JP2005125204A - Particulate, method for manufacturing particulate and manufacturing device - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for manufacturing a particulate capable of efficiently pulverizing an organic compound by optical crushing, a manufacturing device and a particulate. <P>SOLUTION: The manufacturing device 1A is constituted by a treatment chamber 3 for storing a liquid 2 to be treated comprising liquid nitrogen 4, i.e., a solvent becoming a vapor phase at normal temperature and a liquid phase at low temperature and a material particle 5 of the organic compound existing in the liquid nitrogen 4; a heat insulation layer 30 provided on a periphery of the treatment chamber 3 and retaining the liquid nitrogen 4 in the liquid phase; a laser light source 10 for irradiating the liquid 2 to be treated with laser light; and a light path change device 11 for changing a light path of the laser light. Further, the material particle 5 is optically crushed by irradiating the liquid 2 to be treated in which the liquid nitrogen 4 is retained in the liquid phase with the laser light to manufacture the particulate of the organic compound. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to fine particles of organic compounds such as drugs, a method for producing fine particles, and a production apparatus.

  The micronization of organic compounds results in an extreme increase in surface area. For this reason, there exists an advantage that the property intrinsic | native to a substance becomes easy to appear by atomizing an organic compound. In addition, when the particles are hardly soluble or insoluble, the particles are pseudo-solubilized in a solvent such as water by the micronization (the particles are suspended in the solvent, but the light scattering It is also possible to make it appear to be pseudo-solubilized because there is little.

Conventionally, there is a method disclosed in Patent Document 1 (Japanese Patent Application Laid-Open No. 2001-113159) as such a fine particle forming method. Here, a method of generating fine particles of an organic compound by irradiating a laser beam is disclosed. In this method, organic pigments and aromatic condensed polycyclic compounds having an intermediate property between an inorganic substance and an organic substance and having a hard molecular structure and an aromatic condensed polycyclic compound are targeted for micronization. Non-patent documents 1 to 3 also describe the formation of fine particles of an organic compound by laser light irradiation.
JP 2001-113159 A Y. Tamaki et al., "Tailoring nanoparticles of aromatic and dye molecules by excimer laser irradiation", Applied Surface Science Vol. 168, p.85-88 (2000) Y. Tamaki et al., "Nanoparticle Formation of Vanadyl Phthalocyanine by Laser Ablation of Its Crystalline Powder in a Poor Solvent", J. Phys. Chem. A 2002, 106, p.2135-2139 (2002) B. Li et al., "Enhancement of organic nanoparticle preparation by laser ablation in aqueous solution using surfactants", Applied Surface Science Vol. 210, p.171-176 (2003)

  If the above-described micronization technology is used, there is a possibility that a new raw material adjustment method can be provided, and application in a wide range of fields is expected. For example, in drug discovery, if the solubility of a synthesized new substance in a solvent such as water is low, physicochemical research or screening of the substance cannot be performed, or an ADME test (absorption / distribution / metabolism / General toxicity, general pharmacology, pharmacology, and biochemical studies in preclinical studies in animals such as excretion tests). On the other hand, there is a possibility that various drug discovery candidate substances can be studied by atomizing organic compounds.

  Here, in an organic compound such as a drug to be microparticulated, a structure having a high degree of freedom of movement of molecules is formed by the binding between molecules based on relatively weak intermolecular forces. For this reason, the above-described micronization method has a problem that the light crushing action on the organic compound due to laser light irradiation is relaxed by the large degree of freedom of movement, and the organic compound cannot be micronized with high efficiency.

  The present invention has been made to solve the above-described problems, and an object of the present invention is to provide a fine particle production method, a production apparatus, and fine particles capable of efficiently atomizing an organic compound.

  In order to achieve such an object, the method for producing fine particles according to the present invention is a production method for producing fine particles of an organic compound by photocrushing an organic compound in a solvent of a liquid to be treated. As a liquid solvent, a solvent that is in a gas phase at room temperature (for example, 25 ° C.) and in a liquid phase at a predetermined temperature lower than room temperature is used. By doing so, the method is characterized by comprising a micronization step for micronizing an organic compound in a solvent.

  The fine particle production apparatus according to the present invention is a production apparatus for producing fine particles of an organic compound by photocrushing an organic compound in a solvent of a liquid to be treated. A processing chamber for storing a liquid to be processed using a solvent that becomes a liquid phase at a predetermined temperature, liquid phase holding means for holding the solvent of the liquid to be processed in the liquid phase, and the solvent stored in the processing chamber in the liquid phase And a laser light source for irradiating a laser beam having a predetermined wavelength for making the organic compound in the solvent into fine particles with respect to the liquid to be treated.

  According to the fine particle production method and apparatus described above, a solution containing an organic compound to be atomized in a solvent that is in a gas phase at room temperature and in a liquid phase at low temperature is used as a liquid to be treated, and the particles are formed by laser light irradiation. Is going. By setting the temperature sufficiently low with such a solvent, micronization is performed in a state where the degree of freedom of molecular motion of the organic compound is lowered. Therefore, relaxation of the light crushing energy due to molecular motion is suppressed, and the organic compound can be efficiently made into fine particles. Also, with such a solvent, the fine particles can be easily recovered by evaporating the solvent at room temperature. Here, it is preferable to use liquid nitrogen, liquid argon, or liquid helium as the solvent that becomes a gas phase at room temperature and a liquid phase at low temperature.

  In the manufacturing method and apparatus described above, the wavelength of the laser beam irradiated from the laser light source and used in the micronization step is preferably 900 nm or more. Thereby, the fine particle formation of the organic compound by laser light irradiation can be suitably realized.

  Moreover, it is preferable that the manufacturing method and apparatus perform the laser beam irradiation while moving the irradiation position of the laser beam to the liquid to be processed in the micronization step. As a result, it is possible to prevent a decrease in the efficiency of atomization caused by heating due to continuous irradiation with laser light at an irradiation position fixed to the liquid to be processed.

  In this case, the manufacturing method may move the irradiation position by changing the optical path of the laser beam in the micronization step. Similarly, the manufacturing apparatus may include an optical path changing unit that moves the irradiation position by changing the optical path of the laser light from the laser light source to the processing chamber.

  Alternatively, the manufacturing method may obtain the same effect by moving the irradiation position by flowing the liquid to be processed in the micronization step. Similarly, the manufacturing apparatus may obtain the same effect by moving the irradiation position by flowing the liquid to be processed in the processing chamber.

  Moreover, it is preferable that the manufacturing method includes a fine particle collection step of collecting the organic compound fine particles by evaporating the solvent by spraying the liquid to be treated after the fine particle formation step. Similarly, it is preferable that the manufacturing apparatus includes a fine particle collecting unit that vaporizes the solvent by ejecting the liquid to be processed, which has been irradiated with the laser light, from the processing chamber to collect the fine particles of the organic compound. . In this way, a solution in which an organic compound is contained in a solvent that is in a gas phase at room temperature and in a liquid phase at low temperature is used as a liquid to be processed, and the liquid to be processed is injected following laser light irradiation to form fine particles. The dried organic compound powder is obtained.

  In addition, an organic compound that is to be microparticulated by laser light irradiation may be used as a drug. In this case, the photochemical reaction with the drug due to laser light irradiation can be sufficiently prevented, and the fine particles can be produced without losing the drug efficacy. Moreover, since the surface area of the drug is increased by making the drug fine particles and the absorbability to living tissue is improved, drug fine particles having immediate effect can be obtained.

  The fine particles according to the present invention are fine particles produced by the above-described fine particle production method. According to such fine particles, fine particles of an organic compound that are efficiently manufactured and in a good state can be obtained.

  According to the present invention, it is possible to efficiently atomize an organic compound by performing atomization by laser light irradiation using a solvent that becomes a gas phase at normal temperature and a liquid phase at low temperature.

  Hereinafter, preferred embodiments of a fine particle production method, production apparatus, and fine particles according to the present invention will be described in detail with reference to the drawings. In the description of the drawings, the same elements are denoted by the same reference numerals, and redundant description is omitted. Further, the dimensional ratios in the drawings do not necessarily match those described.

  FIG. 1 is a block diagram schematically showing an embodiment of a fine particle production apparatus according to the present invention. The fine particle production apparatus 1A is an apparatus for producing fine particles by photo-crushing an organic compound in a solvent of a liquid to be treated. In the liquid 2 to be treated in the present embodiment, liquid nitrogen 4 is used as a solvent for containing the raw material particles 5 with respect to the raw material particles 5 of the organic compound to be atomized. The liquid nitrogen 4 is a solvent that becomes a gas phase at room temperature (here, 25 ° C.) and a liquid phase at a predetermined temperature lower than room temperature. That is, the boiling point of liquid nitrogen 4 is −195.8 ° C., and it is liquid at a temperature lower than that.

  As shown in FIG. 1, the fine particle manufacturing apparatus 1 </ b> A includes a processing chamber 3 for storing a liquid 2 to be processed. The processing chamber 3 is made of, for example, quartz. In addition, a heat insulating layer 30 is provided around the processing chamber 3. The heat insulating layer 30 is made of, for example, styrene foam, and functions as a liquid phase holding unit that holds the liquid nitrogen 4 of the liquid 2 to be processed stored in the processing chamber 3 in the liquid phase. Thereby, in the process chamber 3, generation | occurrence | production of the vaporization by the external heat in the liquid nitrogen 4 is suppressed.

  In addition, the manufacturing apparatus 1A includes a high-power laser light source 10 that irradiates laser light having a predetermined wavelength onto the liquid 2 to be processed that is contained in the processing chamber 3 and in which liquid nitrogen 4 is held in a liquid phase. The laser light source 10 supplies laser light having a wavelength suitable for making the organic compound raw material particles 5 in the liquid nitrogen 4 into fine particles.

  As the laser light source 10, a fixed wavelength laser light source can be used when the wavelength to be set in the laser light is known in advance. Alternatively, a tunable laser light source may be used as the laser light source 10. In this case, laser light with an appropriate wavelength can be set and irradiated appropriately based on the light absorption characteristics of the organic compound. Moreover, you may provide optical intensity adjustment means, such as an attenuation | damping filter and an optical attenuator, with respect to the laser light source 10 as needed.

  With respect to the laser light source 10, an opening 31 is provided in a portion of the heat insulating layer 30 surrounding the processing chamber 3 on the front side facing the laser light source 10. The opening 31 is a heat insulating air layer 32 having a heat insulating action similar to the heat insulating layer 30, and thereby the heat insulating state of the liquid 2 to be processed in the processing chamber 3 is maintained.

  A light irradiation window 33 made of glass or the like that covers the opening 31 is installed on the outer surface side of the heat insulating layer 30. Further, in order to prevent the outer surface of the light irradiation window 33 from condensing for a long period of time and the laser beam irradiation under favorable conditions cannot be performed, a dry gas (for example, nitrogen gas) is sprayed on the outer surface of the light irradiation window 33. A dry gas spraying device 34 for preventing condensation is installed.

  A magnetic stick 41 is accommodated in the processing chamber 3 together with the liquid 2 to be processed. By the magnetic stick 41 and the magnetic stirrer 42, the liquid nitrogen 4 and the raw material particles 5 of the liquid 2 to be processed are stirred in the processing chamber 3 during the laser light irradiation, and the raw material particles 5 are dispersed in the liquid nitrogen 4. It has become.

  An optical path changing device 11 is installed between the laser light source 10 and the light irradiation window 33 provided on the front side of the processing chamber 3. As schematically shown in FIG. 1, the optical path changing device 11 changes the optical path of the laser light from the laser light source 10 to the processing chamber 3 during laser light irradiation. Further, on the rear surface side of the processing chamber 3, a light shielding layer 35 made of a scatterer such as paper, a reflection mirror, or the like is provided in front of the heat insulating layer 30. The light shielding layer 35 is for preventing damage to the heat insulating layer 30 caused by irradiation with laser light from the laser light source 10.

  The laser light source 10 and the optical path changing device 11 are connected to a control device 15 including a computer. In the present embodiment, the control device 15 is also connected to the dry gas spray device 34 and the magnet stirrer 42. The control device 15 controls the production of fine particles by controlling the operation of each part of the production device 1A.

  Next, a method for producing fine particles according to the present invention using the fine particle production apparatus 1A shown in FIG. 1 will be described.

  First, after mixing liquid nitrogen 4 which is in a liquid phase at a predetermined temperature (low temperature) and raw material particles 5 of an organic compound to be microparticulated, the liquid to be treated 2 is adjusted by stirring. The raw material particles 5 are contained in the liquid nitrogen 4 in a dissolved substance or non-dissolved substance state. Subsequently, the liquid 2 to be processed is introduced into the processing chamber 3. Then, the laser light source 10 is controlled by the control device 15, and laser light having a wavelength set according to the light absorption characteristics of the organic compound constituting the raw material particles 5 is supplied from the laser light source 10 to the liquid 2 to be processed. The

  The laser light supplied from the laser light source 10 is irradiated to the liquid 2 to be processed through the optical path changing device 11, the light irradiation window 33, the air layer 32, and the front surface of the processing chamber 3. By this laser light irradiation, the raw material particles 5 in the liquid nitrogen 4 are atomized in the liquid 2 to be processed in the processing chamber 3 to produce organic compound fine particles (a fine particle forming step).

  In the present embodiment, laser light irradiation is performed while sequentially changing the optical path of the laser light from the laser light source 10 to the processing chamber 3 by the optical path changing device 11. Thereby, the irradiation position of the laser beam with respect to the to-be-processed liquid 2 is moved, and the raw material particle 5 in the to-be-processed liquid 2 is atomized in each irradiation position.

  The effects of the fine particle production method and production apparatus according to the present embodiment will be described.

  According to the method and apparatus for producing fine particles described above, a solution containing organic compound raw material particles 5 to be atomized in liquid nitrogen 4 which is a solvent that becomes a gas phase at room temperature and a liquid phase at low temperature is treated. As the liquid 2, fine particles are formed by laser light irradiation. By making the temperature sufficiently low with such a solvent, micronization is performed in a state where the degree of freedom of movement of the organic compound molecules is lowered. Therefore, the relaxation due to the degree of freedom of molecular movement of the light crushing energy is suppressed, and it becomes possible to efficiently realize the formation of fine particles of the organic compound by irradiating the liquid 2 to be processed with the laser light from the laser light source 10. . Moreover, according to the fine particles produced by the production method described above, fine particles of an organic compound in a good state produced efficiently can be obtained.

  Further, by using a solvent that is in a liquid phase at a low temperature, such as liquid nitrogen 4, it is possible to easily collect organic compound fine particles by vaporizing liquid nitrogen 4 at room temperature after laser light irradiation. In particular, liquid nitrogen 4 is an inexpensive and low boiling point cooling medium, and its chemical reactivity is also low. Therefore, liquid nitrogen 4 is suitable as such a solvent. Alternatively, as a solvent that becomes a gas phase at normal temperature and a liquid phase at low temperature, liquid argon having a boiling point of -185.9 ° C. or liquid helium having a boiling point of −268.9 ° C. may be used.

  In the fine particle manufacturing method and apparatus described above, the fine particles are formed by laser beam irradiation while moving the irradiation position of the laser beam to the liquid 2 to be processed. For example, when laser light is continuously irradiated at an irradiation position fixed to the liquid 2 to be processed, scattering of the laser light due to bubbles in which the liquid nitrogen 4 is vaporized in the vicinity of the irradiation position may be a problem. On the other hand, by reducing the irradiation position of the laser light as described above, it is possible to prevent a reduction in the atomization efficiency. In addition, the efficiency of the micronization process in the entire liquid to be processed 2 is improved.

  Here, the wavelength of the laser light emitted from the laser light source 10 to the liquid to be treated 2 is preferably an infrared wavelength, and more preferably 900 nm or more. Thereby, the fine particle formation of the organic compound by laser light irradiation can be suitably realized. As the laser light source 10, a pulse laser light source is preferably used. In particular, in order to make fine particles with sufficient efficiency while suppressing the occurrence of excessive photochemical reaction and thermal decomposition in the liquid 2 to be treated, one pulse is used as long as the light intensity threshold value causing the light fragmentation phenomenon is exceeded. It is preferable to use a pulsed laser light source having a low irradiation energy and a high repetition frequency.

  Alternatively, the organic compound of the raw material particles 5 to be atomized by laser light irradiation may be a drug (pharmaceutical substance). In this case, the photochemical reaction with the drug due to the laser beam irradiation is sufficiently prevented by efficiently performing the fine particle formation. Therefore, the fine particles can be produced without losing the drug efficacy. In addition, for the photochemical reaction with the drug, the generation of the photochemical reaction is further suppressed by suitably selecting the wavelength of the laser beam irradiated to the liquid 2 (for example, selecting the wavelength of 900 nm or more as described above). Is possible.

  In detail, organic compounds used as drugs often contain relatively weak chemical bonds in the molecular structure, but when such organic compounds are irradiated with light such as ultraviolet light, fine particles are partially generated. At the same time, some of the photochemical reaction of the organic compound may occur through the electronically excited state to generate impurities. In particular, in the case of a drug (medicine) in which an organic compound is administered into the body, such an impurity causes a side effect and may adversely affect the living body. Therefore, such a situation should be avoided as much as possible. On the other hand, the production of impurities can be sufficiently suppressed by manufacturing fine particles of an organic compound by the above-described manufacturing method capable of suppressing the occurrence of a photochemical reaction. Moreover, in the manufacturing method described above, since the liquid 2 to be treated is at a low temperature, deterioration of organic compounds such as drugs due to thermal decomposition during laser light irradiation is also suppressed.

  In addition, as described above, by realizing the microparticulation of the drug while maintaining its medicinal properties without losing its medicinal effect, search for, and determination of candidate compounds such as physicochemical research and screening that could not be evaluated in the form before microparticulation. , ADME test, general toxicity in animal preclinical test, general pharmacology, pharmacology, biochemical research, clinical test, etc. In addition, since a drug that can be administered to an extremely wide variety of living bodies can be obtained by the above-described production method, the drug administration selectivity can be greatly expanded. Moreover, since the surface area of the drug is increased by making the drug fine particles and the absorbability to living tissue is improved, drug fine particles having immediate effect can be obtained. Such a micronization treatment is also effective for organic compounds other than drugs.

  Specific examples of organic compounds to be microparticulated include poorly soluble or insoluble drugs such as clobetasone butyrate and carbamazepine which are drugs. Further, the above-described method and apparatus for producing fine particles can be applied to drug candidate substances (natural products, compound libraries, etc.), quasi-drugs, cosmetics and the like in addition to the drug substances.

  In the fine particle manufacturing apparatus 1A shown in FIG. 1, regarding the stop of the laser light irradiation to the liquid 2 to be processed at the time of fine particle production, the intensity and time of the laser light necessary for the fine particle treatment are obtained in advance. In addition, it is possible to control the laser beam irradiation based on the processing time. Alternatively, monitoring means for monitoring the state of the raw material particles 5 in the liquid 2 to be processed may be installed, and laser light irradiation may be controlled according to the monitoring result.

  In addition, as the optical path changing device 11 for moving the irradiation position of the laser light to the liquid 2 to be processed, various devices can be used specifically as shown in FIGS.

  The optical path changing device 11 shown in FIG. 2 uses an acousto-optic element, and generates ultrasonic waves by the transducer 11b in an optical medium 11a such as tellurium dioxide and travels ultrasonic waves (broken arrows in FIG. 2). The laser beam from the laser light source 10 is diffracted by the wavefront to deflect the light. In such an optical path changing device 11, since there is no mechanical moving part, high-speed scanning of the laser beam can be realized.

  The optical path changing device 11 shown in FIG. 3 uses a reflection mirror. The one end of the reflection mirror 11c is fixed to the rotating shaft 11d, and the other end is mechanically moved in a circular arc so that the laser light from the laser light source 10 is reflected. The laser beam is scanned while changing the reflection direction. As a specific driving method of the reflecting mirror 11c in this case, for example, there is a configuration in which the reflecting mirror 11c is driven by bonding the surface of the speaker and the movable end of the reflecting mirror 11c and vibrating the speaker.

  The optical path changing device 11 shown in FIG. 4 uses a prism. One of the prisms 11e is fixed to the rotating shaft 11f, and the other is mechanically moved in a circular arc as in FIG. The laser beam is scanned while changing the transmission direction. Such a configuration can also be applied to optical components that can transmit laser light other than the prism.

  Next, the content of the present invention will be described more specifically by way of examples. However, the present invention is not limited to the following examples.

  In this example, as an organic compound of the raw material particles 5 to be microparticulated, clobetasone butyrate (Clobetasone Butyrate, an externally used synthetic corticosteroid), which is a poorly soluble drug, was tried. As the liquid 2 to be treated, a solution in which clobetasone butyrate powder as the raw material particles 5 was contained in liquid nitrogen 4 at a concentration of 0.5 mg / ml was used. Further, as the processing chamber 3, a square cell made of quartz of 10 mm × 10 mm × 40 mm was used, and polystyrene foam was used as the heat insulating layer 30.

In the processing chamber 3, while supplementing the liquid nitrogen 4 so that about 3 ml of the liquid nitrogen 4 can be retained, the laser light source 10 is applied to the liquid 2 to be processed while stirring the clobetasone butyrate at a concentration of 0.5 mg / ml. The laser beam from was irradiated. Further, after the light crushing treatment by laser light irradiation was completed, only liquid nitrogen 4 was vaporized at room temperature (room temperature) 25 ° C. Then, after the light crushing powder sample adhering to the inside of the processing chamber 3, 3 ml of water and a surfactant (polysorbate 80, 2.52 × 10 ⁻⁵ mol / l, 2.1 times the critical micelle concentration) and Then, the effect of the light crushing treatment was examined with a particle size distribution measuring device (Shimazu SALD7000).

FIG. 5 is a graph showing the particle size distribution of clobetasone butyrate. In this graph, the horizontal axis indicates the particle diameter (μm) of clobetasone butyrate, and the vertical axis indicates the relative particle amount. FIG. 6 is a graph showing the cumulative particle size distribution of clobetasone butyrate. In this graph, the horizontal axis represents the particle size (μm) of clobetasone butyrate, and the vertical axis represents the accumulated relative particle amount. Note that when a very wide range of particle sizes is measured with the above measuring apparatus, ghosts appear as in the distribution around the particle size of 0.1 μm in FIGS. Evaluation was performed. Here, the irradiation conditions of the laser light to the liquid to be treated are a wavelength of 1064 nm, a light intensity of 688 mJ / cm ² per pulse of the pulsed laser light, a laser beam spot diameter of 5 mm, a repetition frequency of 10 Hz, and an irradiation time of 10 minutes.

  In the graphs of FIGS. 5 and 6, graphs A1 and B1 show the particle size distribution of the clobetasone butyrate powder itself, which is the raw material particles. It can be seen from the graph A1 that most of the raw material particle samples have a diameter of 1 μm or more. From the graph B1, the volume ratio of fine particles having a diameter of 1 μm or less contained in the raw material sample is 1% or less. Graphs A2 and B2 show the particle size distribution when the raw material particles are only cooled with liquid nitrogen, but since the change in the distribution is small, only the raw material sample is cooled with liquid nitrogen. Then, it is thought that there is no effect | action of atomization.

Next, graphs A3 and B3 show particle size distributions when the raw material particles are put in water and light crushing is performed in water. Here, since the irradiation intensity of the laser beam is 688 mJ / cm ^2, which is smaller than the threshold value (about 1700 mJ / cm ² ) at which the photodisruption phenomenon occurs, there is no reduction in particle size due to the laser beam irradiation. Further, graphs A4 and B4 show the particle size distribution when the raw material particles are once cooled with liquid nitrogen and then returned to room temperature, and then light crushing is performed in water. Similarly, no decrease in particle diameter due to laser light irradiation is observed.

  On the other hand, graphs A5 and B5 show the particle size distributions when the raw particles are subjected to light crushing in liquid nitrogen using the production method and apparatus according to the present invention described above. From the graph A5, it can be seen that in this method, the ratio of large particles having a particle size of 10 μm or more is greatly reduced, and the micronization of clobetasone butyrate is progressing. From the graph B5, the ratio of fine particles of 1 μm or less is greatly improved to 10%. In addition, although it is 13% in FIG. 6, 3% for the above-mentioned ghost was subtracted to 10%. These data suggest that the threshold for light fragmentation is lower in liquid nitrogen than in water, and it is thought that the efficiency of micronization is finally improved by these effects. Further, the quality of the fine drug particles after the micronization treatment was investigated using high performance liquid chromatography (HPLC). However, since only the components derived from the raw material particles were detected, the quality degradation in the micronization treatment was not observed.

  FIG. 7 is a block diagram schematically showing another embodiment of the apparatus for producing fine particles according to the present invention. The fine particle manufacturing apparatus 1B includes a processing chamber 3 for containing a liquid 2 to be processed including liquid nitrogen 4 and raw material particles 5, a heat insulating layer 30 provided around the processing chamber 3, an opening 31, an air layer. 32, the light irradiation window 33, the dry gas spraying device 34, the light shielding layer 35, the laser light source 10 for irradiating the liquid 2 to be treated with a laser beam having a predetermined wavelength, and the control for controlling the operation of each part of the manufacturing apparatus 1B. Device 15.

  In the present embodiment, the processing chamber 3 is a flow path in which the liquid 2 to be processed flows downward from the upper part. Correspondingly, a processing liquid supply apparatus 20 that supplies the processing liquid 2 to a predetermined flow rate to the flow path in the processing chamber 3 is installed at the upper part of the processing chamber 3. Further, the lower part of the processing chamber 3 is supplied into the processing chamber 3 from the processing liquid supply apparatus 20 and reaches the lower part of the processing chamber 3 after the micronization process by laser light irradiation from the laser light source 10. It becomes the injection nozzle 25 which injects 2 to the exterior.

  In the liquid 2 to be treated which is sprayed downward from the spray nozzle 25, the liquid nitrogen 4 which is a solvent is vaporized when the temperature becomes normal. Further, a particulate collection chamber 50 is installed below the processing chamber 3 as shown in FIG. Thereby, the spray nozzle 25 and the chamber 50 constitute a particulate collection means, and the light-crushed particulate 6 is collected in the chamber 50 (particulate collection step). In this way, a solution in which the raw material particles 5 of the organic compound are included in the liquid nitrogen 4 that is in the gas phase at room temperature and in the liquid phase at low temperature is used as the liquid 2 to be processed, and the liquid 2 to be processed following the laser beam irradiation. By spraying to the outside of the processing chamber 3, it becomes possible to easily obtain a dry powder of the finely divided organic compound.

  In the present embodiment, the irradiation position of the laser light from the laser light source 10 on the processing liquid 2 is moved by causing the processing liquid 2 to flow in the processing chamber 3. As described above, various configurations other than the optical path changing device 11 shown in FIG. 1 can be used as the configuration for moving the irradiation position of the laser light on the liquid 2 to be processed.

  The fine particle production method, production apparatus, and fine particles according to the present invention are not limited to the above-described embodiments and examples, and various modifications are possible. For example, the material of the processing chamber 3 used in the manufacturing apparatus is not limited to quartz, and various materials may be used in consideration of laser light transmission characteristics and the like. Further, the heat insulating layer 30 provided around the processing chamber 3 may be made of a material other than the polystyrene foam. In addition to the heat-insulating layer 30, the liquid phase holding means for holding a solvent such as liquid nitrogen 4 in the liquid 2 to be processed uses various configurations such as installing the processing chamber 3 in a temperature-retaining room. Good.

  INDUSTRIAL APPLICABILITY The present invention can be used as a fine particle production method, a production apparatus, and fine particles capable of efficiently atomizing an organic compound.

It is a block diagram which shows roughly one Embodiment of the manufacturing apparatus of microparticles | fine-particles. It is a figure which shows the structural example of the optical path changing apparatus used for the manufacturing apparatus shown in FIG. It is a figure which shows the structural example of the optical path changing apparatus used for the manufacturing apparatus shown in FIG. It is a figure which shows the structural example of the optical path changing apparatus used for the manufacturing apparatus shown in FIG. It is a graph which shows the particle diameter distribution of clobetasone butyrate. 2 is a graph showing the cumulative particle size distribution of clobetasone butyrate. It is a block diagram which shows schematically other embodiment of the manufacturing apparatus of microparticles | fine-particles.

Explanation of symbols

  DESCRIPTION OF SYMBOLS 1A, 1B ... Fine particle manufacturing apparatus, 2 ... Liquid to be processed, 3 ... Processing chamber, 4 ... Liquid nitrogen (solvent), 5 ... Raw material particles (organic compound), 6 ... Fine particles, 10 ... Laser light source, 11 ... Optical path change 15 ... Control device, 20 ... Process liquid supply device, 25 ... Injection nozzle, 30 ... Heat insulation layer, 31 ... Opening, 32 ... Air layer for heat insulation, 33 ... Light irradiation window, 34 ... Dry gas spraying device, 35 ... light-shielding layer, 41 ... magnet stick, 42 ... magnet stirrer, 50 ... chamber for collecting fine particles.

Claims (17)

It is a production method for producing fine particles of an organic compound by photocrushing an organic compound in a solvent of a liquid to be treated,
As a solvent for the liquid to be treated, a solvent that is in a gas phase at room temperature and in a liquid phase at a predetermined temperature lower than room temperature is used, and laser light having a predetermined wavelength is applied to the liquid to be processed in which the solvent is held in the liquid phase. A method for producing fine particles, comprising: a fine particle forming step of forming the organic compound in the solvent into fine particles.   The manufacturing method according to claim 1, wherein the solvent is liquid nitrogen, liquid argon, or liquid helium.   The manufacturing method according to claim 1 or 2, wherein a wavelength of the laser beam used in the fine particle forming step is a wavelength of 900 nm or more.   The manufacturing method according to any one of claims 1 to 3, wherein, in the fine particle forming step, the laser light is irradiated while moving an irradiation position of the laser light on the liquid to be processed.   The manufacturing method according to claim 4, wherein in the fine particle forming step, the irradiation position is moved by changing an optical path of the laser beam.   The manufacturing method according to claim 4, wherein in the micronization step, the irradiation position is moved by flowing the liquid to be processed.   7. The method according to claim 1, further comprising a fine particle recovery step of recovering the fine particles of the organic compound by evaporating the solvent by spraying the liquid to be treated after the fine particle formation step. The manufacturing method of description.   The manufacturing method according to claim 1, wherein the organic compound is a drug. It is a production apparatus for producing a fine particle of an organic compound by photocrushing an organic compound in a solvent of a liquid to be treated,
A processing chamber containing the liquid to be processed using a solvent that is a gas phase at room temperature and a liquid phase at a predetermined temperature lower than room temperature;
Liquid phase holding means for holding the solvent of the liquid to be treated in a liquid phase;
A laser light source that irradiates a laser beam having a predetermined wavelength for atomizing the organic compound in the solvent with respect to the liquid to be processed that is contained in the processing chamber and in which the solvent is held in a liquid phase. An apparatus for producing fine particles, comprising:   The manufacturing apparatus according to claim 9, wherein the solvent is liquid nitrogen, liquid argon, or liquid helium.   The manufacturing apparatus according to claim 9 or 10, wherein the wavelength of the laser light emitted from the laser light source is 900 nm or more.   The manufacturing apparatus according to any one of claims 9 to 11, wherein the laser light is irradiated while moving an irradiation position of the laser light with respect to the liquid to be processed.   The manufacturing apparatus according to claim 12, further comprising an optical path changing unit that moves the irradiation position by changing an optical path of the laser light from the laser light source to the processing chamber.   The manufacturing apparatus according to claim 12, wherein the irradiation position is moved by flowing the liquid to be processed in the processing chamber.   It comprises a particulate collection means for vaporizing the solvent by ejecting the liquid to be treated, which has been irradiated with the laser light, from the processing chamber to collect the particulates of the organic compound. The manufacturing apparatus as described in any one of Claims 9-14.   The manufacturing apparatus according to claim 9, wherein the organic compound is a drug.   Fine particles produced by the method for producing fine particles according to claim 1.

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