Particle production equipment and particle production method

Abstract

The particle production equipment includes: a droplet formation unit configured to discharge a liquid from a discharge hole to form droplets; and a particle formation unit configured to solidify the droplets to form particles, wherein the particle formation unit includes a conveying air flow, and the droplet formation unit is configured to discharge the liquid in a manner that satisfies the following formula 1, where in formula 1, Vj represents the droplet discharge velocity (m / s), F represents the discharge driving frequency (kHz), d0 represents the diameter of the droplet (μm), ρ represents the density of the liquid (kg / m<supgt;3< / supgt;), Vx represents the velocity of the conveying air flow (m / s), A represents the shortest distance from the droplet formation unit to the center of the conveying air flow (m), and θ represents the droplet discharge angle (degrees).

Description

Technical Field

[0001] The present disclosure relates to particle production equipment and a particle production method. Background Art

[0002] Conventionally, in the use of drugs, particles containing physiologically active substances such as pharmaceutical compounds have been produced.

[0003] For example, a method for producing pharmaceutical particles by spraying and drying a liquid containing a physiologically active substance via a spray drying method has been proposed (see, for example, PTL1).

[0004] In order to improve the characteristics of particles such as variations in dissolution rate, dissolution amount, and handling ability, and to obtain particles having a small size and a narrow particle size distribution, a particle production method using an inkjet discharge system utilizing a liquid column resonance method has been proposed (see, for example, PTL2).

[0005] A method has been proposed in which a liquid containing portion including a thin film formed with a plurality of nozzles and a piezoelectric element configured to vibrate the thin film is used to discharge a liquid from the plurality of nozzles to form toner particles (see, for example, PTL3).

[0006] Furthermore, in a method for producing particles by solidifying droplets using an air flow, a particle production apparatus has been proposed in which nozzles are provided in a zigzag lattice pattern on a surface on which the nozzles are formed, and the air flow direction intersects the droplet discharge direction at substantially a right angle to prevent the particle size distribution of the obtained particles from broadening when droplets discharged from the nozzles coalesce (hereinafter, may be referred to as "coalescence") (see, for example, PTL4).

[0007] Citation List

[0008] Patent Documents

[0009] PTL1: Japanese Unexamined Patent Application Publication No. 8-281155

[0010] PTL2: Japanese Unexamined Patent Application Publication No. 2017-160188

[0011] PTL3: Japanese Unexamined Patent Application Publication No. 2008-292976

[0012] PTL4: Japanese Patent No. 6103466 Summary of the Invention

[0013] Technical Problem

[0014] An object of the present disclosure is to provide a particle production apparatus capable of mass-producing particles having a narrow particle size distribution.

[0015] Solution to the problem

[0016] According to one aspect of the present disclosure, a particle production apparatus includes: a droplet formation unit configured to discharge a liquid from a discharge hole to form droplets; and a particle formation unit configured to solidify the droplets to form particles. The particle formation unit includes a transport air flow. The droplet formation unit is configured to discharge the liquid in a manner that satisfies Equation 1 below.

[0017] [Equation 1]

[0018]

[0019] In Equation 1, Vj represents the droplet discharge velocity (m / s), F represents the discharge driving frequency (kHz), d0 represents the diameter of the droplet (μm), p represents the density of the liquid (kg / m 3 ), Vx represents the velocity of the transport air flow (m / s), A represents the shortest distance from the droplet formation unit to the center of the transport air flow (m), and θ represents the droplet discharge angle (degrees).

[0020] Advantageous effects of the invention

[0021] According to the present disclosure, a particle production apparatus capable of mass-producing particles having a narrow particle size distribution can be provided. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1A Figure 1A A schematic diagram showing an example of the discharged droplets.

[0023] Figure 1B Figure 1B A schematic diagram showing another example of the discharged droplets.

[0024] Figure 1C Figure 1C A schematic diagram showing an example of the relationship between the discharged droplets and the transport path.

[0025] Figure 1D Figure 1D A schematic diagram showing another example of the relationship between the discharged droplets and the transport path.

[0026] Figure 1E Figure 1E A schematic diagram showing another example of the relationship between the discharged droplets and the transport path.

[0027] Figure 2A Figure 2A ​​​​​​​​​​​​Schematic diagram showing an example of the distribution of the transfer air flow.

[0028] Figure 2B Figure 2B Schematic diagram showing an example of the relationship between the droplet formation unit and the center of the transfer air flow.

[0029] Figure 2C Figure 2C Schematic diagram showing another example of the relationship between the droplet formation unit and the center of the transfer air flow.

[0030] Figure 3A Figure 3A Schematic diagram showing an example of the droplet discharge angle.

[0031] Figure 3B Figure 3B Schematic diagram showing another example of the droplet discharge angle.

[0032] Figure 3C Figure 3C Schematic diagram showing an example of the discharge hole (nozzle) and the droplet discharge angle.

[0033] Figure 3D Figure 3D Schematic diagram showing another example of the discharge hole (nozzle) and the droplet discharge angle.

[0034] Figure 4A Figure 4A Schematic diagram showing an example of the particle production equipment.

[0035] Figure 4B Figure 4B Schematic diagram showing an example of the particle production equipment.

[0036] Figure 5 Figure 5 Schematic diagram showing an example of the component for volume change in the particle production equipment.

[0037] Figure 6A Figure 6A Side view showing an example of the droplet formation unit using the component for nozzle vibration in the particle production equipment.

[0038] Figure 6B Figure 6B Side view showing an example of the droplet formation unit using the component for nozzle vibration in the particle production equipment.

[0039] Figure 7A Figure 7A ​​​​​​​​​​​​​​​​​​​​​​​​To present a schematic diagram of an example of a droplet forming unit using a necking portion generating member in a particle production apparatus.

[0040] Figure 7B Figure 7B To present a schematic diagram of an example of a necking portion generating member in a particle production apparatus. Detailed Description

[0041] (Particle Production Apparatus and Particle Production Method)

[0042] The particle production apparatus of the present disclosure includes: a droplet forming unit configured to discharge a liquid from a discharge hole to form droplets; and a particle forming unit configured to solidify the droplets to form particles. The particle forming unit includes a transport air flow, and the droplet forming unit is configured to discharge the liquid in a manner that satisfies Equation 1 below. The particle production apparatus of the present disclosure includes a liquid storage portion, and further includes other components if necessary.

[0043] [Equation 2]

[0044]

[0045] In Equation 1, Vj represents the droplet discharge velocity (m / s), F represents the discharge driving frequency (kHz), d0 represents the diameter of the droplet (μm), ρ represents the density of the liquid (kg / m 3 ), Vx represents the velocity of the transport air flow (m / s), A represents the shortest distance from the droplet forming unit to the center of the transport air flow (m), and θ represents the droplet discharge angle (degrees).

[0046] The particle production method of the present disclosure includes: discharging a liquid from a discharge hole through a droplet forming unit to form droplets; and solidifying the droplets through a particle forming unit to form particles. The particle forming unit includes a transport air flow, and the droplet forming unit is configured to discharge the liquid in a manner that satisfies Equation 1 below. If necessary, the particle production method of the present disclosure includes other steps.

[0047] [Equation 3]

[0048]

[0049] Wherein in Equation 1, Vj represents the droplet discharge velocity (m / s), F represents the discharge driving frequency (kHz), d0 represents the diameter of the droplet (μm), ρ represents the density of the liquid (kg / m 3 ), Vx represents the velocity of the transport air flow (m / s), A represents the shortest distance from the droplet forming unit to the center of the transport air flow (m), and θ represents the droplet discharge angle (degrees).

[0050] ​​As a result of research on an apparatus for producing particles having a narrow particle size distribution in large quantities, the present inventors have obtained the following findings.

[0051] The droplets discharged from the discharge holes (nozzles) are subject to air resistance, which causes a decrease in velocity. When the transport air flow is weak (the flow velocity of the transport air flow is small), the droplets previously discharged from the nozzle can be caught up by the droplets subsequently discharged from the same nozzle, which can lead to coalescence of the droplets. At the same time, when the transport air flow is strong, the droplets are accelerated by the transport air flow, which makes it possible to prevent the droplets from coalescing with each other (see, for example Figure 1A ).

[0052] The droplets discharged from the discharge holes (nozzles) at a certain initial velocity V 0 are subject to air resistance and their velocity decreases. Finally, the droplets reach a velocity having the same vector as the velocity of the transport air flow. For example, as Figure 1B presented in, when the flow velocity of the transport air flow is small, the droplets coalesce with each other. Therefore, the flow velocity of the transport air flow is desirably large.

[0053] In the conventional art, in the case where the droplets discharged using a transport air flow are solidified, it is necessary to increase the droplet discharge velocity in order to increase the production amount of the particles. However, when the droplet discharge velocity is increased, the distance traveled by the discharged droplets (the horizontal distance from the discharge hole) increases, which can enlarge the apparatus to be designed.

[0054] In addition, the conventional art has the following problem: when the droplet discharge velocity is increased to improve the production efficiency, the droplet discharge diameter becomes smaller, which in some cases cannot achieve particles having a desired size.

[0055] In the case where the particle production apparatus of the present disclosure satisfies each condition for particle production, even when the droplet discharge velocity is increased, particles having a narrow particle size distribution can be produced in large-scale production. That is, even when droplets having a desired diameter are discharged while increasing the discharge velocity, the discharged droplets can be controlled so as not to coalesce with each other. As a result, particles having a narrow particle size distribution can be produced in large-scale production. The particle production apparatus of the present disclosure is particularly suitable for producing particles having a volume average particle diameter of 10 μm or more.

[0056] According to the particle production apparatus of the present disclosure, even particles having a size equal to or larger than a single micron (i.e., particles having a volume average particle diameter of 10 μm or more) can be produced in large-scale production. Therefore, the volume average particle diameter of the particles produced by the production apparatus of the present disclosure is preferably 10 μm or more but 100 μm or less, more preferably 20 μm or more but 40 μm or less.

[0057] The volume-average particle diameter can be measured using, for example, a laser diffraction / scattering particle size distribution analyzer (device name: MICROTRAC MT3000II, available from MicrotracBEL Corp.).

[0058] <Droplet formation step and droplet formation unit>

[0059] The droplet formation step is a step of discharging a liquid from a discharge hole to form droplets, and is carried out by a droplet formation unit.

[0060] The droplet formation unit is configured to discharge the liquid in a manner that satisfies the following formula 1.

[0061] [Equation 4]

[0062]

[0063] In formula 1, Vj represents the droplet discharge velocity (m / s), F represents the discharge driving frequency (kHz), d0 represents the diameter of the droplet (μm), ρ represents the density of the liquid (kg / m 3 ), Vx represents the velocity of the transport air flow (m / s), A represents the shortest distance from the droplet formation unit to the center of the transport air flow (m), and θ represents the droplet discharge angle (degrees). In formula 1, P represents a value obtained by dividing the distance between the center of the droplet (droplet 1) discharged from the discharge hole and the center of the subsequent droplet (droplet 2) discharged from the same discharge hole (each droplet is discharged from a certain discharge hole) by the diameter of the droplet. When the value of P is less than 1, the droplets theoretically coalesce with each other. Therefore, in order to avoid coalescence of the particles, the value of P must be greater than 1.

[0064] Taking into account variations, for example, the value of P is preferably 2 or greater, more preferably 2.5 or greater, still more preferably 3 or greater. In the case where the value of P is 2 or greater, even when the droplet discharge velocity is increased, particles having a size equal to or greater than the desired size can be produced in large-scale production.

[0065] The droplet discharge velocity (Vj) (m / s) is the velocity immediately after the droplet is discharged from the discharge hole.

[0066] For example, the droplet discharge velocity Vj (m / s) is preferably 5 m / s or greater but 50 m / s or less, more preferably 7 m / s or greater but 30 m / s or less.

[0067] The diameter d0 (μm) of the droplet is the diameter of the droplet immediately after the droplet is discharged from the discharge hole.

[0068] The diameter d0 (μm) of the droplet is preferably 5 μm or greater but 100 μm or less, more preferably 10 μm or greater but 50 μm or less.

[0069] The droplet ejection speed and the diameter of the droplet can be measured using a droplet observation device with an LED backlight (device name: EV1000, available from Ricoh Company, Ltd.).

[0070] The droplet ejection angle (degrees) (θ) is the angle formed by the direction of movement of the droplet at the moment of ejecting the droplet from the ejection hole (nozzle) and the direction of the stress received by the droplet from the transport air flow (see, for example Figure 3A and Figure 3B ). When the droplet forming unit includes a plurality of ejection holes (nozzles), there are the following two cases; (i) the case where the ejection holes (nozzles) are present on a plane as presented in Figure 3C ; and (ii) the case where the ejection holes (nozzles) are present on a curved surface as presented in Figure 3D . In particular, in the case of (ii), the directions of ejecting the droplets from the respective ejection holes are different. Therefore, the angle formed by the direction of travel of the droplet at the moment of ejecting the droplet from the ejection hole (nozzle) located at the center of the droplet forming unit and the direction of the stress received by the droplet from the transport air flow is measured as the droplet ejection angle (see, for example Figure 3D ).

[0071] For example, the droplet ejection angle is preferably 40° or greater but 90° or less, more preferably 60° or greater but 75° or less.

[0072] The droplet ejection angle can be appropriately selected by adjusting the directions of the ejection hole and the transport air flow.

[0073] The density ρ (kg / m 3 ) of the liquid is the mass of the liquid per unit volume.

[0074] For example, the density ρ (kg / m 3 ) of the liquid is preferably 500 kg / m 3 or greater but 1500 kg / m 3 or less, more preferably 700 kg / m 3 or greater but 1200 kg / m 3 or less.

[0075] The density p (kg / m 3 ) of the liquid can be measured based on JIS Z 8804:2012.

[0076] The transport air flow prevents the droplet ejection speed from decreasing immediately after the droplet is ejected, and suppresses the aggregation (integration (merging, unification)) of the droplets. The transport air flow is provided for the following reasons.

[0077] When the discharged droplets contact each other before the droplets are dried, multiple droplets are integrated to form one droplet (hereinafter, this phenomenon is referred to as coalescence). In order to obtain particles with a uniform (narrow) particle size distribution, a certain distance must be maintained between the discharged droplets. However, the discharged droplets travel at a certain initial speed, but due to air resistance, the speed of the droplets quickly decreases. The droplets with reduced speed are caught up by the droplets discharged subsequently, which leads to coalescence. This phenomenon often occurs, and therefore the particle size distribution of the resulting particles is not uniform (narrow). In order to prevent the coalescence of droplets, it is necessary to prevent the droplet discharge speed from decreasing, and to solidify / transfer the droplets while preventing the droplets from coalescing by conveying airflow so that the droplets do not contact each other. The flow rate (m / s) of the conveying airflow is defined as the velocity Vx (m / s) of the conveying airflow.

[0078] The conveying airflow is an airflow that dries and solidifies the liquid droplets discharged from the particle production equipment, and is an airflow that flows in a conveying path that can be equipped in, for example, the production equipment. When the conveying airflow flows in the conveying path, it is assumed that the conveying airflow follows the Hagen-Poiseuille formula and is in a laminar state without turbulent changes.

[0079] The velocity distribution of the conveying airflow is defined by the following equation 2, and the velocity distribution presents a parabola (see Figure 2A ).

[0080] [Number 5]

[0081]

[0082] In Formula 2, U(r) represents the flow velocity of the conveying airflow (m / s), r represents the shortest distance (horizontal distance) from the center of the conveying airflow to the discharge hole (m) (where 0<r<a, and a represents the radius of the circular tube), and g represents the gravitational acceleration (m / s 2 ), Ie represents the hydraulic gradient or energy gradient, and v represents the kinematic viscosity coefficient (m 2 / s).

[0083] For example, the velocity Vx (m / s) of the conveying air flow is preferably 4 m / s or more but 50 m / s or less, more preferably 8 m / s or more but 20 m / s or less.

[0084] Here, the velocity of the conveying air flow is an average value.

[0085] When the conveying path has a point-symmetrical structure (e.g., a circular tube and a square tube), the maximum value of the velocity of the conveying airflow is at the center of the tube. However, this does not apply to the case where tubes of different equivalent circle diameters are combined in a cross-sectional shape intersecting the major axis of the conveying path, and the case where the conveying path is bent to form a U-shaped curve.

[0086] In one aspect, the flow velocity of the conveying air current can be adjusted by changing the diameter of the conveying path. For example, as Figure 1C presented in [reference], when the diameter of the tube of the conveying path is large, the cross-sectional area intersecting the direction of the conveying air current in the conveying path becomes large, which reduces the air current velocity under the conveying air current of the same flow velocity. In this case, the droplets are likely to coalesce with each other. From the above viewpoints, the diameter of the tube in the conveying path facing the discharge hole (nozzle) is preferably small, as Figure 1D presented in [reference]. At the same time, as the discharge velocity of the droplets is higher, the horizontal distance that the droplets fly through becomes larger. In such a case, when the diameter of the tube of the conveying path is small, the droplets discharged from the discharge hole (nozzle) collide with the surface of the tube (pice) facing the discharge hole (nozzle) before the droplets are dried. As a result, particles cannot be obtained, which is problematic. Therefore, as Figure 1E presented in [reference], it is necessary to design the diameter or shape of the tube of the conveying path by, for example, reducing the diameter of the tube of the conveying path facing the discharge hole (nozzle) and increasing the diameter of the tube during the conveying process.

[0087] As described below, the present inventors have revealed that when the distance from the discharge hole to the center of the conveying air current is shortened, the influence of the conveying air current on the droplets discharged from the discharge hole can be enhanced, and the droplets are easily conveyed and dried, which positively affects the production of particles having a uniform particle size distribution (see Figure 2B and Figure 2C ).

[0088] The shortest distance A (m) from the droplet forming unit to the center of the conveying air current is the shortest distance (horizontal distance) from the discharge hole of the droplet forming unit to the position where the flow velocity of the conveying air current reaches the maximum value. The flow velocity of the conveying air current generally reaches the maximum value at the center of the conveying path. However, in the case where the conveying path is a tube having a special shape different from the normal shapes (for example, a circular tube, a triangular tube, and a square tube) (see, for example, Figure 2B ), or in the case where the path of the conveying path has a curved structure, or the diameter of the cross section intersecting the long axis of the conveying path changes during the path (see, for example, Figure 2C ), the center of the conveying air current may not always be the position where the flow velocity of the conveying air current reaches the maximum value.

[0089] The discharge driving frequency F (Hz) is the driving period of the vibration imparting member configured to impart vibration to the liquid to continuously discharge droplets.

[0090] For example, the discharge driving frequency F (Hz) is preferably 1 kHz or more but 2000 kHz or less, more preferably 30 kHz or more but 1000 kHz or less.

[0091] Examples of the member for imparting vibration include: (1) a "member for changing volume", which is configured to change the volume of the liquid storage portion by vibration; (2) a "member for causing necking portion", which is configured to discharge liquid from a plurality of discharge holes provided in the liquid storage portion while applying vibration to the liquid storage portion, so as to neck a columnar liquid, and then form droplets; and (3) a "member for vibrating nozzle", which is configured to vibrate a thin film formed thereon with a discharge hole. Each unit will be described hereinafter.

[0092] 《Member for Changing Volume》

[0093] The member for changing volume is not particularly limited and can be appropriately selected depending on the intended purpose, as long as it can change the volume of the liquid storage portion and can vibrate the liquid to discharge droplets. Examples of the member for changing volume include a piezoelectric element that expands and contracts by applying a voltage, and a heat-electric conversion element such as a heating resistor.

[0094] 《Member for Causing Necking Portion》

[0095] Examples of the member for causing necking portion include those using the technique described in Japanese Unexamined Patent Application Publication No. 2007-199463. Japanese Unexamined Patent Application Publication No. 2007-199463 describes that while a vibration portion using a piezoelectric element in contact with a part of the liquid storage portion applies vibration to the liquid storage portion, a raw material liquid is discharged from a plurality of nozzle holes provided in the liquid storage portion, so as to neck the columnar raw material liquid, and then form droplets.

[0096] 《Member for Vibrating Nozzle》

[0097] Examples of the member for vibrating nozzle include those using the technique described in Japanese Unexamined Patent Application Publication No. 2008-292976. Japanese Unexamined Patent Application Publication No. 2008-292976 describes that a raw material liquid is discharged from the plurality of nozzle holes to form droplets by using a thin film provided in a liquid storage portion in which a plurality of nozzles are formed, and a piezoelectric element provided around a region where the film can be deformed and configured to vibrate the film.

[0098] To generate vibration, a piezoelectric element is generally used. The piezoelectric element is not particularly limited, and its shape, size, and material can be selected depending on the intended purpose. For example, a piezoelectric element used in a conventional inkjet discharge system can be suitably used.

[0099] The shape and size of the piezoelectric element are not particularly limited and can be appropriately selected depending on, for example, the shape of the discharge hole.

[0100] The material of the piezoelectric element is not particularly limited and can be appropriately selected depending on the intended purpose. Examples of the material include piezoelectric ceramics (e.g., lead zirconate titanate (PZT)), piezoelectric polymers (e.g., polyvinylidene fluoride (PVDF)), and single crystals (e.g., quartz, LiNbO 3 、LiTaO 3 、and KNbO 3 ).

[0101] -Discharge hole-

[0102] The discharge hole is not particularly limited and can be appropriately selected depending on the intended purpose. Examples of the discharge hole include orifices provided in, for example, a nozzle plate.

[0103] The number, cross-sectional shape, and size of the discharge hole can be appropriately selected.

[0104] The number of the discharge holes is not particularly limited and can be appropriately selected depending on the intended purpose. For example, the number thereof is preferably 2 or more but 3,000 or less. When the number of the discharge holes is 2 or more but 3,000 or less, productivity can be improved.

[0105] The cross-sectional shape of the discharge hole is not particularly limited and can be appropriately selected depending on the intended purpose. Examples of the cross-sectional shape include: (1) a conical shape in which the opening diameter decreases from the liquid contact surface (entrance) of the discharge hole toward the discharge hole (exit); (2) a shape in which the opening diameter narrows while maintaining its circular shape from the liquid contact surface (entrance) of the discharge hole toward the discharge hole (exit); (3) a shape in which the opening diameter narrows while maintaining a certain nozzle angle from the liquid contact surface (entrance) of the discharge hole toward the discharge hole (exit); and (4) a combination of the shape of (1) and the shape of (2). Among them, (3) a shape in which the opening diameter narrows while maintaining a certain nozzle angle from the liquid contact surface (entrance) of the discharge hole toward the discharge hole (exit) is preferable because the pressure applied to the liquid at the discharge hole reaches the maximum value.

[0106] The nozzle angle in the shape of (3) is not particularly limited and can be appropriately selected depending on the intended purpose. The nozzle angle is preferably 60° or more but 90° or less. When the nozzle angle is 60° or more, it is easy to apply pressure to the liquid and easy to perform processing. When the nozzle angle is 90° or less, pressure can be applied at the discharge hole to stabilize the discharge of the liquid droplets. Therefore, the maximum value of the nozzle angle is preferably 90°.

[0107] The size of the discharge holes can be appropriately selected in consideration of the sustained release property of the particles to be produced. For example, the diameter of the discharge holes is preferably 12 μm or more but 100 μm or less, more preferably 15 μm or more but 30 μm or less. When the size of the discharge holes is 12 μm or more but 100 μm or less, particles having a particle size sufficient to achieve sustained release can be obtained.

[0108] 《Liquid storage part》

[0109] The liquid storage part is not particularly limited, and its shape and size can be appropriately selected depending on the intended purpose, as long as it includes a space for temporarily storing the stored liquid containing the physiologically active substance and the polymer.

[0110] -Liquid-

[0111] The liquid contains a physiologically active substance and a polymer, and if necessary, further contains a dispersant, a solvent, and other components.

[0112] --Physiologically active substance--

[0113] The physiologically active substance is not particularly limited and can be appropriately selected depending on the intended purpose. Those same as the physiologically active substance contained in the particles of the present disclosure can be suitably used, which will be described below.

[0114] --Polymer--

[0115] The polymer is not particularly limited and can be appropriately selected depending on the intended purpose. Those same as the polymer contained in the particles of the present disclosure can be suitably used, which will be described below.

[0116] --Dispersant--

[0117] A dispersant can be suitably used to disperse the physiologically active substance. When the physiologically active substance is uniformly dispersed in the liquid, the physiologically active substance can be included in the particles as a solid.

[0118] The dispersant can be a low molecular weight dispersant or a high molecular weight dispersant polymer.

[0119] A low molecular weight dispersant means a compound having a weight average molecular weight of less than 15,000. A high molecular weight dispersant polymer means a compound including repeating covalent bonds between one or more monomers and having a weight average molecular weight of 15,000 or more.

[0120] The low molecular weight dispersant is not particularly limited and can be appropriately selected depending on the intended purpose, as long as it is acceptable as a physiologically active substance such as a drug. Examples of the low molecular weight dispersant include lipids, sugars, cyclodextrins, amino acids, and organic acids. These can be used alone or in combination.

[0121] The lipids are not particularly limited and can be appropriately selected depending on the intended purpose. Examples of lipids include medium-chain or long-chain monoglycerides, diglycerides, or triglycerides, phospholipids, vegetable oils (e.g., soybean oil, avocado oil, squalene oil, sesame oil, olive oil, corn oil, rapeseed oil, safflower oil, and sunflower oil), fish oil, flavoring oils, water-insoluble vitamins, fatty acids, mixtures thereof, and their derivatives. These can be used alone or in combination.

[0122] The sugars are not particularly limited and can be appropriately selected depending on the intended purpose. Examples of sugars include glucose, mannose, idose, galactose, fucose, ribose, xylose, lactose, sucrose, maltose, trehalose, turanose, raffinose, maltotriose, acarbose, glycerol, sorbitol, lactitol, maltitol, mannitol, xylitol, erythritol, polyols, and their derivatives. These can be used alone or in combination.

[0123] The cyclodextrins are not particularly limited and can be appropriately selected depending on the intended purpose. Examples of cyclodextrins include hydroxypropyl-β-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, α-cyclodextrin, and cyclodextrin derivatives. These can be used alone or in combination.

[0124] The amino acids are not particularly limited and can be appropriately selected depending on the intended purpose. Examples of amino acids include valine, lysine, leucine, threonine, isoleucine, asparagine, glutamine, phenylalanine, aspartic acid, serine, glutamic acid, methionine, arginine, glycine, alanine, tyrosine, proline, histidine, cysteine, tryptophan, and their derivatives. These can be used alone or in combination.

[0125] The organic acids are not particularly limited and can be appropriately selected depending on the intended purpose. Examples of organic acids include adipic acid, ascorbic acid, citric acid, fumaric acid, gallic acid, glutaric acid, lactic acid, malic acid, maleic acid, succinic acid, tartaric acid, and their derivatives. These can be used alone or in combination.

[0126] The high-molecular-weight dispersant polymers are not particularly limited and can be appropriately selected depending on the intended purpose. Examples of high-molecular-weight dispersant polymers include water-soluble celluloses, polyalkylene glycols, poly(meth)acrylamides, poly(meth)acrylic acids, poly(meth)acrylates, poly(allylamine)s, polyvinylpyrrolidone, polyvinyl alcohols, polyvinyl acetates, biodegradable polyesters, polyglycolic acids, polyamino acids, gelatins, polymalic acid, polydioxanone, and their derivatives. These can be used alone or in combination.

[0127] The water-soluble celluloses are not particularly limited and can be appropriately selected depending on the intended purpose. Examples of the water-soluble celluloses include alkyl celluloses (e.g., methyl cellulose and ethyl cellulose); hydroxyalkyl celluloses (e.g., hydroxyethyl cellulose and hydroxypropyl cellulose); and hydroxyalkyl alkyl celluloses (e.g., hydroxyethyl methyl cellulose and hydroxypropyl methyl cellulose). These can be used alone or in combination. Among them, hydroxypropyl cellulose and hydroxypropyl methyl cellulose are preferred in terms of improving solubility, and hydroxypropyl cellulose is more preferred.

[0128] As hydroxypropyl cellulose, various products with different viscosities (which are considered to depend on the weight-average molecular weight, degree of substitution, and molecular weight) are commercially available from different companies, and all of them can be used in the present disclosure.

[0129] The weight-average molecular weight of hydroxypropyl cellulose is not particularly limited and can be appropriately selected depending on the intended purpose. Its weight-average molecular weight is preferably 15,000 or more but 400,000 or less. Note that its weight-average molecular weight can be measured by, for example, gel permeation chromatography (GPC).

[0130] The viscosity (at 20 degrees Celsius) of a 2% by mass aqueous solution of hydroxypropyl cellulose is not particularly limited and can be appropriately selected depending on the intended purpose. Its viscosity is preferably 2.0 mPa·s (centipoise, cp) or more but 4,000 mPa·s (centipoise, cp) or less.

[0131] As the hydroxypropyl cellulose, commercially available products can be used. The commercially available products of hydroxypropyl cellulose are not particularly limited and can be appropriately selected depending on the intended purpose. Examples of the commercially available products of hydroxypropyl cellulose include: HPC-SSL (molecular weight of 15,000 or more but 30,000 or less and viscosity of 2.0 mPa·s or more but 2.9 mPa·s or less); HPC-SL (molecular weight of 30,000 or more but 50,000 or less and viscosity of 3.0 mPa·s or more but 5.9 mPa·s or less); HPC-L (molecular weight of 55,000 or more but 70,000 or less and viscosity of 6.0 mPa·s or more but 10.0 mPa·s or less); HPC-M (molecular weight of 110,000 or more but 150,000 or less and viscosity of 150 mPa·s or more but 400 mPa·s or less); and HPC-H (molecular weight of 250,000 or more but 400,000 or less and viscosity of 1,000 mPa·s or more but 4,000 mPa·s or less (all of which are available from Nippon Soda Co., Ltd.)). These can be used alone or in combination. Among them, HPC-SSL (molecular weight of 15,000 or more but 30,000 or less and viscosity of 2.0 mPa·s or more but 2.9 mPa·s or less) is preferred.

[0132] The polyalkylene glycol is not particularly limited and can be appropriately selected depending on the intended purpose. Examples of the polyalkylene glycol include polyethylene glycol (PEG), polypropylene glycol, polybutylene glycol, and their copolymers. These can be used alone or in combination.

[0133] The poly(meth)acrylamides are not particularly limited and can be appropriately selected depending on the intended purpose. Examples of the poly(meth)acrylamides include N-methyl(meth)acrylamide, N-ethyl(meth)acrylamide, N-propyl(meth)acrylamide, N-butyl(meth)acrylamide, N-benzoyl(meth)acrylamide, N-hydroxyethyl(meth)acrylamide, N-phenyl(meth)acrylamide, N-tolyl(meth)acrylamide, N-(hydroxyphenyl)(meth)acrylamide, N-(aminosulfonylphenyl)(meth)acrylamide, N-(phenylsulfonyl)(meth)acrylamide, N-(tolylsulfonyl)(meth)acrylamide, N,N-dimethyl(meth)acrylamide, N-methyl-N-phenyl(meth)acrylamide, and N-hydroxyethyl-N-methyl(meth)acrylamide. These can be used alone or in combination.

[0134] The poly(meth)acrylic acid is not particularly limited and can be appropriately selected depending on the intended purpose. Examples of the poly(meth)acrylic acid include homopolymers (e.g., polyacrylic acid and polymethacrylic acid) and copolymers (e.g., acrylic acid-methacrylic acid copolymer). These can be used alone or in combination.

[0135] The poly(meth)acrylate is not particularly limited and can be appropriately selected depending on the intended purpose. Examples of the poly(meth)acrylate include ethylene glycol di(meth)acrylate, diethylene glycol di(meth)acrylate, propylene glycol di(meth)acrylate, glycerol poly(meth)acrylate, polyethylene glycol (meth)acrylate, trimethylolpropane tri(meth)acrylate, pentaerythritol tetra(meth)acrylate, and 1,3-butanediol di(meth)acrylate.

[0136] The polyallylamine is not particularly limited and can be appropriately selected depending on the intended purpose. Examples of the polyallylamine include diallylamine and triallylamine. These can be used alone or in combination.

[0137] As the polyvinylpyrrolidone, commercially available products can be used. The commercially available products of polyvinylpyrrolidone are not particularly limited and can be appropriately selected depending on the intended purpose. Examples of the commercially available products of polyvinylpyrrolidone include PLASDONE C-15 (available from ISP TECHNOLOGIES), Kollidon VA64, Kollidon K-30, and Kollidon CL-M (all available from KAWARLAL), and Kollicoat IR (available from BASF). These can be used alone or in combination.

[0138] The polyvinyl alcohols are not particularly limited and can be appropriately selected depending on the intended purpose. Examples of the polyvinyl alcohols include silanol-modified polyvinyl alcohol, carboxyl-modified polyvinyl alcohol, and acetoacetyl-modified polyvinyl alcohol. These can be used alone or in combination.

[0139] The polyvinyl acetates are not particularly limited and can be appropriately selected depending on the intended purpose. Examples of the polyvinyl acetates include vinyl acetate-crotonic acid copolymer and vinyl acetate-itaconic acid copolymer. These can be used alone or in combination.

[0140] The biodegradable polyesters are not particularly limited and can be appropriately selected depending on the intended purpose. Examples of the biodegradable polyesters include polylactic acid, poly-ε-caprolactone, succinate-based polymers, and polyhydroxyalkanoates. These can be used alone or in combination.

[0141] The succinate-based polymers are not particularly limited and can be appropriately selected depending on the intended purpose. Examples of succinate-based polymers include polyethylene succinate, polybutylene succinate, and poly(butylene adipate-co-succinate). These can be used alone or in combination.

[0142] The polyhydroxyalkanoates are not particularly limited and can be appropriately selected depending on the intended purpose. Examples of polyhydroxyalkanoates include polyhydroxypropionate, polyhydroxybutyrate, and polyhydroxyvalerate. These can be used alone or in combination.

[0143] The polyglycolic acids are not particularly limited and can be appropriately selected depending on the intended purpose. Examples of polyglycolic acids include lactic acid-glycolic acid copolymers, glycolic acid-caprolactone copolymers, and glycolic acid-trimethylene carbonate copolymers. These can be used alone or in combination.

[0144] The polyamino acids are not particularly limited and can be appropriately selected depending on the intended purpose. Examples of polyamino acids include amino acid homopolymers (e.g., poly-α-glutamic acid, poly-γ-glutamic acid, polyaspartic acid, polylysine, polyarginine, polyornithine, and polyserine) and their copolymers. These can be used alone or in combination.

[0145] The gelatins are not particularly limited and can be appropriately selected depending on the intended purpose. Examples of gelatins include lime-treated gelatin, acid-treated gelatin, gelatin hydrolysates, gelatinase dispersion products, and their derivatives. These can be used alone or in combination.

[0146] The natural dispersant polymers used in gelatin derivatives are not particularly limited and can be appropriately selected depending on the intended purpose. Examples of natural dispersants include proteins, polysaccharides, and nucleic acids. Also included are copolymers formed from natural dispersant polymers or synthetic dispersant polymers. These can be used alone or in combination.

[0147] Gelatin derivatives mean gelatins derived by covalently bonding gelatin molecules with hydrophobic groups. The hydrophobic groups are not particularly limited and can be appropriately selected depending on the intended purpose. Examples of hydrophobic groups include polyesters (e.g., polylactic acid, polyglycolic acid, and poly-ε-caprolactone); lipids (e.g., cholesterol and phosphatidylethanolamine); aromatic groups including alkyl groups and benzene groups; aromatic heterocyclic groups, and mixtures thereof.

[0148] The proteins are not particularly limited and can be appropriately selected depending on the intended purpose. Examples of proteins include collagen, fibrin, and albumin. These can be used alone or in combination.

[0149] The polysaccharide is not particularly limited and can be appropriately selected depending on the intended purpose. Examples of the polysaccharide include chitin, chitosan, hyaluronic acid, alginic acid, starch, and pectin. These can be used alone or in combination.

[0150] Relative to the total amount of the particles of the present disclosure, the amount of the dispersant is preferably 5% by mass or more but 95% by mass or less, more preferably 50% by mass or more but 95% by mass or less. A dispersant amount satisfying 5% by mass or more but 95% by mass or less is advantageous because, for example, the dose as a pharmaceutical composition becomes appropriate, and it is easy to redisperse the drug ingredient in water by the action of the dispersant.

[0151] --Solvent--

[0152] The solvent is not particularly limited and can be appropriately selected depending on the intention. Those that can dissolve and disperse poorly water-soluble compounds or their pharmaceutically acceptable salts are preferred.

[0153] Examples of the solvent include aliphatic halogenated hydrocarbons (e.g., dichloromethane, dichloroethane, and chloroform), alcohols (e.g., methanol, ethanol, and propanol), ketones (e.g., acetone and methyl ethyl ketone), ethers (e.g., diethyl ether, dibutyl ether, and 1,4-dioxane), aliphatic hydrocarbons (e.g., n-hexane, cyclohexane, and n-heptane), aromatic hydrocarbons (e.g., benzene, toluene, and xylene), organic acids (e.g., acetic acid and propionic acid), esters (e.g., ethyl acetate), and amides (e.g., dimethylformamide and dimethylacetamide). These can be used alone or in combination. Among them, in terms of solubility, aliphatic halogenated hydrocarbons, alcohols, ketones, and their mixed solvents are preferred, and dichloromethane, 1,4-dioxane, methanol, ethanol, acetone, and their mixed solvents are more preferred.

[0154] Relative to the total amount of the liquid in the present disclosure, the amount of the solvent is preferably 70% by mass or more but 99.5% by mass or less, more preferably 90% by mass or more but 99% by mass or less. A solvent amount satisfying 70% by mass or more but 99.5% by mass or less is advantageous in terms of the solubility of the material, the viscosity of the solution, and the production stability.

[0155] --Other Ingredients--

[0156] The other ingredients are not particularly limited and can be appropriately selected depending on the intended purpose. They are preferably those that can be conventionally used in pharmaceutical compositions.

[0157] Examples of the other ingredients include water, excipients, fragrances, disintegrants, fluidizing agents, adsorbents, lubricants, flavor masking agents, surfactants, perfumes, colorants, antioxidants, masking agents, antistatic agents, and wetting agents. These can be used alone or in combination.

[0158] There are no particular restrictions on the excipients, and they can be appropriately selected depending on the intended purpose. Examples of excipients include lactose, sucrose, mannitol, glucose, fructose, maltose, erythritol, maltitol, xylitol, palatinose, trehalose, sorbitol, crystalline cellulose, talc, silicon anhydride, anhydrous calcium phosphate, precipitated calcium carbonate, and calcium silicate. These can be used alone or in combination.

[0159] There are no particular restrictions on the flavoring agents, and they can be appropriately selected depending on the intended purpose. Examples of flavoring agents include L-menthol, sucrose, D-sorbitol, xylitol, citric acid, ascorbic acid, tartaric acid, malic acid, aspartame, acesulfame potassium, thaumatin, sodium saccharin, dipotassium glycyrrhizinate, sodium glutamate, sodium 5′-inosinateum, and sodium 5′-guanylate. These can be used alone or in combination.

[0160] There are no particular restrictions on the disintegrants, and they can be appropriately selected depending on the intended purpose. Examples of disintegrants include low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, cross-linked povidone, hydroxypropyl starch, and corn starch. These can be used alone or in combination.

[0161] There are no particular restrictions on the fluidizing agents, and they can be appropriately selected depending on the intended purpose. Examples of fluidizing agents include light anhydrous silicic acid, hydrated silica, and talc. These can be used alone or in combination.

[0162] As the light anhydrous silicic acid, commercially available products can be used. There are no particular restrictions on the commercially available products of light anhydrous silicic acid, and they can be appropriately selected depending on the intended purpose. Examples of the commercially available products of light anhydrous silicic acid include Adsolider 101 (available from Freund Corporation: average pore diameter: 21 nm).

[0163] As the adsorbent, commercially available products can be used. Commercially available products of the adsorbent are not particularly limited and can be appropriately selected depending on the intended purpose. Examples of commercially available products of the adsorbent include product name: CARPLEX (ingredient name: synthetic silica, a registered trademark of Evonik Japan), product name: AEROSIL (a registered trademark of NIPPON AEROSIL CO., LTD.) 200 (ingredient name: hydrophilic pyrogenic silica), product name: SYLYSIA (ingredient name: amorphous silica, a registered trademark of FujiSilysia chemical Ltd.), and product name: ALCAMAC (ingredient name: synthetic hydrotalcite, a registered trademark of Kyowa Chemical Industry Co., Ltd.). These can be used alone or in combination.

[0164] The lubricant is not particularly limited and can be appropriately selected depending on the intended purpose. Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate, stearic acid, polyethylene glycol, and talc. These can be used alone or in combination.

[0165] The flavor masking agent is not particularly limited and can be appropriately selected depending on the intended purpose. Examples of the flavor masking agent include trehalose, malic acid, maltose, potassium gluconate, fennel essential oil, vanilla essential oil, and cardamom essential oil. These can be used alone or in combination.

[0166] The surfactant is not particularly limited and can be appropriately selected depending on the intended purpose. Examples of the surfactant include polysorbate (e.g., polysorbate 80); polyoxyethylene·polyoxypropylene copolymer; and sodium lauryl sulfate. These can be used alone or in combination.

[0167] The fragrance is not particularly limited and can be appropriately selected depending on the intended purpose. Examples of the fragrance include lemon oil, orange oil, and peppermint oil. These can be used alone or in combination.

[0168] The colorant is not particularly limited and can be appropriately selected depending on the intended purpose. Examples of the colorant include titanium oxide, Food Yellow No. 5, Food Blue No. 2, iron oxide, and yellow iron oxide. These can be used alone or in combination.

[0169] The antioxidant is not particularly limited and can be appropriately selected depending on the intended purpose. Examples of the antioxidant include sodium ascorbate, L-cysteine, sodium sulfite, and vitamin E. These can be used alone or in combination.

[0170] The masking agent is not particularly limited and can be appropriately selected depending on the intended purpose. Examples of the masking agent include titanium oxide. These can be used alone or in combination.

[0171] The antistatic agent is not particularly limited and can be appropriately selected depending on the intended purpose. Examples of the antistatic agent include talc and titanium oxide. These can be used alone or in combination.

[0172] The wetting agent is not particularly limited and can be appropriately selected depending on the intended purpose. Examples of the wetting agent include polysorbate 80, sodium lauryl sulfate, sucrose fatty acid ester, polyethylene glycol, and hydroxypropyl cellulose (HPC). These can be used alone or in combination.

[0173] The liquid may not contain a solvent as long as the liquid is in a state where the physiologically active substance is dissolved, the liquid is in a state where the physiologically active substance is dispersed, or the liquid is in a liquid state under the discharge conditions. The liquid may be in a state where the particulate component is melted.

[0174] <Particle formation step and particle formation unit>

[0175] The particle formation step is a step of solidifying droplets to form particles, and is carried out by a particle formation unit.

[0176] The particle formation unit is not particularly limited and can be appropriately selected depending on the intended purpose as long as it is configured to solidify droplets to form particles. For example, when the liquid contains a solid raw material dissolved or dispersed in a volatile solvent, a unit that utilizes a conveying air flow and is configured to discharge droplets into the conveying air flow to dry the droplets is used.

[0177] The method of solidifying droplets using a conveying air flow is not particularly limited and can be appropriately selected depending on the intended purpose. Preferred examples of the method include a method in which the conveying direction of the conveying air flow is a direction substantially perpendicular to the droplet discharge direction. The drying method using a conveying air flow will be described in detail in the description of the drawings (which will be described below).

[0178] In order to dry the solvent, it is preferable to adjust, for example, the temperature and vapor pressure of the conveying air flow, and the type of gas.

[0179] As long as the collected particles remain in a solid state, even when the collected particles are not completely dried, a drying step can be additionally provided in another step after collection.

[0180] In addition, a method of drying droplets by applying a temperature change or a chemical change can be used.

[0181] <Other steps>

[0182] The other steps are not particularly limited and can be appropriately selected depending on the intended purpose. Examples of the other steps include a particle collection step.

[0183] The particle collection step is a step of collecting the dried particles and can be suitably carried out by a particle collection unit.

[0184] The particle collection unit is not particularly limited and can be appropriately selected depending on the intended purpose. Examples of the particle collection unit include cyclone collection and bag filters.

[0185] Since the discharge unit configured to discharge a liquid by using vibration to form droplets is used in the particle production method and particle production equipment of the present disclosure, the droplet discharge size can be easily controlled, the particle size of the particles can be increased, and the particle size distribution can be narrowed. Therefore, the particle production method and particle production equipment of the present disclosure can produce particles having a sustained release property that can be controlled with high precision.

[0186] Here, an example of the particle production equipment used in the particle production method of the present disclosure will be described with reference to Figures 4A - 7B An example of the particle production equipment used in the particle production method of the present disclosure will be described.

[0187] Figure 4A and Figure 4B are schematic diagrams showing an example of the particle production equipment. Figure 5 is a diagram showing an example of the droplet forming unit used in the particle production equipment. Figure 6A is a diagram showing another example of the droplet forming unit used in the particle production equipment. Figure 6B is shown in Figure 6A a side view of an example of the droplet forming unit shown in Figure 7A is a diagram showing another example of the droplet forming unit used in the particle production equipment. Figure 7B is shown in Figure 7A a side view of an example of the droplet forming unit shown in

[0188] Figure 4A and Figure 4BThe particle production apparatus 1 presented includes a droplet formation unit 2, a drying and collection unit 60, a transfer air flow discharge port 65, and a particle storage unit 63. The droplet formation unit 2 is connected to a liquid storage unit 13 configured to store a liquid 14, and a liquid circulation pump 15 configured to supply the liquid 14 stored in the liquid storage unit 13 to the droplet formation unit 2 through a liquid supply pipe 16 and feed the liquid 14 in the liquid supply pipe 16 under pressure to return to the liquid storage unit 13 through a liquid return pipe 22. Accordingly, the liquid 14 can always be supplied to the droplet formation unit 2. The liquid supply pipe 16 is provided with a pressure gauge P1 and the drying and collection unit is provided with a pressure gauge P2. The pressure for feeding the liquid to the droplet formation unit 2 and the pressure inside the drying and collection unit are controlled by the pressure gauges P1 and P2. When the pressure value measured at P1 is greater than the pressure value measured at P2, there is a risk of the liquid 14 leaking out from the discharge hole. When the pressure value measured at P1 is less than the pressure value measured at P2, there is a risk of gas entering the droplet formation unit 2 to stop the discharge. Therefore, it is preferable that the pressure value measured at P1 and the pressure value measured at P2 are substantially the same.

[0189] Inside the chamber 61, a downward air flow (transfer air flow) 101 generated from the transfer air flow introduction port 64 is formed. The droplets 21 discharged from the droplet formation unit 2 are conveyed downward not only by gravity but also by the transfer air flow 101, pass through the transfer air flow discharge port 65, are collected by the particle collection unit 62, and are stored in the particle storage unit 63.

[0190] In the droplet discharge step, when the discharged droplets come into contact with each other before they are dried, the droplets coalesce to form a single particle (hereinafter, this phenomenon may be referred to as "coagulation"). In order to obtain particles having a uniform particle size distribution, it is necessary to maintain a distance between the discharged droplets. Although the droplets travel at a certain initial velocity, their velocity rapidly decreases due to air resistance. The droplets with decreased velocity are caught up by the subsequently discharged droplets, which results in coagulation. This phenomenon often occurs. Therefore, when the particles formed from the droplets are collected, the particle size distribution deteriorates significantly. In order to prevent coagulation, it is preferable to dry and convey the droplets through the transfer air flow 101 while preventing the velocity of the droplets from decreasing and the droplets from contacting each other to prevent coagulation, and preferably finally convey the particles to the particle collection unit 62.

[0191] As Figure 4A presented, a part of the transfer air flow 101 as the first air flow is provided in the same direction as the droplet discharge direction near the droplet formation unit 2. As a result, a decrease in the velocity of the droplets immediately after they are discharged is prevented, which makes it possible to prevent coagulation.

[0192] Figure 5 For presenting applicable to presented in Figure 4A andFigure 4B A diagram of an example of a droplet forming unit of a particle production apparatus. As Figure 5 shown, the droplet forming unit 2 includes a volume changing member 20, an elastic plate 9, and a liquid storage section 19. When a voltage is applied to the volume changing member 20, the droplet forming unit 2 deforms to reduce the volume of the liquid storage section 19. As a result, the liquid stored in the liquid storage section 19 is discharged as droplets from the discharge holes.

[0193] As described above, after preventing aggregation by the first air flow, the dried particles can be conveyed to the particle collection section by the second air flow.

[0194] The speed of the first air flow is preferably equal to or higher than the droplet discharge speed. When the speed of the conveying air flow 101 for preventing aggregation is lower than the droplet discharge speed, it may be difficult to exhibit the function of preventing the droplets 21 from contacting each other (which is the purpose of the conveying air flow for preventing aggregation).

[0195] As the property of the first air flow, the conditions for preventing the droplets 21 from aggregating can be increased, and the property of the first air flow can be different from that of the second air flow. In addition, a chemical substance that promotes drying of the particle surface can be mixed with or added to the conveying air flow for preventing aggregation, and a physical effect is expected.

[0196] The state of the conveying air flow 101 is not particularly limited to the state of this air flow. The conveying air flow 101 can be a laminar flow, a swirling flow, or a turbulent flow. The type of gas constituting the conveying air flow 101 is not particularly limited and can be appropriately selected depending on the intended purpose. For example, air can be used, or an incombustible gas such as nitrogen can be used. The temperature of the conveying air flow 101 can be appropriately adjusted. Preferably, the temperature is not changed during production. A unit configured to change the air flow conditions of the conveying air flow 101 can be included in the chamber 61. The conveying air flow 101 can be used not only for preventing aggregation of the droplets 21 but also for preventing adhesion to the chamber 61.

[0197] When Figure 4A and Figure 4B the amount of residual solvent contained in the particles obtained by the particle collection unit 62 shown is large, if necessary, secondary drying is preferably performed to reduce the residual solvent. As the secondary drying, known drying units such as fluidized bed drying and vacuum drying can be used. When the solvent remains in the particles, the particle characteristics (for example, heat-resistant storage stability, fixing property, and charging property) change over time, and the solvent volatilizes when fixing is performed using heat, which can increase the possibility of adverse effects on the user and peripheral devices. Therefore, sufficient drying is preferably performed.

[0198] When the amount of the residual solvent contained in the obtained particles is large, secondary drying is preferably performed if necessary. As the secondary drying, known drying units such as fluidized bed drying and vacuum drying can be used.

[0199] When the solvent remains in the produced particles, the particle properties (e.g., heat-resistant storage stability, fixability, and charging properties) may change over time. Therefore, sufficient drying is preferably performed.

[0200] Another example of the particle production equipment used in the particle production method of the present disclosure is the particle production equipment described in Japanese Patent Application Laid-Open No. 2007-199463. As Figure 7A and Figure 7B presented in, the particle production equipment includes at least a liquid storage section 111 configured to store the particle raw material fluid, a vibration unit 102, and through holes 104. The particle raw material fluid to be released from the through holes 104 is quantitatively supplied to the liquid storage section 111 and quantitatively released from the through holes 104 to form the particle raw material fluid into a liquid column. In this production equipment, the number X of the vibration units and the number Y of the through holes satisfy the following expression:

[0201] 10*X ≤ Y ≤ 10000*X.

[0202] The vibration unit is in contact with a part of the liquid storage section and vibrates the particle raw material fluid via the liquid storage section.

[0203] The vibration forms the particle raw material fluid into droplets, which are expected to be dried into solid particles.

[0204] For example, as Figure 7A and Figure 7B presented in, a preferred particle production equipment includes at least the following as a droplet forming unit: a liquid storage section 111 configured to store the particle raw material fluid, a vibration unit 102, a support unit configured to support the vibration unit, and a plurality of through holes 104, wherein the particle raw material fluid released from the through holes 104 is quantitatively supplied to the liquid storage section 111. Another example is suitably an equipment including: a liquid supply unit 116 configured to quantitatively release the particle raw material fluid from the through holes, a solvent removal section as a particle forming unit 106, and a particle collection section 107.

[0205] (Particles)

[0206] The particles of the present disclosure can be suitably produced by the particle production method of the present disclosure.

[0207] The particles produced by the particle production method of the present disclosure preferably contain a physiologically active substance and, if necessary, further contain other components.

[0208] -Bioactive substance-

[0209] The bioactive substance is not particularly limited and can be appropriately selected depending on the intended purpose. Examples of the bioactive substance include pharmaceutical compounds, functional food compounds, and functional cosmetic compounds. When the bioactive substance in the particle is a solid dispersion, the bioactive substance exists in the particle in a uniformly dispersed state.

[0210] --Pharmaceutical compound--

[0211] The pharmaceutical compound is not particularly limited and can be appropriately selected depending on the intended purpose as long as it can achieve the form of the functional particle or pharmaceutical composition. Examples of the pharmaceutical compound include poorly water-soluble compounds and water-soluble compounds.

[0212] In particular, for example, when a poorly water-soluble compound used as a solid dispersion is produced as a particle by the following particle production method of the present disclosure, its bioavailability can be increased even when administered orally, for example.

[0213] The poorly water-soluble compound has a logP value of the water / octanol partition coefficient of 3 or more. The water-soluble compound refers to a compound having a logP value of the water / octanol partition coefficient of less than 3. The water / octanol partition coefficient can be measured by the shake flask method according to JIS Z7260-107(2000). The pharmaceutical compound includes any form of compound such as salts and hydrates as long as it is effective as a drug.

[0214] The poorly water-soluble compounds are not particularly limited and can be appropriately selected depending on the intended purpose. Examples of poorly water-soluble compounds include griseofulvin, itraconazole, norfloxacin, tamoxifen, ciclosporin, glibenclamide, troglitazone, nifedipine, phenacetin, phenytoin, digitoxin, nilvadipine, diazepam, chloramphenicol, indomethacin, nimodipine, dihydroergotoxine, cortisone, dexamethasone, naproxen, tulobuterol, beclometasone propionate, fluticasone propionate, pranlukast, tranilast, loratadine, tacrolimus, amprenavir, bexarotene, calcitriol, clofazimine, digoxin, doxercalciferol, dronabinol, etoposide, isotretinoin, lopinavir, ritonavir, progesterone, saquinavir, sirolimus, tretinoin, valproicacid), amphotericin, fenoldopam, melphalan, paricalcitol, propofol, voriconazole, ziprasidone, docetaxel, haloperidol, lorazepam, teniposide, testosterone, valrubicin, quercetin, and allopurinol. These can be used alone or in combination. Among them, cyclosporine and tranilast are preferred, and cyclosporine is more preferred.

[0215] The water-soluble compound is not particularly limited and can be appropriately selected depending on the intended purpose. Examples of water-soluble compounds include abacavir, acetaminophen, aciclovir, amiloride, amitriptyline, antipyrine, atropine, buspirone, caffeine, captopril, chlorquine, chlorpheniramine, cyclophosphamide, desipramine, diazepam, diltiazem, diphenhydramine, disopyramide, doxin, doxycycline, enalapril, ephedrine, ethambutol, ethinylestradiol, fluoxetine, imipramine, clomipramine, glucose, ketorol, ketoprofen, labetalol, levodopa, levofloxacin, metoprolol, metronidazole, midazolam, minocycline, misoprostol, metformin, nifedipine, phenobarbital, prednisolone, promazine, propranolol, quinidine, rosiglitazone, salicylic acid, theophylline, valproic acid, verapamil, zidovudine, and calcitonin. These can be used alone or in combination.

[0216] --Functional food compound--

[0217] The functional food compounds are not particularly limited and can be appropriately selected depending on the intended purpose. Examples of functional food compounds include vitamin A, vitamin D, vitamin E, lutein, zeaxanthin, lipoic acid, flavonoids, and fatty acids (e.g., ω-3 fatty acids and ω-6 fatty acids). These can be used alone or in combination.

[0218] --Functional cosmetic compounds--

[0219] The functional cosmetic compounds are not particularly limited and can be appropriately selected depending on the intended purpose. Examples of functional cosmetic compounds include alcohols, aliphatic alcohols, polyols, aldehydes, alkanolamines, alkoxylated alcohols (e.g., polyethylene glycol derivatives, such as polyethylene glycol derivatives of alcohols and aliphatic alcohols), amides (e.g., alkoxylated amides, alkoxylated amines, and alkoxylated carboxylic acids), amides (e.g., ceramides), including their salts, amines, amino acids, including their salts and alkyl-substituted derivatives, esters, alkyl-substituted and acyl derivatives, polyacrylic acid, acrylamide copolymers, adipic acid copolymers water, aminoorganosilicons, biopolymers and their derivatives, butene copolymers, carbohydrates (e.g., polysaccharides, chitosan, and their derivatives), carboxylic acids, carbomers, esters, ethers, and polymer ethers (e.g., PEG derivatives and PPG derivatives), glycerol esters and their derivatives, halogen compounds, heterocyclic compounds, including their salts, hydrophilic colloids and their derivatives, including their salts and rubbers (e.g., cellulose derivatives, gelatin, xanthan gum, and natural rubber), imidazolines, inorganic substances (e.g., clays, TiO 2 、 and ZnO), ketones (e.g., camphor), hydroxyethyl sulfonates, lanolin, its derivatives, organic salts, phenols (e.g., parabens), including their salts, phosphorus compounds (e.g., phosphorus derivatives), polyacrylates and acrylate copolymers, protein and enzyme derivatives (e.g., collagen), synthetic polymers, including their salts, siloxanes and silanes, sorbitan derivatives, sterols, sulfonic acids and their derivatives, and waxes. These can be used alone or in combination.

[0220] Particles containing a pharmaceutical compound, a functional food compound, or a functional cosmetic compound can be suitably used as, for example, pharmaceuticals, foods, and cosmetics.

[0221] ---Pharmaceuticals---

[0222] A pharmaceutical contains a pharmaceutical compound and, if necessary, further contains a dispersant, an additive, and other components.

[0223] The dosage form of the drug is not particularly limited and can be appropriately selected depending on the intended purpose. Examples of dosage forms include oral preparations such as tablets (e.g., sugar-coated tablets, film-coated tablets, sublingual tablets, buccal tablets, and orally disintegrating tablets), pills, granules, powders, capsules (e.g., soft capsules and microcapsules), syrups, emulsions, suspensions, and films (e.g., orally disintegrating films and mucoadhesive buccal films). Other examples of dosage forms according to different administration methods include parenteral preparations such as injections, drops, transdermal delivery agents (e.g., iontophoresis transdermal delivery agents), suppositories, ointments, intranasal agents, pulmonary agents, and eye drops. In addition, the pharmaceutical composition can be a controlled release preparation such as an immediate release preparation or a sustained release preparation (e.g., sustained release microcapsules).

[0224] ---Food---

[0225] The food contains functional food compounds and, if necessary, further contains dispersants, additives, and other ingredients.

[0226] The food is not particularly limited and can be appropriately selected depending on the intended purpose. Examples of food include: frozen desserts such as ice cream, sherbet, and shaved ice; noodles such as buckwheat noodles, wheat noodles, glass noodles, Chinese dumpling wrappers, pork dumpling wrappers, Chinese noodles, and instant noodles; snacks such as candies, chewing gums, chocolates, sheet snacks, munches, cookies, jellies, jams, creams, baked confectioneries, and breads; seafood such as crabs, salmon, Japanese littleneck clams, tuna, sardines, shrimps, prawns, bonitos, mackerels, whales, oysters, sauries, squids, bloody clams, scallops, abalones, sea urchins, salmon roe, and Sulculus diversicolor supertexta; marine / livestock processed foods such as surimi and steamed fish, hams, and sausages; dairy products such as processed milk and fermented milk; oils and fats and their processed foods such as salad oil, tempura oil, margarine, mayonnaise, shortening, fresh cream, and toppings; seasonings such as sauces and basting; retort pouch foods such as curries, stews, Oyako-don (a bowl of rice topped with boiled chicken and eggs), congee, Zosui (rice soup), Chuka-don (a bowl of rice with a miscellaneous mixture), Katsu-don (pork cutlet over rice), Ten-don (tempura over rice), Una-don (eel over rice), hayashi rice (minced beef with rice), Oden (a dish containing several ingredients such as boiled eggs and radishes), Mapo Tofu, Gyu-don (a bowl of beef rice), meat sauce, egg soup, omelette rice, Chinese dumplings, pork dumplings, hamburger steaks, and meatballs; and various forms of health foods and dietary supplements.

[0227] ---Cosmetics---

[0228] The cosmetics contain functional cosmetic compounds and, if necessary, further contain dispersants, additives, and other ingredients.

[0229] The cosmetics are not particularly limited and can be appropriately selected depending on the intended purpose. Examples of cosmetics include skin care cosmetics, make-up cosmetics, hair care cosmetics, body care cosmetics, and perfume cosmetics.

[0230] The skin care cosmetics are not particularly limited and can be appropriately selected depending on the intended purpose. Examples of skin care cosmetics include cleansing compositions for makeup removal, facial cleansers, milky lotions, lotions, beauty essences, skin moisturizers, pack agents, and shaving cosmetics (e.g., shaving foams, pre-shave lotions, and after-shave lotions).

[0231] The makeup cosmetics are not particularly limited and can be appropriately selected depending on the intended purpose. Examples of makeup cosmetics include foundations, lipsticks, and mascaras.

[0232] The hair care cosmetics are not particularly limited and can be appropriately selected depending on the intended purpose. Examples of hair care cosmetics include shampoos, hair rinses (hair dyes, hair rinses), hair conditioners, hair packs, and hair styling preparations (e.g., hairsprays, hair setting lotions, hair liquids, and hair mists).

[0233] The body care cosmetics are not particularly limited and can be appropriately selected depending on the intended purpose. Examples of body care cosmetics include bath soaps, sunscreen cosmetics, and massage creams.

[0234] The perfume cosmetics are not particularly limited and can be appropriately selected depending on the intended purpose. Examples of perfume cosmetics include colognes (e.g., fragrances and parfums), Eau de parfums (e.g., perfume colognes), Eau de toilettes (e.g., perfumed toilette and parfum de toilette), and Eau de colognes (e.g., colognes and fresh colognes).

[0235] The amount of the physiologically active substance contained in the particles is not particularly limited and can be appropriately selected depending on the intended purpose. The amount of the physiologically active substance is preferably 5% by mass or more but 95% by mass or less, more preferably 5% by mass or more but 50% by mass or less.

[0236] - Polymer -

[0237] The polymer is used in the following manner, for example. The physiologically active substance is allowed to adsorb to the polymer to control the release rate of the physiologically active substance. The physiologically active substance is covered with a coating film made of the polymer to form a capsule.

[0238] The polymer is not particularly limited and can be appropriately selected depending on the intended purpose, as long as it is a polymer that is poorly soluble or insoluble in water and has biocompatibility. Examples of polymers that are biodegradable in organisms include polyfatty acid esters, poly-α-cyanoacrylates, poly-β-hydroxybutyric acid, polyalkylene oxalates, polyorthoesters, polyorthocarbonates, other polycarbonates, and polyamino acids. These can be used alone or in combination.

[0239] Examples of polyfatty acid esters include polylactic acid, polyglycolic acid, and polymalic acid.

[0240] The polyfatty acid ester to be used can be suitably a synthetic product or a commercially available product.

[0241] Examples of commercially available polyfatty acid esters include PLGA-7510 (a copolymer of lactic acid / glycolic acid, available from Wako Pure Chemical Industries, Ltd.).

[0242] Examples of other polymers having biocompatibility include polystyrene, polyurethane, polyvinyl acetate, polyvinyl alcohol, polyacrylamide, polyacrylic acid, polymethacrylic acid, copolymers of acrylic acid and methacrylic acid, polyamino acids, silicone polymers, dextran stearate, maleic anhydride-based copolymers, ethyl cellulose, acetyl cellulose, nitrocellulose, nylon, and TETORON. These can be used alone or in combination.

[0243] - Other Ingredients -

[0244] Other ingredients are not particularly limited and can be appropriately selected depending on the intended purpose. Examples of other ingredients include water, excipients, fragrances, disintegrants, fluidizing agents, adsorbents, lubricants, flavor masking agents, surfactants, perfumes, colorants, antioxidants, masking agents, antistatic agents, and wetting agents listed above. These can be used alone or in combination. Details of these are not mentioned because they are similar to those described above.

[0245] <Volume-average particle diameter (Dv) of the particles>

[0246] The volume-average particle diameter (Dv) of the particles is preferably 10 μm or more but 100 μm or less, more preferably 15 μm or more but 30 μm or less.

[0247] When the volume-average particle diameter (Dv) of the particles is 10 μm or more but 100 μm or less, particles that retain the physiologically active substance (which can be released over a long period) can be obtained.

[0248] When the volume-average particle diameter (Dv) of the particles is 10 μm or more, the polymer can appropriately retain the physiologically active substance to prevent initial burst release, and a long-term sustained release effect can be obtained.

[0249] When the volume-average particle diameter (Dv) of the particles is 100 μm or less, the particles have a size suitable for administration to a living body, and the energy required to dry the droplets in particle production can be reduced.

[0250] <Number-average particle diameter (Dn) of the particles>

[0251] The number-average particle diameter (Dn) of the particles is preferably 10 μm or more but 100 μm or less, more preferably 12 μm or more but 30 μm or less. When the number-average particle diameter (Dn) of the particles is 10 μm or more but 100 μm or less, the surface area per unit mass of the particles can be increased, and the amount of the physiologically active substance eluted per unit time can be increased.

[0252] When the number-average particle diameter (Dn) of the particles is 10 μm or more, a polymer in an amount sufficient to adsorb the physiologically active substance can be contained, and long-term sustained release can be exhibited.

[0253] <Particle size distribution (volume-average particle diameter (Dv) / number-average particle diameter (Dn))>

[0254] The particle size distribution of the particles is a value obtained by dividing the volume-average particle diameter (Dv) by the number-average particle diameter (Dn). The particle size distribution of the particles is preferably 1.00 or more but 1.50 or less, more preferably 1.00 or more but 1.20 or less, still more preferably 1.00 or more but 1.10 or less.

[0255] When the particle size distribution is 1.00 or more but 1.50 or less, the particle sizes become uniform, and the amounts of the physiologically active substance and the polymer contained in each particle become uniform. As a result, the amount of the active ingredient, the deliverability to a specific site, and the sustained release can be strictly controlled.

[0256] The volume-average particle diameter (Dv), the number-average particle diameter (Dn), and the particle size distribution (Dv / Dn) of the particles can be measured using, for example, a laser diffraction / scattering particle size distribution analyzer (device name: MICROTRAC MT3000II, available from MicrotracBEL Corp.).

[0257] <Amount of the physiologically active substance in the particles>

[0258] In terms of the mass ratio to the particles after drying, the amount of the physiologically active substance contained in the particles is preferably 25% by mass or more, more preferably 25% by mass or more but 75% by mass or less.

[0259] In the particle production method and apparatus of the present disclosure, the amount of the physiologically active substance contained in the particles can be controlled by adjusting the formulation of the liquid mixture. The particle production method and apparatus of the present disclosure can produce particles containing the physiologically active substance at a higher ratio than in other production methods. For example, in terms of the mass ratio to the particles after drying, the particles can be allowed to contain the physiologically active substance in an amount of 15% by mass or more or 20% by mass or more. The amount of the physiologically active substance can be controlled depending on the desired release property. In particular, when the amount of the physiologically active substance contained in the particles is 25% by mass or more, the particles can elute the physiologically active substance over a long period and in a stable manner.

[0260] Moreover, when the amount of the physiologically active substance contained in the particles is 25% by mass or more but 75% by mass or less, the release property can be precisely controlled while increasing the amount of the physiologically active substance contained in the particles.

[0261] The particles of the present disclosure contain a physiologically active substance and a polymer. The amount of the physiologically active substance is 25% by mass or more relative to the mass of the particles after drying. When the volume average particle diameter (Dv) of the particles is 10 μm or more but 100 μm or less and the particle size distribution (volume average particle diameter (Dv) / number average particle diameter (Dn)) of the particles is 1.00 or more but 1.50 or less, the release property can be highly precisely controlled and the particles can be allowed to contain a high concentration of the physiologically active substance.

[0262] Examples

[0263] Examples of the present disclosure will be described below. However, the present disclosure should not be construed as being limited to these examples.

[0264] (Example 1)

[0265] -Production of particles by a member (piezoelectric system) that changes volume-

[0266] <Preparation of liquid mixture A>

[0267] Clomipramine hydrochloride (obtained from Wako Pure Chemical Industries, Ltd.) (8 parts by mass) was dissolved in methanol (obtained from Wako Pure Chemical Industries, Ltd.) (40 parts by mass). The obtained solution (48 parts by mass), lactic acid-glycolic acid copolymer (product name: PLGA-5010, obtained from Wako Pure Chemical Industries, Ltd.) (12 parts by mass), and acetone (obtained from Wako Pure Chemical Industries, Ltd.) (40 parts by mass) were mixed for 1 hour with stirring at 1,000 rpm using a stirring device (device name: magnetic stirrer, obtained from AS ONE Corporation), and then the resulting mixture was passed through a 1-μm filter (product name: Millex SLFA05010, obtained from Merck) to prepare liquid mixture A.

[0268] <Formation of Particle 1>

[0269] Using a droplet discharging device 1 (device name: GEN4, obtained from Ricoh Company, Ltd.) including a droplet forming unit 2 having a member for volume change as presented in Figure 5 (the same as "2" in Figure 4B ), droplets were formed using the prepared liquid mixture A under the following particle formation conditions, and then the formed droplets were dried to form particle 1. Note that, as the discharging system of the droplet discharging device, inkjet discharging using a piezoelectric element was used. In Figure 4B , the lengths of respective parts (D1 - D5) were D1: 0.02 m, D2: 0.1 m, D3: 0.5 m, D4: 0.2 m, and D5: 1.0 m.

[0270] -Particle Formation Conditions-

[0271] --Droplet Forming Unit--

[0272] · Shape of discharge hole: perfect circle

[0273] · Diameter of discharge hole: 24 μm

[0274] · Number of open discharge holes: 384

[0275] · Discharge driving frequency (F): 32 kHz

[0276] --Liquid--

[0277] · Density (ρ) of liquid: 1050 kg / m 3

[0278] --Liquid droplets to be discharged--

[0279] ·Diameter of liquid droplet discharge (d0): 30 μm

[0280] ·Angle of liquid droplet discharge (θ): 65°

[0281] ·Velocity of liquid droplet discharge (Vj): 15 m / s

[0282] --Particle formation unit--

[0283] ·Transport gas flow: Air

[0284] ·Temperature of transport gas flow: 50 degrees Celsius

[0285] ·Velocity of transport gas flow (Vx): 18 m / s

[0286] ·Height of transport path (D 5 ): 1 m

[0287] ·Distance from liquid droplet formation unit to the center of transport gas flow (A): 0.01 m

[0288] Note that the "diameter of liquid droplet discharge (d0)" and the "velocity of liquid droplet discharge (Vj)" were measured using a liquid droplet observation device with an LED backlight (device name: EV1000, obtained from Ricoh Company, Ltd.).

[0289] The "angle of liquid droplet discharge (θ)" was adjusted to 65°, where the angle (θ) is the angle formed by the direction of travel of the liquid droplet at the moment of discharge from the discharge hole (nozzle) and the direction of the stress received by the liquid droplet from the transport gas flow (see, for example Figure 3A and Figure 3B ).

[0290] The "density of the liquid (ρ)" was measured using a pycnometer (device name: pycnometer (Wadon), obtained from SIBATASCIENTIFIC TECHNOLOGY LTD.).

[0291] Based on the above particle formation conditions, the value of P was calculated using Equation 1 below. The results are presented in Table 1.

[0292] [Equation 6]

[0293]

[0294] (Example 2)

[0295] -Producing particles by a nozzle vibration member-

[0296] <Formation of Particle 2>

[0297] Particles 2 were formed in the same manner as in Example 1, except that: the droplet forming unit 2 was changed to include Figure 6A and 6B the droplet forming unit of the nozzle vibration member presented in

[0298] Figure 6A and 6B the thin film in the nozzle vibration member presented in

[0299] The discharge holes were provided only in the form of a dogtooth lattice pattern within a range of 5 mm in diameter from the center of the thin film, such that the distance between the centers of the discharge holes would be 100 μm. Note that the angle formed by the traveling direction of the instantaneous droplet and the direction of the transfer air flow when the droplet was discharged from the discharge hole (nozzle) located at the center of the nozzle vibration member was measured as the angle θ at which the droplet was to be discharged from the nozzle vibration member.

[0300] -Particle formation conditions-

[0301] --Droplet forming unit--

[0302] · Shape of discharge hole: perfect circle

[0303] · Diameter of discharge hole: 25 μm

[0304] · Number of open discharge holes: 64

[0305] · Discharge driving frequency (F): 108 kHz

[0306] --Liquid--

[0307] · Density of liquid (ρ): 1050 kg / m 3

[0308] --Droplets to be discharged--

[0309] · Discharge diameter of droplet (d0): 30 μm

[0310] · Discharge angle of droplet (θ): 65°

[0311] · Discharge speed of droplet (Vj): 7 m / s

[0312] --Particle forming unit--

[0313] · Transfer air flow: air

[0314] · Temperature of the conveying air flow: 50 degrees Celsius

[0315] · Velocity (Vx) of the conveying air flow: 18 m / s

[0316] · Height (D 5 ) of the conveying path: 1 m

[0317] · Distance (A) from the droplet forming unit to the center of the conveying air flow: 0.01 m

[0318] (Example 3)

[0319] - Production of particles by the nozzle vibration member-

[0320] <Formation of Particle 3>

[0321] Particle 3 was formed in the same manner as in Example 2, except that: the diameter of the discharge hole was changed to 30 μm and the height (D 5 ) of the conveying path was changed to 2 m.

[0322] (Example 4)

[0323] - Formation of particles by the necking portion generating member-

[0324] <Formation of Particle 4>

[0325] Particle 4 was formed in the same manner as in Example 1, except that: the droplet forming unit 2 was changed to a droplet forming unit including Figure 7B the necking portion generating member shown in, and the particle forming conditions in Example 1 were changed to the following particle forming conditions.

[0326] Regarding the portion of the necking portion generating member where there is a through hole as shown in Figure 7B , using a femtosecond laser, by the mask reduction projection method, via machining removal (laser ablation), 10 through holes having a perfect circular shape and an outlet diameter of 30 μm were concentrically formed on a nickel plate having a thickness of 20 μm. The portion where there is a through hole falls within the range of a square with a side length of 0.5 mm.

[0327] - Particle forming conditions-

[0328] -- Droplet forming unit--

[0329] · Shape of the discharge hole: Perfect circle

[0330] · Diameter of the discharge hole: 50 μm

[0331] · Number of open discharge holes: 10

[0332] · Discharge drive frequency (F): 150 kHz

[0333] --Liquid--

[0334] ·Density of the liquid (ρ): 1050 kg / m 3

[0335] --Liquid droplets to be discharged--

[0336] ·Diameter of the discharged liquid droplets (d0): 60 μm

[0337] ·Discharge angle of the liquid droplets (θ): 65°

[0338] ·Discharge velocity of the liquid droplets (Vj): 30 m / s

[0339] --Particle formation unit--

[0340] ·Transport gas flow: Air

[0341] ·Temperature of the transport gas flow: 50 degrees Celsius

[0342] ·Velocity of the transport gas flow (Vx): 18 m / s

[0343] ·Height of the transport path (D 5 ): 5 m

[0344] ·Distance from the liquid droplet formation unit to the center of the transport gas flow (A): 0.01 m

[0345] (Example 5)

[0346] -Producing particles through the necking part generating member-

[0347] <Formation of Particle 5>

[0348] Particle 5 is formed in the same manner as in Example 4, except that: the diameter of the discharge hole is changed to 25 μm, the discharge driving frequency is changed to 600 kHz, and the height of the transport path (D 5 ) is changed to 2 m.

[0349] (Comparative Example 1)

[0350] -Forming particles through the nozzle vibration member-

[0351] <Formation of Particle 6>

[0352] Particle 6 is formed in the same manner as in Example 2, except that: the liquid droplet discharging device is changed to Figure 4BThe droplet discharging device presented (D1: 1.0 m, D2: none, D3: 1.0 m, D4: 1.0 m, and D5: 1.0 m). However, before the formation of particles, the discharged droplets coalesce with each other to form large droplets, particles cannot be formed in the transfer path, and the droplets fall to the bottom of the device as they are. Therefore, particles cannot be formed.

[0353] (Comparative Example 2)

[0354] - Producing particles by a nozzle vibration member -

[0355] <Formation of Particle 7>

[0356] Particle 7 was formed in the same manner as in Example 2, except that the droplet discharge angle was changed from 65° to 10°.

[0357] (Comparative Example 3)

[0358] - Producing particles by a nozzle vibration member -

[0359] <Formation of Particle 8>

[0360] Particle 8 was formed in the same manner as in Example 2, except that the velocity of the transfer air flow was changed to 2 m / s.

[0361] (Comparative Example 4)

[0362] - Producing particles by a necking portion generating member -

[0363] <Formation of Particle 9>

[0364] Particle 9 was formed in the same manner as in Example 5, except that the droplet discharge velocity was changed to 10 m / s, the velocity of the transfer air flow was changed to 2 m / s, the height of the transfer path (D 5 ) was changed to 1 m, and the discharge driving frequency (F) was changed to 108 kHz.

[0365] (Comparative Example 5)

[0366] - Producing particles by a necking portion generating member -

[0367] <Formation of Particle 10>

[0368] Particle 10 was formed in the same manner as in Example 5, except that the droplet discharge angle was changed to 120°, the velocity of the transfer air flow was changed to 2 m / s, the height of the transfer path (D 5 ) was changed to 1 m, and the discharge driving frequency (F) was changed to 108 kHz.

[0369] [Table 1]

[0370]

[0371] Then, the "particle size distribution [volume-average particle size (Dv) / number-average particle size (Dn)]" of particles 1-10 obtained in Examples 1-5 and Comparative Examples 1-5 was measured and evaluated in the following manner. The results are presented in Table 2.

[0372] <Particle size distribution [volume-average particle size (Dv) / number-average particle size (Dn)]>

[0373] The particle size distribution was measured using a laser diffraction / scattering particle size distribution analyzer (device name: MICROTRAC MT3000II, obtained from MicrotracBEL Corp.). Note that the measurement and analysis conditions were set as follows.

[0374] --Measurement and analysis conditions for particle size distribution--

[0375] ·Measurement mode: Transparent mode

[0376] ·Particle refractive index: 1.40

[0377] ·Set zero time: 10 seconds

[0378] ·Measurement time: 10 seconds

[0379] The particle size distribution was evaluated based on the following evaluation criteria.

[0380] <Evaluation criteria>

[0381] A: 1.0 ≤ (Dv) / (Dn) ≤ 1.5

[0382] B: 1.0 > (Dv) / (Dn), or (Dv) / (Dn) > 1.5

[0383] [Table 2]

[0384]

[0385] Aspects of the present disclosure are as follows, for example.

[0386] <1> A particle production apparatus, comprising:

[0387] A droplet formation unit configured to discharge a liquid from a discharge hole to form droplets; and

[0388] A particle formation unit configured to solidify the droplets to form particles,

[0389] wherein the particle formation unit includes a transport gas flow, and

[0390] the droplet formation unit is configured to discharge the liquid in a manner that satisfies the following formula 1:

[0391] [Number 7]

[0392]

[0393] In Formula 1, Vj represents the droplet ejection speed (m / s), F represents the ejection drive frequency (kHz), d0 represents the diameter of the droplet (μm), ρ represents the density of the liquid (kg / m 3 ), Vx represents the speed of the transfer air flow (m / s), A represents the shortest distance from the droplet formation unit to the center of the transfer air flow (m), and θ represents the droplet ejection angle (degrees).

[0394] <2>The particle production equipment according to <1>,

[0395] where the value of P is 2 or greater.

[0396] <3>The particle production equipment according to <1> or <2>,

[0397] where the droplet ejection angle is 40° or greater but 90° or less.

[0398] <4>The particle production equipment according to any one of <1> to <3>,

[0399] where the droplet formation unit is configured to vibrate the liquid to eject the droplets.

[0400] <5>The particle production equipment according to any one of <1> to <4>,

[0401] where the droplet formation unit includes a piezoelectric element.

[0402] <6>The particle production equipment according to any one of <1> to <5>,

[0403] where the droplet formation unit is provided in a thin film including an ejection hole.

[0404] <7>The particle production equipment according to any one of <1> to <6>,

[0405] where the average particle diameter of the formed particles is 10 μm - 100 μm.

[0406] <8>The particle production method, which includes:

[0407] Ejecting a liquid from an ejection hole through a droplet formation unit to form droplets; and

[0408] Solidifying the droplets through a particle formation unit to form particles,

[0409] where the particle formation unit includes a transfer air flow, and

[0410] the droplet formation unit is configured to eject the liquid in a manner that satisfies the following Formula 1:

[0411] [Number 8]

[0412]

[0413] Among them, in Formula 1, Vj represents the droplet ejection speed (m / s), F represents the ejection driving frequency (kHz), d0 represents the diameter of the droplet (μm), ρ represents the density of the liquid (kg / m 3 ), Vx represents the speed of the transfer air flow (m / s), A represents the shortest distance from the droplet forming unit to the center of the transfer air flow (m), and θ represents the droplet ejection angle (degrees).

[0414] The particle production equipment according to any one of <1> to <7> and the particle production method according to <8> can solve the problems conventionally existing and achieve the object of the present disclosure.

[0415] List of reference numerals

[0416] 1: Particle production equipment

[0417] 2: Droplet forming unit

[0418] 13: Liquid storage part

[0419] 14: Liquid

[0420] 20: Component for volume change

[0421] 21, 113: Droplets

[0422] 101, 114: Transfer air flow

Claims

1. A method for producing particles, which comprises: discharging a liquid from a discharge hole through a droplet forming unit to form droplets; and solidifying the droplets through a particle forming unit to form particles, wherein the particle forming unit includes a conveying air flow, and the droplet forming unit is configured to discharge the liquid in a manner that satisfies the following formula 1: [Formula 1] In Formula 1, Vj represents the droplet ejection speed (m / s), F represents the ejection driving frequency (kHz), d0 represents the diameter of the droplet (μm), ρ represents the density of the liquid (kg / m 3 ), Vx represents the speed of the conveying air flow (m / s), A represents the shortest distance from the droplet forming unit to the center of the conveying air flow (m), and θ represents the droplet ejection angle (degrees). wherein the particles contain a physiologically active substance.

2. The method for producing particles according to claim 1, wherein the value of P is 2 or greater.

3. The method for producing particles according to claim 1 or 2, wherein the droplet discharge angle is 40° or greater but 90° or less.

4. The method for producing particles according to claim 1 or 2, wherein the droplet forming unit is configured to vibrate the liquid to discharge the droplets.

5. The method for producing particles according to claim 1 or 2, wherein the droplet forming unit includes a piezoelectric element.

6. The method for producing particles according to claim 1 or 2, wherein the droplet forming unit is provided in a thin film including a discharge hole.

7. The method for producing particles according to claim 1 or 2, wherein the volume average particle diameter of the formed particles is 10 μm - 100 μm.

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