JP5933234B2 - Fine particle production equipment - Google Patents

Description

  The present invention relates to a fine particle production apparatus including supply means for supplying a fluid, mixing means for mixing a substance in the fluid, and injection means for injecting a fluid mixed with the substance from a nozzle to adiabatic expansion.

There are many poorly water-soluble substances such as drugs and natural products. In particular, about 40% of drugs are said to be poorly water-soluble, and it is required to improve the dissolution rate by making these drugs fine particles to increase the specific surface area.
As a conventional manufacturing apparatus for producing fine particles of a substance, various apparatuses adopting, for example, a supercritical method (RESS), a micellization method, a miniaturization (pulverization) method, and the like are known (for example, patents). Reference 1 and Non-Patent Document 1).

International Publication No. 2006/046670 Satoshi Nishikino, “Drug Delivery System”, 24-5, 2009, p.492-498

  However, the apparatus according to any method has not yet been able to stably and reliably produce fine particles having a diameter of 100 nm or less (hereinafter, fine particles having this size are defined as nanoparticles). This is because even if the nanoparticles can be produced once, the produced nanoparticles cannot be maintained in the dispersed state and reaggregate. In order to prevent this reaggregation, for example, the surface of the nanoparticles may be coated with an additive such as a surfactant, but the additive has some adverse effect on the human body. In some cases, these nanoparticles cannot be used in the manufacture of pharmaceuticals and foods.

  An object of the present invention is to provide a fine particle production apparatus that can stably and reliably produce nanoparticles having a diameter of 100 nm or less.

A first characteristic configuration according to the fine particle production apparatus of the present invention includes: a supply unit that supplies a fluid; a mixing unit that mixes a substance in the fluid; and an ejection unit that adiabatically expands by ejecting a fluid mixed with the substance from a nozzle. The nozzle inner surface of the nozzle is made of an insulator , the fluid is a supercritical fluid or liquefied carbon dioxide, the substance is a drug or a natural product, and the nozzle is a poly It is made of ether ether ketone, and the inner diameter of the inner surface of the nozzle is 20 μm to 100 μm .

[Action and effect]
According to this configuration, when the substance passes through the flow path inside the nozzle in the spraying means, it is charged with static electricity due to friction with the inner surface of the nozzle, so the nanoparticles are also charged with this static electricity. Since these nanoparticles are charged with static electricity having the same sign as each other, the nanoparticles repel each other by electrostatic force (repulsive force), and re-aggregation is prevented. Therefore, re-aggregation can be prevented without particularly using an additive such as a surfactant, and as a result, nanoparticles having an average particle diameter of 100 nm or less can be stably produced.

  The second characteristic configuration is that the length of the nozzle is 20 mm to 600 mm.

[Action and effect]
As in this configuration, by setting the nozzle length to 20 mm to 600 mm, friction is easily generated between the substance and the inner surface of the nozzle, and the substance can be more reliably charged with static electricity.

  A third characteristic configuration is that the fluid is liquefied carbon dioxide.

[Action and effect]
Liquefied carbon dioxide has a higher density than carbon dioxide in the gas state including the supercritical state, and can disperse, mix, or dissolve more substances, so that nanoparticles can be produced efficiently. . Furthermore, liquefied carbon dioxide is harmless, and even if it is absorbed by the human body, it does not have any adverse effect, so it is effective when manufacturing pharmaceuticals and foods. In addition, since liquefied carbon dioxide can be kept at a low temperature around room temperature or lower, it can also be used in the case of using nanoparticles for the production of pharmaceuticals and foods that dislike high temperatures.

  A fourth characteristic configuration is that a heating means for heating the nozzle is provided.

[Action and effect]
When a fluid is ejected from a nozzle to cause adiabatic expansion, the temperature of the nozzle decreases and condensation occurs, which may freeze and block the flow path in the nozzle. However, according to this configuration, by heating the nozzle by the heating means, it is possible to prevent the nozzle from lowering the temperature and suppress the occurrence of condensation, and as a result, blockage of the flow path in the nozzle caused by condensation is achieved. Can be prevented.

It is the figure which showed notionally the microparticle preparation apparatus of this invention. It is the figure which showed notionally other embodiment of the microparticle preparation apparatus of this invention. It is the figure which showed the electron micrograph (SEM) of the nanoparticle of sesamin produced using the microparticle preparation apparatus of this invention. It is the figure which showed the electron micrograph (SEM) of the sesamin raw material before forming into a nanoparticle. It is the figure which showed the electron micrograph (SEM) of the nanoparticle of naproxen produced using the microparticle preparation apparatus of this invention. It is the figure which showed the analysis pattern of the powder X-ray analysis (PXRD) of the nanoparticle and raw material of sesamin. It is the figure which showed the elution pattern of the nanoparticle and raw material of sesamin.

An embodiment of a fine particle production apparatus of the present invention will be described with reference to the drawings.
Embodiment
As shown in FIG. 1, the fine particle production apparatus according to the present invention includes a supply means for supplying a fluid, a mixing means for mixing a substance in the fluid, and adiabatic expansion by ejecting a fluid mixed with the substance from a nozzle. And a collecting means for collecting the produced fine particles.

[Supply means]
The supply means 1 includes a fluid storage container 5 for storing fluid, a supply pump 6 for transferring the fluid to the mixing means 2, and a primary valve 7 for adjusting the flow rate of the fluid. A fluid storage container 5 and a mixing means 2 to be described later are connected via a pipe 8, and a supply pump 6 and a primary valve 7 are provided in the middle of the pipe 8. When the primary valve 7 is opened, the fluid in the fluid storage container 5 is transferred through the pipe 8 by the supply pump 6 and supplied to the pressure-resistant container (not shown) of the mixing means 2.

  The fluid applicable to the present invention is not particularly limited as long as it is a fluid that can disperse, mix, or dissolve a substance. However, the fluid can be dispersed, mixed, or dissolved at a higher density. A fluid that is easy to cause and has little influence on the human body is desirable. Examples of such fluids include supercritical fluids such as supercritical carbon dioxide, and liquefied carbon dioxide, but liquefied carbon dioxide is particularly preferable.

[Mixing means]
The mixing means 2 is a pressure vessel (not shown) for dispersing, mixing or dissolving a substance in a fluid under a predetermined pressure, and for filtering the fluid after the substance is dispersed, mixed or dissolved. A filter (not shown) is provided. The substance is dispersed, mixed, or dissolved in the fluid in the pressure vessel, but even if a part of the substance is not completely dispersed, mixed, or dissolved, it is removed by the filter. There is no risk that the flow path will be clogged with a substance that could not be dispersed, mixed, or dissolved.

[Injection means]
The ejection means 3 includes a secondary valve 10 for adjusting the flow rate and a nozzle 11 for ejecting the filtered fluid. The mixing means 2 and the nozzle 11 are connected via a pipe 12, and a secondary valve 10 is provided in the middle of the pipe 12. When the secondary valve 10 is opened, the fluid filtered by a filter (not shown) of the mixing unit 2 is transferred through the pipe 12 and supplied to the nozzle 11.

  Inside the nozzle 11, a flow path (not shown) through which a fluid flows is formed. The material of the nozzle 11 itself is not particularly limited, such as an insulator or a conductor, and it is sufficient that at least the inner surface (flow path) of the nozzle 11 is made of an insulator. Examples of the insulator that can be applied to the inner surface of the nozzle 11 include glass and synthetic resin. The synthetic resin is particularly preferably polyetheretherketone (PEEK) having high mechanical strength and excellent workability.

  For example, the inner diameter of the inner surface of the nozzle 11 is 20 μm to 100 μm, preferably 25 μm to 65 μm, and more preferably 40 μm to 60 μm. Moreover, the length of a nozzle is 20 mm-600 mm, Preferably it is 30 mm-400 mm, More preferably, it is 50 mm-200 mm.

[Recovery means]
The collection means 4 is configured to include a collection chamber 13 that covers the front periphery of the nozzle 11, and in the collection chamber 13, a glass bottle 14 for containing the produced nanoparticles, or nanoparticles as shown in FIG. A mica or X-ray diffraction substrate 15 or the like for attachment can be disposed. Further, the recovery chamber 13 may be configured to be hermetically sealed, and an inert gas such as nitrogen may be sealed as necessary.

[Heating means]
When the fluid is ejected from the nozzle 11 and adiabatic expansion is performed, the temperature of the nozzle 11 is lowered to cause dew condensation. This dew condensation freezes and the flow path may be blocked. In order to prevent this, a heating means (not shown) such as a heater for heating the tip of the nozzle 11 may be provided. When the heating means is provided, the fine particle production apparatus can be used even in a place where there is a lot of moisture in the atmosphere. Further, if the spraying is continued for a long time, the temperature of the nozzle 11 is excessively lowered, and the dry ice is likely to adhere around the nozzle 11. If this is left unattended, it will cause clogging, so that the nozzle 11 is warmed by the heating means to prevent the temperature of the nozzle 11 from decreasing, thereby preventing the adhesion of dry ice and the flow path of the nozzle 11. Blockage can be prevented.
Note that the heating means may heat not only the nozzle 11 but also the entire injection means 3 and the mixing means 2.

[Production method of nanoparticles]
The production of nanoparticles using the apparatus configured as described above is performed as follows.

  First, a certain amount of substance is put into a pressure vessel (not shown) of the mixing means 2, the primary valve 7 is opened, and fluid is supplied until a predetermined pressure (for example, 10 MPa) is reached to disperse, mix or dissolve the substance. Let

  Then, the secondary valve 10 is opened, and a fluid in which the substance is dispersed, mixed, or dissolved is sprayed from the nozzle 11 into the recovery chamber 13. At this time, since the volume of the fluid sprayed from the nozzle 11 rapidly expands, a sudden temperature drop occurs due to the Joule-Thompson effect, and the solubility of the substance in the fluid suddenly decreases to deposit the substance. Since this precipitation process occurs in a very short time, nanoparticles with a narrow particle size distribution width are produced.

The produced nanoparticles are collected in a glass bottle 14 or the like previously installed in the collection chamber 13.
In the present invention, when the substance passes through the flow path of the nozzle 11, it is charged with static electricity due to friction with the inner surface of the nozzle, so that the nanoparticles are also charged with this static electricity. Since these nanoparticles are charged with static electricity having the same sign as each other, the nanoparticles repel each other due to electrostatic force (repulsive force) and re-aggregation is prevented. Therefore, according to the present invention, reaggregation can be prevented without particularly using an additive such as a surfactant, and as a result, nanoparticles having an average particle diameter of 100 nm or less can be stably produced. it can.

  Nanoparticles were prepared as follows for each of the two types of compounds, sesamin and naproxen.

  6.4 mg of sesamin is weighed and placed in a sample folder with an internal volume of 1 mL (pressure vessel sealed with a filter with a pore size of 10 μm). It was.

  Then, the secondary valve is opened, and a PEEK shield glass nozzle having an inner diameter of 50 μm and a flow path length of 100 mm (a nozzle in which the inner part including the flow path is made of PEEK and the outer periphery of the inner part is covered with glass) Then, a liquefied carbon dioxide solution in which sesamin was dissolved was sprayed into the collection chamber to adiabatic expansion, thereby producing fine particles. Moreover, 6.0 mg of naproxen was weighed, and fine particles were produced by the same operation as described above.

  The produced fine particles of sesamin and naproxen were deposited on a mica substrate and coated with platinum (Pt) by a sputtering method. In addition, you may make it perform the coating by this sputtering method as needed.

  The particle size of each fine particle of sesamin and naproxen coated with platinum was examined by an electron microscope (SEM). The fine particles of sesamin were examined for primary particle size and crystal state by powder X-ray diffraction (PXRD).

  As shown in FIGS. 3A and 3B, nanoparticles having an average particle size of 50 nm or less were produced for sesamin. In addition, as shown in FIGS. 5A and 5B, nanoparticles having a diameter of about 50 nm were produced for naproxen. Moreover, it was found that none of the nanoparticles was aggregated, and nanoparticles having a good dispersion state were produced.

  Next, powder X-ray analysis (PXRD) was performed to examine the crystalline state of the produced sesamin nanoparticles. As a comparative example, X-ray powder analysis (PXRD) was also performed on sesamin raw materials.

  As shown in FIG. 6, in the powder X-ray analysis of the sesamin raw material (0.4 mg), a sharp sharp peak was observed at around 15 degrees, while the sesamin nanoparticle (0.4 mg) powder X Line analysis did not show a clear peak. This suggests that most of the sesamin nanoparticles are in an amorphous form unlike the sesamin raw material.

  When the primary particle size of the sesamin raw material was calculated from the obtained PXRD peak using the Scherrer equation, it was calculated to be 190 nm to 370 nm.

Next, a dissolution test was performed on the sesamin nanoparticles and raw materials.
After adding 0.5 mg each of sesamin nanoparticles and raw materials to a glass bottle, 5 mL of water was added simultaneously, and the absorbance at a measurement wavelength of 285 nm was measured.

  As shown in FIG. 7, almost all of the sesamin nanoparticles were dissolved immediately after the water was injected, whereas it took at least several tens of hours for the sesamin raw material to dissolve. In other words, it was confirmed that nanoparticulate sesamin was dissolved in water at a significantly higher rate than the raw material.

  Therefore, according to the present invention, regardless of the crystallization state of the particles, the dissolution rate in water of a drug that should be originally hardly water-soluble is significantly increased due to the increase in the specific surface area per unit weight of the drug due to nanoparticulation. It was suggested to improve.

  The fine particle production apparatus according to the present invention can be used for producing nanoparticles of various substances such as natural products and drugs.

DESCRIPTION OF SYMBOLS 1 Supply means 2 Mixing means 3 Injection means 4 Recovery means 5 Fluid storage container 6 Supply pump 7 Primary valve 8 Piping 10 Secondary valve 11 Nozzle 12 Piping 13 Collection chamber 14 Glass bottle 15 Substrate

Claims (4)

A fine particle production apparatus comprising: a supply means for supplying a fluid; a mixing means for mixing a substance in the fluid; and an injection means for injecting a fluid mixed with the substance from a nozzle to adiabatic expansion.
The nozzle inner surface of the nozzle is made of an insulator ,
The fluid is a supercritical fluid or liquefied carbon dioxide;
The substance is a drug or a natural product,
The nozzle is made of polyetheretherketone;
A fine particle production apparatus in which an inner diameter of the nozzle inner surface is 20 μm to 100 μm .   The fine particle production apparatus according to claim 1, wherein the nozzle has a length of 20 mm to 600 mm.   The fine particle production apparatus according to claim 1, wherein the fluid is liquefied carbon dioxide.   The fine particle production apparatus according to any one of claims 1 to 3, further comprising a heating means for heating the nozzle.