JP2009082855A - Method and apparatus for producing fine particle dispersion liquid - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method and apparatus for efficiently producing a fine particle dispersion liquid in a short period of time. <P>SOLUTION: The method for producing the fine particle dispersion liquid includes: a dissolution step for dissolving a hardly soluble medicine and dispersion stabilizer into a volatile organic solvent in a container 30; a stabilization step for evaporating and removing the organic solvent contained in a dissolution liquid obtained in the dissolution step, and yielding a pellet residue 1 by the removal of organic solvent so that the residue 1 is stabilized on the inner wall of the container 30; an irradiation step for pouring water 2 in the container 30 to immerse the residue 1 in the water 2, starring the water 2 by the rotation of a magnetic stirrer 51 to irradiate the residue 1 with a laser beam L output from a light irradiation part 20 in a state that the water 2 flows in the vicinity of the interface between the residue 1 and the water 2. With the steps, the residue 1 is crushed into fine particles, and the fine particles are dispersed in the water 2, so that the fine particle dispersion liquid is produced. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a method and an apparatus for producing a fine particle dispersion.

  In the development of new pharmaceuticals in recent years, combinatorial chemistry techniques have been adopted when synthesizing candidate compounds. This combinatorial chemistry is a technique for synthesizing various compounds at once in a short period of time using a combination. The compounds obtained by this method often have solubility problems. That is, even if an excellent physiological activity can be found in the compound itself, there are many examples where the development of the compound is abandoned when the compound has a property that it is difficult to dissolve in water. In addition, compounds obtained by extraction from natural products are also subjected to various organic synthesis and structural optimization to improve solubility. Some drugs already on the market have low solubility. These vary in the amount of drug absorption within and between individual patients, and are burdensome for both the using doctor and the using patient, such as blood concentration management.

  Fine particle preparations are attracting attention as a solution that can solve these problems. The fine particle formulation is obtained by stably dispersing insoluble water particles having poorly soluble drug particles having a size of micrometer or less. By using the fine particle preparation, it is possible to increase the absorption rate and amount of the drug in vivo. In addition, it is possible to expect a reduction in the amount of absorption within and between patients and an increase in the effective utilization rate with respect to the dose. Patent Documents 1 and 2 disclose the invention of a method for producing such a fine particle preparation.

The invention disclosed in Patent Document 1 obtains ultrafine particles of an organic compound by irradiating an organic compound dispersed in a solvent with laser light. The invention disclosed in Patent Document 2 irradiates an organic bulk crystal dispersed in a solvent with an ultrashort pulse laser beam, thereby inducing ablation due to nonlinear absorption and pulverizing the organic bulk crystal to produce a highly dispersible scattered matter. The ultra-fine particles of the organic compound are obtained by collecting the highly dispersible scattered matter with a solvent.
JP 2001-113159 A JP 2005-238342 A

  However, in the inventions disclosed in Patent Documents 1 and 2, since the organic compound or organic bulk crystal to be crushed is in a state dispersed in a solvent, laser light irradiation to the organic compound or organic bulk crystal is accidental. There is a problem that the processing efficiency is low.

  The present invention has been made to solve the above-described problems, and an object of the present invention is to provide a method and an apparatus capable of producing a fine particle dispersion in a high efficiency and in a short time.

  The method for producing a fine particle dispersion according to the present invention includes (1) a dissolution step of dissolving a poorly soluble drug and a dispersion stabilizer in a volatile organic solvent, and (2) a solution obtained in this dissolution step. A fixing step of evaporating and removing the organic solvent and fixing the residue obtained by removing the organic solvent to the inner wall of the container; and (3) after this fixing step, water is injected into the container to leave the residual in the container. A fine particle in which fine particles containing a poorly soluble drug and a dispersion stabilizer are dispersed in water by irradiating light on the residue fixed on the inner wall of the container while flowing water near the interface between the product and water. And an irradiation step for producing a dispersion.

  One container may be used throughout the dissolution process, the fixing process, and the irradiation process. Further, the container used in the steps until obtaining the residue and the container used in the steps after fixing the residue may be different from each other.

  According to this fine particle dispersion manufacturing method, the poorly soluble drug and the dispersion stabilizer are dissolved in the volatile organic solvent in the dissolving step. In the subsequent fixing step, the organic solvent contained in the solution obtained in the dissolving step is removed by evaporation, and the residue obtained by removing the organic solvent is fixed to the inner wall of the container. In the subsequent irradiation step, water is injected into the container, and light is applied to the residue fixed on the inner wall of the container while water is flowing near the interface between the residue and water inside the container. Is irradiated to produce a liquid in which fine particles containing a poorly soluble drug and a dispersion stabilizer are dispersed in water.

  In the method for producing a fine particle dispersion according to the present invention, in the irradiation step, the water injected into the container may be stirred, or the water injected into the container is vibrated (preferably ultrasonic vibration). Alternatively, water may be supplied to the inside of the container, and in any case, the water can flow near the interface between the residue inside the container and the water.

  In the method for producing a fine particle dispersion according to the present invention, in the irradiation step, when water is supplied to the inside of the container, it is preferable to keep the temperature of the water supplied to the inside of the container constant. It is also preferable to collect the produced fine particle dispersion in a collection container different from the container, or alternatively, water supply and gas supply are alternately performed inside the container, and the fine particles are supplied during the gas supply. It is also suitable to collect the dispersion in a collection container.

  The fine particle dispersion manufacturing apparatus according to the present invention is (1) a residue obtained by dissolving a poorly soluble drug and a dispersion stabilizer in a volatile organic solvent, and evaporating and removing the organic solvent contained in the solution. A container in which an object is fixed to the inner wall and water is injected therein; (2) a light irradiator for irradiating light on the residue fixed on the inner wall of the container; and (3) a residue in the container. And a flow means for flowing water in the vicinity of the interface between water and water. Furthermore, the fine particle dispersion manufacturing apparatus according to the present invention causes water to flow in the vicinity of the interface between the residue and water inside the container by the flow means, and irradiates the residue with light by the light irradiation unit. It is characterized by producing a fine particle dispersion in which fine particles containing a poorly soluble drug and a dispersion stabilizer are dispersed in water.

  In this fine particle dispersion manufacturing apparatus, a hardly soluble drug and a dispersion stabilizer are dissolved in a volatile organic solvent, and a residue obtained by evaporating and removing the organic solvent contained in the dissolved solution is deposited on the inner wall of the container. Fixed. Then, water is injected into the inside of the container, and light is applied to the residue fixed on the inner wall of the container in a state where the water is flowing near the interface between the residue inside the container and the water by the flow means. Light is irradiated from the part to produce a liquid in which fine particles containing a poorly soluble drug and a dispersion stabilizer are dispersed in water.

  In the fine particle dispersion producing apparatus according to the present invention, the flow means may include a stirring means for stirring the water injected into the container, and the water injected into the container is vibrated (preferably (Vibration means for ultrasonic vibration) may be included, or water supply means for supplying water to the inside of the container may be included, and in any case, the vicinity of the interface between the residue inside the container and water The water can be made to flow.

  In the fine particle dispersion producing apparatus according to the present invention, when the flow means includes the water supply means, it is preferable that the water supply means keeps the temperature of the water supplied into the container constant. Alternatively, it is also preferable to further include a collecting means for collecting the fine particle dispersion produced inside the container. Alternatively, an air supply means for supplying gas to the inside of the container is further provided, and the supply of water by the water supply means and the supply of gas by the air supply means are alternately performed and recovered when the gas is supplied by the air supply means. It is also preferable to collect the fine particle dispersion by means.

  According to the present invention, a fine particle dispersion can be produced with high efficiency and in a short time. In addition, according to the present invention, since a high-concentration fine particle dispersion can be produced, an injectable preparation that can administer a necessary amount of an active ingredient in a short time to a poorly water-soluble drug that has been used as an infusion preparation so far It can be.

  The best mode for carrying out the present invention will be described below in detail with reference to the accompanying drawings. In the description of the drawings, the same elements are denoted by the same reference numerals, and redundant description is omitted.

  (First embodiment)

  First, a first embodiment of a fine particle dispersion manufacturing method and a fine particle dispersion manufacturing apparatus according to the present invention will be described. FIG. 1 is a configuration diagram of a fine particle dispersion producing apparatus 11 according to the first embodiment. As shown in this figure, the fine particle dispersion production apparatus 11 includes a light irradiation unit 20, a container 30, a temperature control unit 40, a magnetic stirrer 51, and a stirrer base 52, and includes fine particles containing a poorly soluble drug and a dispersion stabilizer. Is a fine particle dispersion in which is dispersed in water.

  The container 30 contains a liquid to be processed, and is made of a material that can transmit the laser light L output from the light irradiation unit 20, and is preferably made of quartz glass. In this figure, a residue 1 described later is fixed to the inner wall of the container 30 and water 2 is injected into the container 30.

  The temperature control unit 40 includes a thermostatic bath, a thermometer, and temperature control means. By the feedback control by the thermometer and the temperature control means, the container 30 accommodated in the thermostatic bath and the liquid to be processed contained in the container 30 are stored. Keep the temperature constant. In the thermostatic chamber, a portion through which the laser beam L output from the light irradiation unit 20 passes is a transparent window.

  The light irradiation unit 20 emits the laser light L toward the container 30 and includes a laser light source 21 and an irradiation light control unit 22. The laser light source 21 preferably emits infrared laser light L having a wavelength of 900 nm or more. The irradiation light control unit 22 adjusts both and / or one of the intensity and the irradiation time of the laser light L emitted from the laser light source 21 and irradiated onto the container 30.

  The magnetic stirrer 51 is placed inside the container 30 during the irradiation step S3 described later, driven by the stirrer base 52, and rotated on the bottom surface of the container 30, thereby being injected into the container 30. By stirring the water 2, the water 2 flows in the vicinity of the interface between the residue 1 inside the container 30 and the water 2. That is, the magnetic stirrer 51 and the stirrer base 52 act as an agitation means for agitating the water 2 injected into the container 30 and also remove the water 2 in the vicinity of the interface between the residue 1 and the water 2 inside the container 30. Acts as a fluid means for fluidization.

  Next, the operation of the fine particle dispersion manufacturing apparatus 11 according to the first embodiment will be described, and the fine particle dispersion manufacturing method according to the first embodiment will be described. FIG. 2 is a flowchart for explaining the fine particle dispersion manufacturing method according to the first embodiment. In the method for producing a fine particle dispersion according to the present embodiment, a fine particle dispersion in which fine particles containing a hardly soluble drug and a dispersion stabilizer are dispersed in water by sequentially performing the dissolution step S1, the fixing step S2, and the irradiation step S3. To manufacture.

  In the dissolution step S1, the poorly soluble drug and the dispersion stabilizer are dissolved in the volatile organic solvent in the container 30. Here, the poorly soluble drug is a drug that hardly dissolves in water, and the solubility is not particularly limited, but it is desirable that the solubility at a temperature of 25 ° C. is 50 μg / mL or less. Examples of poorly soluble drugs include cyclosporine, tacrolimus, nifedipine, nicardipine hydrochloride, phenytoin, digitoxin, diazepam, nitrofurantoin, benoxaprofen, griseofulvin, sulfathiazole, piroxicam, carbamazepine, phenacetin, tolbutamide, theophylline, griseofulvin, There are over-the-counter drugs such as lambfenicol, paclitaxel, camptothecin, cisplatin, daunorubicin, methotrexate, mitomycin C, docetaxel, vincristine, amphotericin B, nystatin, clostatazone butyrate and other new drug candidates under development Can be mentioned.

  The dispersion stabilizer is preferably a polymer or a surfactant. The high molecular weight polymer is desirably a substance that has high water solubility and is easily soluble in various organic solvents. High molecular polymers include, for example, cellulose derivatives such as hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, sodium carboxymethylcellulose, cellulose acetate phthalate, agar, gelatin, sodium alginate, polyvinyl Examples include pyrrolidone, aminoalkyl methacrylate copolymer, methacrylic acid copolymer, carboxyvinyl polymer, polyvinyl alcohol, and polyethylene glycol. The surfactant is desirably low-toxic, and examples thereof include sodium lauryl sulfate, cholic acid, deoxycholic acid, and polyoxyethylene sorbitan fatty acid ester.

  Examples of the organic solvent include alcohols such as methanol, ethanol and propanol, acetone, acetonitrile, methyl acetate, ethyl acetate, diethyl ether and the like, and alcohols such as methanol, ethanol and propanol are more preferable.

  In the fixing step S2 following the dissolving step S1, the organic solvent contained in the dissolving liquid obtained in the dissolving step S1 is removed by evaporation, and the residue 1 in the form of pellets is obtained by removing the organic solvent. Fixed to 30 inner walls.

  In the irradiation step S3 subsequent to the fixing step S2, water 2 is injected into the container 30 and the residue 1 fixed to the inner wall of the container 30 is immersed in the water 2 (see FIG. 1). Further, in the irradiation step S3, the magnetic stirrer 51 placed in the container 30 is driven by the stirrer base 52 and rotated on the bottom surface of the container 30, and the water 2 injected into the container 30 is stirred. The water 2 flows near the interface between the residue 1 and the water 2 inside the container 30.

  In the irradiation step S <b> 3, the laser light L output from the laser light source 21 in this stirring state is adjusted on the inner wall of the container 30 by adjusting the intensity and / or irradiation time by the irradiation light control unit 22. The fixed residue 1 is irradiated. Note that the stirring by the stirring means may be performed continuously or intermittently. Thereby, the residue 1 is pulverized into fine particles, and a fine particle dispersion in which the fine particles are dispersed in the water 2 is manufactured. The fine particles contain a poorly soluble drug and a dispersion stabilizer.

  According to the fine particle dispersion manufacturing apparatus 11 according to the first embodiment or the fine particle dispersion manufacturing method according to the first embodiment, the laser light L is efficiently applied to the pellet-like residue 1 fixed to the inner wall of the container 30. Since the irradiation is performed, the fine particle dispersion can be produced with high efficiency and in a short time. In addition, since infrared pulse laser light having a wavelength of 900 nm or more is preferably emitted and fine particles are generated even by relatively weak light irradiation that does not cause a multiphoton process, problems such as drug decomposition can be suppressed.

  In the present embodiment, in the irradiation step S3, the water 2 injected into the container 30 is agitated by the rotation of the magnetic stirrer 51, and the water near the interface between the residue 1 and the water 2 inside the container 30 is agitated. 2 flows. As a result, in the vicinity of the interface between the residue 1 and the water 2, the fine particles generated by the irradiation with the laser light L are suppressed from staying or depositing. If stirring is not performed, fine particles stay or deposit near the interface between the residue 1 and the water 2, and the laser light L is scattered by the fine particles, and new fine particles generated by irradiation with the laser light L are scattered. Generation is hindered. However, in this embodiment, since the fine particles generated by the irradiation with the laser beam L are suppressed or accumulated near the interface between the residue 1 and the water 2, new fine particles by the irradiation with the laser beam L are suppressed. Generation is not hindered. Therefore, also in this respect, the fine particle dispersion can be produced with high efficiency and in a short time.

  From the fine particle dispersion thus produced, fine particles containing a poorly soluble drug and a dispersion stabilizer are produced. Further, the fine particle dispersion is freeze-dried to produce freeze-dried fine particles. Furthermore, a preparation for oral administration containing a fine particle dispersion, fine particles or freeze-dried fine particles is produced, and for injection administration containing a dispersion obtained by resuspending the fine particle dispersion, fine particles or freeze-dried fine particles in water A formulation is manufactured.

  In the irradiation step S3, as shown in FIG. 1, the laser beam L is irradiated from the outside of the region where the residue 1 is fixed on the inner wall of the container 30, and the irradiated laser beam L is left in the container 30. It is preferable to proceed in the order of product 1 and water 2. By doing so, fine particles are generated in the vicinity of the interface between the residue 1 and the water 2, and the fine particles are immediately dispersed in the water 2.

  In the irradiation step S3, it is preferable that the laser beam L having a wavelength of 900 nm or more is irradiated from the light irradiation unit 20 to the residue 1. By irradiating the residue 1 with the laser beam L having such a wavelength, the photodegradation of the drug contained in the residue 1 can be further suppressed. In addition, since the laser beam L reaches the interface through the residue 1 and fine particles are generated at the interface, the laser beam L having a wavelength smaller in absorbance than the residue 1 is irradiated to the residue 1. Is preferred. Specifically, it is preferable to irradiate the residue 1 with a laser beam L having a wavelength of about 0.01 or less with respect to the residue 1.

  In the irradiation step S3, it is preferable to adjust the intensity and / or time of the light irradiation to the residue 1 by the irradiation light control unit 21, and in this way, the fine particles generated by the light irradiation The particle size of can be controlled. Moreover, it is preferable that the irradiation region or the inside of the container is maintained at a constant temperature by the temperature control unit 40 when the residue 1 is irradiated with light, and in this way, particles of fine particles generated by light irradiation are stored. The diameter is stabilized.

  It is preferable that an airtight container is used as the container 30, and the dissolution step S1, the fixing step S2, and the irradiation step S3 are performed under sterilization. That is, in this embodiment, since it is a simple method of only irradiating light from the outside of the container 30, it can also be implemented in a sealed container, and the injection preparation under sterilization is easy.

  Next, a modified example of the container 30 used in the fine particle dispersion manufacturing apparatus 11 according to the first embodiment or the fine particle dispersion manufacturing method according to the first embodiment will be described.

  FIG. 3 is a configuration diagram of a first modification of the container 30 used in the first embodiment. In contrast to the container 30 shown in FIG. 1, the container 30A of the first modification shown in FIG. 3 is different in that a mesh plate 31 for dividing the interior into upper and lower parts is provided. When such a container 30A is used, in the fixing step S2, the pellet-like residue 1 obtained by removing the organic solvent is fixed to the inner wall below the mesh plate 31 in the container 30A. Further, in the irradiation step S <b> 3, the water 2 is injected from the container 30 </ b> A to above the mesh plate 31, and the magnetic stirrer 51 is disposed on the mesh plate 31. Then, due to the rotation of the magnetic stirrer 51 on the mesh plate 31, the water 2 under the mesh plate 31 is also stirred, and the water 2 flows in the vicinity of the interface between the residue 1 and the water 2. In this stirring state, the laser beam L output from the light irradiation unit 20 is irradiated to the residue 1 fixed to the inner wall of the container 30A.

  FIG. 4 is a configuration diagram of a second modification of the container 30 used in the first embodiment. Compared with the container 30 shown in FIG. 1, the container 30B of the second modified example shown in FIG. 4 is different in that a recess 32 is provided in the annular region of the peripheral portion of the bottom surface. When such a container 30B is used, in the fixing step S2, the pellet-like residue 1 obtained by removing the organic solvent is fixed to the concave portion 32 at the peripheral edge portion of the bottom surface of the container 30B. In the irradiation step S <b> 3, the water 2 is injected into the container 30, the water 2 is stirred by the rotation of the magnetic stirrer 51, and the water 2 flows near the interface between the residue 1 and the water 2. At this time, the magnetic stirrer 51 does not contact the residue 1. In this stirring state, the laser beam L output from the light irradiation unit 20 is irradiated to the residue 1 fixed to the inner wall of the container 30B.

  Even when these modified containers 30A and 30B are used, the pellet-like residue 1 fixed to the inner wall is irradiated with the laser light L with high efficiency, so that a fine particle dispersion can be produced with high efficiency and in a short time. can do. In addition, since infrared pulse laser light having a wavelength of 900 nm or more is preferably emitted and fine particles are generated even by relatively weak light irradiation that does not cause a multiphoton process, problems such as drug decomposition can be suppressed. Furthermore, since the fine particles generated by the irradiation with the laser light L are suppressed or accumulated near the interface between the residue 1 and the water 2, the generation of new fine particles by the irradiation with the laser light L is prevented. In this respect, the fine particle dispersion can be produced with high efficiency and in a short time.

  (Second Embodiment)

  Next, a second embodiment of the fine particle dispersion manufacturing method and the fine particle dispersion manufacturing apparatus according to the present invention will be described. FIG. 5 is a configuration diagram of the fine particle dispersion producing apparatus 12 according to the second embodiment. As shown in this figure, the fine particle dispersion manufacturing apparatus 12 includes a light irradiation unit 20, a container 30, a temperature control unit 40, an ultrasonic probe 61, and a driving unit 62, and includes a poorly soluble drug and a dispersion stabilizer. A fine particle dispersion in which fine particles are dispersed in water is produced.

  Compared with the configuration of the fine particle dispersion manufacturing apparatus 11 according to the first embodiment shown in FIG. 1, the fine particle dispersion manufacturing apparatus 12 according to the second embodiment shown in FIG. 5 includes a magnetic stirrer 51 and a stirrer base. The difference is that an ultrasonic probe 61 and a drive unit 62 are provided in place of 52.

  The ultrasonic probe 61 is immersed in the water 2 injected into the container 30 during the irradiation step S3 and is driven by the drive unit 62 to generate an ultrasonic wave, thereby being injected into the container 30. The water 2 is caused to flow in the vicinity of the interface between the residue 1 inside the container 30 and the water 2 by ultrasonically vibrating the water 2. That is, the ultrasonic probe 61 and the drive unit 62 act as vibration means for vibrating the water 2 injected into the container 30, and the water 2 near the interface between the residue 1 and the water 2 inside the container 30. It acts as a fluid means for fluidizing.

  Next, the operation of the fine particle dispersion manufacturing apparatus 12 according to the second embodiment will be described, and the fine particle dispersion manufacturing method according to the second embodiment will be described. The flowchart for explaining the method for producing a fine particle dispersion according to the second embodiment is the same as that shown in FIG. The fine particle dispersion manufacturing method according to the present embodiment also provides a fine particle dispersion in which fine particles containing a hardly soluble drug and a dispersion stabilizer are dispersed in water by sequentially performing the dissolving step S1, the fixing step S2, and the irradiation step S3. To manufacture. Each of the dissolution step S1 and the fixing step S2 in the second embodiment is the same as in the case of the first embodiment.

  In the irradiation step S3 in the second embodiment, water 2 is injected into the container 30, and the residue 1 fixed to the inner wall of the container 30 is immersed in the water 2 (see FIG. 5). Further, in the irradiation step S3, the ultrasonic probe 61 placed in the container 30 is driven by the drive unit 62 to generate ultrasonic waves, and the water 2 injected into the container 30 vibrates, so that the container 30 The water 2 flows in the vicinity of the interface between the residue 1 and the water 2 inside.

  In the irradiation step S3, in this vibration state, the laser light L output from the laser light source 21 is adjusted by the irradiation light control unit 22 in terms of intensity and / or irradiation time, and reflected by the mirror 23. The residue 1 fixed to the inner wall of the container 30 is irradiated. The vibration by the vibration means may be performed continuously or intermittently. Thereby, the residue 1 is pulverized into fine particles, and a fine particle dispersion in which the fine particles are dispersed in the water 2 is manufactured. The fine particles contain a poorly soluble drug and a dispersion stabilizer.

  According to the fine particle dispersion manufacturing apparatus 12 according to the second embodiment or the fine particle dispersion manufacturing method according to the second embodiment, the laser beam L is efficiently applied to the pellet-like residue 1 fixed to the inner wall of the container 30. Since the irradiation is performed, the fine particle dispersion can be produced with high efficiency and in a short time. In addition, since infrared pulse laser light having a wavelength of 900 nm or more is preferably emitted and fine particles are generated even by relatively weak light irradiation that does not cause a multiphoton process, problems such as drug decomposition can be suppressed.

  In the present embodiment, the water 2 injected into the container 30 vibrates due to the generation of ultrasonic waves by the ultrasonic probe 61 in the irradiation step S <b> 3, and the interface between the residue 1 and the water 2 inside the container 30. Water 2 flows in the vicinity. As a result, the fine particles generated by the irradiation with the laser beam L are restrained from staying or depositing in the vicinity of the interface between the residue 1 and the water 2, thereby preventing the generation of new fine particles by the irradiation with the laser beam L. It will never be done. Therefore, also in this respect, the fine particle dispersion can be produced with high efficiency and in a short time.

  From the fine particle dispersion thus produced, fine particles containing a poorly soluble drug and a dispersion stabilizer are produced. Further, the fine particle dispersion is freeze-dried to produce freeze-dried fine particles. Furthermore, a preparation for oral administration containing a fine particle dispersion, fine particles or freeze-dried fine particles is produced, and for injection administration containing a dispersion obtained by resuspending the fine particle dispersion, fine particles or freeze-dried fine particles in water A formulation is manufactured.

  Also in the present embodiment, in the irradiation step S3, the laser beam L is irradiated from the outside of the region of the inner wall of the container 30 where the residue 1 is fixed, and the irradiated laser beam L is converted into the container 30, the residue 1 and It is preferable to proceed in the order of water 2. In the irradiation step S3, it is preferable that the residue 1 is irradiated with laser light L having a wavelength of 900 nm or more from the light irradiation unit 20, and the laser light L reaches the interface via the residue 1 and Since fine particles are generated at the interface, it is preferable to irradiate the residue 1 with laser light L having a wavelength with a small absorbance with respect to the residue 1. In the irradiation step S3, it is preferable that the intensity and / or time of the light irradiation on the residue 1 is adjusted by the irradiation light control unit 21, and the irradiation is performed when the residue 1 is irradiated with light. The region or the inside of the container is preferably maintained at a constant temperature by the temperature controller 40. Further, it is preferable that a sealed container is used as the container 30 and the dissolution step S1, the fixing step S2, and the irradiation step S3 are performed under sterilization.

  Next, a modification of the vibration means used in the fine particle dispersion manufacturing apparatus 12 according to the second embodiment or the fine particle dispersion manufacturing method according to the second embodiment will be described. FIG. 6 is a view showing a modification of the vibration means used in the second embodiment. In the modification shown in this figure, an ultrasonic wave generating element 63 is attached to the outer wall of the container 30 as a vibrating means. The ultrasonic wave generated by the ultrasonic wave generating element 63 is transmitted to the water 2 through the container 30, whereby the water 2 injected into the inside of the container 30 is ultrasonically vibrated, and the residue 1 in the inside of the container 30. Water 2 flows near the interface with water 2. Further, since the fine particles generated by the irradiation with the laser light L are suppressed or accumulated near the interface between the residue 1 and the water 2, the generation of new fine particles by the irradiation with the laser light L is prevented. The fine particle dispersion can be produced with high efficiency and in a short time.

  Further, as a modification of the vibration means in the second embodiment, an ultrasonic cleaner (for example, B5510 manufactured by BRANSON) is used, and the container 30 is placed in the ultrasonic cleaner, and the water in the container 30 is ultrasonically vibrated. You may let them. Alternatively, as a modification of the vibration means in the second embodiment, a test tube mixer (for example, HM-10H manufactured by AS ONE) is used, and the container 30 is placed in the test tube mixer to vibrate the water inside the container 30. May be. Also in these cases, the water 2 vibrates and the water 2 flows in the vicinity of the interface between the residue 1 inside the container 30 and the water 2. Further, since the fine particles generated by the irradiation with the laser light L are suppressed or accumulated near the interface between the residue 1 and the water 2, the generation of new fine particles by the irradiation with the laser light L is prevented. The fine particle dispersion can be produced with high efficiency and in a short time.

  In the second embodiment, the residue 1 fixed to the inner wall of the container 30 is not only pulverized into fine particles by applying light energy by laser light irradiation but also given vibration energy. May be pulverized into fine particles. Therefore, in the second embodiment, the fine particle dispersion can be manufactured with high efficiency and in a short time also in this respect.

  (Third embodiment)

  Next, a third embodiment of the fine particle dispersion manufacturing method and the fine particle dispersion manufacturing apparatus according to the present invention will be described. FIG. 7 is a configuration diagram of the fine particle dispersion manufacturing apparatus 13 according to the third embodiment. As shown in this figure, the fine particle dispersion manufacturing apparatus 13 includes a light irradiation unit 20, a container 70, a water supply unit 80, and a recovery unit 90, and fine particles containing a poorly soluble drug and a dispersion stabilizer are dispersed in water. A fine particle dispersion is produced. The light irradiation unit 20 in the third embodiment has the same configuration as the light irradiation unit 20 in the second embodiment.

  The container 70 used in the third embodiment contains a liquid to be processed, and is made of a material that can transmit the laser light L output from the light irradiation unit 20, and is preferably made of glass. An inflow path 72 and an outflow path 73 are provided between the internal space 71 of the container 70 and the outside. When the upper plate 74 is mounted on the container 70, the internal space 71 and the outside are connected only by the inflow path 72 and the outflow path 73. In this figure, a state in which the residue 1 is fixed to the bottom surface of the internal space 71 of the container 70 and water 2 is injected into the internal space 71 of the container 70 is shown.

  The water supply unit 80 is connected to the inflow path 72 of the container 70 by a water supply pipe, and supplies water to the internal space 71 of the container 70, whereby the residual 1 and water 2 inside the container 70 are supplied. Water 2 is allowed to flow in the vicinity of the interface. That is, the water supply unit 80, the inflow channel 72, and the water supply pipe 84 act as water supply means for supplying water to the inside of the container 70, and the water 2 near the interface between the residue 1 and the water 2 inside the container 70. It acts as a fluid means for fluidizing.

  The water supply unit 80 includes a water supply container 81, a temperature control unit 82, and a water supply pump 83. The water supply container 81 stores water to be supplied into the container 70. The temperature control unit 82 maintains the water contained in the water supply container 81 at a predetermined temperature, and can thereby supply water at a predetermined temperature into the container 70. The water supply pump 83 sends water contained in the water supply container 81 to the inflow path 72 of the container 70.

  A peristaltic pump is preferably used as the water supply pump 83. In this case, if the inlet of the water supply pump 83 is immersed in the water in the water supply container 81, the water is supplied into the container 70. Further, if the inlet of the water supply pump 83 is placed in a gas (air or the like), the gas is supplied into the container 70. That is, the water supply pump 83 can also act as an air supply unit that supplies gas into the container 70.

  The collection unit 90 is connected to the outflow passage 73 of the container 70 by a drain pipe 91 and collects and stores the fine particle dispersion produced in the container 70. That is, the collection unit 90, the outflow path 73, and the drain pipe 91 function as a collection unit that collects the fine particle dispersion produced inside the container 70.

  Next, the operation of the fine particle dispersion manufacturing apparatus 13 according to the third embodiment will be described, and the fine particle dispersion manufacturing method according to the third embodiment will be described. The flowchart for explaining the method for producing a fine particle dispersion according to the third embodiment is the same as that shown in FIG. The fine particle dispersion manufacturing method according to the present embodiment also provides a fine particle dispersion in which fine particles containing a hardly soluble drug and a dispersion stabilizer are dispersed in water by sequentially performing the dissolving step S1, the fixing step S2, and the irradiation step S3. To manufacture.

  In the dissolution step S1, the poorly soluble drug and the dispersion stabilizer are dissolved in the volatile organic solvent in the container 70. The hardly soluble drug, the dispersion stabilizer and the organic solvent are as exemplified in the first embodiment. In the fixing step S2 following the dissolving step S1, the organic solvent contained in the dissolving liquid obtained in the dissolving step S1 is removed by evaporation, and the residue 1 in the form of pellets is obtained by removing the organic solvent. It is fixed to the bottom surface of 70.

  After the fixing step S 2, the upper plate 74 is mounted on the container 70, the water supply unit 80 is connected to the inflow path 72 of the container 70 by the water supply pipe 84, and the drain pipe is connected to the outflow path 73 of the container 70. The collection unit 90 is connected by 91, and the irradiation step S3 is performed.

  In the irradiation step S <b> 3, the water in the water supply container 81 maintained at a constant temperature by the temperature control unit 82 in the water supply unit 80 is sent out by the water supply pump 83. The water delivered from the water supply unit 80 is supplied to the internal space 71 through the water supply pipe and the inflow path 72 of the container 70. As a result, the residue 1 fixed to the bottom surface of the internal space 71 of the container 70 is immersed in the water 2. Further, during a period in which water is supplied to the internal space 71 of the container 70 by the water supply means, the water 2 flows near the interface between the residue 1 and the water 2.

  In the irradiation step S3, in this state, the laser light L output from the laser light source 21 is adjusted by the irradiation light control unit 22 in intensity and / or irradiation time, and is reflected by the mirror 23. Irradiation is applied to the residue 1 fixed to the bottom surface of the container 70. Thereby, the residue 1 is pulverized into fine particles, and a fine particle dispersion in which the fine particles are dispersed in the water 2 is manufactured. The fine particles contain a poorly soluble drug and a dispersion stabilizer. The fine particle dispersion produced inside the container 70 is transferred to the collection unit 90 via the outflow path 73 and the discharge pipe 91 and collected.

  According to the fine particle dispersion manufacturing apparatus 13 according to the third embodiment or the fine particle dispersion manufacturing method according to the third embodiment, the laser light L is efficiently applied to the pellet-like residue 1 fixed to the inner wall of the container 70. Since the irradiation is performed, the fine particle dispersion can be produced with high efficiency and in a short time. In addition, since infrared pulse laser light having a wavelength of 900 nm or more is preferably emitted and fine particles are generated even by relatively weak light irradiation that does not cause a multiphoton process, problems such as drug decomposition can be suppressed.

  In the present embodiment, in the irradiation step S3, the water 2 flows in the vicinity of the interface between the residue 1 and the water 2 inside the container 70 by supplying water into the container 70 by the water supply means. As a result, the fine particles generated by the irradiation with the laser beam L are restrained from staying or depositing in the vicinity of the interface between the residue 1 and the water 2, thereby preventing the generation of new fine particles by the irradiation with the laser beam L. It will never be done. Therefore, also in this respect, the fine particle dispersion can be produced with high efficiency and in a short time.

  Fine particles containing a poorly soluble drug and a dispersion stabilizer are produced from the fine particle dispersion thus produced and collected. Further, the fine particle dispersion is freeze-dried to produce freeze-dried fine particles. Furthermore, a preparation for oral administration containing a fine particle dispersion, fine particles or freeze-dried fine particles is produced, and for injection administration containing a dispersion obtained by resuspending the fine particle dispersion, fine particles or freeze-dried fine particles in water A formulation is manufactured.

  Also in the present embodiment, in the irradiation step S3, the laser beam L is irradiated from the outside of the region of the inner wall of the container 70 where the residue 1 is fixed, and the irradiated laser beam L is applied to the container 70, the residue 1 and It is preferable to proceed in the order of water 2. In the irradiation step S3, it is preferable that the residue 1 is irradiated with laser light L having a wavelength of 900 nm or more from the light irradiation unit 20, and the laser light L reaches the interface via the residue 1 and Since fine particles are generated at the interface, it is preferable to irradiate the residue 1 with laser light L having a wavelength with a small absorbance with respect to the residue 1. In the irradiation step S3, it is preferable that the intensity and / or time of the light irradiation on the residue 1 is adjusted by the irradiation light control unit 21, and the irradiation is performed when the residue 1 is irradiated with light. The region or the inside of the container is preferably maintained at a constant temperature by the temperature controller 40. In addition, it is preferable that a sealed container is used as the container 70 and the dissolution step S1, the fixing step S2, and the irradiation step S3 are performed under sterilization.

  Note that the water supply to the internal space 71 of the container 70 by the water supply means may be performed continuously or intermittently. Compared with the case where water is supplied continuously, when water is supplied intermittently, the concentration of fine particles in the collected fine particle dispersion is high, so that it is easy to produce an injection.

  Alternatively, the water supply by the water supply means and the gas supply by the air supply means may be alternately performed, and the fine particle dispersion may be recovered by the recovery means when the gas is supplied by the air supply means. Also in this case, since the fine particle concentration in the collected fine particle dispersion is high, it is easy to produce an injection.

  When the capacity of the internal space 71 of the container 70 is sufficiently large, the obtained fine particle dispersion may be kept in the internal space 71 of the container 70 without providing the recovery unit 90. At this time, it is preferable that the water injected from the inflow path 72 into the internal space 71 in the container 70 is supplied to the vicinity of the interface between the residue 1 and the water 2. By doing so, the fine particle concentration in the vicinity of the interface between the residue 1 and the water 2 can be efficiently kept small.

  Next, more specific examples of the fine particle dispersion manufacturing apparatus or the fine particle dispersion manufacturing method according to the present embodiment will be described.

  First, Example 1 will be described. Example 1 corresponds to the third embodiment. In Example 1, a fine particle dispersion of an immunosuppressant Cyclosporin A (cyclosporin A, hereinafter referred to as “CsA”), which is a poorly soluble drug, was prepared. CsA bulk powder (50 mg) as a poorly soluble drug, polyvinylpyrrolidone (250 mg) and sodium lauryl sulfate (10 mg) as a dispersion stabilizer were placed in a test tube and dissolved in ethanol (5 mL) as a volatile organic solvent. . This solution was placed in a container 70, and ethanol was dried to dryness under reduced pressure to obtain a mixture (residue) of a drug and a dispersion stabilizer. Water was added to the resulting mixture and sealed.

While supplying water to the container 70, the mixture fixed to the inner wall of the container 70 was irradiated with Nd: YAG pulsed laser light. The irradiation conditions were a wavelength of 1064 nm, an irradiation light intensity of 0.61 J / cm ² / pulse, a pulse width of 5 to 7 ns, and a repetition frequency of 10 Hz. Irradiation was performed for 60 minutes to obtain a uniformly turbid dispersion. In this example, all the above operations were performed at room temperature (20 ° C.).

  The amount of CsA contained in the obtained dispersion was quantified by measuring the absorbance at a wavelength of 210 nm using high performance liquid chromatography (hereinafter referred to as “HPLC”) (FIG. 8). The separation was carried out at a temperature of 50 ° C. using ODS-C18 (manufactured by Tosoh Corporation) as a separation carrier and acetonitrile-isopropanol-water (2: 5: 3) as a mobile phase. As a sample, CsA bulk powder dissolved in acetonitrile-water (1: 1) so as to be 1 mg / mL was used. CsA elutes at a position of about 8 minutes, and the CsA amount in the sample was calculated by comparing and calculating the amount of CsA in the sample based on the peak area obtained by measuring the sample. As a result, the amount of CsA in the fine particle dispersion was 9.29. It was ± 0.14 mg / mL (n = 3). A fine particle dispersion having a sufficiently high concentration as compared with the solubility in water (23 μg / mL) could be prepared. On the HPLC chart, no increase in the contaminant peak due to laser irradiation was observed.

  The particle size distribution of the fine particles contained in the fine particle dispersion obtained in Example 1 was measured. The measuring device used for the particle size measurement was SALD-7000 (manufactured by Shimadzu Corporation). In the particle size range of 200 to 1000 nm, particle size distributions having peaks at 300 nm and 800 nm were obtained (FIG. 9). It is considered to be a uniform fine particle suspension with a uniform particle size.

  An electron micrograph of the fine particles contained in the fine particle dispersion obtained in Example 1 was taken (FIG. 10). A scanning electron microscope S4200 (manufactured by Hitachi, Ltd.) was used as the measuring device. When this photograph was seen, the shape of the fine particles was spherical, and many fine particles having a particle diameter of about 300 to 400 nm were observed. This is consistent with the particle size distribution data and is considered to be a uniform group of fine particles.

  As described above, a fine particle dispersion in which CsA fine particles having a uniform particle diameter were dispersed could be prepared. By changing the liquid phase temperature, irradiation intensity, and irradiation time during laser irradiation, it was possible to prepare fine particle dispersions having different particle diameters (see Examples below). Further, even when the obtained dispersion was allowed to stand at room temperature for several days, almost no precipitation was observed. Furthermore, lyophilization was possible, and no significant difference was observed in the particle size distribution and electron microscopic image of the dispersion before and after lyophilization.

  In general, the smaller the temperature of the water supplied at the time of laser light irradiation, the smaller the particle size and the smaller the fine particles were obtained. When the water temperature was around 4 ° C., a fine particle dispersion having a particle size of 100 nm or less was obtained.

  Next, Example 2 will be described. In Example 2, poloxamer 407 (50 mg) was used as a dispersion stabilizer. Other manufacturing conditions and microscope observation conditions are the same as in Example 1. When an electron micrograph of the fine particles contained in the fine particle dispersion obtained in Example 2 was viewed, the shape of the fine particles was spherical, and many fine particles having a particle size of micrometer size or less were observed.

Next, Example 3 will be described. In Example 3, the intensity of the laser light applied to the mixture (residue) in the test tube was 0.30 or 0.61 J / cm ² / pulse. Other manufacturing conditions and microscope observation conditions are the same as in Example 1. When the electron micrograph of the fine particles contained in the fine particle dispersion obtained in Example 3 was viewed, the shape of the fine particles was spherical, the particle diameter varied with the irradiation intensity, and the smaller the irradiation light intensity, the smaller the particle diameter. It was small. From these results, it is considered that the particle diameter of the generated fine particles increases as the irradiation light intensity increases.

  Next, Example 4 will be described. In Example 4, the time for irradiating the residue fixed on the inner wall of the container 70 with laser light was 10, 60, or 180 minutes. Other manufacturing conditions and microscope observation conditions are the same as in Example 1. When the electron micrograph of the fine particles contained in the fine particle dispersion obtained in Example 4 was viewed, the shape of the fine particles was spherical, and the particle diameter changed with the irradiation time. The sample with an irradiation time of 10 minutes has many fine particles having a particle size of 200 to 500 nm, whereas the sample with an irradiation time of 60 minutes has many fine particles with a particle size of 500 nm to 1 μm, and the sample with an irradiation time of 180 minutes has a particle size exceeding 1 μm. Many fine particles were observed. From these results, it is considered that the particle diameter of the generated fine particles increases as the irradiation time is longer.

  Next, Example 5 will be described. In Example 5, a microparticle dispersion of clobetasone butyrate was prepared using the anti-inflammatory drug clobetasone butyrate (clobetasone butyrate) as a poorly soluble drug. Other manufacturing conditions, particle size distribution measurement conditions, and microscope observation conditions are the same as in Example 1. From the particle size distribution and electron micrograph of the fine particles contained in the fine particle dispersion obtained in Example 5, the shape of the fine particles is spherical, and many fine particles having a particle size of micrometer size or less are observed. Exists between 200 nm and 1 μm, and is considered to be a uniform fine particle suspension with uniform particle size.

  Next, Example 6 will be described. In Example 6, a fine particle dispersion of nifedipine was prepared using an antiepileptic drug nifedipine (nifedipine) as a poorly soluble drug. Other manufacturing conditions and particle size distribution measurement conditions are the same as in Example 1. From the particle size distribution of the fine particles contained in the fine particle dispersion obtained in Example 6, the fine particles in the dispersion are present between 200 nm and 2 μm, and have a particle size peak at 400 nm and 1.2 μm, respectively. It is thought that.

  Next, Example 7 will be described. In Example 7, a fine particle dispersion of ibuprofen was prepared using the anti-inflammatory drug ibuprofen (ibuprofen) as a poorly soluble drug. Other manufacturing conditions and particle size distribution measurement conditions are the same as in Example 1. From the particle size distribution of the fine particles contained in the fine particle dispersion obtained in Example 7, the fine particles in the dispersion are present between 250 nm and 1 μm, and uniform fine particles having a particle size peak at 700 nm. It is considered to be a suspension.

It is a block diagram of the fine particle dispersion manufacturing apparatus 11 which concerns on 1st Embodiment. It is a flowchart explaining the fine particle dispersion manufacturing method which concerns on 1st Embodiment. It is a block diagram of the 1st modification of the container 30 used in 1st Embodiment. It is a block diagram of the 2nd modification of the container 30 used in 1st Embodiment. It is a block diagram of the fine particle dispersion manufacturing apparatus 12 which concerns on 2nd Embodiment. It is a figure which shows the modification of the vibration means used in 2nd Embodiment. It is a block diagram of the fine particle dispersion manufacturing apparatus 13 which concerns on 3rd Embodiment. 2 is an HPLC chart of nanoparticulated cyclosporin A obtained in Example 1. FIG. 2 is a graph showing the particle size distribution of cyclosporin A nanoparticles obtained in Example 1. FIG. 2 is an electron microscopic image of cyclosporin A nanoparticles obtained in Example 1. FIG.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 ... Residue, 2 ... Water, 11-13 ... Fine particle dispersion manufacturing apparatus, 20 ... Light irradiation part, 21 ... Laser light source, 22 ... Irradiation light control part, 30, 30A, 30B ... Container, 40 ... Temperature control part , 51 ... Magnetic stirrer, 52 ... Stirrer base, 61 ... Ultrasonic probe, 62 ... Drive unit, 63 ... Ultrasonic generator, 70 ... Container, 71 ... Internal space, 72 ... Inflow path, 73 ... Outflow path, 74 ... Upper plate, 80 ... water supply part, 81 ... water supply container, 82 ... temperature control part, 83 ... water supply pump, 84 ... water supply pipe, 90 ... collection part, 91 ... drainage pipe, L ... laser beam.

Claims (14)

A dissolution step of dissolving a poorly soluble drug and a dispersion stabilizer in a volatile organic solvent;
A fixing step of evaporating and removing the organic solvent contained in the dissolving solution obtained in this dissolving step, and fixing the residue obtained by removing the organic solvent to the inner wall of the container;
After the fixing step, water is injected into the container, and the residue fixed to the inner wall of the container while flowing the water in the vicinity of the interface between the residue and the water inside the container. Irradiating with light to produce a fine particle dispersion in which fine particles containing the poorly soluble drug and the dispersion stabilizer are dispersed in water;
A method for producing a fine particle dispersion, comprising:   The water is flowed in the vicinity of the interface between the residue and the water inside the container by stirring the water injected into the container in the irradiation step. A method for producing a fine particle dispersion as described.   The said irradiation process WHEREIN: The said water is made to flow in the interface vicinity of the said residue and the said water inside the said container by vibrating the water inject | poured into the said container. A method for producing a fine particle dispersion as described.   2. The fine particle according to claim 1, wherein, in the irradiation step, the water flows in the vicinity of an interface between the residue inside the container and the water by supplying water into the container. Dispersion manufacturing method.   The method for producing a fine particle dispersion according to claim 4, wherein, in the irradiation step, the temperature of water supplied to the inside of the container is maintained constant.   5. The method for producing a fine particle dispersion according to claim 4, wherein in the irradiation step, the fine particle dispersion produced in the container is collected in a collection container different from the container.   7. In the irradiation step, water and gas are alternately supplied to the inside of the container, and the fine particle dispersion is recovered in the recovery container when the gas is supplied. A method for producing a fine particle dispersion as described. The hardly soluble drug and the dispersion stabilizer are dissolved in a volatile organic solvent, and the residue obtained by evaporating and removing the organic solvent contained in the solution is fixed to the inner wall, and water is injected into the inside. A container,
A light irradiation unit configured to irradiate light to the residue fixed to the inner wall of the container;
Fluid means for causing the water to flow in the vicinity of the interface between the residue inside the container and the water;
With
By flowing the water in the vicinity of the interface between the residue and the water inside the container by the flow means, and irradiating the residue with light by the light irradiation unit, the poorly soluble drug and the Producing a fine particle dispersion in which fine particles containing a dispersion stabilizer are dispersed in water;
An apparatus for producing a fine particle dispersion.   The flow means includes stirring means for stirring water injected into the container, and the stirring means causes the water to flow in the vicinity of the interface between the residue and the water inside the container. The apparatus for producing a fine particle dispersion according to claim 8.   The flow means includes vibration means for vibrating water injected into the container, and the vibration means causes the water to flow in the vicinity of the interface between the residue inside the container and the water. The apparatus for producing a fine particle dispersion according to claim 8.   The flow means includes water supply means for supplying water to the inside of the container, and the water is caused to flow in the vicinity of the interface between the residue inside the container and the water by the water supply means. The fine particle dispersion manufacturing apparatus according to claim 8.   12. The fine particle dispersion producing apparatus according to claim 11, wherein the water supply means maintains a constant temperature of water supplied to the inside of the container.   12. The apparatus for producing a fine particle dispersion according to claim 11, further comprising a collecting means for collecting the fine particle dispersion produced in the container. An air supply means for supplying gas into the container;
The supply of water by the water supply means and the supply of gas by the air supply means are alternately performed,
The fine particle dispersion is recovered by the recovery means when the gas is supplied by the air supply means;
The apparatus for producing a fine particle dispersion according to claim 13.