Method for producing composite particles containing amorphous organic compound

Abstract

Provided is a method for producing composite particles comprising an easily amorphized organic compound.　The method for producing composite particles includes a compounding step in which core particles having no amorphous stabilizing action and crystalline organic compound particles are mechanically stirred and mixed to promote the pulverization and amorphization of the crystalline organic compound particles by the action of the core particles that accompanies the mechanical action of the stirring and mixing, thereby causing amorphous organic compound particles derived from the crystalline organic compound particles to adhere to the surface of the core particles. Composite particles comprising amorphous organic compound particles on the surface of core particles are obtained thereby.

Description

Method for producing composite particles containing amorphous organic compound

[0001] (Cross-reference to related applications) This application claims priority to Japanese Patent Application No. 2023-111045, filed on July 5, 2023, the contents of which are incorporated herein by reference. This specification relates to a method for producing composite particles containing an amorphous organic compound, etc.

[0002] Amorphization of crystalline organic compounds, which are active ingredients of pharmaceuticals, is a promising method for improving the solubility and dissolution rate in aqueous media. Methods for amorphizing crystalline organic compounds include a method in which crystalline powder is dissolved in an organic solvent and sprayed onto core particles to amorphize and granulate (Patent Document 1), a method in which an amorphous stabilizer is thermally melted to amorphize and granulate the crystalline powder, and a method in which crystalline powder is pulverized using a ball mill to amorphize it.

[0003] Japanese Patent Application Laid-Open No. 2021-113183

[0004] However, such methods have the problems of residual organic solvents, the complicated manufacturing process involving heat melting for amorphization, and the influence of heat on the compound.

[0005] The present specification provides a method for producing composite particles comprising an organic compound that can be easily made amorphous, and the like.

[0006] The present inventors, through various investigations into the amorphization of crystalline powder, have discovered that it is possible to generate amorphous organic compound particles from crystalline particles by mechanically stirring and mixing core particles and crystalline organic compound particles smaller than the core particles, and pulverizing and amorphizing the crystalline organic compound particles through the action of the core particles accompanying the mechanical action of the amorphization, and that it is possible to cause the amorphous organic compound particles generated in situ to adhere and deposit on the core particles. Based on this discovery, the present specification provides the following means.

[0007] [1] A method for producing composite particles, comprising: a composite step of mechanically stirring and mixing core particles that do not have an amorphous stabilizing effect with crystalline organic compound particles, promoting the pulverization and amorphization of the crystalline organic compound particles by the action of the core particles during the stirring and mixing, thereby adhering amorphous organic compound particles derived from the crystalline organic compound particles to the surfaces of the core particles, thereby producing composite particles comprising the amorphous organic compound particles on the surfaces of the core particles. [2] The method according to [1], wherein the average particle size of the core particles in the composite step is 1.5 to 30.0 times the average particle size of the crystalline organic compound particles. [3] The method according to [1] or [2], wherein the mass of the core particles in the composite step is 3.0 to 10.0 times the mass of the crystalline organic compound particles. [4] The method according to any one of [1] to [3], wherein the composite step further comprises mechanically stirring and mixing amorphous stabilizer particles in addition to the core particles and the crystalline organic compound particles. [5] The method according to any one of [1] to [4], wherein the composite step is carried out so as to maintain the temperature inside a container in which the composite step is carried out below the glass transition temperature of the organic compound of the amorphous organic compound particles. [6] The method according to any one of [1] to [5], wherein the core particles are selected from pharmaceutically acceptable excipients. [7] The method according to [6], wherein the core particles are one or more selected from the group consisting of lactose, glucose, starch, corn starch, crystalline cellulose, and methylcellulose. [8] A composite particle comprising: a core particle having no amorphous stabilizing activity; and a layer on the surface of the core particle derived from the amorphous organic compound particles and the amorphous stabilizer particles. [9] The manufacturing method according to [1], wherein the compounding step further comprises mechanically stirring and mixing amorphous stabilizer particles in addition to the core particles and the crystalline organic compound particles, and the temperature inside a container in which the compounding step is carried out is maintained below the glass transition temperature of the organic compound of the amorphous organic compound particles.

[10] The manufacturing method according to [3], wherein the compounding step further comprises mechanically stirring and mixing amorphous stabilizer particles in addition to the core particles and the crystalline organic compound particles.

[11] The manufacturing method according to [3], wherein the compounding step is carried out so that the temperature inside a container in which the compounding step is carried out is maintained below the glass transition temperature of the organic compound of the amorphous organic compound particles.

[12] The manufacturing method according to [3], wherein the compounding step includes mechanically stirring and mixing amorphous stabilizer particles in addition to the core particles and the crystalline organic compound particles, and wherein the compounding step is carried out so that the temperature inside a container in which the compounding step is carried out is maintained below the glass transition temperature of the organic compound of the amorphous organic compound particles.

[0008] 1 is a diagram showing the effect of core particles in the method for producing composite particles disclosed in the present specification. 2 is a diagram showing an example of a composite particle disclosed in the present specification. 3 is a diagram showing another example of a composite particle disclosed in the present specification. 4 is a diagram showing a schematic configuration of a horizontal composite device to explain composite parameters. 5 is a diagram showing the relationship between various numerical elements in a composite device and the compression efficiency, which is a composite parameter. 6 is a diagram showing an X-ray diffraction spectrum (a), a Raman spectrum (b), and a DSC curve (c) in an example. 7 is a diagram showing scanning electron microscope photographs (a1) and (a2) (a1 is 600x magnification, a2 is 5000x magnification, the same applies below) of core particles which are crystalline cellulose particles, composite particles (b1) and (b2) mixed for 30 minutes, and composite particles (c1) and (c2) mixed for 180 minutes. 8 is a diagram showing mixing time and the content of amorphous indomethacin (relative to the active ingredient) in the composite particles. 9 is a diagram showing the results of a dissolution test of composite particles. 10 is a diagram showing the results of a physical stability test of composite particles in the presence of silica gel at 25°C. Fig. 1 shows X-ray diffraction spectra and Raman spectra of composite particles obtained by processing at different rotor rotation speeds in Example 4. Fig. 2 shows X-ray diffraction spectra and Raman spectra of composite particles obtained by processing for different processing times in Example 4. Fig. 3 shows X-ray diffraction spectra and Raman spectra of composite particles obtained by processing with different sample actual volumes in Example 5.

[0009] Representative and non-limiting examples of the disclosure of this specification will be described in detail below, with reference to the accompanying drawings as appropriate. This detailed description is intended simply to provide those skilled in the art with details for implementing preferred examples of the present invention, and is not intended to limit the scope of the disclosure of this specification. In addition, the additional features and inventions disclosed below can be used separately or together with other features and inventions to provide a further improved "method for producing composite particles containing an amorphous organic compound."

[0010] Furthermore, the combinations of features and steps disclosed in the following detailed description are not essential to practicing the invention in its broadest sense, but are specifically described solely to illustrate representative embodiments of the disclosure herein. Furthermore, the various features of the representative embodiments described above and below, and those described in the independent and dependent claims, do not necessarily have to be combined in the exact embodiments described herein, or in the exact order listed, to provide additional and useful embodiments of the disclosure herein.

[0011] All features described in this specification and / or claims are intended to be disclosed individually and independently of one another as limitations on the original disclosure and claimed particulars, apart from any configuration of features described in the examples and / or claims. Furthermore, all numerical ranges and group or aggregate descriptions are intended to disclose intermediate configurations thereof as limitations on the original disclosure and claimed particulars.

[0012] The present disclosure relates to a method for producing composite particles containing an amorphous organic compound. The production method of the present disclosure includes a composite step of mechanically stirring and mixing core particles that do not have an amorphous stabilizing effect with crystalline organic compound particles, promoting the pulverization and amorphization of the crystalline organic compound particles by the action of the core particles associated with the mechanical action of the stirring and mixing, and attaching the amorphous organic compound particles derived from the crystalline organic compound particles to the surfaces of the core particles, thereby producing the composite particles having the amorphous organic compound particles on the surfaces of the core particles.

[0013] According to the above-described manufacturing method, as shown in FIG. 1, the core particles function as a medium that promotes the pulverization and amorphization of the crystalline organic compound particles due to the mechanical action of stirring and mixing. The core particles collide with and compress the crystalline organic compound particles, pulverizing and amorphizing the crystalline organic compound particles. Furthermore, the pulverized and amorphized amorphous organic compound particles have enhanced cohesive adhesion. As a result, composite particles containing an organic compound with improved solubility and dissolution rate in water can be obtained more easily.

[0014] Furthermore, since no solvent is used and no thermal melting is involved, residual solvent is avoided, workability is excellent, and costs can be reduced.

[0015] Furthermore, by mixing amorphous stabilizer particles together in the composite process, recrystallization of the amorphous organic compound particles can be suppressed, and composite particles can be obtained that can stably maintain the amorphous nature of the amorphous particles.

[0016] Furthermore, this manufacturing method can be widely applied to crystalline organic compound particles that can be made amorphous by mechanical treatment using, for example, a ball mill, and to organic compounds that can be made amorphous.

[0017] Hereinafter, the method for producing composite particles (hereinafter also simply referred to as the present production method) will be described in detail in this specification.

[0018] (Method for producing composite particles) This production method includes a composite step in which core particles that do not have an amorphous stabilizing effect and crystalline organic compound particles (hereinafter simply referred to as crystalline particles) are mechanically stirred and mixed, and the action of the core particles accompanying the mechanical action of the stirring and mixing promotes the pulverization and amorphization of the crystalline particles, so that the amorphous organic compound particles (hereinafter simply referred to as amorphous particles) derived from the crystalline particles are attached to the surfaces of the core particles. In carrying out this production method, the core particles and crystalline particles to be subjected to the composite step are each prepared.

[0019] (Core particle) The core particle is a particle that constitutes the core of the composite particle and serves as a carrier particle supported by the amorphous particle. The core particle is not particularly limited, but it is meaningful to have a shape such as a sphere, a block, a cube, a polyhedron such as a rectangular parallelepiped, etc., in terms of the impact force on the crystalline particle and its own breaking strength. That is, it is meaningful not to have a plate-like, flaky, rod-like, needle-like, columnar, spongy, etc. This is because plate-like, flaky, needle-like, rod-like, columnar, spongy, etc., tend to have insufficient impact force and breaking strength. Although not particularly limited, a spherical, blocky, or polyhedral core particle having a maximum diameter and a minimum diameter of, for example, 0.7 to 1.3, 0.8 to 1.2, 0.85 to 1.15, 0.9 to 1.1, or for example, 0.95 to 1.05, may be preferable in terms of impact force and breaking strength.

[0020] The core particles are suppressed from being pulverized during the compounding process, so that their particle shape is maintained. By using such core particles, they can more easily act as a pulverizing medium for the crystalline particles, such as balls or beads, in ball mill pulverization. Pulverization can be suppressed by taking into account the breaking strength depending on the shape and size of the core particles.

[0021] Although the core particles are not particularly limited, typically, pharmaceutically acceptable excipient particles can be used. Examples include monosaccharides and disaccharides known as excipients, such as lactose, sucrose, mannitol, and glucose; polysaccharides known as excipients, such as starch (including corn starch), crystalline cellulose, methylcellulose, and hydroxypropylmethylcellulose; and inorganic compounds known as excipients, such as magnesium aluminometasilicate and anhydrous calcium phosphate. In addition to naturally occurring sugars, monosaccharides, disaccharides, and polysaccharides may also be used, as appropriate, including their known derivatives (e.g., deoxysugars, aminosugars, thiosugars, ester derivatives, etc.). Crystalline cellulose may be preferred. Furthermore, it is preferable to use core particles that do not have an amorphous stabilizing effect. Core particles also function as carrier particles supporting crystalline particles, and it is more convenient from a formulation standpoint to utilize the carrier particle's function alone.

[0022] The average particle diameter d1 of the core particles is not particularly limited in relation to the average particle diameter d2 of the crystalline particles, but it may be preferable that the average particle diameter d1 is larger than the average particle diameter d2. When the average particle diameter d1 is larger than d2, the impact force of the core particles when they collide with the crystalline particles increases, and the destruction of the lattice structure of the crystalline organic compound particles (amorphization) is promoted. The average particle diameter d1 may be, for example, 1.1 times or more, 1.2 times or more, 1.3 times or more, 1.5 times or more, 1.8 times or more, 2.0 times or more, 2.5 times or more, or, for example, 3.0 times or more, 3.5 times or more, 4.0 times or more, 4.5 times or more, 5.0 times or more, 5.5 times or more, 6.0 times or more, 7.0 times or more, 8.0 times or more, 9.0 times or more, 10.0 times or more, 12.0 times or more, 14.0 times or more, etc., of the average particle diameter d2.

[0023] On the other hand, if the average particle diameter d1 is too large compared to the average particle diameter d2, the collision frequency tends to decrease and the efficiency of amorphization tends to decrease. Therefore, the average particle diameter d1 may be, for example, 30.0 times or less, 25.0 times or less, 20.0 times or less, 18.0 times or less, 16.0 times or less, 14.0 times or less, 12.0 times or less, 10.0 times or less, 8.0 times or less, 7.0 times or less, 6.0 times or less, 5.0 times or less, 4.0 times or less, 3.5 times or less, or 3.0 times or less of the average particle diameter d2.

[0024] The range of the ratio of the average particle diameter d1 to the average particle diameter d2 is not particularly limited, and can be set by appropriately combining the upper and lower limits described above. For example, the ratio can be 1.5 to 30.0 times, 1.5 to 25.0 times, 1.5 to 20.0 times, 1.5 to 15.0 times, 1.5 to 10.0 times, 1.5 to 5 times, or 1.5 to 3.0 times.

[0025] The average particle diameter d1 of the core particles is not particularly limited, but can be, for example, 10 μm or more, 15 μm or more, 20 μm or more, 25 μm or more, 30 μm or more, 35 μm or more, 40 μm or more, 45 μm or more, 50 μm or more, 60 μm or more, 70 μm or more, 80 μm or more, 90 μm or more, 100 μm or more, 125 μm or more, 150 μm or more, 175 μm or more, 200 μm or more, 225 μm or more, 250 μm or more, 300 μm or more, 350 μm or more, 400 μm or more, 450 μm or more, or 500 μm or more.

[0026] The average particle diameter d1 of the core particles is not particularly limited, but from the viewpoint of ensuring that the breaking strength of the core particles does not exceed the impact force of the core particles, it may be, for example, 600 μm or less, 550 μm or less, 500 μm or less, 450 μm or less, 400 μm or less, 350 μm or less, 300 μm or less, 250 μm or less, 200 μm or less, 175 μm or less, 150 μm or less, 125 μm or less, 100 μm or less, 90 μm or less, 80 μm or less, 70 μm or less, 60 μm or less, 50 μm or less, 40 μm or less, 30 μm or less, or 20 μm or less.

[0027] The range of the average particle diameter d1 of the core particles is not particularly limited, and can be set by appropriately combining the upper and lower limits described above, for example, 10 μm to 500 μm, 15 μm to 500 μm, 20 μm to 500 μm, 20 μm to 400 μm, 20 μm to 350 μm, 20 μm to 300 μm, 10 μm to 200 μm, 20 μm to 200 μm, 20 μm to 150 μm, 20 μm to 100 μm, 10 μm to 30 μm, or 10 μm to 20 μm.

[0028] The average particle diameter d1 of the core particles and the average particle diameter d2 of the crystalline particles can both be obtained as a volume-based median diameter (central diameter) by a laser diffraction / scattering method.

[0029] (Crystalline organic compound particles) The crystalline particles are typically crystalline powders of an organic compound. The crystalline particles may be single crystals or polycrystals. They may also be polymorphic. The shape of the crystalline particles is not particularly limited, and may take various forms such as spherical, cubic, blocky, plate-like, columnar, rod-like, needle-like, dendritic, spongy, and irregular shapes.

[0030] The type of organic compound in the crystalline organic compound particles is not particularly limited, but any organic compound that can be made amorphous by grinding using a ball mill or the like can be made amorphous using this production method. It is useful for the organic compound to be an organic compound that can be an active ingredient in a pharmaceutical, and it is even more useful for the organic compound to be poorly soluble in water due to its crystallinity. It should be noted that crystalline organic compounds that can be made amorphous using this production method can be confirmed in advance as to whether they can be made amorphous by grinding using a ball mill or the like, or whether they can be made amorphous using this production method using crystalline cellulose as core particles.

[0031] The crystalline particles are particles that are pulverized by collisions with core particles and compression actions that accompany the mechanical action during stirring and mixing. These actions also destroy the lattice structure of the crystalline particles, turning them into amorphous particles, and the pulverized amorphous particles adhere to and accumulate on the surfaces of the core particles. As already explained, the average particle size d2 of the crystalline particles is made smaller than the average particle size d1 of the core particles. This makes it easier for the crystalline particles to be pulverized by collisions with the core particles. It is preferable that the average particle size d2 of the crystalline particles has the same relationship as the average particle size d1 of the core particles as already explained.

[0032] The average particle diameter d2 of the crystalline particles is not particularly limited, but may be, for example, 3 μm or more, 4 μm or more, 5 μm or more, 6 μm or more, 7 μm or more, 8 μm or more, 9 μm or more, 10 μm or more, 12 μm or more, 14 μm or more, 15 μm or more, 16 μm or more, 18 μm or more, or 20 μm or more. The average particle diameter d2 may be, for example, 50 μm or less, 40 μm or less, 30 μm or less, 28 μm or less, 25 μm or less, 22 μm or less, or 20 μm or less. The average particle diameter d2 can be set by appropriately selecting the upper and lower limits described above, and may be, for example, 3 μm or more and 50 μm or less, 5 μm or more and 30 μm or less, 5 μm or more and 20 μm or less, or 10 μm or more and 20 μm or less. In addition, in the particle size distribution measured by the above-described method, it may be advantageous that, for example, 80% or more, 85% or more, 90% or more, or 95% or more of the particles have a particle size of 100 μm or less on a volume basis within the particle size range of 100 μm or less.

[0033] The core particles and the crystalline particles can be subjected to the composite process at any ratio, but taking into consideration the size of the core particles and the composition of the composite particles, the mass ratio of the core particles can be, for example, more than 1 time, or 2 times or more, 3 times or more, 4 times or more, 5 times or more, 6 times or more, 8 times or more, 9 times or more, 10 times or more, 12 times or more, 14 times or more, 16 times or more, etc. The mass ratio can also be set to, for example, 20 times or less, 18 times or less, 16 times or less, 14 times or less, 12 times or less, etc. For example, the mass ratio can be set to 2 times or more and 20 times or less, 3 times or more and 16 times or less, or 3 times or more and 10 times or less.

[0034] In the compounding process, the lattice structure of the crystalline particles is destroyed to form amorphous particles, but because the amorphous state is unstable, recrystallization may occur. In the compounding process, it may be effective to first mix amorphous stabilizer particles (hereinafter also referred to as stabilizer particles) and compound them with the amorphous particles into the core particles. Known amorphous stabilizers can be used as the stabilizer particles. Examples of amorphous stabilizers include polymeric stabilizers, low-molecular-weight stabilizers, and inorganic stabilizers. Polymeric additives are not particularly limited, but include cellulose derivatives such as polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), methacrylic acid copolymer (MAEA), polyvinylpyrrolidone-vinyl acetate copolymer (PVPVA), hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), ceracephate (CAP), hypromellose phthalate (HPMCP), and hypromellose acetate succinate (HPMCAS). Examples of low molecular weight stabilizers include, but are not limited to, low molecular weight compounds having a carbonyl group or an amino group, more specifically, amino acids such as arginine and tryptophan, and organic acids such as tartaric acid and citric acid. Examples of inorganic additives include, but are not limited to, porous materials such as calcium carbonate and silicon dioxide.

[0035] The average particle diameter d3 of the stabilizer particles is not particularly limited, but it is preferable that the stabilizer particles be directly attached to the surface of the core particles having an average particle diameter d1, or that the stabilizer particles be crushed in the compounding process and the crushed particles be attached to the surface of the core particles. This allows the amorphous particles and particles derived from the stabilizer particles to adhere to the surface of the core particles, and ultimately accumulate, which is effective in stably maintaining the amorphous state of the amorphous particles. The average particle diameter d3 may be, for example, 2.0 times or less, 1.5 times or less, 1.2 times or less, 1.0 times or less, 0.8 times or less, 0.9 times or less, 0.8 times or less, 0.7 times or less, 0.6 times or less, or 0.5 times or less relative to the average particle diameter d2 of the crystalline particles. Furthermore, the average particle diameter d3 may be, for example, 0.2 times or more, 0.3 times or more, 0.4 times or more, 0.5 times or more, or 0.6 times or more relative to the average particle diameter d2.

[0036] The average particle diameter d3 of the stabilizer particles is not particularly limited, and may be, for example, 5 μm or more, 10 μm or more, 20 μm or more, 25 μm or more, or 30 μm or more. The average particle diameter d3 may be, for example, 50 μm or less, 40 μm or less, 30 μm or less, or 20 μm or less. The range of the average particle diameter d3 can be set by appropriately selecting the upper and lower limits described above, and may be, for example, 5 μm or more and 50 μm or less, or 10 μm or more and 40 μm or less. The average particle diameter d3 of the stabilizer particles can also be obtained by the same measurement method as the average particle diameters d1 and d2 described above.

[0037] The amount of stabilizer particles to be blended is not particularly limited and is set appropriately depending on the type of stabilizer, etc. For example, it can be set appropriately within a range of 0.01 to 100 times the mass of the crystalline particles. For example, in the case of a polymer stabilizer, it can be set to 0.05 to 100 times, 0.1 to 5 times, or 0.5 to 2 times, and in the case of a low-molecular-weight stabilizer and an inorganic stabilizer, it can be set to 0.01 to 10 times, etc.

[0038] In the compounding process, the core particles and crystalline particles are mechanically stirred and mixed, and the crystalline particles are pulverized by the impact and compression forces of the core particles associated with this mechanical action, thereby reducing the crystalline particles to fine particles and making them amorphous. Furthermore, the amorphous particles obtained by pulverization have strong adhesive and cohesive properties, so they can adhere to the surface of the core particles and achieve compounding. According to this manufacturing method, the action of the core particles associated with the mechanical action allows the crystalline particles to be pulverized into amorphous particles without the use of an amorphous stabilizer, and at the same time, they can be compounded with the core particles, which are excipients.

[0039] The mechanical action of the stirring and mixing used in the compounding step can be effectively achieved, for example, by using an apparatus equipped with a grinding mechanism that exerts high shearing force. High shearing stress can have a significant effect on the core particles. As such a compounding apparatus, a known stirring granulation apparatus or compounding apparatus having rotating stirring blades (rotating blades, rotors, etc.) can be used. Such apparatuses are commercially available as appropriate. For example, a high-speed stirring granulator (TMG1 / 6, etc.) manufactured by Glatt, a dry compounding apparatus such as the Nobilta NOBMINI manufactured by Hosokawa Micron Corporation, and similar apparatuses can be used.

[0040] In these composite devices, composite particles in which amorphous particles are composited with core particles can be obtained by adjusting the rotation speed and mixing (composite) time. For example, composite particles can be obtained by using the high-speed agitation granulator manufactured by Glatt at 1000 rpm for about 180 minutes, or by using the dry composite device manufactured by Hosokawa Micron Corporation at 7000 rpm for about 10 minutes.

[0041] Here, the agitator blade in the vessel of the compounding device that performs mixing and agitation may rotate around a vertical axis as in the above-mentioned high-speed agitator granulator, or may rotate around a horizontal axis as in the above-mentioned dry compounding device, or may rotate around an axis inclined in an oblique direction. The shape of the agitator blade is not particularly limited, but examples include a plate-like blade extending perpendicularly from the rotation axis. When the rotor is a plate-like blade, the blade may be attached parallel to the rotation axis as in the above-mentioned dry compounding device, or may be attached obliquely to the rotation axis as in the above-mentioned high-speed agitator granulator.

[0042] (Combination Parameters) In order to efficiently obtain composite particles by the present production method, it may be preferable to use, for example, a device that can exhibit specific parameters as a composite device for carrying out the composite step. Hereinafter, the composite parameters will be described using, as an example, a horizontal composite device (for example, the above-mentioned dry composite device) that has rotors that rotate around an axis along a substantially horizontal direction and is provided inside a cylindrical container extending along the horizontal direction.

[0043] Figure 4 shows a schematic diagram of the horizontally placed composite device to explain the composite parameters. As shown in Figure 4(a), the container (cylinder) is placed horizontally, so the composite sample (nuclear particles and crystalline particles) is deposited on the lower inner wall of the container. The sample height (h ０ ) can be calculated from the actual volume of the sample (for example, the volume of a right circular cylinder with a missing part - High-precision calculation site (casio.jp) (https: / / keisan.casio.jp / exec / system / 1440737868)). The actual volume of the sample can be determined from the true density of the sample measured with a gas displacement pycnometer and the mass of the sample. The true density is determined as follows. The composite sample contains all of the core particles, crystalline particles, stabilizer particles and / or anti-adhesion agent used in the composite, and the true density of each component can be measured and the true density of the composite sample can be obtained from the weighted average of the true densities of the individual components, or the true density of the composite sample, which is a mixture, can also be measured.

[0044] As shown in Figure 4(b), when the rotor rotates, the sample is forced to pass through the gap between the rotor blades and the inner wall of the container, so the sample height (h ０ ) to the clearance (h ｃ At this time, the bulk density of the sample is defined by the following formula:

[0045]

[0046] Next, as shown in Figure 4(c), four sets of two 18 mm wide rotating blades are attached to a rotor with a total length of 56 mm, so that when the rotor makes one rotation, the sample deposited on the inner wall of the container is compressed an average of (18 x 2 ÷ 56) x 4 = 2.57 times. When the rotation speeds are 7000 rpm (116.7 rps), 5000 rpm (83.3 rps), and 3000 rpm (50.0 rps), the number of times the sample is compressed per second is 300, 214, and 129, respectively.

[0047] Here, the compression efficiency is defined as the product of the bulkiness and the number of compressions. The values ​​of various elements based on FIG. 4 and the calculation results of the compression efficiency obtained from these are shown in FIG. 5. Compression efficiency (s －１ ) = Bulkiness x Number of compressions

[0048] In the above explanation, the composite parameters have been described as being related to a horizontally placed composite device that has rotors that rotate around a substantially horizontal axis and are housed in a cylindrical container that extends horizontally, but the present invention is not limited to such devices. The present invention can also be applied to a vertically placed composite device that has rotors that rotate around a vertical axis and are housed in a cylindrical container that extends vertically.

[0049] In this case, it can be assumed that the sample adheres uniformly to the inner wall of the container due to the centrifugal force generated by the rotor rotation. ０ ) can be calculated from the actual volume of the sample using the formula for calculating the volume of a hollow cylinder (https: / / keisan.casio.jp / exec / system / 1340326914). Using this sample height (h0), the bulk density can be calculated in the same manner as above, and the compression efficiency can be calculated from the number of compressions.

[0050] This compression efficiency increases as the rotor rotation speed increases and as the bulkiness increases. It is believed that the higher the compression efficiency in the compounding process, the better the compounding efficiency and the shorter the compounding time. According to the present inventors, by setting the compression efficiency to, for example, 150 or more, 155 or more, 160 or more, 165 or more, 170 or more, 175 or more, 180 or more, 190 or more, 195 or more, 200 or more, 205 or more, or 210 or more, composite particles can be obtained efficiently. The upper limit of the compression efficiency is not particularly limited, as it depends on the rotor rotation speed and container volume allowed for the compounding device, but is, for example, 300 or less, 280 or less, 260 or less, 240 or less, 230 or less, or 220 or less.

[0051] In order to obtain a desirable compression efficiency, the actual volume of the sample to be composited is adjusted to obtain a desirable bulkiness. ０ In order to obtain a desired number of compressions, the rotation speed of the rotor can be increased or the number of rotor blades around the rotation shaft can be increased.

[0052] Furthermore, a compounding apparatus that can achieve a degree of bulkiness and number of compressions that result in such effective compression efficiency can be said to be a compounding apparatus that is useful for carrying out the compounding step of the present manufacturing method.

[0053] (Combining Apparatus) A combining apparatus suitable for this manufacturing method can include, for example, a cylindrical container for mixing and stirring, with its longitudinal axis aligned horizontally or vertically, a rotor arranged within the cylindrical container along the longitudinal axis, and impellers arranged perpendicular to the rotor toward the inner wall of the cylindrical container. The rotor of such a combining apparatus can rotate at a rotation speed of, for example, 5,000 rpm or more, or 7,000 rpm or more, in order to increase the number of compressions, and the number of impellers can be, for example, three, four, five, or six or more, around the rotor. In addition, in order to increase the degree of bulkiness, the combining apparatus can have a distance of, for example, 2 mm or less, 1 mm or less, between the impellers and the inner wall of the cylindrical container.

[0054] In addition, in order to prevent the composite particles from adhering to the inner wall of the container used for mixing and stirring the device, lubricants and fluidizing agents such as light anhydrous silicic acid, talc, magnesium stearate, calcium stearate, sodium stearyl fumarate, and sucrose fatty acid esters can be used as appropriate. Among these, light anhydrous silicic acid and talc may be particularly useful. The average particle size of these anti-adhesion agents is not particularly limited, but may be, for example, 10 μm or less, 1 μm or less, or 100 nm or less. The amount of the anti-adhesion agent may be, for example, 0.1% by mass or more and 10% by mass or less, or 0.5% by mass or more and 2% by mass or less, based on the total mass of the crystalline particles and stabilizer particles.

[0055] In the composite process, it is effective to perform the mechanical stirring and mixing operation by maintaining the temperature inside the container in which the core particles and the crystalline particles are stirred and mixed at a temperature that can suppress recrystallization. More specifically, it is effective to maintain the temperature below the glass transition temperature of the organic compound of the amorphous particles. If the temperature is higher than the glass transition temperature, the amorphous particles soften (liquefy), making the composite particles more likely to aggregate and increasing the recrystallization rate of the amorphous particles. Depending on the type of organic compound of the crystalline particles, the temperature inside the stirring and mixing container can be set to, for example, 40°C or less, 35°C or less, 30°C or less, 25°C or less, 20°C or less, 15°C or less, or 10°C or less. To set the temperature inside the stirring and mixing container to such a value, the jacket temperature that externally controls the temperature of the stirring and mixing container can be set to, for example, 25°C or less, 20°C or less, 15°C or less, 10°C or less, 5°C or less, or 0°C or less.

[0056] In the compounding process, in addition to the core particles and crystalline particles, stabilizer particles and anti-adhesion agents are fed into the container of the compounding apparatus. These may all be added to the container at once, simultaneously, or individually, or may be added individually, continuously or intermittently. The order of addition is not particularly limited. Typically, the entire amount is added at once at the same time, or the entire amount of core particles may be added followed by the addition of crystalline particles and other particles. For example, after the entire amount of core particles is added, a predetermined amount of crystalline particles may be continuously supplied uniformly per hour for a predetermined time required to compound a predetermined amount of crystalline particles relative to the amount of core particles added. When other agents such as stabilizer particles and anti-adhesion agents are used in addition to the crystalline particles, a mixture of the crystalline particles and these other agents may be continuously supplied to the container at a predetermined ratio from one supply system as described above. Alternatively, one or more types selected from the group consisting of crystalline particles and other agents may be appropriately combined and continuously supplied to the container from two or more supply systems at a predetermined ratio.

[0057] The composite particles obtained in the composite process have amorphous particles attached to the surface of core particles, and depending on the amount of amorphous particles, the amorphous particles accumulate on the surface of the core particles to form an amorphous particle layer. The composite particles also have a mixed layer of amorphous particles and stabilizer particles attached and thus accumulated on the surface of the core particles, or a solid dispersion phase in which the amorphized organic compound is dispersed within or together with the stabilizer particles. This is because, when amorphous particles are stabilized by stabilizer particles, the amorphous particles may disperse with or in the stabilizer particles at the molecular level to form an amorphous solid dispersion. In this case, it may be difficult to clearly distinguish between the two when observed, for example, with an electron microscope.

[0058] By providing the surface layer with amorphous particles or an amorphous particle layer, or a layer of amorphous particles and stabilizer particles, or a mixed layer of these (solid dispersion phase), even a small amount of stabilizer particles can come into effective contact with the amorphous particles, thereby stably maintaining the amorphous state of the amorphous particles.

[0059] The degree of amorphousness of the amorphous particles in the composite particles is not particularly limited, but a higher degree of amorphousness is useful, for example, 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, or 99% or more.

[0060] In addition, when the composite particles obtained in the composite process are a layer in which amorphous particles are attached or deposited on the surface of a core particle, stabilizer particles may be further attached or deposited on these particles or layers.

[0061] As explained above, this production method is a practical method for producing composite particles that can simultaneously achieve amorphization and composite formation with core particles through the action of core particles accompanied by mechanical action due to stirring and mixing, without the need for solvents, amorphous stabilizers, or thermal melting, and these composite particles can be used as raw materials (components) for various preparations such as fine granules, granules, capsules, and tablets.

[0062] (Composite Particles) The composite particles disclosed herein can comprise a core particle that does not have an amorphous stabilizing effect, and a layer derived from amorphous organic compound particles on the surface of the core particle. As shown in Figure 2, this composite particle (composite particle of the first embodiment) is formed by amorphizing and compounding the crystalline organic compound particles through the mechanical action in the compounding step and the action of the core particle without using an amorphous stabilizer, and therefore comprises amorphous particles on the core particle that does not contain an amorphous stabilizer. The various embodiments already described can be applied to the core particle and the amorphous particle in this composite particle.

[0063] The composite particle includes a core particle that does not have an amorphous stabilizing effect and a layer derived from amorphous organic compound particles and amorphous stabilizer particles. This layer may be a mixed layer of amorphous particles and stabilizer particles attached to the surface of the core particle, or a solid dispersion phase. As shown in Figure 3, this composite particle (composite particle of the second embodiment) can effectively suppress recrystallization of the amorphous particles.

[0064] Examples will be described below as specific examples to more specifically explain the disclosure of this specification. The following examples are provided to illustrate the disclosure of this specification and are not intended to limit the scope thereof. In the following, the average particle size is the volume-based median diameter (central diameter) measured by a laser diffraction / scattering method.

[0065] (Production of Composite Particles by Dry Layering Granulation) In this example, the possibility of amorphizing drugs was investigated using layering granulation, a granulation method in which smaller particles are attached and layered on a larger core particle without using a solvent. Indomethacin (IND) (average particle size: 20.5 μm), which is easily mechanically amorphized and has a relatively stable amorphous phase, was used as a model drug. Five types of MCC spherical particles (CELLETS 127, 175, 200, 300, 500, Advanced Drug Delivery Technologies Ltd.) with different particle sizes were used as core particles (core particles). The D of CELLETS 127, 175, 200, 300, and 500 were used. ５０The particle diameters were 140 μm, 195 μm, 275 μm, 414 μm, and 649 μm, respectively (hereinafter referred to as MCCs-XS, MCCs-S, MCCs-M, MCCs-L, and MCCs-XL). IND crystals (30 g) and MCC spherical particles (300 g) were charged into a high-speed mixing granulator (TMG1 / 6, manufactured by Glatt) and mixed for up to 180 minutes at an impeller rotation speed of 1000 rpm (circumferential speed of 10.0 m / sec). The physical properties of the resulting composite particles were evaluated to determine whether they could be made amorphous. The results are shown in Figures 6 and 7.

[0066] Figure 6 (a) to (c) show the powder X-ray diffraction (XRPD) pattern, Raman spectrum, and differential scanning calorimetry (DSC) curve of the composite particles obtained using MCCs-S. As shown in Figure 6 (a), the XRPD pattern of the simple physical mixture (PM) showed sharp peaks (11.9°, 17.1°, 20.0°, 22.2°, and 26.9°) derived from IND crystals (γ-form) and broad peaks (14.7°, 22.5°, and 34.6°) derived from MCC crystals of about several nanometers in size. As the mixing time increased, the peaks derived from IND crystals became smaller, suggesting that the IND crystals were amorphized by the mixing process. However, no new peaks were observed due to the mixing process, and the emergence of crystalline polymorphs was not confirmed.

[0067] As shown in FIG. 6(b), the Raman spectrum shows peaks specific to crystalline IND and amorphous IND at 1698 cm －１ and 1680 cm －１ As the mixing time increased, the peak of IND crystals became smaller and the peak of amorphous IND became larger. These results demonstrate that high-speed mixing resulted in the amorphization of IND crystals without any crystal transition.

[0068] As shown in Figure 6(c), the DSC measurement results showed a baseline shift due to the glass transition of amorphous IND and an exothermic peak due to crystallization in the composite particles, which supported the presence of amorphous IND, similar to the results of XRPD and Raman spectroscopy.

[0069] Electron microscope images of the composite particles obtained after mixing for 30 minutes and 180 minutes are shown in Figure 7. As shown in Figure 7, IND particles with a particle diameter of about 1 µm adhered to and layered on the surface of the composite particles mixed for 30 minutes, making the particle diameter of the composite particles larger than that of the MCC particles. Similar to the case of acetaminophen (AAP) crystals previously confirmed by the present inventors, it is believed that the IND crystals were pulverized by mixing with the MCC particles and layered into granules.

[0070] The surface condition and particle size of the composite particles processed for 180 minutes were equivalent to those processed for 30 minutes, indicating that the pulverization and granulation of the IND crystals were completed by the 30-minute mixing time. Meanwhile, as shown in Figure 6, the amorphization of the IND crystals continued even after the 30-minute mixing time. These results indicate that the IND crystals are amorphized simultaneously with the pulverization in the early stages of the mixing process. After that, the pulverized IND particles are no longer further refined, but amorphization progresses due to collisions between the MCC spherical particles. These results demonstrate that the ball milling effect of the MCC spherical particles causes amorphization in addition to layering granulation of the IND crystals.

[0071] (Effect of particle size of core particles) Since the ball mill effect of the MCC spherical particles caused the drug crystals to become amorphous during the mixing process, the effect of the particle size of the MCC spherical particles was investigated. Raman spectra of composite particles prepared using MCC spherical particles of various particle sizes were measured, and the 1698 cm －１ and the peak height of 1680 cm specific to amorphous IND －１ The degree of amorphization of IND was calculated from the ratio of the peak heights of the two peaks. The results are shown in Figure 8.

[0072] As shown in Figure 8, the amorphization rate of IND increased with increasing particle size of the MCC spherical particles, and when MCCs-L and MCCs-XL were used, 100% amorphization of IND crystals was achieved. This result suggests that MCC spherical particles with a large particle size promote amorphization. To examine the effect of particle size in detail, the ratios of the average particle size, volume, and specific surface area of ​​each MCC spherical particle to the smallest MCCs-XS (volume and surface area were calculated assuming that the MCCs were spheres) are shown in Table 1.

[0073]

[0074] As previously explained, the amorphization of IND crystals occurs due to the ball milling effect, i.e., collision, of MCC spherical particles. The impact force due to the collision is determined by the mass and acceleration of the MCC spherical particles and is therefore proportional to the volume (cubed particle diameter). Assuming equal acceleration, the collision force of each MCC spherical particle increases approximately three times in the order of MCCs-XS, MCCs-S, MCCs-M, MCCs-L, and MCCs-XL, with the collision force of MCCs-XL being approximately 90 times that of MCCs-XS. Therefore, MCC spherical particles with larger particle diameters generate stronger collision forces during mixing, promoting the amorphization of IND crystals. On the other hand, because the specific surface area is inversely proportional to particle diameter, the collision frequency of MCC spherical particles decreases as the particle diameter increases. In other words, the larger the MCC spherical particle diameter, the lower the amorphization efficiency.

[0075] As can be seen in Figure 8, the amorphization rate was faster when MCCs-XL was used than when MCCs-L was used. However, the amorphization rate of MCCs-XL was slower than expected from the difference in volume (collision force) between MCCs-XL and MCCs-L. This is thought to be due to a decrease in collision frequency due to an increase in particle size. The D of composite particles made using each MCC spherical particle ５０ The values, drug contents and drug recovery rates (expressed as the ratio of measured drug contents to theoretical drug contents) are shown in Table 2.

[0076]

[0077] As shown in Table 2, except when MCCs-XL was used, the particle size of the composite particles was larger than that of the MCC spherical particles. Furthermore, the drug recovery rate exceeded 90%, suggesting that most of the IND particles were layered on the MCC spherical particles. On the other hand, when MCCs-XL was used, a decrease in particle size and drug content was observed. This is thought to be due to the destruction of the MCC spherical particles during the mixing process, resulting in the release of the IND particles held by the MCC spherical particles and their adhesion to the granulator walls. Based on the above, in this study, when MCCs-L was used for 180 minutes of mixing, it was possible to produce composite particles in which completely amorphous IND particles were layered and granulated.

[0078] A dissolution test was conducted on the composite particles obtained using MCCs-L under supersaturated conditions (10 times the solubility of IND crystals). The results are shown in Figure 9. As shown in Figure 9, the composite particles exhibited supersaturation, with the dissolution concentration reaching 2.5 times the crystalline solubility at 10 minutes of dissolution. On the other hand, as a comparative example, amorphous IND prepared by the melt quenching (QC) method exhibited a dissolution concentration equivalent to that of the composite particles, but this required a dissolution time of 120 minutes. The particle diameter of the amorphous IND layered on the composite particles was approximately 1 μm, which was smaller than that of QC IND. Furthermore, while QC IND formed aggregates immediately after the dissolution test, aggregation was suppressed in the composite particles because the amorphous IND was retained on the surface of the MCC spherical particles. Therefore, it is believed that the amorphous IND layered on the MCC spherical particles had a larger effective surface area than QC IND, resulting in a faster dissolution rate.

[0079] Furthermore, a physical stability test was conducted on the composite particles in the presence of silica gel at 25°C. The results are shown in Figure 10. As shown in Figure 10, more than 90% of the amorphous IND layered on the MCC spherical particles crystallized after one day of storage and was almost completely crystallized after one week. This crystallization rate was faster than that of QC-IND, which is thought to be due to the small particle size and large surface area of ​​the amorphous IND. Therefore, polyvinylpyrrolidone (PVP) was added at 10% of the IND mass and mixed with the MCC spherical particles to prepare composite particles.

[0080] The amorphous IND in these composite particles can maintain its amorphous state for at least 4 weeks, demonstrating that the use of additives that stabilize the amorphous state can suppress crystallization of the layered amorphous particles. Furthermore, by using the amino acid arginine as a coformer for IND, we have succeeded in producing spherical particles layered with the IND-ARG amorphous complex, which have high dissolution properties and physical stability.

[0081] These results demonstrate the applicability of the dry layering granulation method using a high-speed agitator granulator to the design of amorphous formulations.

[0082] (Study on the Production of Composite Particles) In this example, cornstarch (average particle size: 20.1 μm) was used as the core particles, and indomethacin (IND) (average particle size: 14.0 μm) was used. A total of 9 g of the core particles and IND at a mass ratio of 10:1 was placed in a dry-type composite device (NOBMINI, manufactured by Hosokawa Micron Corporation, 0.02 liter vessel) and mixed for 10 minutes at a rotor rotation speed of 3000 to 7000 rpm. The jacket temperature of the vessel was set to 20°C. The processed product was evaluated for powder X-ray diffraction and Raman spectroscopy crystallinity. The results are shown in FIG. 11.

[0083] As shown in FIG. 11, as the rotor rotation speed increases, the powder X-ray diffraction peaks (11.9°, 17.1°, 20.0°, 22.2°, 26.9°) and the Raman spectrum peak (1698 cm) of the IND crystal become larger. －１ ) disappeared, and the peak of amorphous IND (1680 cm －１ At a rotor rotation speed of 7000 rpm, the peaks derived from crystals disappeared, indicating that complete amorphization of IND could be achieved in a treatment time of 10 minutes.

[0084] Furthermore, a total of 9 g of core particles and IND at a mass ratio of 10:3 was placed in the dry-type compounding apparatus and mixed for 10 to 90 minutes at a rotor rotation speed of 7,000 rpm. The jacket temperature of the vessel was set to 20°C. The results of powder X-ray diffraction and Raman spectroscopy crystallinity evaluation of the mixture are shown in Figure 12. As shown in Figure 12, as the mixing time increased, the powder X-ray diffraction peaks and Raman spectroscopy peaks of IND crystals disappeared, and peaks of amorphous IND appeared. At a mixing time of 90 minutes, the peaks derived from the crystals disappeared. This indicates that complete amorphization can be achieved in a short time, even when crystalline particles are contained at a high concentration.

[0085] The dry-type compounding device used in this example rotates along the inner wall of a cylindrical vessel with rotating blades attached to the rotor. When the core particles and crystalline particles are interposed between the inner wall and the end of the rotating blades facing the inner wall, a strong shear compressive force acts on them. This action promotes the pulverization and amorphization of the crystalline particles due to the collision and compression of the core particles, and it is believed that the mechanical action of the compounding device itself also contributed to the pulverization and amorphization of the crystalline particles IND.

[0086] (Study of Compounding Parameters) In this example, cornstarch (average particle size: 20.1 μm) was used as core particles, and indomethacin (IND) (average particle size: 14.0 μm) was used. The core particles and IND were mixed at a mass ratio of 10:1. Samples with actual volumes of 4.0 ml, 5.0 ml, and 6.0 ml (masses of 6.02 g, 7.53 g, and 9.04 g, respectively) were placed in the dry compounding apparatus used in Example 4 and compounded for 10 minutes at a rotor rotation speed of 7000 rpm. The jacket temperature of the vessel was set to 20°C. The dry compounding apparatus used in this example had the element configuration shown in Figure 4 and exhibited the compression efficiency relative to the sample's actual volume shown in Figure 5. The samples after 10 minutes of compounding treatment in this apparatus were evaluated for powder X-ray diffraction and Raman spectroscopy crystallinity. The results are shown in Figure 13.

[0087] As shown in FIG. 13, in the range of the actual volume of the sample from 4.0 to 6.0 mL, the powder X-ray diffraction peaks (11.9°, 17.1°, 20.0°, 22.2°, 26.9°) of the indomethacin crystal and the peak of the Raman spectrum (1698 cm －１ ) completely disappeared, and the peak of amorphous indomethacin (1680 cm －１ ) appeared. When the rotor rotation speed was 7000 rpm, complete amorphization was achieved in a processing time of 10 minutes even when the sample filling volume was reduced. When the rotor rotation speed was 7000 rpm, the compression efficiency was 202-225 ( / s) even when the actual sample volume was 4.0-6.0 ml. It was considered that complete amorphization of indomethacin was achieved when the compression efficiency was 200 / s or higher.

[0088] On the other hand, when the rotor rotation speed was reduced even though the actual volume of the sample was 6.0 mL, the efficiency of amorphizing indomethacin decreased significantly, which was thought to be due to a decrease in compression efficiency.

[0089] From this example and Example 4, it was found that the compression efficiency can be used as an index of compounding. It was also found that efficient compounding is possible when the compression efficiency is 200 or more.

Claims

1. A method for producing composite particles, comprising: a composite step of mechanically stirring and mixing core particles not having an amorphous stabilizing effect with crystalline organic compound particles, promoting the pulverization and amorphization of the crystalline organic compound particles by the action of the core particles accompanying the mechanical action of the stirring and mixing, and attaching the amorphous organic compound particles derived from the crystalline organic compound particles to the surfaces of the core particles; and producing the composite particles comprising the amorphous organic compound particles on the surfaces of the core particles.

2. The manufacturing method according to claim 1, wherein the average particle size of the core particles in the composite process is 1.5 to 30.0 times the average particle size of the crystalline organic compound particles.

3. The manufacturing method according to claim 1, wherein the mass of the core particles in the composite process is 3.0 to 10.0 times the mass of the crystalline organic compound particles.

4. The manufacturing method according to claim 1, wherein the compounding step further comprises mechanically stirring and mixing amorphous stabilizer particles in addition to the core particles and the crystalline organic compound particles.

5. The method according to claim 1, wherein the compounding step is carried out so that the temperature inside a vessel in which the compounding step is carried out is maintained below the glass transition temperature of the organic compound of the amorphous organic compound particles.

6. The manufacturing method according to claim 1, wherein the compounding step further comprises mechanically stirring and mixing amorphous stabilizer particles in addition to the core particles and the crystalline organic compound particles, and the compounding step is carried out so as to maintain a temperature inside a container below the glass transition temperature of the organic compound of the amorphous organic compound particles.

7. The manufacturing method described in claim 3, wherein the compounding step further comprises mechanically stirring and mixing amorphous stabilizer particles in addition to the core particles and the crystalline organic compound particles.

8. The method according to claim 3, wherein the compounding step is carried out so that the temperature inside a vessel in which the compounding step is carried out is maintained below the glass transition temperature of the organic compound of the amorphous organic compound particles.

9. The manufacturing method according to claim 3, wherein the compounding step further comprises mechanically stirring and mixing amorphous stabilizer particles in addition to the core particles and the crystalline organic compound particles, and the compounding step is carried out so as to maintain a temperature inside a container that carries out the compounding step below the glass transition temperature of the organic compound of the amorphous organic compound particles.

10. The method of claim 1, wherein the core particles are selected from pharma-ceutically acceptable excipients.

11. The method according to claim 10, wherein the core particles are one or more selected from the group consisting of lactose, glucose, starch, corn starch, crystalline cellulose and methyl cellulose.

12. A composite particle comprising: a core particle having no amorphous stabilizing effect; and a layer derived from an amorphous organic compound particle and an amorphous stabilizer particle on the surface of the core particle.

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