Composite particle comprising crystalline organic compound and method for producing same

Abstract

Provided are composite particles each obtained by compositing, on a core particle, a crystalline organic compound in the form of fine particles. The composite particles each comprise: a core particle; and crystalline organic compound particles that are present on the surface of the core particle and that contain a crystalline organic compound. The specific surface area of the composite particles is 0.0015-60 m2 / g.

Description

Composite particles comprising crystalline organic compounds and method for producing the same

[0001] (Cross-reference of related applications) This application claims priority based on Japanese Patent Application No. 2024-192291, filed on 31 October 2024, and the contents of said Japanese Patent Application are incorporated herein by reference as constituting a part of this Specification.

[0002] This specification relates to composite particles comprising crystalline organic compounds and methods for producing the same.

[0003] From the standpoint of bioavailability and other factors, it can be effective to miniaturize crystalline organic compounds used as active ingredients in pharmaceuticals by forming them into nanoparticles or other fine particles. Generally, nanoparticle formation technologies include a method of dispersing crystals of the active ingredient in water and crushing them into balls (Patent Document 1), and a method of crystallizing a drug dissolved in an organic solvent into fine particles (Patent Document 2).

[0004] International Publication No. 2016 / 140219, International Publication No. 2014 / 050910

[0005] However, all of these methods require a medium such as water or an organic solvent. Therefore, in addition to the problem of residual organic solvents, there are energy costs associated with removing the medium, the effect of heat during drying on the active ingredients, and the risk of inactivation due to particle aggregation. Furthermore, when using ball grinding, metal contamination may occur. Also, finely particulated crystalline organic compounds can sometimes be difficult to handle from a formulation perspective, as they tend to aggregate easily.

[0006] This specification provides a technology for producing composite particles in which crystalline organic compounds are compounded as fine particles on a core particle. Furthermore, this specification provides a novel crystalline organic compound material suitable for applications such as pharmaceutical raw materials.

[0007] The inventors have conducted various studies on amorphousization of crystalline powders and have found that by mechanically stirring and mixing nucleation particles and crystalline organic compound particles smaller than the nucleation particles, the crystalline organic compound particles can be pulverized and amorphousized by the action of the nucleation particles accompanying the mechanical action of stirring and mixing, thereby generating amorphous organic compound particles from crystalline particles, and that the amorphous organic compound particles generated in situ can be attached to and deposited on the nucleation particles.

[0008] The inventors have found that by adjusting the degree of amorphousness of amorphous organic compound particles, when particles composed of amorphous organic compound particles are stored under certain conditions, the amorphous organic compound particles can be crystallized into particles of a desired size. Based on this finding, this specification provides the following means.

[0009] Furthermore, the inventors have found that by deliberately promoting the recrystallization of amorphous organic compound particles on the core particles, composite particles having fine crystalline organic compound particles on their surface can be obtained. Based on this finding, this specification further provides the following means relating to composite particles and methods for producing the same.

[0010] [1] A method for producing composite particles, comprising: a step of mechanically stirring and mixing a core particle and crystalline organic compound particles to promote the pulverization and amorphousization of the crystalline organic compound particles to produce a first composite particle having amorphous organic compound particles derived from the crystalline organic compound particles on the surface of the core particle; and a step of storing the first composite particle under certain conditions to recrystallize the amorphous organic compound particles to produce a second composite particle having recrystallized organic compound particles on its surface, wherein the step of producing the first composite particle includes adjusting the degree of amorphousization of the amorphous organic compound particles so that the recrystallized organic compound particles are of a desired size. [2] The method for producing the composite particle according to [1], wherein the core particle comprises a particle having an amorphous stabilizing effect. [3] The method for producing the composite particle according to [1] or [2], wherein the step of producing the second composite particle includes storing the first composite particle in the presence of water vapor. [4] The manufacturing method according to [1] or [2], wherein the step of producing the second composite particle comprises storing the first composite particle in the presence of an organic solvent vapor. [5] The manufacturing method according to [4], wherein the organic solvent vapor comprises the vapor of one or more organic solvents selected from organic solvents having a boiling point of 80°C or less. [6] The manufacturing method according to any one of [1] to [5], wherein the step of producing the second composite particle comprises storing the first composite particle at a temperature below the glass transition temperature of the organic compound of the crystalline organic compound particle. [7] The manufacturing method according to any one of [1] to [6], wherein the step of producing the first composite particle comprises adjusting the degree of amorphousness so that the recrystallized organic compound particle has a smaller diameter than the amorphous organic compound particle. [8] The manufacturing method according to any one of [1] to [7], wherein the step of producing the first composite particle comprises performing the stirring and mixing under conditions such that the degree of amorphousness obtained based on the Raman spectrum or powder X-ray diffraction spectrum of the amorphous organic compound particle is 75% or more. [9] The manufacturing method according to [8], wherein the step of producing the first composite particles is to carry out the stirring and mixing under conditions that result in a degree of amorphization of 95% or more.

[10] The manufacturing method according to [8], wherein the step of producing the first composite particles is to perform the stirring and mixing in a range that does not exceed the condition for the degree of amorphousness to reach 100%.

[11] The manufacturing method according to any one of [1] to [9], further comprising the step of measuring the Raman spectrum or powder X-ray diffraction spectrum of the amorphous organic compound particles after the step of producing the first composite particles to confirm the degree of amorphousness of the amorphous organic compound particles.

[12] A second composite particle obtained by the manufacturing method of composite particles according to any one of [1] to

[11] .

[13] A pharmaceutical composition containing the second composite particle according to

[12] .

[14] A pharmaceutical raw material containing a plurality of second composite particles, each comprising a core particle and a coating layer formed to cover the periphery of each particle and containing a plurality of recrystallized particles with a particle size of 1 μm or less.

[15] A pharmaceutical composition containing the pharmaceutical raw material according to

[14] .

[0011]

[16] A composite particle comprising: a core particle; and crystalline organic compound particles containing a crystalline organic compound present on the surface of the core particle, wherein the specific surface area of ​​the composite particle is 0.0015 m². ２ / g or more, 60m ２

[17] A composite particle having a particle size of 0.0 μm or less per gram.

[18] The composite particle according to

[17] , wherein the average particle diameter of the crystalline organic compound particles is 4.0 μm or less.

[19] The composite particle according to

[18] , wherein the average particle diameter of the crystalline organic compound particles is 0.60 μm or less.

[20] The specific surface area of ​​the composite particle is 0.075 m². ２ / g or more, 30m ２ A composite particle according to any one of

[16] to

[19] , wherein the specific surface area of ​​the composite particle is 0.10 m². ２ / g or more, 10m ２

[16] to

[19] or less.

[22] A composite particle according to any one of

[16] to

[21] , wherein the mass ratio of the nucleus particle to the crystalline organic compound particle (nucleus particle:crystalline organic compound particle) is 100:1 or more and 1:5 or less.

[23] A composite particle according to any one of

[16] to

[22] , wherein the molecular weight of the crystalline organic compound is 200 or more and 1,300 or less.

[24] A composite particle according to any one of

[16] to

[22] , wherein the molecular weight of the crystalline organic compound is 350 or more and 720 or less.

[25] A composite particle according to any one of

[16] to

[24] , wherein the crystalline organic compound particle is a particle obtained by recrystallizing amorphous organic compound particles by storing them under certain conditions for a predetermined period of time.

[26] A composite particle according to

[25] , wherein the crystalline organic compound particle is obtained by storing the amorphous organic compound particle for 1 hour or more.

[27] The composite particle according to

[25] or

[26] , wherein the crystalline organic compound particles are obtained by storing them at a temperature at least 10°C lower than the glass transition temperature of the pre-amorphous organic compound particles.

[28] The composite particle according to any one of

[16] to

[27] , wherein the core particles are one or more selected from the group consisting of crystalline cellulose, hydroxypropyl cellulose, and methylcellulose.

[29] The composite particle according to any one of

[16] to

[28] , wherein the crystalline organic compound particles are bonded to each other to form a porous layer having interparticle gaps.

[30] A pharmaceutical composition comprising the composite particle according to any one of

[16] to

[29] or the crystalline organic compound particles.

[31] A method for producing composite particles, comprising: a first step of mechanically stirring and mixing a core particle and crystalline organic compound particles to promote the pulverization and amorphousization of the crystalline organic compound particles, thereby producing a first composite particle having amorphous organic compound particles derived from the crystalline organic compound particles on the surface of the core particle; and a second step of storing the first composite particle under certain conditions to recrystallize the amorphous organic compound particles, thereby producing a second composite particle having recrystallized organic compound particles on its surface, wherein the specific surface area of ​​the second composite particle is 0.0015 m². ２ / g or more, 60m ２A manufacturing method comprising carrying out the first and second steps so that the amount is less than or equal to / g.

[0012] This figure shows an overview of the method for producing the second composite particles disclosed herein. This figure shows the relationship between particle size, nuclei, and processing time of recrystallized particles on the second composite particles. This figure shows the Raman spectra and scanning electron microscope (SEM) images of the first and second composite particles produced in Example 1. This figure shows the Raman spectra and SEM images of the first and second composite particles produced in Example 2. This figure shows the Raman spectra of the second composite particles produced in Example 3 with stirring times of 30 minutes and 45 minutes. This figure shows the SEM images of the second composite particles produced in Example 3 with stirring times of 30 minutes and 45 minutes. This figure shows the relationship between the ratio of crystalline to amorphous indomethacin and the Raman spectrum. This figure shows the Raman spectra of the second composite particles produced in Example 3 with stirring times from 1 hour to 10 hours. This figure shows the SEM images of the second composite particles produced in Example 3 with stirring times from 1 hour to 10 hours. This figure shows the Raman spectra of the second composite particles produced in Example 4. This figure shows an SEM image of the second composite particle produced in Example 4. This figure shows the Raman spectrum of the second composite particle produced under water vapor in Example 5. This figure shows the parameters related to the calculation of bulkiness. This figure shows the calculation results of bulkiness. This figure shows the powder X-ray diffraction spectrum and scanning electron microscope (SEM) image during the production process of the simvastatin composite particle produced in Example 6. This figure shows the powder X-ray diffraction spectrum and scanning electron microscope (SEM) image during the production process of the carvedilol composite particle produced in Example 6. This figure shows the scanning electron microscope (SEM) image during the production process of the indomethacin composite particle produced in Example 6. This figure shows the powder X-ray diffraction spectrum and scanning electron microscope (SEM) image during the production process of the aprepitant composite particle produced in Example 6.

[0013] Hereafter, representative and non-limiting examples of the disclosure herein will be described in detail with reference to the drawings as appropriate. This detailed description is intended simply to show those skilled in the art details for carrying out preferred examples of the invention and is not intended to limit the scope of the disclosure herein. Furthermore, additional features and inventions disclosed below may be used separately from or in conjunction with other features and inventions to provide further improved methods for producing composite particles and composite particles.

[0014] Furthermore, the combinations of features and processes disclosed in the following detailed description are not essential for carrying out the invention in the broadest sense, and are described solely to illustrate representative examples of the disclosure herein. Moreover, the various features of the representative examples described above and below, as well as the various features of those described in the independent and dependent claims, do not necessarily have to be combined in the same way as the examples described herein, or in the order listed, to provide additional and useful embodiments of the disclosure herein.

[0015] All features described herein and / or in the claims are intended to be disclosed individually and independently of each other, as limitations to the original disclosure and claimed specific subject matter, separate from the features described in the examples and / or claims. Furthermore, all descriptions of numerical ranges and groups or clusters are intended to disclose intermediate configurations between them, as limitations to the original disclosure and claimed specific subject matter.

[0016] The first aspect of the disclosure herein relates to a method for producing composite particles containing crystalline organic compound particles. The production method disclosed herein comprises the steps of: mechanically stirring and mixing a core particle that does not have an amorphous stabilizing effect with crystalline organic compound particles (hereinafter simply referred to as crystalline particles) to promote the pulverization and amorphousization of the crystalline particles, thereby producing a first composite particle having amorphous organic compound particles (hereinafter simply referred to as amorphous particles) derived from the crystalline particles on the surface of the core particle; and storing the first composite particle under certain conditions to recrystallize the amorphous particles, thereby producing a second composite particle having recrystallized organic compound particles (hereinafter also referred to as recrystallized particles) on its surface. Furthermore, in the step of producing the first composite particle, the production method adjusts the degree of amorphousization of the amorphous particles so that the recrystallized particles are of a desired size.

[0017] An overview of this manufacturing method is shown in Figure 1A. According to this manufacturing method, as shown in Figure 1, crystalline organic compound particles are amorphous due to collisions with nucleation particles, etc., and are provided on the surface of the nucleation particles as amorphous particles, thereby forming first composite particles. By recrystallizing the amorphous particles on these first composite particles, second composite particles are formed.

[0018] According to the inventors, by varying the time of mechanical mixing and stirring, the process was continued even after the mixture appeared completely amorphous based on Raman spectroscopy and powder X-ray diffraction spectroscopy, and then the amorphous organic compound particles were recrystallized. As a result, it was found that depending on the length of the processing time, recrystallized particles with a particle size smaller than that of the amorphous organic compound particles could be obtained, gradually increasing from recrystallized particles with a particle size similar to that of the amorphous organic compound particles.

[0019] Although the material appears completely amorphous in Raman spectra and other measurements, it is known that amorphous materials produced by mechanical stirring retain crystal nuclei (fine particles of nanoscale or smaller) that cannot be detected by Raman spectra or powder X-ray diffraction spectra. Furthermore, it is known that crystallization of amorphous materials occurs during the processes of crystal nucleation and crystal growth. In other words, the more crystal nuclei there are beforehand, the more the crystal growth is promoted.

[0020] From these findings, the inventors concluded that even if the material appears completely amorphous in Raman spectroscopy, crystal nuclei remain after mechanical treatment, and the number of remaining nuclei decreases with prolonged mechanical treatment. Furthermore, the degree to which these nuclei remain is thought to determine the particle size of the recrystallized particles obtained through recrystallization. This is supported by the fact that as the treatment time increases, the crystallization temperature of amorphous indomethacin rises, making crystal growth less likely (resulting in fewer nuclei). Figure 1B shows the relationship between the treatment time of mechanical stirring and mixing, the number of nuclei, and the particle size of the recrystallized particles.

[0021] As shown in Figure 1B, if many crystal nuclei remain in amorphous particles, the region where crystal growth can occur is small, and therefore the recrystallized particles will have a smaller diameter than the amorphous particles. On the other hand, if the number of crystal nuclei in amorphous particles decreases, the region where crystal growth can occur becomes larger, and the resulting recrystallized particles will have a particle size close to that of the amorphous particles.

[0022] From the above, the inventors have unexpectedly found that recrystallized particles can be made to a desired particle size by adjusting the degree of amorphousness of amorphous particles, that is, the degree of amorphousness or the degree of remaining crystal nuclei based on Raman spectroscopy or powder X-ray diffraction spectroscopy as described herein.

[0023] For example, if you want to obtain recrystallized particles with a smaller diameter than amorphous particles, you can mechanically process the amorphous particles until, for example, the peaks originating from the initially remaining amorphous organic compounds disappear in the Raman spectrum or powder X-ray diffraction spectrum. This is because at this stage, there are still many crystal nuclei in the amorphous particles.

[0024] On the other hand, if it is desired to obtain recrystallized particles with a particle size close to that of amorphous particles from recrystallized particles with an even larger diameter, the degree of amorphousness of the amorphous particles should be reduced by continuing mechanical treatment even after the peaks originating from amorphous organic compounds disappear, for example, in Raman spectroscopy or powder X-ray diffraction spectroscopy. This is because fewer crystal nuclei remain in the amorphous particles.

[0025] In order to obtain recrystallized particles with a desired particle size, for example, preliminary experiments may be conducted as follows. That is, by varying the mechanical stirring and mixing treatment time and the like, first composite particles having amorphous particles with various degrees of amorphization are obtained. Then, the amorphous particles of the first composite particles are stored under certain conditions to obtain second composite particles having recrystallized particles. By evaluating the particle size of the recrystallized particles on the second composite particles with various treatment times, treatment conditions such as the mechanical stirring treatment time that can obtain recrystallized particles with a desired particle size can be determined.

[0026] According to this production method, since crystallized particles with a desired particle size can be obtained without using liquids such as water and organic solvents, problems associated with evaporation of the liquid and contamination of metals from the mill can be suppressed or avoided. Further, as shown in FIG. 1A, since the recrystallized particles can be obtained as composite particles in which the recrystallized particles are combined with the core particles, treatments such as granulation can be omitted during formulation. Thus, according to this production method, it is possible to contribute to the efficiency improvement and cost reduction of the development and production of recrystallized particle preparations, particularly with a small diameter, for example, a nano size.

[0027] Further, the second aspect of the present specification relates to composite particles including crystalline organic compound particles and the like. The composite particles disclosed in the present specification include core particles and crystalline organic compound particles on the surface of the core particles. The specific surface area of the composite particles is 0.0015 m ２ / g or more and 60 m ２ / g or less. According to this composite particle, for example, treatments such as granulation can be omitted during the formulation of the crystalline organic compound. According to this composite particle, it is possible to contribute to the efficiency improvement and cost reduction of the development and production of recrystallized particle preparations, particularly with a small diameter, for example, a nano size.

[0028] First, the method for producing composite particles including crystalline organic compound particles according to the first aspect will be described below, and then the composite particles and the like according to the second aspect will be described.

[0029] (Method for manufacturing composite particles) This manufacturing method comprises the steps of: mechanically stirring and mixing core particles and crystalline particles to promote the pulverization and amorphousization of the crystalline particles in order to produce first composite particles having amorphous particles derived from the crystalline particles on the surface of the core particles; and storing the first composite particles under certain conditions to recrystallize the amorphous particles in order to produce second composite particles having recrystallized particles on the surface.

[0030] (Process for manufacturing the first composite particle) In carrying out this manufacturing method, core particles and crystalline particles to be used in the process for manufacturing the first composite particle are prepared separately.

[0031] (Nuclear Particles) The nuclear particles constitute the nuclei of the first and second composite particles and serve as carrier particles that support the amorphous particles and recrystallized particles. While the nuclear particles are not particularly limited in form, it is beneficial from the viewpoint of impact force against crystalline particles and their own fracture strength to have morphologies such as spheres, lumps, cubes, rectangular prisms, or other polyhedral shapes. In other words, it is beneficial that they are not plate-shaped, flake-shaped, rod-shaped, needle-shaped, columnar, or spongy. This is because plate-shaped, flake-shaped, needle-shaped, rod-shaped, columnar, or spongy particles tend to have insufficient impact force and fracture strength. While not particularly limited, it may be preferable from the viewpoint of impact force and fracture strength if the longest and minimum transverse dimensions of the core particles are, 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, and the particle is spherical, lumpy, or polyhedral.

[0032] In the process of manufacturing the first composite particles, the core particles are designed to suppress pulverization and maintain their particle shape. Using such core particles makes them more suitable as grinding media, such as balls or beads, in ball mill grinding for crystalline particles. Pulverization can be suppressed by considering the fracture strength based on the shape and size of the core particles.

[0033] These core particles are not particularly limited, but 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 hydroxypropyl methylcellulose; and inorganic compounds known as excipients, such as magnesium aluminometasilicate and anhydrous calcium phosphate. Monosaccharides, disaccharides, and polysaccharides can be naturally derived sugars, as well as their known derivatives (e.g., deoxy sugars, amino sugars, thio sugars, ester derivatives, etc.) as appropriate. Crystalline cellulose may be preferred in some cases.

[0034] The core particles may or may not have an amorphous stabilizing effect. If the core particles have an amorphous stabilizing effect, they may inhibit recrystallization in the process of manufacturing the second composite particles. On the other hand, if they do not have an amorphous stabilizing effect, it may be easier to obtain recrystallized particles. The absence of an amorphous stabilizing effect in the core particles includes cases where the core particles themselves do not have an amorphous stabilizing effect, as well as cases where the core particles do not contain known amorphous stabilizers. Furthermore, since the core particles are also carrier particles that support crystalline particles, it is more advantageous from a formulation perspective to allow the carrier particles to function on their own. In addition, by not containing an amorphous stabilizer, the core particles and thus the formulation can be made smaller, and the content of the active ingredient can be increased. As a result, it may be possible to reduce the dosage or number of administrations of the pharmaceutical composition. Furthermore, amorphous stabilizers generally have high hygroscopic properties (especially polymer-based stabilizers), which can reduce the water content of the core particles and ultimately the resulting composite particles, thereby increasing storage stability (physical and chemical stability in the sense of the amorphous material crystallizing).

[0035] The average particle diameter d1 of the nucleus particles is not particularly limited in relation to the average particle diameter d2 of the crystal particles, but it is sometimes 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 exerted by the nucleus particles when they collide with the crystal particles increases, which promotes the breakdown (amorphization) of the lattice structure of the crystal particles. The average particle diameter d1 can be, for example, 1.1 times or more the average particle diameter d2, as well as 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, as well as, 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, and so on.

[0036] 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 decreases. Therefore, the average particle diameter d1 can 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.

[0037] The range of the ratio between the average particle diameter d1 and the average particle diameter d2 is not particularly limited, but can be set by appropriately combining the upper and lower limits mentioned above. For example, it could be 1.5 times or more and 30.0 times or less, 1.5 times or more and 25.0 times or less, 1.5 times or more and 20.0 times or less, 1.5 times or more and 15.0 times or less, 1.5 times or more and 10.0 times or less, 1.5 times or more and 5 times or less, 1.5 times or more and 3.0 times or less, etc.

[0038] The average particle diameter d1 of the nucleus particles is not particularly limited, but may 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.

[0039] The average particle diameter d1 of the nuclear particles is not particularly limited, but from the viewpoint of ensuring that the fracture strength of the nuclear particles does not exceed the impact force of the nuclear 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.

[0040] The range of the average particle diameter d1 of the nucleus particles is not particularly limited, but can be set by appropriately combining the upper and lower limits mentioned above. For example, it could be 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.

[0041] The average particle diameter d1 of the nucleus particles and the average particle diameter d2 of the crystalline particles can both be obtained as volume-based median diameters (central diameters) by laser diffraction and scattering methods.

[0042] (Crystalline Organic Compound Particles) Crystalline organic compound particles (crystalline particles) are typically crystalline powders of organic compounds. Crystalline particles may be single crystals or polycrystalline. They may also be polymorphic. The shape of the crystalline particles is not particularly limited, but they can take various forms such as spherical, cubic, massive, plate-like, dendritic, spongy, and irregular shapes.

[0043] The type of organic compound used in the crystalline particles is not particularly limited, but any organic compound that can be amorphous by a grinding method such as a ball mill can be amorphous and recrystallized in this manufacturing method. In the process of manufacturing the first composite particles, it is sometimes preferable to stir-mix the organic compound at a temperature lower than the glass transition temperature in order to amorphousize it from crystal. For this reason, considering the stirring and mixing temperature, the glass transition temperature (Tg) of the organic compound may be, for example, 25°C or higher, 30°C or higher, 35°C or higher, 40°C or higher, 45°C or higher, 50°C or higher, etc.

[0044] Furthermore, the organic compound can be any of the organic compounds known as low molecular weight, medium molecular weight, or high molecular weight pharmaceuticals, and its molecular weight is not particularly limited. However, from the viewpoint of ease of crystallization of amorphous materials, for example, organic compounds with molecular weights of 5000 or less, 4000 or less, 3000 or less, 2000 or less, 1000 or less, 500 or less, and 400 or less are recommended.

[0045] Furthermore, it is significant that the organic compounds used are those that can be active ingredients in pharmaceuticals, such as indomethacin and nifedipine, and it is even more significant that they are organic compounds that are poorly soluble in water due to their crystalline nature. It is also possible to pre-confirm whether crystalline organic compounds that can be amorphous using this manufacturing method can be amorphous by grinding methods such as ball milling, or whether they can be amorphous using this manufacturing method with crystalline cellulose as a core particle.

[0046] Crystalline particles are particles that are pulverized by collisions with core particles and compression actions that occur due to mechanical action during stirring and mixing. These actions also destroy the lattice structure of the crystalline particles, causing them to become amorphous. The pulverized amorphous particles then adhere to and accumulate on the surface of the core particles. The average particle diameter d2 of the crystalline particles is made smaller than the average particle diameter d1 of the core particles, as previously explained. This makes them easier to pulverize by collisions with the core particles. It is preferable that the average particle diameter d2 of the crystalline particles has the relationship with the average particle diameter d1 of the core particles as previously described.

[0047] The average particle diameter d2 of the crystal grain is not particularly limited, but for example, it may be 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. Also, the average particle diameter d2 may be 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, but for example, it may be 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. Furthermore, in the particle size distribution measured by the method described above, it may be advantageous if, on a volume basis, for example, 80% or more, 85% or more, 90% or more, or 95% or more of particles are 100 μm or smaller within the range of particle size 100 μm or less.

[0048] The core particles and crystalline particles can be used in any ratio in the process of manufacturing the first composite particles. However, considering the size of the core particles and the composition of the first composite particles, the mass ratio of the core particles can be, for example, more than 1, 2, 3, 4, 5, 6, 8, 9, 10, 12, 14, 16, etc., compared to the crystalline particles. The above mass ratio can also be set, for example, to 20 or less, 18 or less, 16 or less, 14 or less, 12 or less, etc. For example, it can be set to 2 to 20 times, 3 to 16 times, or 3 to 10 times.

[0049] In this process, the core particles and crystalline particles are mechanically stirred and mixed. The impact and compressive forces of the core particles resulting from this mechanical action pulverize the crystalline particles, thereby reducing them to fine particles and making them amorphous. Furthermore, the amorphous particles obtained by pulverization have strong adhesive and cohesive properties, allowing them to adhere to the surface of the core particles and achieve compounding. According to this manufacturing method, the actions of the core particles resulting from the mechanical action allow for the pulverization of crystalline particles into amorphous particles without the use of amorphous stabilizers, and simultaneously compounding with the core particles, which act as excipients.

[0050] The mechanical action of stirring and mixing used in this process is effectively generated by using a device equipped with a grinding mechanism that exhibits high shear force, for example. High shear stress can have a significant effect on the core particles. Such compounding devices can be known stirring granulators or compounding devices having rotating stirring blades (rotating blades, rotors, etc.). Such devices are commercially available as appropriate. For example, dry compounding devices such as Glatt's high-speed stirring granulator (TMG1 / 6, etc.), Hosokawa Micron's Novilta NOB MINI, and high-speed stirring granulators (MM-10, Okada Seikou Co., Ltd.), as well as similar devices, can be used.

[0051] In these compounding devices, by adjusting the rotation speed and mixing (compounding) time, a first composite particle can be obtained in which amorphous particles are compounded with core particles. For example, with the above-mentioned high-speed stirring granulator manufactured by Glatt, the rotation speed can be set to approximately 1000 rpm for 180 minutes; with the above-mentioned dry compounding device manufactured by Hosokawa Micron, the rotation speed can be set to approximately 7000 rpm for 10 minutes; and with the high-speed stirring granulator (MM-10, manufactured by Okada Seikou Co., Ltd.), the rotation speed can be set to approximately 2000 rpm for 45 minutes to 10 hours, with a predetermined time depending on the particle size of the amorphous particles to be obtained.

[0052] For example, if the particle size is 1.5 μm or less, 1.4 μm or less, 1.2 μm or less, or 1.0 μm or less, it becomes easier to obtain nano-sized (e.g., less than 1 μm, 800 nm or less, 600 nm or less, 500 nm or less) recrystallized particles in the second composite particle.

[0053] Here, the stirring blades in the container of the compounding apparatus that performs mixing and stirring may rotate around an axis along the vertical direction, as in the high-speed stirring granulator described above, or they may rotate around a horizontal axis, as in a known dry compounding apparatus, or they may rotate around an axis inclined at an angle. Furthermore, the shape of the stirring blades is not particularly limited, but examples include a plate-shaped blade extending perpendicularly from the axis of rotation. In the case of a plate-shaped blade, the blades may be mounted parallel to the axis of rotation, as in a known dry compounding apparatus, or they may be mounted obliquely to the axis of rotation, as in the high-speed stirring granulator described above.

[0054] Furthermore, in order to efficiently obtain the first composite particles in this manufacturing method, it is sometimes preferable to use a composite apparatus capable of exhibiting specific parameters as the composite apparatus for carrying out the composite process. Below, the composite parameters will be described using as an example a horizontal composite apparatus (for example, the dry composite apparatus described above) that has a rotating blade that rotates around an axis along a substantially horizontal direction, housed in a cylindrical container extending along the horizontal direction.

[0055] Figure 8 schematically shows the configuration of a horizontally positioned composite apparatus to explain the composite parameters. As shown in Figure 8(a), because the container (cylinder) is positioned horizontally, the composite sample (nucleus particles and crystalline particles) accumulates on the lower inner wall of the container. The sample height (h) at this time is... ０ The volume can be calculated from the actual volume of the sample (for example, the volume of a partially missing right cylindrical cylinder - 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 includes all of the nucleus particles, crystalline particles, stabilizing particles and / or anti-adhesion agents used in the composite. The true density of the composite sample can be obtained by measuring the true density of each component and taking the weighted average of the true densities of each component, or the true density of the composite sample, which is a mixture, can be measured.

[0056] As shown in Figure 8(b), when the rotor rotates, the sample is forced to pass through the gap between the rotating blades and the inner wall of the container, so the sample height (h ０ ) The clearance (h) between the inner wall of the container and the inner wall side edge of the rotating blade ｃ It is compressed to 1.0 mm. At this time, the bulk of the sample is defined by the following formula.

[0057]

[0058] Next, as shown in Figure 8(c), since there are four sets of two rotating blades, each 18 mm wide, aligned in the same straight line on a rotor with a total length of 56 mm, the sample accumulated on the inner wall of the container is compressed an average of (18 × 2 ÷ 56) × 4 = 2.57 times when the rotor rotates once. At rotational speeds of 7000 rpm (116.7 rpm), 5000 rpm (83.3 rpm), and 3000 rpm (50.0 rpm), the number of times the sample is compressed per second is 300, 214, and 129, respectively.

[0059] Here, compression efficiency is defined as the product of bulkiness and number of compressions. Figure 9 shows the numerical values ​​of various elements based on Figure 8 and the results of calculating the compression efficiency obtained from these values. Compression efficiency (s －１ ) = Bulkiness × Number of Compressions

[0060] In the above explanation, we described a horizontally mounted composite device that has a rotor rotating around an axis approximately aligned horizontally, housed in a cylindrical container extending horizontally. However, the explanation is not limited to this type of device. It can also be applied to a vertically mounted composite device that has a rotor rotating around an axis aligned vertically, housed in a cylindrical container extending vertically.

[0061] In this case, it can be assumed that the sample adheres uniformly to the inner wall of the container due to the centrifugal force caused by the rotor rotation. At this time, the sample height (h ０ The volume can be calculated from the actual volume of the sample using the volume calculation formula for a hollow cylinder (https: / / keisan.casio.jp / exec / system / 1340326914). Using this sample height (h0), the bulkiness can be calculated in the same manner as above, and the compression efficiency can be calculated from the number of compressions.

[0062] This compression efficiency increases with increasing rotor speed and with increasing bulk. 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 inventors, by setting such a 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, the first composite particles can be efficiently obtained. The upper limit of the compression efficiency is not particularly limited, as it depends on the rotor speed and container volume allowed in the compounding device, but for example, it could be 300 or less, 280 or less, 260 or less, 240 or less, 230 or less, or 220 or less.

[0063] To obtain a desirable compression efficiency, the actual volume of the sample to be composited is adjusted to obtain a desirable bulkiness, and the sample height (h ０ This allows for increasing the size of the rotor blades or reducing the clearance between the inner wall of the container and the agitator blades. In addition, to obtain a desirable number of compression cycles, the rotor speed can be increased or the number of rotor blades around the rotating shaft can be increased.

[0064] Furthermore, a composite device capable of achieving a bulkiness and number of compression cycles that result in such effective compression efficiency can be said to be a useful composite device for carrying out the process of producing the first composite particles in this manufacturing method.

[0065] (Compounding apparatus) A compounding apparatus suitable for this manufacturing method may include, for example, a cylindrical container with its long axis arranged horizontally or vertically for mixing and stirring, a rotor arranged within the cylindrical container along the long axis, and a rotor arranged perpendicularly from the rotor toward the inner wall of the cylindrical container. The rotor of such a compounding apparatus can rotate at speeds of, for example, 2000 rpm or more, 5000 rpm or more, or 7000 rpm or more in order to increase the number of compression cycles, and the rotor is equipped with, for example, three, four, five, or six or more blades around the rotor. Furthermore, in order to increase the bulkiness of the compounding apparatus, the distance between the rotor and the inner wall of the cylindrical container can be, for example, 2 mm or less, 1 mm or less, etc.

[0066] Furthermore, in order to prevent the first composite particles from adhering to the inner wall of the container for mixing and stirring the apparatus, lubricants and fluidizers 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% to 10% by mass, or 0.5% to 2% by mass, relative to the total mass of the crystalline particles and the stabilizing agent particles.

[0067] In this step, the size and degree of amorphousness of the amorphous particles are adjusted so that the recrystallized particles on the second composite particle reach the desired size.

[0068] As shown in Figure 1B, the recrystallized particles in the second composite particle range from smaller in diameter than the amorphous particles in the first composite particle to a size less than or equal to the particle diameter of the amorphous particles. Also, as shown in Figure 1B, the size of the recrystallized particles in the second composite particle is thought to depend on the degree of amorphousness of the amorphous particles and the crystal nuclei remaining within the amorphous particles. The degree of amorphousness can be determined based on Raman spectroscopy or, for example, X-ray analysis. Raman spectroscopy can be convenient in obtaining the degree of amorphousness of amorphous particles.

[0069] The particle size of amorphous particles can be obtained within a desired range, for example, by appropriately setting the composite parameters described above. Furthermore, according to the inventors, it is generally preferable to carry out mechanical stirring and mixing under conditions such that the degree of amorphousness is, for example, 75% or more, 80% or more, for example, 85% or more, for example, 90% or more, for example, 95% or more, for example, 99% or more, or for example, exactly 100%. By doing so, in the process of producing the second composite particles, the amorphous particles can be recrystallized into particles with a smaller diameter than the amorphous particles, for example, 30% to 80% of the particle size of the amorphous particles, for example, 30% to 70%, or for example, 30% to 60%. The degree of amorphousness can be 100% or less, 99% or less, 95% or less, 90% or less, etc.

[0070] If the degree of amorphousness is less than 75%, a large amount of crystalline phase remains in the amorphous particles. Therefore, even if the process to manufacture the second composite particle is carried out, the crystalline phase remains, and recrystallization tends to be inhibited.

[0071] As shown in Figure 1B, the crystalline nuclei in the amorphous particles of the first composite particle continue to decrease by continuing stirring and mixing, for example, after the degree of amorphousness based on the Raman spectrum reaches 100%. As a result, the particle size of the recrystallized particles in the second composite particle gradually approaches that of the amorphous particles. Therefore, by further increasing the mixing time while maintaining the rotation speed in the composite apparatus, for example, beyond the condition when the degree of amorphousness based on the Raman spectrum reaches 100%, the particle size of the recrystallized particles can be controlled within the range of the particle size of the amorphous particles by reducing the crystalline nuclei.

[0072] If the goal is to make the recrystallized particles smaller in diameter than the amorphous particles, it may be preferable to use conditions that result in 100% amorphousness or conditions that do not significantly exceed this (for example, using the same compounding apparatus and the same rotation speed, the stirring and mixing time should be about 1.5 times longer).

[0073] Conditions for obtaining the desired particle size of recrystallized particles, such as the conditions for the amorphous particle size of the first composite particle and the conditions for the degree of amorphousness to reach 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 99% or more, and 100%, can be obtained from preliminary experiments. For example, when using the same composite apparatus, the same sample amount, and the same rotation speed, the degree of amorphousness and, consequently, the particle size of the recrystallized particles can be adjusted by the stirring and mixing process time. That is, the process of manufacturing the first composite particle is carried out under the same conditions except for different mechanical stirring and mixing processes to achieve various degrees of amorphousness, and the process of manufacturing the second composite particle is carried out on the obtained first composite particle. The particle size of the recrystallized particles of the second composite particle obtained as a result is evaluated. From the evaluation results, the mechanical stirring and mixing process time in the process of manufacturing the first composite particle is determined.

[0074] The particle size of amorphous particles in the first composite particle and the particle size of recrystallized particles in the second composite particle are evaluated using the gas adsorption method as follows: Using a gas adsorption apparatus (NOVA600, manufactured by Anton Paar), the sample (first composite particle or second composite particle, hereinafter simply referred to as composite particle) is dried under vacuum, for example at 25°C for 12 hours or more. Then, Ar gas is adsorbed onto the sample with liquid nitrogen (77K) at a relative pressure in the range of 0.05 to 0.3, and the adsorption data is applied to the BET formula to determine the specific surface area diameter (DSP) of the sample. drug This is calculated using the following formula.

[0075] Here, SSA ｃｐ SSA ｄｒｕｇ SSA ｃｏｒｅ These represent the specific surface area of ​​the composite particle, the specific surface area of ​​the organic compound particle, and the specific surface area of ​​the nuclear particle, respectively. ｃｐ , W ｄｒｕｇ , W ｃｏｒｅ These represent the mass of the composite particles, the mass of the organic compound particles, and the mass of the core particles, respectively. The specific surface area of ​​the organic compound particles and core particles is measured by gas adsorption as needed. DC represents the mass ratio of organic compound particles in the sample composite particles. Also, ρ ｄｒｕｇφ represents the true density of organic compound particles. The true density of organic compound particles can be measured using a helium gas displacement true density meter (Ultra Pycnometer 1000, manufactured by Cantachrome). φ represents the shape factor of the organic compound particles. Assuming the particle shape of the organic compound particles is spherical, the shape factor φ is 6. Note that the gas adsorption device and true density meter can be replaced with devices that have equivalent or better accuracy and measurement precision.

[0076]

[0077] The degree of amorphousness of amorphous particles in the first composite particle and recrystallized particles in the second composite particle can be measured by Raman spectroscopy and powder X-ray diffraction spectroscopy. When using Raman spectroscopy, the following method can be employed: Raman spectra are acquired using a PR-1W (manufactured by JASCO Corporation), and the degree of amorphousness is calculated using multivariate analysis with the imaging model analysis program of the Spectrum Manager (manufactured by JASCO Corporation). Note that the above apparatus and program can be replaced with equipment having equivalent or greater accuracy and measurement precision.

[0078] For example, in the case of indomethacin, when processed using a high-speed stirring granulator (MM-10, manufactured by Okada Seikou Co., Ltd.) at 10°C and 2000 rpm, the degree of amorphousness was approximately 80% after 30 minutes, over 85% after 45 minutes, a slight amorphous-specific peak was observed after 1 hour, and 100% after 2 hours.

[0079] In this manufacturing method, after the step of producing the first composite particles, a mechanical mixing and stirring process may be performed for a predetermined time to obtain the desired particle size. Then, a confirmation step may be performed to obtain a Raman spectrum or the like for the amorphous particles and confirm the degree of crystallinity based on this spectrum. By doing so, recrystallized particles can be reliably obtained in the step of producing the second composite particles. The degree of amorphousness can also be obtained by known methods using powder X-ray diffraction spectroscopy.

[0080] In this process, the mechanical stirring and mixing operation is most effective when the temperature inside the container in which the core particles and crystalline particles are stirred and mixed is maintained at a temperature that suppresses recrystallization. More specifically, it is effective to maintain the temperature so as not to exceed 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 will soften (liquefy), making it easier for the composite particles to aggregate, and the tendency for the amorphous particles to recrystallize in this process will increase. 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 lower, 35°C or lower, 30°C or lower, 25°C or lower, 20°C or lower, 15°C or lower, or 10°C or lower. To set the temperature inside the stirring and mixing container to these temperatures, the jacket temperature for external temperature control of the stirring and mixing container can be set to, for example, 25°C or lower, 20°C or lower, 15°C or lower, or 10°C or lower, 5°C or lower, or 0°C or lower.

[0081] In this process, in addition to the core particles and crystalline particles, for example, an anti-adhesion agent will be supplied to the container of the compounding apparatus, but the order and method of supplying these materials during compounding are not particularly limited.

[0082] The first composite particle obtained in this process has amorphous particles on the surface of the core particle, and depending on the amount of amorphous particles, the amorphous particles may be deposited on the surface of the core particle to form an amorphous particle layer.

[0083] (Process for manufacturing the second composite particle) In this process, the first composite particle is stored under certain conditions to recrystallize the amorphous particle and manufacture a second composite particle having recrystallized particles on its surface. In this process, by storing the first composite particle at a temperature at which recrystallization is possible for a predetermined time, a second composite particle having recrystallized particles of a desired particle size on the core particle can be obtained.

[0084] In this process, the temperature at which the first composite particles are stored is not particularly limited, but for example, it can be 5°C or higher and below the glass transition temperature of the organic compound constituting the amorphous particles. In the case of indomethacin, the storage temperature can be approximately 5°C to 40°C. Normally, the first composite particles are stored at a constant temperature. According to the inventors, as long as the storage temperature is below the glass transition temperature of the organic compound of the amorphous particles, the higher the storage temperature, the faster recrystallization proceeds. If the temperature is above the glass transition temperature, the amorphous particles may liquefy and become a supercooled liquid, which may result in the formation of granules or aggregates of nanoparticles.

[0085] Therefore, for example, since the glass transition temperature of amorphous indomethacin is 42°C, storage at a temperature below 42°C, such as 5°C, required 14 days for complete recrystallization, 1 day at 25°C, and 2 hours at 40°C. Thus, by storing at a higher temperature, below the glass transition temperature of the organic compound of the amorphous particles, a second composite particle containing recrystallized particles can be efficiently obtained. Note that the particle size of the recrystallized particles may or may not be affected by the storage temperature in this process.

[0086] The storage time should be set to allow for complete recrystallization. The crystallization state of the recrystallized particles can be confirmed by Raman spectroscopy or powder X-ray diffraction spectroscopy.

[0087] In this specification, the glass transition temperature can be measured using a differential scanning calorimeter (DSC-60 plus, manufactured by Shimadzu Corporation). Specifically, 5 mg of the organic compound is packed into a sealed aluminum cell, and a pinhole is made in the container lid. The cell is heated at a heating rate of 5°C / min to +20°C above the melting point of the organic compound, held for 5 minutes to allow it to melt completely, and then cooled at a cooling rate of 10°C / min to -50°C. After that, it is heated again at a heating rate of 5°C / min to +20°C above the melting point. The midpoint of the baseline shift measured at this time is defined as the glass transition temperature.

[0088] However, if the glass transition is accompanied by enthalpy relaxation and an endothermic peak is observed rather than a baseline shift, the onset temperature of the endothermic peak should be used as the glass transition temperature. Alternatively, a differential scanning calorimeter with accuracy and measurement precision equivalent to or better than the above-mentioned device can be used.

[0089] The first composite particles can be stored under reduced water vapor conditions or in the presence of water vapor. Storing them in the presence of water vapor promotes recrystallization and shortens the storage time until complete recrystallization. For example, in the case of indomethacin, complete recrystallization can be achieved in 4 hours when stored at 25°C under water vapor (compared to 1 day in a dry state).

[0090] Furthermore, the first composite particles may be stored in the presence of an organic solvent vapor. Storing in the presence of an organic solvent vapor promotes recrystallization and further shortens the storage time until complete recrystallization. Examples of organic solvents include those with a vapor pressure above a certain level at the storage temperature. For example, organic solvents with a boiling point of 80°C or lower (at 1 atmosphere) are used. Ethanol, acetone, etc., are preferred. For example, indomethacin can be completely recrystallized in 1 minute when stored at 25°C in the presence of ethanol vapor or acetone vapor. This increases molecular mobility and promotes crystallization.

[0091] Furthermore, the particle size of the recrystallized particles is not affected by the atmosphere used in the process of manufacturing the second composite particle, whether it is a dry state or various vapor atmospheres.

[0092] The second composite particle comprises the aforementioned core particle at its center, and for example, a recrystallized particle covering the core particle. More specifically, the second composite particle can take the form of a coating layer of multiple recrystallized particles with a particle size of 1 μm or less. The average particle size of the second composite particle is, for example, 10 μm or more and 1000 μm or less. This average particle size can also be, for example, 50 μm or more, 100 μm or more, 150 μm or more, 200 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. For example, this average particle diameter can be 900 μm or less, 800 μm or less, 700 μm or less, 600 μm or less, 500 μm or less, 400 μm or less, 300 μm or less, 250 μm or less, 200 μm or less, 150 μm or less, 100 μm or less, or 50 μm or less.

[0093] The particle size of the recrystallized particles is, for example, 1 nm or more and 1 μm or less. The particle size of the recrystallized particles may also be, for example, 5 nm or more, 10 nm or more, 20 nm or more, 30 nm or more, 40 nm or more, 50 nm or more, 100 nm or more, 150 nm or more, 200 nm or more, 250 nm or more, 300 nm or more, 350 nm or more, 400 nm or more, 450 nm or more, or 500 nm or more. For example, the particle size of the recrystallized particles may also be 950 nm or less, 900 nm or less, 850 nm or less, 800 nm or less, 750 nm or less, 700 nm or less, 650 nm or less, 600 nm or less, 550 nm or less, 500 nm or less, 450 nm or less, 400 nm or less, 350 nm or less, 300 nm or less, 250 nm or less, 200 nm or less, 150 nm or less, or 100 nm or less. The particle diameter of the recrystallized particles can be obtained by the gas adsorption method, as previously described. It should be noted that, for example, the particle diameter of all recrystallized particles constituting the coating layer does not necessarily have to be within the specified numerical range; at least some recrystallized particles that are not included in the specified range may be present.

[0094] The thickness of the coating layer (thickness based on the difference in the average particle diameters of the second composite particle and the core particle) is, for example, 0.1 μm or more and 200 μm or less. This thickness can be 1 μm or more, 2 μm or more, 3 μm or more, 4 μm or more, 5 μm or more, 10 μm or more, 15 μm or more, 20 μm or more, 25 μm or more, 30 μm or more, 40 μm or more, or 50 μm or more. Alternatively, this thickness can be 150 μm or less, 100 μm or less, 50 μm or less, 45 μm or less, 40 μm or less, 35 μm or less, 30 μm or less, or 25 μm or less. The average particle diameter of the first and second composite particles can be obtained as the volume-based median diameter (central diameter) by laser diffraction / scattering.

[0095] As explained above, this manufacturing method comprises a step of manufacturing a first composite particle and a step of manufacturing a second composite particle, thereby enabling the production of composite particles in which recrystallized particles with controlled particle size are supported on a core particle without the use of liquid. Furthermore, this manufacturing method is useful because it allows for the acquisition of composite particles in the form of miniaturized crystalline particles (composite particles) that are formed as a layer or film on the core particle. In addition, the second composite particle has improved solubility compared to the organic compound initially used, resulting in improved dissolution in dissolution tests, making it useful as an oral formulation and an orally disintegrating formulation. Moreover, the second composite particle can be used as a raw material (component) for various formulations such as fine granules, granules, capsules, and tablets.

[0096] According to this specification, the present manufacturing method can provide a composite particle comprising a core particle and crystallized organic compound particles provided on the surface of the core particle. Various embodiments already described can be applied to the core particle and the crystallized organic compound particles (corresponding to the "recrystallized particles" in the above description) in this composite particle.

[0097] The second composite particles disclosed herein can be used, for example, as a pharmaceutical powder containing a plurality of the second composite particles, for example, as a raw material for pharmaceuticals, etc. Alternatively, they can be used, for example, as a pharmaceutical composition itself, or as an active ingredient in a pharmaceutical composition. Depending on the dosage form and application, the pharmaceutical composition may appropriately contain various known additives usable as pharmaceuticals, such as excipients, stabilizers, preservatives, buffers, flavoring agents, suspending agents, emulsifiers, flavoring agents, solubilizers, colorants, and viscosity modifiers.

[0098] Furthermore, as previously mentioned, the core particles may contain amorphous stabilizers. Examples of amorphous stabilizers include polymeric stabilizers, low molecular weight stabilizers, and inorganic stabilizers. Examples of polymeric additives are not limited to polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), methacrylic acid copolymer (MAEA), polyvinylpyrrolidone / vinyl acetate copolymer (PVPVA), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), ceracephate (CAP), hypromellose phthalate (HPMCP), and hypromellose acetate succinate (HPMCAS), which are cellulose derivatives. Examples of low molecular weight stabilizers are not limited to low molecular weight compounds having carbonyl or amino groups, and more specifically, amino acids such as arginine and tryptophan, and organic acids such as tartaric acid and citric acid. Inorganic additives are not particularly limited, but examples include porous materials of calcium carbonate and silicon dioxide.

[0099] <Composite Particles> Next, composite particles relating to a second aspect of the disclosure herein will be described. The composite particles disclosed herein comprise a core particle and a crystalline organic compound particle.

[0100] (Nuclear Particles) Nuclear particles are particles that constitute the nucleus of composite particles and serve as carrier particles that support crystalline organic compound particles. The characteristics of nuclear particles, such as their shape, material, and average particle diameter, are as described in the first aspect, and the various embodiments apply.

[0101] (Crystalline Organic Compound Particles) The organic compounds that are crystalline organic compounds in the composite particles relating to the second aspect will be described. The type of organic compound is not particularly limited. Considering the manufacturing method described later, any organic compound that can be amorphous by grinding using a ball mill, for example, is acceptable. The molecular weight of the crystalline organic compound is not particularly limited, but for example, it is between 200 and 1,300. From the viewpoint of making it easier to obtain crystalline organic compound particles, the lower limit of the molecular weight is, for example, 300 or more, 350 or more, 380 or more, 400 or more, 450 or more, 500 or more, and 530 or more. Similarly, the upper limit is, for example, 720 or less, 700 or less, 650 or less, 600 or less, 550 or less, and 500 or less. The range of molecular weight of the crystalline organic compound can be, for example, 350 or more and 720 or less, 350 or more and 550 or less, etc.

[0102] Considering the manufacturing method described later, the glass transition temperature (Tg) of the crystalline organic compound may be, for example, 25°C or higher, 30°C or higher, 35°C or higher, 40°C or higher, 45°C or higher, 50°C or higher, etc. The glass transition temperature can be measured by the method already described.

[0103] As crystalline organic compounds, organic compounds that can be used as active ingredients in pharmaceuticals can be used. Examples of such compounds include indomethacin, nifedipine, as well as various other compounds such as simvastatin, carvedilol, and aprepitant. The crystalline organic compound of the composite particles can be determined by considering the manufacturing method described later, confirming in advance whether amorphous formation is possible by grinding methods such as ball milling, or whether amorphous formation is possible when used as a suitable nucleus particle, and by confirming in advance the subsequent recrystallization.

[0104] The crystalline organic compound particles contain a crystalline organic compound, preferably with a mass ratio of 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, 99% or more, etc. The crystalline organic compound may be a single crystal or a polycrystalline compound. It may also be polymorphic. The degree of amorphousness of the crystalline organic compound particles in the composite particles can be measured by the method already described.

[0105] The shape of the crystalline organic compound particles in the composite particles of the second aspect is not particularly limited. The shape of the crystalline organic compound particles may vary depending on the type of organic compound, the conditions for amorphization and recrystallization in the manufacturing method described later, etc. For example, although the shape of the crystalline organic compound particles is not particularly limited, they can take various forms such as spherical, cubic, massive, plate-like, dendritic, spongy, and irregular shapes.

[0106] The size of the crystalline organic compound particles in the composite particles of the second aspect is not particularly limited, but for example, if the average particle diameter is 4.0 μm or less, a predetermined specific surface area can be secured for the composite particles. The average particle diameters are, for example, 3.8 μm or less, 3.6 μm or less, 3.5 μm or less, 3.4 μm or less, 3.0 μm or less, 2.8 μm or less, 2.6 μm or less, 2.4 μm or less, 2.2 μm or less, 2.0 μm or less, 1.8 μm or less, 1.6 μm or less, 1.4 μm or less, 1.2 μm or less, 1.0 μm or less, 0.90 μm or less, 0.80 μm or less, 0.70 μm or less, 0.60 μm or less, 0.50 μm or less, 0.40 μm or less, 0.30 μm or less, 0.25 μm or less, 0.20 μm or less, 0.15 μm or less, and 0.10 μm or less. For example, if the average particle diameter is 0.050 μm or more, it is useful as a composite particle. The average particle diameter is also, for example, 0.10 μm or larger, 0.15 μm or larger, 0.20 μm or larger, 0.25 μm or larger, 0.30 μm or larger, 0.40 μm or larger, 0.50 μm or larger, 0.60 μm or larger, 0.70 μm or larger, 0.80 μm or larger, 0.90 μm or larger, and 1.0 μm or larger.

[0107] For example, if the average particle diameter is 1.00 μm or less, the specific surface area of ​​the composite particles can be sufficiently secured, which may further contribute to drug absorption. Furthermore, if the average particle diameter is 0.6 μm or less, the specific surface area of ​​the composite particles can be further increased, which may further contribute to drug absorption. In addition, if the average particle diameter is 0.10 μm or more and 0.20 μm or less, when administered into the body of a human or other organism by subcutaneous injection, intramuscular injection, etc., it may be easier for the drug to accumulate in specific areas.

[0108] While not particularly limited, the average particle size of crystalline organic compound particles can be 0.10 μm or more and 0.60 μm or less, 0.10 μm or more and 0.55 μm or less, 0.10 μm or more and 0.50 μm or less, 0.15 μm or more and 0.60 μm or less, 0.15 μm or more and 0.55 μm or less, 0.10 μm or more and 0.50 μm or less, etc.

[0109] The average particle size of crystalline organic compound particles is obtained as the specific surface area diameter using the gas adsorption method as follows: Using a gas adsorption apparatus (NOVA600, manufactured by Anton Paar), the sample (a composite particle comprising organic compound particles that are crystalline organic compound particles or amorphous organic compound particles on a core particle) is dried under vacuum, for example, at 25°C for 12 hours or more. Then, Ar gas is adsorbed onto the sample with liquid nitrogen (77K) at at least 5 points within the relative pressure range of 0.05 to 0.3, and the adsorption data is applied to the BET formula to obtain the specific surface area diameter DSP of the sample. drug This is calculated using the formula described above.

[0110] Here, SSA ｃｐ SSA ｄｒｕｇ SSA ｃｏｒｅ These represent the specific surface area of ​​the composite particles, the specific surface area of ​​the organic compound particles, and the specific surface area of ​​the nuclear particles, respectively, and can be measured by the method already described.

[0111] (Composite Particles) Composite particles have crystalline organic compound particles on the surface of a core particle. The mass ratio of the core particle to the crystalline organic compound particles (core particle:crystalline organic compound particles) is not particularly limited, but for example, it is 100:1 or more and 1:5 or less. Considering the stability of the composite particles, this mass ratio can be 20:1 or more and 1:1 or less, 15:1 or more and 5:1 or less, etc.

[0112] The composite particle may have a porous layer containing crystalline organic compound particles on the surface of the core particle. The porous layer has a porous structure formed by interparticle gaps created by the interconnection of multiple or many crystalline organic compound particles. The porous layer covers at least a portion of the surface of the core particle, but typically covers 80%, 90%, or 95% or more of the core particle's surface.

[0113] The porous layer is a three-dimensional porous layer of a predetermined thickness, formed by the interconnection of crystalline organic compound particles. The composite particles are formed by the recrystallization of amorphous organic compound particles on core particles using a manufacturing method described later. By recrystallizing the amorphous organic compound particles while simultaneously refining them, a porous structure can be obtained in which finer crystalline organic compound particles are interconnected. The porous layer exhibits different appearances depending on the type of crystalline organic compound and the recrystallization method.

[0114] The thickness of the porous layer is not particularly limited, but for example, it is between 0.1 μm and 200 μm. This thickness can be 1 μm or more, 2 μm or more, 3 μm or more, 4 μm or more, 5 μm or more, 10 μm or more, 15 μm or more, 20 μm or more, 25 μm or more, 30 μm or more, 40 μm or more, or 50 μm or more. Alternatively, this thickness can be 150 μm or less, 100 μm or less, 50 μm or less, 45 μm or less, 40 μm or less, 35 μm or less, 30 μm or less, or 25 μm or less. The thickness of the porous layer is based on the difference in the average particle diameters of the composite particles and the core particles, and can be determined as the difference in the average particle diameters of the core particles and the composite particles. These average particle diameters can be obtained as volume-based median diameters (central diameters) by laser diffraction and scattering methods.

[0115] The composite particle has crystalline organic compound particles on its surface, resulting in a thickness of 0.0015 m ２ / g or more, 60m ２ It can have a specific surface area of ​​less than or equal to 1 / g. Having a specific surface area within this range allows it to be used as a composite particle material with suitable surface properties, for example, as a raw material for pharmaceuticals. The specific surface area can also be, for example, 0.050 m². ２ / g or more, 0.075m ２ / g or more, 0.10m ２ / g or more, 0.20m ２ / g or more, 0.30m ２ / g or more, 0.40m ２ / g or more, 0.50m ２ It is 1 / g or more. Also, the specific surface area is 50 m². ２ / g or less, 40m ２ / g or less, 30m ２ / g or less, 25m ２ / g or less, 20m ２ / g or less, 15m ２ / g or less, 10m ２ / g or less, 8.0m ２ / g or less, 6.0m ２ / g or less, 4.0m ２ / g or less, 2.5m ２ / g or less, 2.0m ２ / g or less, 1.8m ２ / g or less, 1.6m ２ / g or less, 1.4m ２ / g or less, 1.2m ２ / g or less, 1.0m ２ It is less than or equal to / g.

[0116] The specific surface area range of composite particles is, for example, 0.075 m². ２ / g or more, 30m ２ 0.10 m / g or less ２ / g or more, 10m ２ / g or less, 0.30m ２ / g or more, 5.0m ２ / g or less, 0.30m ２ / g or more, 5.0m ２ / g or less, 0.30m ２ / g or more, 3.0m ２ / g or less, 0.30m ２ / g or more, 2.5m ２ It may be less than / g.

[0117] Furthermore, crystalline organic compound particles are, for example, 0.10 m ２ / g or more, 100m ２ It can have a specific surface area of ​​less than or equal to 0.50 m². ２ / g or more, 50m ２ / g or less, 1.0m ２ / g or more, 50m ２ / g or less, 5.0m ２ / g or more, 50m ２ / g or less, 5.0m ２ / g or more, 40m ２ It is less than or equal to / g. The specific surface area of ​​crystalline organic compound particles is determined by their average particle diameter.

[0118] The specific surface area of ​​both composite particles and crystalline organic compound particles can be obtained using the gas adsorption method already described.

[0119] Due to their specific surface area, the composite particles exhibit improved solubility compared to the organic compounds initially used, resulting in enhanced dissolution in dissolution tests and other applications. They are therefore useful, for example, in oral and orally disintegrating formulations. Furthermore, the composite particles can be used as raw materials (components) for various formulations such as fine granules, granules, capsules, and tablets.

[0120] (Pharmaceutical Composition) A pharmaceutical composition may contain composite particles or crystalline organic compounds. A pharmaceutical composition may be in the form of composite particles, i.e., containing crystalline organic compound particles together with core particles, or in another form in which the crystalline organic compound is dissolved or remains as particles. Furthermore, this other form of the pharmaceutical composition may also be in which the core particles are dissolved or remains as particles. In addition, a pharmaceutical composition is a concept that includes not only the preparation but also the raw materials used in the preparation of the preparation.

[0121] Pharmaceutical compositions can take various known formulation forms. Typical pharmaceutical compositions may be used in the form of pharmaceutical formulations, for example, solid, semi-solid, or liquid, and contain organic or inorganic carriers or excipients suitable for external, intra-intestinal, or parenteral (including injection (vascular, subcutaneous, or intramuscular)) applications.

[0122] Depending on its dosage form and intended use, the pharmaceutical composition may appropriately contain various known additives that can be used as pharmaceuticals, such as excipients, stabilizers, preservatives, buffers, flavoring agents, suspending agents, emulsifiers, flavoring agents, solubilizers, colorants, and viscosity enhancers.

[0123] Furthermore, as previously mentioned, the core particles may contain amorphous stabilizers. As amorphous stabilizers, for example, the various embodiments described above can be used.

[0124] (Method for producing composite particles) The method for producing composite particles comprises: a first step of mechanically stirring and mixing a core particle and a first crystalline organic compound particle as a raw material to promote the pulverization and amorphousization of the first crystalline organic compound particle, thereby producing a first composite particle having amorphous organic compound particles derived from the first crystalline organic compound particle on the surface of the core particle; and a second step of storing the first composite particle under certain conditions to recrystallize the amorphous organic compound particle, thereby producing a second composite particle having a second crystalline organic compound particle on its surface. Herein, the specific surface area of ​​the second composite particle is 0.0015 m². ２ / g or more, 60m ２ The first and second steps are carried out so that the amount is less than or equal to / g. The second composite particle in this manufacturing method is the composite particle as defined in this specification.

[0125] According to the present inventors, the first crystalline organic compound particles were amorphous in various ways by varying the mechanical mixing and stirring processing time, and then the amorphous organic compound particles were recrystallized by storing them at different storage temperatures. As a result, it was found that by controlling the processing time and storage temperature, composite particles with a desired average particle size and a suitable specific surface area can be obtained.

[0126] The specific surface area of ​​the composite particles and the particle size of the crystalline organic compound particles can be adjusted, for example, by controlling the degree of amorphousization and the degree of recrystallization. In particular, composite particles with a desired specific surface area can be obtained by storing the recrystallized amorphous organic compound at a temperature a certain amount lower than its glass transition temperature and allowing it to recrystallize.

[0127] Regarding the degree of amorphousization, it is more useful for controlling the increase in the specific surface area of ​​composite particles to a degree where some crystal nuclei remain, rather than completely amorphizing the material. On the other hand, reducing the number of crystal nuclei as much as possible by promoting amorphousization is useful for controlling the suppression of the specific surface area of ​​composite particles.

[0128] To obtain composite particles with a desired specific surface area and / or crystalline organic compound particles with a desired average particle size, preliminary experiments can be conducted, for example, as follows: First composite particles comprising amorphous particles of various degrees of amorphousness are obtained by varying the mechanical stirring and mixing time (which may include the processing temperature). Then, the amorphous particles of the first composite particles are stored at different temperatures to obtain second composite particles comprising recrystallized particles. By evaluating the stirring and mixing time and temperature, storage temperature and time, the specific surface area of ​​the composite particles, and the average particle size of the crystalline organic compound particles, the processing conditions for obtaining composite particles with a desired specific surface area and crystalline organic compound particles with a desired average particle size can be determined.

[0129] The second aspect disclosed herein, the method for producing composite particles, will be described in detail below.

[0130] (Step for manufacturing the first composite particles) In carrying out this manufacturing method, core particles and first crystalline organic compound particles to be used in the step for manufacturing the first composite particles are prepared. The core particles are as previously described. The type of organic compound for the first crystalline organic compound particles is as previously described. However, in the manufacturing method, the average particle size and mass ratio of the core particles and the first crystalline organic compound particles can be prepared, for example, in the manner described above.

[0131] (Combination apparatus) As a combination apparatus suitable for this manufacturing method, for example, the various types of combination apparatus described above can be used.

[0132] In the first step, it is preferable to perform mechanical stirring and mixing under conditions such that the degree of amorphousness of the amorphous particles is, for example, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 99% or more, or exactly 100%. By doing so, in the step of producing the second composite particles, the amorphous particles can be recrystallized into particles with a smaller diameter than the amorphous particles, for example, 30% to 80% of the particle diameter of the amorphous particles, 30% to 70%, or 30% to 60%. The degree of amorphousness can be 100% or less, 99% or less, 95% or less, 90% or less, etc.

[0133] If the degree of amorphousness is less than 75%, a large amount of crystalline phase remains in the amorphous particles. Therefore, even if the process to manufacture the second composite particle is carried out, the crystalline phase remains, and recrystallization tends to be inhibited.

[0134] If the goal is to make the recrystallized particles smaller in diameter than the amorphous particles, it may be preferable to use conditions that result in 100% amorphousness or conditions that do not significantly exceed this (for example, using the same compounding apparatus and the same rotation speed, the stirring and mixing time should be about 1.5 times longer).

[0135] Conditions for obtaining the desired particle size of recrystallized particles, such as the conditions for the amorphous particle size of the first composite particle and the conditions for the degree of amorphousness to reach 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 99% or more, and 100%, can be obtained from preliminary experiments. For example, when using the same composite apparatus, the same sample amount, and the same rotation speed, the degree of amorphousness and, consequently, the particle size of the recrystallized particles can be adjusted by the stirring and mixing process time. That is, the process of manufacturing the first composite particle is carried out under the same conditions except for different mechanical stirring and mixing processes to achieve various degrees of amorphousness, and the process of manufacturing the second composite particle is carried out on the obtained first composite particle. The particle size of the recrystallized particles of the second composite particle obtained as a result is evaluated. From the evaluation results, the mechanical stirring and mixing process time in the process of manufacturing the first composite particle is determined.

[0136] For example, in the case of indomethacin, when processed using a high-speed stirring granulator (MM-10, manufactured by Okada Seikou Co., Ltd.) at 10°C and 2000 rpm, the degree of amorphousness was approximately 80% after 30 minutes, over 85% after 45 minutes, a slight amorphous-specific peak was observed after 1 hour, and 100% after 2 hours.

[0137] In this manufacturing method, after the step of producing the first composite particles, a mechanical mixing and stirring process may be performed for a predetermined time to obtain the desired particle size. Then, a confirmation step may be performed to obtain a Raman spectrum or the like for the amorphous particles and confirm the degree of crystallinity based on this spectrum. By doing so, recrystallized particles can be reliably obtained in the step of producing the second composite particles. The degree of amorphousness can be measured by the method described above.

[0138] In this process, the mechanical stirring and mixing operation is most effective when the temperature inside the container in which the core particles and the first crystalline organic compound particles are stirred and mixed is maintained at a temperature that suppresses recrystallization. More specifically, it is effective to maintain the temperature so as not to exceed 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 will soften (liquefy), making the composite particles more likely to aggregate, and the tendency for the amorphous particles to recrystallize in this process will increase. 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 lower, 35°C or lower, 30°C or lower, 25°C or lower, 20°C or lower, 15°C or lower, or 10°C or lower. To set the temperature inside the stirring and mixing container to such a temperature, the jacket temperature for external temperature control of the stirring and mixing container can be set to, for example, 25°C or lower, 20°C or lower, 15°C or lower, or 10°C or lower, 5°C or lower, or 0°C or lower.

[0139] In this process, in addition to the core particles and the first crystalline organic compound particles, for example, an anti-adhesion agent will be supplied to the container of the compounding apparatus, but the order and method of supplying these materials during compounding are not particularly limited.

[0140] The first composite particle obtained in this process has amorphous particles on the surface of the core particle, and depending on the amount of amorphous particles, the amorphous particles may be deposited on the surface of the core particle to form an amorphous particle layer.

[0141] (Process for manufacturing the second composite particle) In this process, the first composite particle is stored under certain conditions to recrystallize the amorphous particle and manufacture a second composite particle having a second crystalline organic compound particle on its surface. In this process, by storing the first composite particle at a temperature at which recrystallization is possible for a predetermined time, a second composite particle can be obtained having a second crystalline organic compound particle of a desired particle size on a core particle.

[0142] In this process, the storage temperature for the first composite particles is not particularly limited, but it is preferable to store them at a temperature 10°C or lower than the glass transition temperature of the organic compound used. If the storage temperature exceeds 10°C below the glass transition temperature, recrystallization may proceed too rapidly, potentially leading to the formation of granules or aggregates of nanoparticles. On the other hand, if the storage temperature is too low compared to the glass transition temperature, recrystallization becomes difficult. Normally, the first composite particles are stored at a constant temperature.

[0143] According to the present inventors, by storing the amorphous particles at a temperature of <(Tg-10)°C> or lower, which is 10°C lower than the glass transition temperature of the organic compound, the recrystallization of the amorphous particles can be controlled, making it easier to obtain composite particles with a large specific surface area. For example, the upper limit of the storage temperature is a temperature of <(Tg-15)°C> or lower, 15°C lower than the glass transition temperature, 20°C lower than the glass transition temperature, 25°C lower than the glass transition temperature, and 30°C lower than the glass transition temperature. Preferably, the storage temperature is 5°C or higher. The lower limit of the storage temperature is a temperature of <(Tg-60)°C> or higher, 50°C lower than the glass transition temperature, and 40°C lower than the glass transition temperature.

[0144] The preferred storage temperature is not particularly limited, but may be, for example, between <(Tg-32)°C> and <(Tg-10)°C>, between <(Tg-32)°C> and <(Tg-15)°C>, between <(Tg-32)°C> and <(Tg-20)°C>, or between <(Tg-31)°C> and <(Tg-20)°C>.

[0145] The storage time is not particularly limited, as long as the intended recrystallization state is achieved, but it is at least 1 hour, for example, 10 days or less. Alternatively, storage times can be 10 hours or more, 20 hours or more, 24 hours or more, 36 hours or more, 48 hours or more, 60 hours or more, 72 hours or more, 96 hours or more, 120 hours or more, or for example, 216 hours or less, 192 hours or less, or 168 hours or less. Alternatively, storage times can be 120 hours or more and 240 hours or less, 120 hours or more and 216 hours or less, or 144 hours or more and 192 hours or less.

[0146] When storing the first composite particles, it is preferable to do so in a dry atmosphere. For example, in an atmosphere where a desiccant such as silica gel is present, the storage should be carried out in a relative humidity environment such as 50% RH or less, 40% RH or less, or 30% RH or less.

[0147] As explained above, this manufacturing method comprises a step of manufacturing a first composite particle and a step of manufacturing a second composite particle, thereby enabling the production of composite particles with controlled specific surface area without the use of liquid.

[0148] This manufacturing method is suitable for producing composite particles. The composite particles obtained by this manufacturing method have a predetermined specific surface area derived from the crystalline organic compound particles and, consequently, the porous layer.

[0149] The following examples illustrate the disclosures of this specification in more detail. The following examples are for illustrative purposes only and do not limit the scope of the disclosures of this specification. In the following, unless otherwise specified, the average particle diameter and particle diameter range are measured by laser diffraction and scattering, and the average particle diameter is the volume-based median diameter.

[0150] (Production of the second composite particle 1) In this example, indomethacin (IND) (average particle size: 14.1 μm) was used as the crystalline organic compound. Crystalline cellulose granules (Cellphia CP-507 (manufactured by Asahi Kasei), particle size range 500 μm to 710 μm) were used as the core particles. 20 g of indomethacin and 200 g of crystalline cellulose granules were placed in a high-speed stirring granulator (MM-10, manufactured by Okada Seikou Co., Ltd.), and the stirring blades at the bottom of the granulator were rotated at 2000 rpm. A stirring and mixing process (process for producing the first composite particle) was carried out at 10°C for 2 hours. The obtained granulated first composite particle was stored in a constant temperature oven (silica gel drying) set to 25°C for 7 days to carry out a storage process (process for producing the second composite particle). The Raman spectrum and SEM image of the obtained second composite particle are shown in Figure 2.

[0151] As shown in Figure 2, Raman spectroscopy and SEM imaging revealed that after a 2-hour stirring and mixing treatment, indomethacin completely amorphousized into particles of approximately 1 μm in size and adhered to the surface of crystalline cellulose grains. Furthermore, Raman spectroscopy and SEM imaging showed that after storing the composite particles at 25°C for 7 days, the amorphous indomethacin completely recrystallized into recrystallized particles with a particle size of 500 nm or less.

[0152] (Production of the second composite particle 2) In this example, nifedipine (average particle size: 14.8 μm) was used as the crystalline organic compound, and the stirring and mixing process and storage process were carried out in the same manner as in Example 1, except that the stirring and mixing time in the stirring and mixing process was set to 3 hours, to obtain the second composite particle. The powder X-ray diffraction spectrum and SEM image of the obtained second composite particle are shown in Figure 3.

[0153] As shown in Figure 3, powder X-ray diffraction spectra and SEM images revealed that after a 3-hour stirring and mixing treatment, nifedipine completely amorphousized into particles of approximately 1-2 μm in size and adhered to the surface of crystalline cellulose grains. Furthermore, powder X-ray diffraction spectra and SEM images showed that after storing the composite particles at 25°C for 7 days, the amorphous nifedipine completely recrystallized into recrystallized particles with a particle size of 500 nm or less.

[0154] (Relationship between the degree of amorphousness of amorphous particles on the first composite particle and the particle size of recrystallized particles on the second composite particle) In this embodiment, the degree of amorphousness (number of crystal nuclei) of the amorphous particles in the first composite particle was varied, and the relationship between the degree of amorphousness of the amorphous particles and the particle size of the recrystallized particles of the second composite particle obtained in the end was evaluated.

[0155] Indomethacin (average particle size: 14.1 μm) was used as the crystalline organic compound, and the stirring and mixing process (10°C, 2000 rpm) and storage process (25°C, silica gel drying, 7 days) were carried out in the same manner as in Example 1, except that the stirring and mixing times were 30 minutes, 45 minutes, 1 hour, 2 hours, 6 hours, and 10 hours, to obtain the second composite particles. The Raman spectra and SEM images of the obtained second composite particles are shown in Figures 4A to 4B and Figures 5A to 5B. In addition, the results of the evaluation of the degree of amorphousness in the Raman spectra obtained with a PR-1W manufactured by JASCO Corporation are shown in Figure 4C.

[0156] As shown in Figures 4A and 4B, indomethacin, after a 30-minute stirring time, reaches a temperature of 1680 cm², which is characteristic of its amorphous form. －１ We were able to observe a peak of 1698 cm² originating from the crystalline material. －１ A peak was observed. Based on this Raman spectrum, the degree of amorphousness was calculated using multivariate analysis with the imaging model analysis program of Spectrum Manager (manufactured by JASCO Corporation). The degree of amorphousness was 78% after 30 minutes of stirring, 86% after 45 minutes, 94% after 1 hour, and 100% after 2 hours.

[0157] Furthermore, after 1 hour of stirring, a slight peak originating from crystals was observed in the Raman spectrum, and after 2 hours, it was found to have become completely amorphous. On the other hand, no changes were observed in the Raman spectrum after 6 and 10 hours of stirring.

[0158] Furthermore, as shown in Figures 4A and 4B, it was found that amorphous indomethacin, regardless of the stirring time, crystallized completely after storage. Figure 4C shows the results of Raman spectroscopy measurements of amorphous and crystalline indomethacin mixed in various ratios. The characteristic peak of the amorphous form is at 1680 cm⁻¹. －１ And the specific peak of the crystal is 1698 cm⁻¹. －１Referring to the peak heights for and , when crystalline indomethacin is present in a ratio of 0.2, these characteristic peak heights are in roughly agreement. For example, referring to Figure 4B, these characteristic peak heights are in roughly agreement even in the product that has been stirred and mixed for 30 minutes. Based on these peak heights, the degree of amorphousness of the first composite particles after stirring and mixing for 30 minutes can be estimated to be 80%.

[0159] As shown in Figures 5A and 5B, the particle size of the amorphous indomethacin particles obtained (immediately after the stirring and mixing step) was the same regardless of the stirring and mixing time (approximately 1 μm). On the other hand, during the storage step (7 days), although recrystallized particles were present in the 30-minute stirring and mixing step, the recrystallized particles clustered due to the crystalline phase remaining within the amorphous particles.

[0160] Furthermore, at 30 minutes, 45 minutes, 1 hour, and 2 hours, where the degree of amorphousness determined by multivariate analysis was between 78% and 100%, the amorphous particles were recrystallized particles of nanosize less than 1 μm (according to the gas adsorption method, 706 nm at 30 minutes, 562 nm at 45 minutes, 503 nm at 1 hour, and 553 nm at 2 hours). On the other hand, at 6 hours and 10 hours, the size of the recrystallized particles gradually increased, reaching 915 nm at 6 hours (according to the gas adsorption method) and 988 nm at 10 hours (according to the gas adsorption method), which was equivalent to the size of the amorphous particles.

[0161] The particle size of the recrystallized particles is determined by drying the sample (first composite particle or second composite particle) under vacuum at a temperature of 25°C for 12 hours or more using a gas adsorption device (NOVA 600, manufactured by Anton Paar). Then, Ar gas is adsorbed onto the sample with liquid nitrogen (77K) at a relative pressure of 0.05 to 0.3, and the adsorption data is applied to the BET formula to determine the specific surface area diameter (DSP) of the sample. drug This was calculated using the formula described above.

[0162] From the above, it was found that the particle size of amorphous particles on the first composite particle tends to be constant regardless of the stirring and mixing time, while the particle size of recrystallized particles, which is thought to be based on the degree of amorphousness and the number of crystal nuclei of the amorphous particles, is highly dependent on the stirring and mixing time.

[0163] Furthermore, it was found that if the degree of amorphousness based on the Raman spectrum is between 75% and 100%, recrystallized particles smaller than the initial crystalline particles (particle diameter approximately 14.1 μm) and amorphous particles (particle diameter approximately 1 μm), at the nanoscale level, can be obtained. In addition, it was found that when the stirring and mixing time was between 2 hours, 6 hours, and 10 hours, the particle diameter of the resulting recrystallized particles gradually increased even though there was no change in the Raman spectrum. It was also found that a degree of amorphousness of 75% or more, 80% or more, 85% or more, 90% or more, and 95% or more may be preferable in some cases. Furthermore, it was found that a degree of amorphousness of 100% or less, 99% or less, and 95% or less may be preferable in some cases. It should be noted that the crystal morphology is thought to differ depending on the compound.

[0164] From the above, it was considered that crystal nuclei, which cannot be detected by Raman spectroscopy, remain in the amorphous particles after the stirring and mixing process, and that these crystal nuclei decrease with increasing stirring and mixing time. Therefore, it was considered that when the stirring and mixing time is relatively short and the degree of amorphousness is 75-100%, many crystal nuclei remain, resulting in smaller particle sizes of recrystallized particles, and as the stirring and mixing time increases, the number of crystal nuclei decreases, making it less likely for the growth of crystal grains to be inhibited, thus increasing the particle size of the recrystallized particles (see Figure 1B).

[0165] (Investigation of storage temperature and storage time in the process of producing the second composite particle (storage process)) In this example, the storage temperature and storage time in the process of producing the second composite particle were investigated. The stirring, mixing, and storage process was carried out in the same manner as in Example 1, except that the temperature (5°C to 40°C) and time (1 hour to 14 days) in the storage process were varied. The Raman spectra and SEM images of the final composite particles are shown in Figures 6A and 6B.

[0166] As shown in Figure 6A, when stored at 5°C, recrystallization began two days after the start of storage and took 14 days to complete. Furthermore, as the storage temperature increased, the recrystallization of amorphous indomethacin in the second composite particle accelerated, with complete recrystallization occurring in one day at 25°C and in two hours at 40°C.

[0167] As shown in Figure 6B, regardless of the storage temperature, the amorphous particles were completely crystallized, ultimately forming nano-sized recrystallized particles.

[0168] From the above, it was found that if the storage temperature is lower than the glass transition temperature of the organic compound of amorphous particles (around 42°C in the case of indomethacin), recrystallized particles can be reliably obtained, and that the higher the storage temperature, the more quickly recrystallized particles can be obtained.

[0169] (Investigation of the atmosphere in the process of producing the second composite particle (storage process)) In this example, the atmosphere in the process of producing the second composite particle was investigated. The stirring and mixing process and the storage process were carried out in the same manner as in Example 1, except that the atmosphere in the storage process (silica gel drying) was changed to water vapor, acetone vapor, and ethanol vapor. The results are shown in Figure 7.

[0170] The water vapor atmosphere was created by storing a sufficient amount of water in a constant temperature bath at 25°C with the water vapor fully saturated inside. The acetone vapor and ethanol vapor atmospheres were created in the same manner.

[0171] As shown in Figure 7, when the storage process was carried out under a water vapor atmosphere, complete recrystallization occurred after 4 hours of storage, which was faster than under drying conditions. Moreover, the recrystallized particles that were completely recrystallized were nano-sized, similar to those produced when silica gel was dried. From the above, it was found that storage under a water vapor atmosphere can promote the recrystallization of amorphous particles without affecting the particle size of the recrystallized particles. In the case of acetone vapor and ethanol vapor, complete recrystallization was achieved within 1 minute from the start of storage.

[0172] (Production of Composite Particles) In this example, various compounds shown in Table 1 were used as the crystalline organic compound. Also, as the core particles, crystalline cellulose particles (Celluia CP-203 (manufactured by Asahi Kasei), particle size range 150 μm to 300 μm) were used. 20 g of the compound and 200 g of the crystalline cellulose particles were put into a high-speed stirring granulator (MM-10, manufactured by Okada Seiko Co., Ltd.) (volume ratio 30 to 40%), and the stirring blades at the bottom of the granulator were rotated at 2000 rpm, and a stirring and mixing step (step of producing the first composite particles) was carried out at 10°C for 2 hours. The first composite particles as the obtained granulated product were stored for 7 days in a constant temperature machine (silica gel drying) set at each temperature shown in Table 1, and a storage step (step of producing the second composite particles) was carried out. The X-ray diffraction spectra and SEM images of the obtained composite particles are shown in FIGS. 10 to 13. Also, the crystallinity of the first composite particles and the second composite particles was observed by Raman spectra.

[0173] In the following examples, the measurement methods of various indexes were as follows. [1] Average particle diameter and specific surface area of crystalline organic compound particles (on composite particles) and specific surface area of composite particles By using the gas adsorption method, the specific surface area diameter was obtained by the following method. Using a gas adsorption apparatus (NOVA600, manufactured by Anton Paar), the sample (composite particles having organic compound particles which are crystalline organic compound particles or amorphous organic compound particles on the core particles) was dried under vacuum at 25°C for 12 hours or more. Then, the sample was adsorbed with Ar gas at least at 5 points within the range of relative pressure of 0.05 to 0.3 at liquid nitrogen (77 K), and the adsorption data was applied to the BET equation to obtain the specific surface area diameter DSP of the sample. drug was calculated using the formulas described as the above-mentioned formulas 1 to 3.

[0174] Here, SSA ｃｐ 、SSA ｄｒｕｇ 、SSA ｃｏｒｅ respectively represent the specific surface area of the composite particles, the specific surface area of the organic compound particles, and the specific surface area of the core particles, and W ｃｐ 、W ｄｒｕｇ 、W ｃｏｒｅThe masses of the composite particles, organic compound particles, and core particles are shown, respectively. The specific surface areas of the organic compound particles and core particles were measured by gas adsorption as needed. DC indicates the mass ratio of organic compound particles in the composite particles. Also, ρ ｄｒｕｇ φ represents the true density of the organic compound particles. The true density of the organic compound particles was measured using a helium gas displacement true density meter (Ultra Pycnometer 1000, manufactured by Cantachrome). φ represents the shape factor of the organic compound particles. In this example, assuming that the particle shape of the crystalline organic compound particles is spherical, a shape factor of φ of 6 was used. The mass of the crystalline organic compound particles in the composite particles was measured by dispersing the finally obtained composite particles in methanol, in which the nucleus particles do not dissolve but the organic compound particles do, filtering the mixture through a membrane filter (pore size 0.45 μm), and measuring the concentration of the organic compound in the filtrate using a UV-Vis spectrophotometer (U-2900, manufactured by Hitachi, Ltd.). The mass of the nucleus particles on the filter paper was also measured.

[0175] [2] Evaluation of Amorphization and Recrystallization Measurements were taken using a powder X-ray diffractometer (SmartLab, Rigaku). The system configuration was as follows: X-ray source: CuKα (40kV, 30mA), Measurement unit: ASC-6 attachment, Detector: High-speed one-dimensional detector (DteXUltra250). The composite particles were packed into an aluminum cell dedicated to the ASC-6 attachment and scanned at a speed of 5° / min in the range of 2θ: 5 to 35° while rotating at 20 rpm. Broad peaks originating from crystalline cellulose were observed in the physical mixture (PM) and composite particles at 2θ: 14.7°, 22.5°, and 34.6°. When the peaks originating from the crystals of the crystalline organic compound particles used as raw materials were no longer observed within the composite particles, it was determined that the drug had completely amorphous. Due to recrystallization, peaks originating from the crystals of the crystalline organic compound particles appear, so when the intensity of the diffraction peaks became constant after measurement over time, it was determined that the substance had completely crystallized.

[0176]

[0177] As shown in Fig. 10, simvastatin was mixed at a jacket temperature of 5°C for 240 minutes to be amorphized to 80% or more. Then, when stored at 25°C for 7 days, the storage temperature was "5.7°C" lower than the glass transition temperature (Tg) (30.7°C) of simvastatin. The average particle diameter and specific surface area of the crystalline organic compound particles generated by recrystallization were 972 nm and 5.46 m ２ / g, respectively, and the specific surface area of the composite particles was 0.272 m ２ / g. Also, when stored at 5°C (25.7°C lower than the Tg of simvastatin) for 7 days, the average particle diameter and specific surface area of the crystalline organic compound particles generated by recrystallization were 281 nm and 18.1 m ２ / g, respectively, and the specific surface area of the composite particles was 0.898 m ２ / g. It was found that even when recrystallized at a temperature about 6°C or lower than Tg, it was difficult for the crystalline organic compound particles to be miniaturized. On the other hand, when recrystallized at a temperature about 25°C lower than Tg, it was found that the crystalline organic compound particles were likely to be miniaturized.

[0178] As shown in Fig. 11, when carvedilol was mixed at a jacket temperature of 10°C for 120 minutes, it was completely amorphized. On the other hand, in the case of a 60-minute mixing treatment, minute crystal peaks were observed. When the 120-minute treated product was stored at 25°C for 7 days, the storage temperature was "13.2°C" lower than the Tg (38.2°C) of carvedilol. The average particle diameter and specific surface area of the crystalline organic compound particles generated by recrystallization were 1091 nm and 4.24 m ２ / g, respectively, and the specific surface area of the composite particles was 0.369 m ２ / g. It was found that when the amorphization of the crystalline organic compound progressed too far, it was difficult for the crystalline organic compound particles to be miniaturized.

[0179] Also, when the 60-minute treated product was stored at 35°C (3.2°C lower than the Tg of carvedilol) for 7 days, the average particle diameter and specific surface area of the crystalline organic compound particles generated by recrystallization were 3588 nm and 1.24 m ２ / g, respectively, and the specific surface area of the composite particles was 0.129 m ２The result was / g. It was found that even when recrystallization was performed at a low temperature of 5°C or less from Tg, the crystalline organic compound particles were not easily miniaturized.

[0180] As shown in Figure 12, indomethacin was mixed at a jacket temperature of 10°C for 120 minutes to completely amorphize it. Afterward, it was stored at 25°C for 7 days. The storage temperature was 18.4°C lower than the glass transition temperature (Tg) of indomethacin (43.4°C). The average particle size and specific surface area of ​​the crystalline organic compound particles produced by recrystallization were 553 nm and 7.85 m², respectively. ２ The value is / g, and the specific surface area of ​​the composite particles is 0.564 m². ２ The result was / g. Furthermore, when stored at 40°C (3.4°C lower than the Tg of indomethacin) for 7 days, the average particle diameter and specific surface area of ​​the crystalline organic compound particles produced by recrystallization were 992 nm and 4.45 m, respectively. ２ The value is / g, and the specific surface area of ​​the composite particles is 0.311 m². ２ The result was / g. Similar to simvastatin and carvedilol, it was found that indomethacin also does not easily become smaller when recrystallized at a low temperature of 5°C or less from Tg. On the other hand, it was found that crystalline organic compound particles are easily made smaller when recrystallized at a temperature approximately 20°C lower than Tg.

[0181] As shown in Figure 13, aprepitant was mixed at a jacket temperature of 10°C for 120 minutes to completely amorphize it. When then stored at 25°C for 7 days, the storage temperature was 62.5°C lower than the glass transition temperature (Tg) of aprepitant (87.5°C), and recrystallization was not completed in 7 days, requiring more than 4 weeks. On the other hand, when stored at 60°C (27.5°C lower than the Tg of aprepitant) for 7 days, the average particle size and specific surface area of ​​the crystalline organic compound particles produced by recrystallization were 157 nm and 26.5 nm, respectively. ２ The value is / g, and the specific surface area of ​​the composite particles is 2.07 m². ２ The result was / g. It was found that recrystallization is difficult to proceed at temperatures 50°C to 60°C lower than Tg and is not practical, while recrystallization at temperatures approximately 30°C lower than Tg makes it easier to miniaturize crystalline organic compound particles.

[0182] Ritonavir and itoconazole were mixed and treated at a jacket temperature of 10°C to completely amorphousize them, and then stored at 25°C (21.7°C lower than the Tg of ritonavir and 29.7°C lower than the Tg of itoconazole, respectively). However, crystallization did not occur for more than 6 months. These results suggest that the high molecular weights (721 and 706 for ritonavir and itoconazole, respectively) result in low molecular mobility, making the amorphous state relatively stable.

[0183] From the above, it was found that for various crystalline organic compounds, if the degree of amorphousness ranges from 80% to complete amorphous, and the storage temperature is 5°C to approximately 30°C (effectively 28°C) above the Tg of the organic compound, or for example, 10°C to 28°C, 20°C to 28°C, or 25°C to 28°C, composite particles having a porous layer containing miniaturized crystalline organic compound particles can be obtained.

[0184] Furthermore, as shown in Figures 10 to 13, it was found that a porous layer is formed on the surface of the crystalline cellulose grains, which are the core particles, in which crystalline organic compound particles are interconnected and the gaps between these particles serve as pores.

Claims

1. A composite particle comprising: a core particle; and crystalline organic compound particles containing a crystalline organic compound present on the surface of the core particle, wherein the specific surface area of ​​the composite particle is 0.0015 m². ２ / g or more, 60m ２ Composite particles that are less than or equal to / g.

2. The composite particle according to claim 1, wherein the average particle diameter of the crystalline organic compound particles is 4.0 μm or less.

3. The composite particle according to claim 2, wherein the average particle diameter of the crystalline organic compound particles is 1.0 μm or less.

4. The composite particle according to claim 3, wherein the average particle size of the crystalline organic compound particles is 0.60 μm or less.

5. The specific surface area of ​​the composite particles is 0.075 m². ２ / g or more, 30m ２ The composite particles according to claim 1, wherein the amount is less than or equal to / g.

6. The specific surface area of ​​the composite particles is 0.10 m². ２ / g or more, 10m ２ The composite particles according to claim 1, wherein the amount is less than or equal to / g.

7. The composite particle according to claim 1, wherein the mass ratio of the nucleus particle to the crystalline organic compound particle (nucleus particle:crystalline organic compound particle) is 100:1 or more and 1:5 or less.

8. The composite particle according to claim 1, wherein the molecular weight of the crystalline organic compound is 200 or more and 1,300 or less.

9. The composite particle according to claim 1, wherein the molecular weight of the crystalline organic compound is 350 or more and 720 or less.

10. The composite particle according to any one of claims 1 to 9, wherein the crystalline organic compound particles are particles obtained by recrystallizing amorphous organic compound particles by storing them under certain conditions for a predetermined period of time.

11. The composite particle according to claim 10, wherein the crystalline organic compound particles are obtained by storing the amorphous organic compound particles for one hour or more.

12. The composite particle according to claim 10, wherein the crystalline organic compound particles are obtained by storing them at a temperature at least 10°C lower than the glass transition temperature of the amorphous organic compound particles.

13. The composite particle according to any one of claims 1 to 9, wherein the core particle is one or more selected from the group consisting of crystalline cellulose, hydroxypropyl cellulose, and methylcellulose.

14. The composite particle according to any one of claims 1 to 9, wherein the crystalline organic compound particles are bonded to each other to form a porous layer having interparticle gaps.

15. A pharmaceutical composition comprising the composite particles described in any one of claims 1 to 9 or the crystalline organic compound.

16. A method for producing composite particles, comprising: a first step of mechanically stirring and mixing a core particle and a first crystalline organic compound particle to promote the pulverization and amorphousization of the crystalline organic compound particle, thereby producing a first composite particle having amorphous organic compound particles derived from the first crystalline organic compound particle on the surface of the core particle; and a second step of storing the first composite particle under certain conditions to recrystallize the amorphous organic compound particle, thereby producing a second composite particle having recrystallized organic compound particles on its surface, wherein the specific surface area of ​​the second composite particle is 0.0015 m². ２ / g or more, 60m ２ A manufacturing method comprising carrying out the first and second steps so that the amount is less than or equal to / g.

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