosan, and 18.7 mg of polyvinyl pyrrolidone, and water is further added to make 100 mL. It was. The concentrations of sodium hydroxide, triclosan, and polyvinylpyrrolidone in the first liquid are 40 mM, 533 mg / L, and 187 mg / L, respectively. An aqueous solution in which sodium dihydrogen phosphate (Wako Pure Chemical Industries) was dissolved in water to a concentration of 200 mM was used as the second liquid. Each of the first liquid and the second liquid was adjusted to 20 ° C. The mass ratio of polyvinylpyrrolidone / triclosan is 0.35.

  Using the micromixer 100 used in Example 1, the first liquid and the second liquid were each sent by a syringe pump so that the mixing volume ratio was the former / the latter = 3/1 and the total flow rate was 6 ml / min. Then, they were passed through the mixing pores 22 to prepare a triclosan nanoparticle dispersion. The obtained triclosan nanoparticle dispersion was designated as Example 9.

<Comparative Example 1>
A triclosan nanoparticle dispersion obtained in the same manner as in Example 1 except that polyvinylpyrrolidone was not dissolved in the first liquid was used as Comparative Example 1. The mass ratio of polyvinylpyrrolidone / triclosan is zero.

<Comparative example 2>
A triclosan nanoparticle dispersion obtained in the same manner as in Example 1 except that the content of polyvinylpyrrolidone in the first liquid was 200 mg was used as Comparative Example 2. The concentration of polyvinyl pyrrolidone in the first liquid is 2000 mg / L. The mass ratio of polyvinylpyrrolidone / triclosan is 2.5.

<Comparative Example 3>
A 100 mL volumetric flask was charged with 1 M aqueous sodium hydroxide solution (10 mL), triclosan (50 mg), and polyvinylpyrrolidone (6.3 mg), and water was further added to make 100 mL. . The concentrations of sodium hydroxide, triclosan, and polyvinylpyrrolidone in the first liquid are 100 mM, 500 mg / L, and 63 mg / L, respectively. An aqueous solution obtained by diluting phosphoric acid (Wako Pure Chemical Industries) with water to a concentration of 250 mM was used as the second solution. Each of the first liquid and the second liquid was adjusted to 20 ° C. The mass ratio of polyvinylpyrrolidone / triclosan is 0.125.

  While stirring 20 mL of the first liquid in a 50 ml test tube and stirring with a touch mixer, 5 mL of the second liquid was added all at once, thereby preparing a nanoparticle dispersion of triclosan. The obtained triclosan nanoparticle dispersion was designated as Comparative Example 3.

<Comparative example 4>
A triclosan nanoparticle dispersion obtained in the same manner as in Comparative Example 3 except that the content of polyvinylpyrrolidone in the first liquid was 17.5 mg was used as Comparative Example 4. The concentration of polyvinyl pyrrolidone in the first liquid is 175 mg / L. The mass ratio of polyvinylpyrrolidone / triclosan is 0.35.

<Comparative Example 5>
A triclosan nanoparticle dispersion obtained in the same manner as in Comparative Example 3 except that the content of polyvinylpyrrolidone in the first liquid was 25 mg was set as Comparative Example 5. The concentration of polyvinyl pyrrolidone in the first liquid is 250 mg / L. The mass ratio of polyvinylpyrrolidone / triclosan is 0.5.

(Test evaluation method)
For each of Examples 1 to 9 and Comparative Examples 1 to 5, measurement of average particle diameter and appearance evaluation (immediately after preparation and after storage at room temperature for 1 day) were performed. For the particle size measurement, a zeta potential / particle size measurement system (model number: ELS-Z2 manufactured by Otsuka Electronics Co., Ltd.) was used. Since Comparative Examples 4 and 5 contained a white precipitate, the filtrate filtered using a membrane filter (Sartorius) having a mesh size of 1.2 microns was subjected to average particle size measurement.

(Test evaluation results)
Table 1 shows average particle diameters and appearance evaluations of Examples 1 to 9 and Comparative Examples 1 to 5, respectively.

  According to Table 1, the average particle size is 204 nm in Example 1, 123 nm in Example 2, 51 nm in Example 3, 153 nm in Example 4, 132 nm in Example 5, 80 nm in Example 6, and Example 7 Is 133 nm, Example 8 is 58 nm, and Example 9 is 55 nm, and Comparative Example 1 is 1130 nm, Comparative Example 2 is 29 nm, Comparative Example 3 is 193 nm, Comparative Example 4 is 169 nm, and Comparative Example 5 is 108 nm. It was.

  In addition, in Examples 1 to 9, the appearance evaluation was immediately after adjustment, Examples 3, 6, 8, and 9 were transparent, Examples 1, 2, and 7 were translucent, and Examples 4 and 5 were slightly precipitated. No change was found in any of Examples 1 to 9 after storage for 1 day. In Comparative Examples 1 to 5, immediately after adjustment, Comparative Example 2 was transparent, Comparative Example 1 was suspended, Comparative Example 3 was slightly precipitated, Comparative Examples 4 and 5 were precipitated, and after storage for 1 day, Comparative Example 1 All of ~ 5 had precipitation.

  From the above, with respect to the average particle diameter, Examples 1 to 9 were comparable or smaller than Comparative Examples 1 to 5, and regarding the appearance, Comparative Examples 1 to 5 were significantly precipitated after storage for 1 day after preparation. In contrast to the generation (comparative examples 4 to 5 were generated immediately after preparation), in Examples 1 to 9, it was found that almost no precipitate was generated and no change in state was observed.

[Test evaluation 2]
(Nanoparticle dispersion)
The nanoparticle dispersion liquid of the triclosan of the following Examples 10-17 was prepared.

<Examples 10 and 11>
A triclosan nanoparticle dispersion obtained in the same manner as in Example 3 except that the total flow rate (total flow rate) of the first liquid and the second liquid was 3 mL / min was defined as Example 10. In addition, a nanoparticle dispersion of triclosan obtained in the same manner as in Example 10 except that the total flow rate (total flow rate) of the first liquid and the second liquid was 1 mL / min was used as Example 11. The value (U ³ / d) obtained by dividing the cube of the in-hole flow velocity (U) of the total of the first liquid and the second liquid by the pore diameter (d) of the mixing pores 22 is 1210000 m ² during the preparation of Example 3. / ^{s 3,} the preparation of example 10 is 151000m ² / ^{s 3,} and the preparation of example 11 is 5590m ² / ^{s 3.}

<Examples 12 to 14>
A micromixer 100 having a first configuration shown in FIG. 3 in which the pore diameter of the mixing pores 22 of the cylindrical pore is 0.3 mm and the pore length is 0.9 mm is used. The triclosan nanoparticle dispersion obtained in the same manner as in Example 3 except that the total flow rate (total flow rate) was 48 mL / min was used as Example 12. A triclosan nanoparticle dispersion obtained in the same manner as in Example 12 except that the total flow rate (total flow rate) of the first liquid and the second liquid was 12 mL / min was used as Example 13. A triclosan nanoparticle dispersion obtained in the same manner as in Example 12 except that the total flow rate (total flow rate) of the first liquid and the second liquid was 3 mL / min was used as Example 14. The value (U ³ / d) obtained by dividing the cube of the in-hole flow velocity (U) of the first liquid and the second liquid by the hole diameter (d) of the mixing pores 22 is 4830000 m ² during the preparation of Example 12. / ^{s 3,} prepared during the 75500m ² / ^{s 3} of example 13, and the preparation of example 14 is 1180m ² / ^{s 3.}

<Examples 15 to 17>
A 100 mL volumetric flask was charged with 2 mL of 1M aqueous sodium hydroxide solution, 80 mg of triclosan, and 28 mg of polyvinylpyrrolidone, and water was further added to make 100 mL. The concentrations of sodium hydroxide, triclosan, and polyvinylpyrrolidone in the first liquid are 20 mM, 800 mg / L, and 280 mg / L, respectively. An aqueous solution in which HEPES (Wako Pure Chemical Industries) was dissolved in water to a concentration of 100 mM was used as the second solution. Each of the first liquid and the second liquid was adjusted to 20 ° C. The mass ratio of polyvinylpyrrolidone / triclosan is 0.35.

Using the micromixer 100 having the third configuration shown in FIG. 8, the first liquid and the second liquid are respectively syringe pumps so that the mixing volume ratio is the former / the latter = 1/1 and the total flow rate is 30 ml / min. Then, they were passed through the mixing pores 22 to prepare a triclosan nanoparticle dispersion. The obtained triclosan nanoparticle dispersion was designated as Example 15. The mixing pores 22 of the micromixer 100 were cylindrical holes with a hole diameter of 0.3 mm and a hole length of 0.8 mm. The first liquid and the second liquid were the same as in Example 15 except that the liquid volume was fed by a syringe pump so that the mixing volume ratio was the former / the latter = 1/1 and the total flow rate was 12 ml / min. The triclosan nanoparticle dispersion obtained in this manner was used as Example 16. Except that the first and second liquids were each sent by a syringe pump so that the mixing volume ratio was the former / the latter = 1/1 and the total flow rate was 3 ml / min, the same as in Example 15. The obtained triclosan nanoparticle dispersion was designated as Example 17. The value (U ³ / d) obtained by dividing the cube of the in-hole flow velocity (U) of the total of the first liquid and the second liquid by the hole diameter (d) of the mixing pores 22 is 118000 m ² during the preparation of Example 15. / ^{s 3,} the preparation of example 16 is 75500m ² / ^{s 3,} and the preparation of example 17 is 1180m ² / ^{s 3.}

(Test evaluation method)
About each of Examples 10-17, the average particle diameter was measured. For the particle size measurement, a zeta potential / particle size measurement system (model number: ELS-Z2 manufactured by Otsuka Electronics Co., Ltd.) was used.

(Test evaluation results)
Table 2 shows the average particle diameters of Examples 10 to 17. Table 2 also shows the values calculated by dividing the cube of the in-hole flow velocity U of the liquid flowing through the mixing pores by the pore diameter d of the mixing pores (unit: m ² / s ³ ). .

  According to Table 2, the average particle size is 51 nm for Example 3, 94 nm for Example 10, 123 nm for Example 11, 61 nm for Example 12, 103 nm for Example 13, 144 nm for Example 14, and Example 15 Was 83 nm, Example 16 was 114 nm, and Example 17 was 159 nm.

Further, FIG. 10 shows a value (U ³ / d) obtained by dividing the cube of the in-hole flow velocity (U) by the pore diameter (d) of the mixing pores based on the results of Example 3 and Examples 10-17. ) And the average particle size.

According to FIG. 10, between the value (U ³ / d) obtained by dividing the cube of the in-hole flow velocity (U) by the pore diameter (d) of the mixing pores and the average particle diameter, It can be seen that there is a correlation regardless of the size. Specifically, as the value (U ³ / d) becomes larger than 1000 (m ² / s ³ ), the average particle size becomes smaller, and the value (U ³ / d) becomes 100,000 (m ² / s ^3). ), The average particle size is found to be about 100 nm or less.

  The present invention relates to a method for producing a nanoparticle dispersion of triclosan that is used by being added to household, medical, and commercial cleaning agents, antifouling agents, deodorizing and deodorizing agents, cosmetics, cosmetics, hygiene products, etc. Useful for.

It is a figure which shows the structure of a fluid mixing system. It is explanatory drawing which shows a liquid contact part and the pore for mixing. It is sectional drawing which shows the micro mixer of a 1st structure. It is sectional drawing which shows the modification of the micro mixer of a 1st structure. It is sectional drawing which shows the other modification of the micro mixer of a 1st structure. It is a figure which shows the micro mixer of a 2nd structure. It is a figure which shows the modification of the micro mixer of a 2nd structure. FIG. 9A is a longitudinal sectional view showing a micro mixer of a third configuration, FIG. 8B is a transverse sectional view of VIIIB-VIIIB in FIG. 8A, and FIG. 8C is a transverse sectional view of VIIIC-VIIIC in FIG. It is the (a) longitudinal cross-sectional view which shows the modification of the micro mixer of a 3rd structure, and (b) IXB-IXB cross-sectional view in Fig.9 (a). It is a graph showing the relationship between the value obtained by dividing the cube of mixing pores having a pore diameter (d) of the hole extension velocity (U) and (U 3 ^{/ d)} and average particle size.

Explanation of symbols

22 Pore for mixing

Claims (3)

A liquid contact step in which the first liquid of the alkaline aqueous solution in which triclosan is dissolved and the second liquid of the acid are caused to flow, and are brought into contact with each other so as to be in a mixed state;
A liquid mixing step of obtaining a triclosan nanoparticle dispersion by flowing and mixing the first liquid and the second liquid mixed in the liquid contact step through the mixing pores;
With
A method for producing a triclosan nanoparticle dispersion in which polyvinyl pyrrolidone is dissolved and contained in the first liquid and / or the second liquid so that the total content is 0.1 to 0.5 in terms of mass ratio to the triclosan content. . In the liquid mixing step, a value obtained by dividing the in-bore flow velocity of the total of the first liquid and the second liquid flowing through the mixing pore by the cube of the in-hole flow velocity by the pore diameter of the mixing pore. The method for producing a triclosan nanoparticle dispersion according to claim 1, which is set to be 1000 (m ² / s ³ ) or more.   The method for producing a triclosan nanoparticle dispersion according to claim 1 or 2, wherein in the liquid mixing step, the average particle size of the triclosan nanoparticles contained in the obtained nanoparticle dispersion is 100 nm or less.

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