JP2005125258A - Particulates, and method and apparatus of forming particulates - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method of forming particulates, which can atomize efficiently organic compounds by optical crushing, its producing apparatus, and particulates. <P>SOLUTION: The producing apparatus 1A comprises a treating chamber 3 containing a workpiece 2 of a particulate state (a solid state) consisting of a raw material particle 5 of the organic compound, a cooling medium 41 cooling the workpiece 2 to a predetermined temperature, a pressure device 42 pressurizing the inside of the treating chamber 3, a laser beam source 10 irradiating the workpiece 2 with a laser beam of a predetermined wavelength, and an optical path change apparatus 11 changing a beam-path of the laser beam. The workpiece 2 in a cooled state is irradiated with the laser beam, by which the raw material particle 5 is optically crushed to form the particulates 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.

  As such a fine particle forming method, there is a method disclosed in Patent Document 1 (Japanese Patent Laid-Open No. 2001-113159). Here, a method of generating fine particles of an organic compound by irradiating the organic compound in the solvent with laser light 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.

On the other hand, there is a method disclosed in Patent Document 2 (Japanese Patent Laid-Open No. 11-128730) as a method for forming inorganic fine particles. Here, ceramic fine particles are manufactured by irradiating an amorphous ceramic film deposited on a glass substrate with pulsed laser light having a wavelength of 248 nm.
JP 2001-113159 A JP-A-11-128730 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 technique is used, there is a possibility that a new raw material preparation 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. In addition, in the method described in Patent Document 2, since the object to be microparticulated is an inorganic substance and has high thermal stability, any countermeasures are taken against deterioration of the object due to heating or fusion of microparticles during laser light irradiation. Not.

  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 solve the above problems, the inventor of the present application has pursued a laser light irradiation method that enables efficient atomization of an organic compound. As a result, even when the object of atomization is an organic compound, the solid state Thus, the inventors have found that it is possible to make fine particles by laser light irradiation and that the solidification efficiency of the organic compound can be improved by cooling the solid of the organic compound, and the present invention has been completed.

  That is, the method for producing fine particles according to the present invention is a method for producing fine particles by photo-crushing an organic compound, and the object to be treated is kept at a predetermined temperature relative to a solid object to be treated comprising the organic compound. By irradiating a laser beam having a predetermined wavelength in a cooled state, the organic compound in the object to be processed is made fine particles.

  The fine particle production apparatus according to the present invention is a production apparatus for photodisrupting an organic compound to produce fine particles, a treatment chamber containing a solid treatment object made of an organic compound, and a treatment object. A cooling means for cooling to a predetermined temperature; and a laser light source for irradiating the cooled object to be processed with a laser beam having a predetermined wavelength for atomizing an organic compound in the object to be processed. Features.

  According to the fine particle manufacturing method and apparatus described above, it is possible to make fine particles using an object to be processed in which the organic compound to be atomized is in a solid state. In addition, fine particles are formed by laser beam irradiation while the object to be processed is cooled. Thus, by sufficiently cooling the object to be processed to a low temperature, the fine particles are formed 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. In addition, since the object is not a solution in which an organic compound is contained in a solvent but a solid object to be processed, steps such as removal of the solvent are not required when obtaining powdery fine particles.

  In the manufacturing method and apparatus described above, the wavelength of the laser light emitted from the laser light source 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 a manufacturing method irradiates a laser beam in the state which pressurized the inside of the process chamber in which a to-be-processed object is accommodated. Similarly, the manufacturing apparatus preferably includes a pressurizing unit that pressurizes the inside of the processing chamber in which the target object is accommodated. Thereby, the heat which arises in a to-be-processed object at the time of laser beam irradiation can be thermally radiated effectively.

  Furthermore, it is preferable that the manufacturing method and apparatus irradiate the laser beam in a state in which the inside of the processing chamber in which the target object is accommodated is filled with nitrogen gas or a rare gas. By using such a gas, generation of a photochemical reaction due to laser light irradiation can be prevented.

  Further, in the manufacturing method, a cooling unit may be disposed on the rear surface side of the processing chamber in which the object to be processed is accommodated when viewed from the laser light irradiation direction. Similarly, in the manufacturing apparatus, the cooling unit may include a cooling medium disposed on the rear surface side when viewed from the laser beam irradiation direction with respect to the processing chamber in which the target object is accommodated.

  Moreover, it is preferable that a manufacturing method and an apparatus perform laser beam irradiation, moving the irradiation position of the laser beam with respect to a to-be-processed object. Thereby, laser light can be irradiated to each position of the solid object to be processed, and the organic compound at each position in the object can be efficiently atomized by laser light irradiation.

  Moreover, the to-be-processed object which consists of an organic compound is good also as a surfactant being included.

  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, there is no interference such as light scattering due to agglomeration of the generated fine particles, compared to a wet system in which fine particles are formed in a liquid phase. For this reason, highly efficient fine particle formation is attained. In addition, by using a cooled solid made of an organic compound as an object to be processed and atomizing by laser light irradiation, it is possible to realize particle formation efficiently and with reduced thermal deterioration due to light irradiation of the organic compound. It becomes. Here, the micronization method described in Patent Document 1 and Non-Patent Documents 1 to 3 is a wet system performed in a liquid phase, and the dry system of the present invention in which micronization is performed in a powder state or the like. Is different. As an advantage of the dry system, there can be mentioned that fine particles having a wide use range can be obtained directly without aggregation of fine particles which are problematic in the wet process.

  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. FIG. 2 is a perspective view showing a processing chamber used in the manufacturing apparatus shown in FIG. This fine particle production apparatus 1A is an apparatus for producing fine particles by photo-crushing a solid organic compound. In the present embodiment, a powdery object 2 made of organic compound raw material particles 5 is used as a solid object to be finely divided.

  As shown in FIG. 1, the fine particle manufacturing apparatus 1 </ b> A includes a processing chamber 3 for accommodating an object 2 to be processed. The processing chamber 3 is made of, for example, quartz. Further, the space 30 in the processing chamber 3 is filled with a predetermined gas. About this gas, in order to prevent generation | occurrence | production of the photochemical reaction of the gas by the laser beam irradiation and the raw material particle 5, it is preferable to fill the space 30 with nitrogen gas or a noble gas (Helium, argon, xenon, krypton, etc.).

  A pressurizing device 42 is connected to the processing chamber 3. The gas in the space 30 in the processing chamber 3 is pressurized to a high pressure by the pressurizing device 42. Such pressurization to the processing chamber 3 is effective for effectively diffusing and dissipating heat generated in the object to be processed 2 when the laser beam is irradiated. A cooling medium 41 is installed on the rear side of the processing chamber 3. The cooling medium 41 is a cooling unit that cools the workpiece 2 to a predetermined temperature. In FIG. 2, the pressure device 42 and the like are not shown.

  The manufacturing apparatus 1 </ b> A also includes a high-power laser light source 10 that irradiates a target object 2 that is contained in the processing chamber 3 and is cooled by the cooling medium 41 with a laser beam having a predetermined wavelength. The laser light source 10 supplies laser light having a wavelength suitable for making the organic compound raw material particles 5 in the object to be processed 2 fine.

  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, a light irradiation window 31 is provided on the front surface side facing the laser light source 10 in the outer surface of the processing chamber 3. Behind the light irradiation window 31, there is an air layer 37 formed by a spacer 36 of a heat insulating material in order to improve heat insulation with the processing chamber 3. Further, in order to prevent the outer surface of the light irradiation window 31 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 31. A dry gas spraying device 34 for preventing condensation is installed.

  An optical path changing device 11 is installed between the laser light source 10 and the light irradiation window 31 located 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 target object 2 in the processing chamber 3 during laser light irradiation.

  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 spraying device 34 and the pressurizing device 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, a powdery (solid) object 2 made of organic compound raw material particles 5 is prepared. Subsequently, a part or the whole of the processing chamber 3 is filled with the target object 2, the target object 2 is cooled to a predetermined temperature by the cooling medium 41, and the pressure in the processing chamber 3 is increased by the pressurizing device 42. Pressurize. 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 target object 2. The

  The laser light supplied from the laser light source 10 is irradiated to the object 2 through the optical path changing device 11 and the light irradiation window 31. By this laser light irradiation, the powdery organic compound raw material particles 5 are atomized in the object 2 to be processed in the processing chamber 3 to produce organic compound particles.

  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 object 2 is moved within the required irradiation range for a short time, and the raw material particle 5 in the to-be-processed object 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 above-described method and apparatus for producing fine particles, it is possible to make fine particles using the target object 2 in which the organic compound to be atomized is in a solid state. In addition, the object to be processed 2 is cooled by the cooling medium 41 and is atomized by laser light irradiation. In this way, by sufficiently cooling the object to be processed 2 to a low temperature, the fine particles are formed in a state where the degree of freedom of movement of the organic compound molecules is lowered. Therefore, the light crushing energy is less likely to dissipate energy due to molecular motion, so that it is possible to efficiently realize fine particles of the organic compound by irradiating the object 2 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, in the manufacturing apparatus 1A described above, the microparticulation is directly performed on the solid object 2 instead of the solution in which the organic compound is contained in the liquid solvent. For this reason, after the laser light irradiation, a process such as removal of a solvent is not required when obtaining powdery fine particles. Thus, even when the object of atomization is an organic compound, it has been found for the first time by the present inventor that atomization by laser light irradiation in a solid state is possible. In addition, about the solid to-be-processed object of the organic compound, although it was set as the powder-like to-be-processed object in the said embodiment, you may use the to-be-processed object of a film | membrane form or a bulk solid.

  Alternatively, the object to be processed made of an organic compound may contain a surfactant. For example, when a powdery organic compound is used, a powdery surfactant is preferably included in the object to be treated. This is effective when, for example, organic compound fine particles obtained by laser light irradiation are dissolved in a solvent such as water.

  Moreover, in the said embodiment, the heat which generate | occur | produces in the to-be-processed object 2 is effectively performed by irradiating a laser beam in the state which pressurized the inside of the process chamber 3 in which the to-be-processed object 2 is accommodated with the pressurization apparatus 42. Dissipates heat. This is effective for holding the object to be processed 2 in a sufficiently cooled state and efficiently and stably performing the above-described micronization process.

  Thus, when using the solid to-be-processed object 2, about the to-be-processed object 2, cooling with the cooling medium 41 is performed efficiently, and fine formation of the organic compound by laser beam irradiation is sufficient with respect to the depth direction. In order to carry out to the depth, it is preferable to arrange the object to be processed 2 sufficiently thin when viewed from the laser light irradiation direction in consideration of a decrease in intensity due to scattering of the laser light. Further, in order to arrange the object to be processed 2 in this way, it is preferable that the processing chamber 3 for accommodating the object to be processed 2 is formed sufficiently thin.

  In the fine particle manufacturing method and apparatus described above, fine particles are formed by laser light irradiation while moving the irradiation position of the laser light on the object 2 to be processed. Thereby, each position of the solid object 2 is sequentially irradiated with laser light, and the organic compound at each position in the object 2 is uniformly and efficiently atomized by laser light irradiation. can do. Further, when laser beam irradiation is continuously performed on the same raw material particles 5 in the object 2 to be processed, the heat deterioration of the raw material particles 5 or the fusion of fine particles may occur due to heating. On the other hand, by scanning the laser beam, alteration of the raw material particles 5 due to heating is suppressed.

  Further, a cooling medium 41 for the object to be processed 2 accommodated in the processing chamber 3 is arranged on the rear surface side when viewed from the irradiation direction of the laser beam with respect to the processing chamber 3. Thereby, cooling of the to-be-processed object 2 by the cooling medium 41 and laser beam irradiation from the laser light source 10 with respect to the to-be-processed object 2 are suitably realizable. As the cooling medium 41, specifically, a Peltier element, dry ice, liquid nitrogen, liquid argon, liquid helium, or the like is preferably used. As a specific configuration of the cooling medium 41, a configuration in which the cooling medium is installed as a cooling source or the cooling medium is circulated can be used.

  Here, the wavelength of the laser light emitted from the laser light source 10 to the workpiece 2 is preferably an infrared wavelength, and more preferably 900 nm or more. Thereby, it is possible to suitably realize the formation of fine particles of the organic compound by laser light irradiation while preventing the deterioration of the organic compound due to the photochemical reaction. As the laser light source 10, a pulse laser light source is preferably used. In particular, it suppresses the occurrence of excessive photochemical reaction and thermal decomposition in the object 2 to be processed, and the fusion of fine particles due to melting, etc., and the fine particles are formed with sufficient efficiency. If it is, it is preferable to use a pulse laser light source having a low irradiation energy per pulse and a high repetition frequency.

  That is, when the irradiation energy per pulse in the laser light irradiated to the object to be processed 2 increases, the cooling ability of the object to be processed 2 by the cooling medium 41 must be increased accordingly. Therefore, the laser light used for light fragmentation has a high frequency within a range where a light intensity exceeding the threshold for light fragmentation can be obtained, and as described above, the pulse laser light with low repetition energy and high repetition frequency. It is preferable that Specifically, there is a configuration in which the capacity of a discharge capacitor for oscillating the laser light source 10 is reduced, and the frequency is increased by charging in a short time and then quickly discharging.

  In recent years, in the medical field, attempts have been made to make pharmaceutical powder fine particles with the aim of increasing drug efficacy and reducing side effects caused by the administered drug. As a mechanical particle crushing method, a jet mill method by collision of particles is promising, but it is difficult to produce fine particles having a particle diameter of less than 1 μm by this method.

  On the other hand, by applying the manufacturing method and apparatus described above using the organic compound of the raw material particles 5 to be microparticulated by laser light irradiation as a drug (pharmaceutical-related substance), it is possible to realize the micronization of pharmaceutical powder. is there. 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 object 2 (for example, selecting the wavelength of 900 nm or more as described above). Is possible.

  Specifically, an organic compound used as a drug often contains a relatively weak chemical bond in the molecular structure. However, when such an organic compound is irradiated with light such as ultraviolet light (see Patent Document 2 regarding inorganic substances). ), Although fine particles can be partially produced, at the same time, a photochemical reaction of an organic compound may occur through an electronically excited state, and impurities may be produced. 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 object to be processed 2 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 irradiation of the laser beam to the workpiece 2 during the production of the fine particles, 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 atomization of the raw material particles 5 in the object to be processed 2 may be installed, and laser light irradiation may be controlled according to the monitoring result.

  As the optical path changing device 11 for moving the irradiation position of the laser beam on the object 2 to be processed, various devices can be used specifically, as shown in the examples in FIGS.

  The optical path changing device 11 shown in FIG. 3 uses an acousto-optic element, and generates ultrasonic waves by a transducer 11b in an optical medium 11a such as tellurium dioxide and travels ultrasonic waves (broken arrows in FIG. 3). 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. 4 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. 5 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.

  First, the change in the particle size of the organic compound due to the fine particle treatment will be described. 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 processing chamber 3, a slide glass cell having a thickness of 200 μm in which a spacer is sandwiched between two slide glasses was used.

In a slide glass cell, 2 mg of clobetasone butyrate powder as raw material particles 5 is arranged in a circle having a diameter of φ5 mm to form a powdery (solid) object 2, and a laser light source 10 is applied to this object 2. The laser beam from was irradiated. The irradiation condition of the laser beam on the workpiece 2 is as follows: wavelength 1064 nm, light intensity 1732 mJ / cm ² per pulse of the pulsed laser beam, laser beam spot diameter φ5 mm, repetition frequency 10 Hz, pulse time width FWHM 5 ns, irradiation time 1 Minutes. Then, after finishing the photocrushing treatment by laser light irradiation, a surfactant (polysorbate 80, 2.52 × 10 ⁻⁵ mol / l, 2.1 times the critical micelle concentration) for preventing aggregation is added. The sample after light crushing was dispersed in water, and the effect of the light crushing treatment was examined by a particle size distribution measuring device (Shimadzu Corporation SALD7000). In addition, the surfactant similar to the above was also added to other samples used for comparison, and the particle size distribution was measured.

  FIG. 6 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. Note that when a very wide range of particle sizes is measured with the above measuring apparatus, a ghost appears like the distribution in the vicinity of the particle size of 0.1 μm in FIG. went.

  In the graph of FIG. 6, the graph A1 is the particle size distribution of the raw material clobetasone butyrate powder itself, the graph A2 is the particle size distribution when only low temperature treatment is performed with liquid nitrogen, and the graph A3 is the crobetazone butyrate powder. The particle size distribution when the light crushing treatment is performed at room temperature, graph A4 is the case where the light crushing treatment is performed on the powder of clobetasone butyrate while cooling with liquid nitrogen as a cooling medium (-195.8 ° C.). The particle size distribution of each is shown.

  Comparing graphs A1 and A2 among these graphs A1 to A4, it can be seen that the particle diameter of clobetasone butyrate hardly changes only by cooling the sample to the liquid nitrogen temperature. Further, comparing the graphs A1 and A3, the fine particles can be formed by irradiating the organic compound in a powder (solid) state with laser light even at room temperature. Further, comparing graphs A3 and A4, the efficiency of atomization is improved by performing laser light irradiation while cooling the powder as compared with the case of normal temperature.

  Next, changes in the purity of the organic compound due to the fine particle treatment will be described. In this example, as described above, an attempt was made to micronize clobetasone butyrate, which is a poorly soluble drug, as the organic compound of the raw material particles 5 to be micronized. The processing chamber 3 was a slide glass cell in which a spacer having a thickness of 200 μm was sandwiched between two slide glasses.

In a slide glass cell, 2 mg of clobetasone butyrate powder as raw material particles 5 is arranged in a circle having a diameter of φ5 mm to form a powdery (solid) object 2, and a laser light source 10 is applied to this object 2. The laser beam from was irradiated. The laser beam irradiation conditions for the object 2 were a wavelength of 1064 nm, a light intensity of 1732 mJ / cm ² per pulse of the pulse laser beam, a laser beam spot diameter of 5 mm, a repetition frequency of 10 Hz, and an irradiation time of 10 minutes. In the experiment of FIG. 6, the irradiation time was 1 minute. However, in this experiment, the irradiation time was 10 minutes in order to evaluate the deterioration caused by excessive irradiation. And after finishing the photocrushing process by laser beam irradiation, the to-be-processed object 2 was melt | dissolved with acetonitrile, and the purity of the clobetasone butyrate was quantified by the high performance liquid chromatography (HLPC).

  In this quantitative result, when the light crushing process was performed at room temperature without cooling the object to be processed with the cooling medium, 0.6% impurities were generated in clobetasone butyrate in the object to be processed. This is a decrease in purity due to thermal decomposition accompanying laser beam irradiation. On the other hand, when light crushing treatment was performed under cooling conditions (-195.8 ° C.) using liquid nitrogen as a cooling medium, clobetasone butyrate in the object to be treated did not contain any detectable level of impurities. . This confirms that the degradation of the object to be processed due to heating, which has been a problem when performing the light crushing process in a solid state, is suppressed by performing the light crushing process while cooling the object to be processed. It was.

  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 processing chamber 3 used in the manufacturing apparatus is not limited to the above-described slide glass cell, and various types of processing chambers 3 may be used depending on the state and quantity of the object to be processed such as powder, film, and bulk solid. May be used. As for pressurization in the processing chamber 3 by the pressurizing device 42, laser light irradiation may be performed at normal pressure without pressurization.

  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 perspective view which shows the processing chamber 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 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.

Explanation of symbols

  DESCRIPTION OF SYMBOLS 1A ... Fine particle manufacturing apparatus, 2 ... To-be-processed object, 3 ... Processing chamber, 5 ... Raw material particle (organic compound), 10 ... Laser light source, 11 ... Optical path changing apparatus, 15 ... Control apparatus, 30 ... Space in chamber, DESCRIPTION OF SYMBOLS 31 ... Light irradiation window, 34 ... Dry gas spraying apparatus, 36 ... Spacer, 37 ... Air layer, 41 ... Cooling medium, 42 ... Pressurization apparatus.

Claims (17)

A method for producing fine particles of an organic compound by photocrushing,
By irradiating a laser beam having a predetermined wavelength with the object to be processed cooled to a predetermined temperature on a solid object to be processed made of the organic compound, the organic compound on the object to be processed is finely divided. A method for producing fine particles, characterized in that   The manufacturing method according to claim 1, wherein the laser beam has a wavelength of 900 nm or more.   The manufacturing method according to claim 1, wherein the laser beam is irradiated in a state where a processing chamber in which the object to be processed is accommodated is pressurized.   The manufacturing method according to claim 1, wherein the laser beam is irradiated in a state where a processing chamber in which the object to be processed is accommodated is filled with nitrogen gas or a rare gas.   The manufacturing method according to any one of claims 1 to 4, wherein a cooling unit is disposed on a rear surface side of the processing chamber in which the object to be processed is accommodated when viewed from the irradiation direction of the laser beam.   The manufacturing method according to claim 1, wherein the laser light irradiation is performed while moving an irradiation position of the laser light on the object to be processed.   The manufacturing method according to claim 1, wherein the object to be processed includes a surfactant.   The manufacturing method according to claim 1, wherein the organic compound is a drug. A manufacturing apparatus for producing fine particles by photocrushing an organic compound,
A processing chamber containing a solid object to be processed made of the organic compound;
Cooling means for cooling the object to be processed to a predetermined temperature;
An apparatus for producing fine particles, comprising: a laser light source for irradiating a laser beam having a predetermined wavelength for making the organic compound on the object to be finely divided into the object to be treated in a cooled state. .   The manufacturing apparatus according to claim 9, wherein a wavelength of the laser light emitted from the laser light source is 900 nm or more.   The manufacturing apparatus according to claim 9, further comprising a pressurizing unit that pressurizes the inside of the processing chamber.   The manufacturing apparatus according to any one of claims 9 to 11, wherein the laser light is irradiated in a state where the processing chamber is filled with nitrogen gas or a rare gas.   The manufacturing apparatus according to claim 9, wherein the cooling unit includes a cooling medium disposed on a rear surface side when viewed from the irradiation direction of the laser beam with respect to the processing chamber.   The manufacturing apparatus according to claim 9, wherein the laser light is irradiated while moving an irradiation position of the laser light on the object to be processed.   The manufacturing apparatus according to claim 9, wherein the object to be processed includes a surfactant.   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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