Particles and their uses

Abstract

The present invention provides particles in which the core particles are coated with a coating layer, thereby ensuring their strength. It also provides orally disintegrating tablets and the like with improved physical properties (particularly compression moldability, disintegration properties, tablet compression defects, tablet hardness after humidification, and abrasion resistance after humidification). [Solution] The particles according to this disclosure have a core particle covered with a coating layer, and the coating layer contains cellulose nanofibers. The orally disintegrating tablets according to this disclosure have particles containing cellulose nanofibers with an average particle diameter of less than 10 μm.

Description

[Technical Field]

[0001] (Invention 1) The present invention relates to a particle having a coating layer containing cellulose nanofibers. The present invention also relates to a composition containing the particles, and a method for producing the particles. Furthermore, the present invention relates to a method for ensuring the strength of a particle in which core particles are coated with a coating layer.

[0002] (Invention 2) The present invention relates to an orally disintegrating tablet having particles containing cellulose nanofibers, and to disintegrating particles. The present invention also relates to a method for producing the above-mentioned orally disintegrating tablet, and to a method for improving physical properties of the above-mentioned orally disintegrating tablet. [Background Art]

[0003] (Invention 1) Core particles have problems such that bitterness may occur depending on the type of active ingredient contained therein, and sufficient stability may not be obtained when they are used alone. Therefore, functional coating techniques for coating core particles have been developed for the purpose of improving the bitterness and stability of active ingredients.

[0004] For example, Patent Document 1 describes a medicinal particle formed of a spherical core portion containing a medicinal ingredient, and a coating portion that covers the spherical core portion and includes a release control layer and an outermost layer containing mannitol.

[0005] (Invention 2) Tablets may be difficult to take for elderly people and pediatric patients who have difficulty swallowing, and also for patients who are subject to water restriction. Orally disintegrating tablets (also referred to as "Orally Disintegrating Preparation: OD tablets") are applicable to such patients, and are therefore useful for formulating various active ingredients.

[0006] Orally disintegrating tablets have properties different from ordinary tablets, and technological development is being carried out from different perspectives (e.g., compressibility, disintegration in the oral cavity, etc.). For example, Patent Document 2 describes a disintegrating particle composition used in orally disintegrating tablets, which includes a disintegrant component and microfibrous cellulose. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] Japanese Patent Application Publication No. 2022-024336 [Patent Document 2] International Publication No. 2015 / 163135 [Overview of the Initiative] [Problems that the invention aims to solve]

[0008] (Invention 1) However, the pharmacokinetic particles described in Patent Document 1 had room for improvement in terms of particle strength.

[0009] Therefore, one aspect of the present invention aims to provide particles in which the core particles are coated with a coating layer and in which the strength of the particles is ensured. Another aspect of the present invention aims to provide a method for ensuring the strength of particles in which the core particles are coated with a coating layer.

[0010] (Invention 2) However, the orally disintegrating tablet described in Patent Document 1 had room for improvement in terms of its physical properties, particularly its compressibility, disintegration properties, tableting defects, tablet hardness after humidification, and abrasion rate after humidification.

[0011] Therefore, one aspect of the present invention aims to provide an orally disintegrating tablet with improved physical properties, and disintegrable particles used in said orally disintegrating tablets. Another aspect of the present invention aims to provide a method for manufacturing an orally disintegrating tablet with improved physical properties, and a method for improving the physical properties of an orally disintegrating tablet. [Means for solving the problem]

[0012] (Invention 1) As a result of diligent research to solve the above problems, the inventors have discovered for the first time that the strength of the core particles can be ensured by coating them with a coating layer containing cellulose nanofibers, and have completed the present invention. That is, one aspect of the present invention includes the following configuration. <1> The core particles are covered with a coating layer, Particles characterized in that the coating layer contains cellulose nanofibers. <2> The core particles and the coating layer are characterized by including an intermediate layer between them. <1> The particles described. <3> The coating layer is characterized by not containing any additives other than the cellulose nanofibers. <1> or <2> The particles described. <4> The average fiber diameter of the cellulose nanofibers is less than 1 μm. <1> ~ <3> Particles as described in any of the following. <5> <1> ~ <4> A composition comprising the particles described in any of the following. <6> The use of the composition is at least one selected from the group consisting of pharmaceuticals, food products, and cosmetics. <5> The composition described above. <7> A method for producing particles in which core particles are coated with a coating layer, A method comprising the step of coating the core particles with a coating layer containing cellulose nanofibers. <8> A method for ensuring the strength of particles in which core particles are coated with a coating layer, A method characterized by comprising the step of incorporating cellulose nanofibers into the coating layer.

[0013] (Invention 2) As a result of diligent research to solve the above problems, the present inventors have discovered for the first time that by incorporating cellulose nanofibers (hereinafter also referred to as "CNF") with an average particle diameter of less than 10 μm into the particles constituting the orally disintegrating tablet, the physical properties of the orally disintegrating tablet (particularly its compressibility, disintegration, tableting defects, tablet hardness after humidification, and abrasion after humidification) are improved, and have completed the present invention. That is, one aspect of the present invention includes the following configuration. <9> An orally disintegrating tablet characterized by having particles containing cellulose nanofibers with an average particle diameter of less than 10 μm. <10> The aforementioned particles are disintegrable particles. <9> Orally disintegrating tablets as described above. <11> The cellulose nanofibers are characterized in that their average fiber diameter is 0.001 to 1 μm. <9> or <10> Orally disintegrating tablets as described above. <12> The particles have a core and a coating layer, The cellulose nanofiber is characterized in that it is included in the coating layer. <9> or <10> Orally disintegrating tablets as described above. <13> The disintegrable particles comprise a sugar alcohol and organic and inorganic hydrophilic and water-insoluble additives. The aforementioned organic hydrophilic and water-insoluble additive comprises at least one selected from the group consisting of starch, starch derivatives, and crospovidone. The inorganic hydrophilic and water-insoluble additive is characterized by comprising light anhydrous silicic acid and / or magnesium aluminometasilicate. <10> Orally disintegrating tablets as described above. <14> An orally disintegrating tablet characterized by having cellulose nanofibers with an average fiber length of less than 10 μm. <15> Disintegrable particles characterized by containing cellulose nanofibers with an average particle diameter of less than 10 μm. <16> Particles containing drugs and cellulose nanofibers with an average particle size of less than 10 μm. <17> This is a method for manufacturing orally disintegrating tablets containing particles. A production method comprising a step of incorporating cellulose nanofibers having an average particle diameter of less than 10 µm into the particles. <18>A method for improving physical properties of an orally disintegrating tablet containing particles, characterized by comprising a step of incorporating cellulose nanofibers having an average particle diameter of less than 10 µm into the particles, the method, wherein the physical property is at least one of the following physical properties: (1) compression moldability, (2) disintegratability, (3) tableting troubles, (4) tablet hardness after humidification, and (5) friability after humidification. Effects of the Invention

[0014] (Invention 1) According to one aspect of the present invention, particles with ensured strength, in which core particles are coated with a coating layer, can be provided. Further, according to one aspect of the present invention, a method for ensuring the strength of particles in which core particles are coated with a coating layer can be provided.

[0015] (Invention 2) According to one aspect of the present invention, an orally disintegrating tablet with improved various physical properties (in particular, compression moldability, disintegratability, tableting troubles, tablet hardness after humidification, and friability after humidification), and disintegratable particles used for such an orally disintegrating tablet and the like can be provided. Further, according to one aspect of the present invention, a method for producing an orally disintegrating tablet with improved the aforementioned physical properties, and a method for improving the aforementioned physical properties in an orally disintegrating tablet can be provided. Brief Description of the Drawings

[0016] [Figure 1] It is a schematic diagram showing particles according to an embodiment of the present invention in (Invention 1). [Figure 2] It is a diagram showing the results of dissolution tests using particles and tablets in Examples 1 to 3 and Comparative Examples 1 to 3. [Figure 3] It is a diagram showing the measurement results of particle strength using particles in Example 4 and Comparative Examples 4 to 7. [Figure 4] This figure shows the measurement results of particle strength using particles in Example 5 and Comparative Example 8. [Figure 5] This figure shows the results of the dissolution tests using particles and tablets in Example 6 and Comparative Example 9. [Figure 6] This figure shows the measurement results of particle strength using particles in Example 6 and Comparative Example 9. [Figure 7] This figure shows the results of the dissolution tests using particles and tablets in Example 7 and Comparative Example 10. [Figure 8] This figure shows the measurement results of particle strength using particles in Example 7 and Comparative Example 10. [Figure 9] This figure shows the results of dissolution tests using particles and tablets in Example 8 and Comparative Example 11. [Figure 10] This figure shows the measurement results of particle strength using particles in Example 8 and Comparative Example 11. [Figure 11] This figure shows CNF (CNF-1) used in the embodiment of (Invention 2) as captured by a scanning electron microscope (JSM-IT200, top two rows) and a scanning probe microscope (SPM-Nanoa, bottom row). [Figure 12] This figure shows the relationship between tablet compression pressure and tablet hardness (compression moldability), and the relationship between tablet hardness and disintegration time (disintegration) in Examples 1-1 to 3-1 and Comparative Examples 1-1 to 2-1. [Figure 13] This figure shows the tablet hardness and abrasion degree after humidification for Examples 1-1 to 3-1 and Comparative Examples 1-1 to 2-1. [Figure 14] This figure shows the relationship between tablet hardness and disintegration time (disintegration) in Examples 1-1, 4-1, and 5-1, as well as Comparative Examples 1-1 and 3-1. [Figure 15] This figure shows the tablet hardness and abrasion degree after humidification for Examples 1-1, 4-1, and 5-1, and Comparative Examples 1-1 and 3-1. [Figure 16]This figure shows the relationship between tablet compression pressure and tablet hardness (compression moldability), and the relationship between tablet hardness and disintegration time (disintegrability) in Examples 6-1 and 7-1, and Comparative Example 4-1. [Figure 17] This figure shows the relationship between tablet hardness and disintegration time (disintegration) in Example 8-1 and Comparative Example 5-1. [Figure 18] This figure shows the measurement results of particle strength using particles in Example 9-1 and Comparative Example 6-1. [Modes for carrying out the invention]

[0017] One embodiment of the present invention will be described in detail below. Unless otherwise specified in this specification, "A to B" representing a numerical range means "greater than or equal to A and less than or equal to B".

[0018] (Invention 1) [1. Outline of the present invention] A particle according to one embodiment of the present invention (hereinafter referred to as "the particle") is characterized in that a core particle is covered with a coating layer, and the coating layer contains cellulose nanofibers.

[0019] Furthermore, a composition according to one embodiment of the present invention (hereinafter referred to as "the Composition") is characterized by containing the particles.

[0020] Furthermore, a method for producing particles in which core particles are coated with a coating layer according to one embodiment of the present invention (hereinafter referred to as "this production method") is characterized by including a step of coating the core particles with a coating layer containing cellulose nanofibers.

[0021] In addition, a method for ensuring the strength of core particles coated with a coating layer according to one embodiment of the present invention (hereinafter referred to as "this method") is characterized in that the coating layer contains cellulose nanofibers.

[0022] Particles with functional coatings, as described in Patent Document 1, have conventionally faced the problem of cracking of the functional coating layer due to tableting stress, and consequently, leakage of the active ingredient (e.g., drug) contained in the core particle. Furthermore, conventional particles in which the core particle is covered with a coating layer also had room for improvement in terms of strength.

[0023] Therefore, the inventors diligently conducted studies from the viewpoint of ensuring the strength of particles in which the core particles are coated with a coating layer, and succeeded in obtaining the following findings. • By coating the core particles with a coating layer containing cellulose nanofibers, the strength of the particles can be improved. In a particle system comprising a core particle, an intermediate layer, and a coating layer, the strength of the particle can be improved and cracking of the intermediate layer during tableting can be prevented by incorporating cellulose nanofibers into the coating layer.

[0024] Until now, it was not known that cellulose nanofibers contribute to particle strength. Therefore, it is remarkable that the inventors focused on cellulose nanofibers to ensure particle strength and applied them to the coating layer within the particles, thereby improving particle strength and preventing cracking of the intermediate layer during tableting. Furthermore, in these particles, particle strength can be ensured by incorporating cellulose nanofibers into the outer layer (e.g., the coating layer) of the core particles, without adding cellulose nanofibers to the core particles themselves.

[0025] Thus, because these particles exhibit advantageous effects based on the above findings, they can be used very advantageously in various fields where particles containing a coating layer are used as raw materials.

[0026] [2. Particles] These particles consist of a core particle covered with a coating layer, and the coating layer contains cellulose nanofibers. The inclusion of cellulose nanofibers in the coating layer ensures the particle's strength.

[0027] In this specification, "ensuring particle strength" means "improving particle strength" and / or "preventing cracking of the intermediate layer during tableting." In other words, "ensuring particle strength" means increasing or maintaining particle strength.

[0028] Embodiments of the present invention will be described below with reference to Figure 1. The embodiments shown below are merely illustrative examples of the present invention, and the present invention is not limited to these embodiments.

[0029] Furthermore, these particles can be used in a variety of applications, including pharmaceuticals, food products, and cosmetics. Below, we will describe their use in pharmaceutical applications as an example. It goes without saying that the applications of these particles are not limited to pharmaceuticals.

[0030] <Embodiment 1> Embodiment 1 is shown in the upper diagram of Figure 1. In Embodiment 1, core particles 1 are covered with an intermediate layer 3, and the intermediate layer 3 is further covered with a coating layer 2. The coating layer 2 contains cellulose nanofibers. In Embodiment 1, the covering of core particles 1 with the intermediate layer 3 and the coating layer 2 has the effect of improving particle strength. It also has the effect of preventing cracking of the intermediate layer during tableting.

[0031] Core particle 1 is located in the innermost part of the particle and contains the active ingredient. The active ingredient contained in core particle 1 is not particularly limited, but examples include drugs, food ingredients, nutrients, micronutrients, flavoring agents, fragrances, etc.

[0032] The coating layer 2 is located outside the intermediate layer 3. In embodiments where the particles do not include the intermediate layer 3, the coating layer 2 is located outside the core particle 1.

[0033] Coating layer 2 contains cellulose nanofibers. In this specification, "cellulose nanofibers" means cellulose fibers with a nanoscale diameter prepared by mechanically treating cellulose.

[0034] The average fiber diameter of the cellulose nanofibers is preferably less than 1 μm, more preferably 500 nm or less, even more preferably 300 nm or less, particularly preferably 200 nm or less, and most preferably 100 nm or less. Having an average fiber diameter of less than 1 μm allows for proper coating and maintains an appropriate particle size after coating. The average fiber diameter of the cellulose nanofibers refers to the average value of the fiber diameters measured for any 10 or more cellulose nanofibers in images acquired by a scanning probe microscope.

[0035] The fiber length of the cellulose nanofiber is not particularly limited, but is, for example, 0.001 to 100 μm, preferably 0.01 to 50 μm, more preferably 0.05 to 25 μm, and even more preferably 0.1 to 10 μm. A fiber length of 0.001 to 100 μm allows for proper coating and maintains an appropriate particle size after coating. The fiber length of the cellulose nanofiber is measured by image analysis.

[0036] The cellulose nanofiber content is, for example, 0.1 to 10.0% by mass, preferably 0.4 to 9.0% by mass, more preferably 0.6 to 8.0% by mass, and even more preferably 0.8 to 7.0% by mass, relative to the total mass of the core particles 1 and the intermediate layer 3. When the cellulose nanofiber content is 0.1 to 10.0% by mass relative to the total mass of the core particles 1 and the intermediate layer 3, the effects of the present invention (i.e., ensuring particle strength) can be achieved.

[0037] In one embodiment of the present invention, the coating layer 2 may be a functional coating layer. The functional coating layer is not particularly limited as long as it is a layer that exhibits a desired function by coating the core particles 1, but examples include layers containing bitterness masking agents, enteric coating agents, sustained-release agents, moisture-proof agents, light-resistant agents, shielding agents, and the like.

[0038] In one embodiment of the present invention, the coating layer 2 does not contain any additives other than the cellulose nanofibers. That is, in one embodiment of the present invention, the coating layer 2 may consist only of cellulose nanofibers.

[0039] The intermediate layer 3 is located between the core particles 1 and the coating layer 2. In one embodiment of the present invention, the intermediate layer 3 may be a functional coating layer. As the functional coating layer, those described in (Coating Layer) are used.

[0040] The intermediate layer 3 may be a single layer or a multilayer layer. If the intermediate layer 3 is a multilayer layer, the number of layers is not particularly limited, but for example, it may be 2, 3, 4, 5, etc. If the intermediate layer 3 is a multilayer layer, each layer may be the same functional coating layer or different functional coating layers. Preferably, each layer is different functional coating layers.

[0041] The core particle 1, coating layer 2, and intermediate layer 3 in this particle may contain additives such as excipients, binders, lubricants, disintegrants, surfactants, plasticizers, and colorants.

[0042] Excipients are not particularly limited, but examples include D-mannitol, lactose (e.g., lactose monohydrate), sucrose, corn starch, calcium phosphate, sorbitol, crystalline cellulose, and light anhydrous silicic acid. Preferably, crystalline cellulose and lactose (e.g., lactose monohydrate) are used.

[0043] The binder is not particularly limited, but examples include hydroxypropylcellulose, hydroxypropylmethylcellulose (also called "hypromellose"), povidone, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, copolymers of N-vinylpyrrolidone and vinyl acetate, or combinations thereof, pregelatinized starch, gelatin, agar, and gum arabic. Hypromellose is preferably used.

[0044] The lubricant is not particularly limited, but examples include inert substances such as talc, kaolin, and titanium dioxide, magnesium stearate, calcium stearate, stearic acid, light anhydrous silicic acid, finely ground silicon dioxide, sodium stearyl fumarate, and glycerin fatty acid esters. Glycerin fatty acid esters are preferably used.

[0045] The disintegrant is not particularly limited, but examples include crospovidone, low-substituted hydroxypropylcellulose, sodium starch glycolate, croscarmellose sodium, carmellose, carmellose calcium, potato starch, etc. Crospovidone is preferably used.

[0046] The coloring agent is not particularly limited, but examples include yellow coloring agents (e.g., yellow iron(III) oxide, yellow iron oxide, food yellow No. 4 aluminum lake, red iron oxide, etc.), red coloring agents (e.g., iron(III) oxide, food red No. 2, food red No. 3, food red No. 102, etc.), black coloring agents (e.g., black iron oxide, carbon black, medicinal charcoal, etc.), blue coloring agents (e.g., blue No. 2 aluminum lake, etc.), caramel, etc. Preferably, yellow iron(III) oxide and blue No. 2 aluminum lake are used.

[0047] The content of each of the above-mentioned additives is not particularly limited and can be appropriately determined by those skilled in the art based on conventionally known techniques.

[0048] In one embodiment of the present invention, the particle is composed of a core particle 1, a shielding layer (intermediate layer 3), and a bitterness masking functional coating layer (coating layer 2) containing cellulose nanofibers.

[0049] <Embodiment 2> Embodiment 2 is shown in the middle diagram of Figure 1. In Embodiment 2, the core particles 1 are covered with a coating layer 2. The coating layer 2 contains cellulose nanofibers. In Embodiment 2, the covering of the core particles 1 with the coating layer 2 has the effect of improving particle strength.

[0050] In Embodiment 2, the particles do not contain the intermediate layer 3. In this case, the cellulose nanofiber content is, for example, 0.1 to 10.0% by mass, preferably 0.4 to 9.0% by mass, more preferably 0.6 to 8.0% by mass, and even more preferably 0.8 to 7.0% by mass, relative to the mass of the core particle 1. When the cellulose nanofiber content is 0.1 to 10.0% by mass, relative to the mass of the core particle 1, the effects of the present invention (i.e., ensuring particle strength) can be achieved.

[0051] In Embodiment 2, the coating layer 2 only needs to contain cellulose nanofibers and may contain any other additives. Examples of such additives include those described in Embodiment 1.

[0052] Furthermore, in Embodiment 2, the "core particles" are those described in Embodiment 1.

[0053] <Embodiment 3> Embodiment 3 is shown in the lower part of Figure 1. In Embodiment 3, similar to Embodiment 2, the core particles 1 are covered with a coating layer 2. The coating layer 2 is composed solely of cellulose nanofibers. In Embodiment 3, the covering of the core particles 1 with the coating layer 2 has the effect of improving particle strength.

[0054] In Embodiment 3, the particles do not contain an intermediate layer 3. In this case, the cellulose nanofiber content is, for example, 0.1 to 10.0% by mass, preferably 0.4 to 9.0% by mass, more preferably 0.6 to 8.0% by mass, and even more preferably 0.8 to 7.0% by mass, relative to the mass of the core particle 1. When the cellulose nanofiber content is 0.1 to 10.0% by mass, relative to the mass of the core particle 1, the effects of the present invention (i.e., ensuring particle strength) can be achieved.

[0055] In Embodiment 3, the "core particle" is the same as that described in Embodiment 1.

[0056] [3. Composition] This composition contains the particles described in [2. Particles] (i.e., the particles described herein). Because this composition contains particles with ensured strength, the active ingredients contained in the core particles can be utilized more effectively.

[0057] This composition can be used for various purposes based on the active ingredients contained in the core particles. While not particularly limited, its uses may include pharmaceuticals, food products (e.g., functional foods, supplements), cosmetics, and the like.

[0058] In addition to the particles, this composition may contain various additives depending on the application. For example, if the application is pharmaceutical, the additives described in <Embodiment 1> may be used.

[0059] [4. Method for manufacturing particles] This manufacturing method is a method for producing particles in which core particles are coated with a coating layer, and includes the step of coating the core particles with a coating layer containing cellulose nanofibers. This manufacturing method ensures the strength of the particles by coating the core particles with a coating layer containing cellulose nanofibers.

[0060] In this manufacturing method, the method for coating the core particles with a coating layer is not particularly limited, and any method known in the art can be used.

[0061] In one embodiment of the present invention, the manufacturing method includes a step of coating core particles with an intermediate layer.

[0062] In another embodiment of the present invention, the present manufacturing method is a method for manufacturing particles in which core particles are coated with a coating layer, comprising the steps of coating the core particles with an intermediate layer, and coating the intermediate layer with a coating layer containing cellulose nanofibers.

[0063] In this method, the "core particles," "coating layer," "cellulose nanofibers," and "intermediate layer" are those described in [2. Particles].

[0064] [5. Methods for ensuring particle strength] This method is a method for ensuring the strength of particles in which core particles are coated with a coating layer, characterized in that the coating layer contains cellulose nanofibers. That is, the method includes the step of incorporating cellulose nanofibers into the coating layer. This method can ensure the strength of particles by incorporating cellulose nanofibers into the coating layer.

[0065] In this method, the method for incorporating cellulose nanofibers into the coating layer is not particularly limited, and any method known in the art can be used.

[0066] In this method, the "core particles," "coating layer," and "cellulose nanofibers" are those described in [2. Particles].

[0067] The present invention is not limited to the embodiments described above, and various modifications are possible within the scope of the claims. Embodiments obtained by appropriately combining the technical means disclosed in different embodiments are also included in the technical scope of the present invention.

[0068] (Invention 2) [6. Summary of the present invention] An orally disintegrating tablet according to one embodiment of the present invention (hereinafter referred to as "this orally disintegrating tablet") is characterized by having particles containing cellulose nanofibers with an average particle diameter of less than 10 μm.

[0069] Furthermore, the disintegrable particles according to one embodiment of the present invention (hereinafter referred to as "the disintegrable particles") are characterized by containing cellulose nanofibers with an average particle diameter of less than 10 μm.

[0070] Furthermore, a method for producing orally disintegrating tablets containing particles according to one embodiment of the present invention (hereinafter referred to as "this manufacturing method") is characterized by comprising a step of incorporating cellulose nanofibers with an average particle diameter of less than 10 μm into the particles.

[0071] In addition, a method for improving the physical properties of an orally disintegrating tablet containing particles according to one embodiment of the present invention (hereinafter referred to as "the Method") is characterized in that the particles contain cellulose nanofibers with an average particle diameter of less than 10 μm, and the physical properties are at least one of the following: (1) compression moldability, (2) disintegrability, (3) tablet compression failure, (4) tablet hardness after humidification, and (5) abrasion degree after humidification.

[0072] As described above, the orally disintegrating tablet described in Patent Document 1 had room for improvement in terms of its physical properties, particularly its compressibility, disintegration properties, tableting defects, tablet hardness after humidification, and abrasion rate after humidification.

[0073] Therefore, the inventors conducted thorough research and succeeded in obtaining the following findings. - By incorporating CNF with an average particle size of less than 10 μm into the particles constituting the orally disintegrating tablet, the physical properties of the orally disintegrating tablet (particularly its compressibility, disintegration properties, tablet compression defects, tablet hardness after humidification, and abrasion after humidification) are improved. The particles containing CNF may be disintegrating particles or drug particles, but disintegrating particles are preferred. If the particles have a core and a coating layer, it is preferable that the CNF is included in the coating layer.

[0074] Until now, it was not known that CNF is involved in various physical properties of orally disintegrating tablets containing CNF particles (particularly compression moldability, disintegration, tableting failure, tablet hardness after humidification, and abrasion after humidification). Therefore, it is surprising that the inventors focused on CNF for the purpose of improving the various physical properties of the orally disintegrating tablets and were able to improve these properties by incorporating CNF into the particles constituting the orally disintegrating tablets.

[0075] Thus, because this orally disintegrating tablet exhibits the advantageous effects based on the above findings, it can be applied to various active ingredients for orally disintegrating applications.

[0076] In this specification, the effects of one embodiment of the present invention (compression moldability, disintegration, tableting failure, tablet hardness after humidification, and abrasion degree after humidification) may be collectively referred to as "various physical properties."

[0077] [7. Orally disintegrating tablets] This orally disintegrating tablet is characterized by having particles containing CNF with an average particle size of less than 10 μm. By containing CNF with the aforementioned specific average particle size, this orally disintegrating tablet has the effect of improving various physical properties of the orally disintegrating tablet.

[0078] (CNF) The particles constituting this orally disintegrating tablet contain CNF. In this specification, "cellulose nanofiber (CNF)" means cellulose fibers with a fiber diameter of nanoscale, which are prepared by mechanically processing cellulose.

[0079] The average particle size of CNF is less than 10 μm, preferably 8.0 μm or less, more preferably 5.0 μm or less, and even more preferably 3.0 μm or less. By having an average particle size of CNF less than 10 μm, various physical properties of the orally disintegrating tablets can be improved. The lower limit of the average particle size of CNF is not particularly limited as long as the effects of the present invention are achieved, but for example, it is 1.0 μm or more, preferably 2.0 μm or more. The average particle size of CNF refers to the volume-based average particle size measured by a laser diffraction particle size analyzer.

[0080] The average fiber diameter of CNF is preferably 0.001 to 1 μm, more preferably 0.002 to 0.5 μm, even more preferably 0.005 to 0.2 μm, particularly preferably 0.01 to 0.1 μm, and most preferably 0.01 to 0.05 μm. An average fiber diameter of 0.001 to 1 μm for CNF can improve various physical properties of orally disintegrating tablets. The average fiber diameter of CNF refers to the average value of the fiber diameters measured for any 10 or more cellulose nanofibers in images acquired by a scanning probe microscope.

[0081] The average fiber length of CNF is preferably less than 10 μm, more preferably 5 μm or less, and even more preferably 2 μm or less. An average fiber length of less than 10 μm of CNF improves various physical properties of orally disintegrating tablets. The lower limit of the average fiber length of CNF is not particularly limited as long as the effects of the present invention are achieved, but is, for example, 0.5 μm or more, preferably 1.0 μm or more. The average fiber length of CNF is measured by image analysis.

[0082] The CNF content is, for example, 0.1 to 10.0% by mass, preferably 0.6 to 8.0% by mass, more preferably 0.8 to 5.0% by mass, and even more preferably 1.0 to 4.0% by mass, relative to the mass of the particles containing CNF (or, as described later, the total mass of the core and coating layer if the particles include a core and a coating layer). When the CNF content is 0.1 to 10.0% by mass relative to the mass of the particles containing CNF, various physical properties of the orally disintegrating tablets can be improved.

[0083] In one embodiment of the present invention, commercially available CNF (e.g., BiNFi-s manufactured by Sugino Machine Co., Ltd.) may be used as the CNF contained in the orally disintegrating tablet. Alternatively, CNF manufactured from commercially available CNF may be used as the CNF contained in the orally disintegrating tablet. The method for manufacturing the CNF contained in the orally disintegrating tablet is not particularly limited, but it can be manufactured, for example, by micronizing general CNF. For example, the CNF in one embodiment of the present invention can be manufactured by wet micronizing commercially available CNF (e.g., Ceolus® (manufactured by Asahi Kasei Corporation) PH grade) under high pressure conditions (e.g., 150 MPa) at a processing speed of 32 to 440 L / h.

[0084] (particle) The particles constituting this orally disintegrating tablet may be disintegrating particles, drug particles, or both. That is, in this orally disintegrating tablet, CNF may be contained in disintegrating particles, in drug particles, or in both. Furthermore, the disintegrating particles may or may not contain the drug.

[0085] The particles constituting this orally disintegrating tablet may contain additives other than CNF, such as excipients, binders, lubricants, disintegrants, surfactants, plasticizers, and colorants.

[0086] Excipients are not particularly limited, but examples include D-mannitol, lactose (e.g., lactose monohydrate), sucrose, corn starch, calcium phosphate, sorbitol, crystalline cellulose, and light anhydrous silicic acid. Preferably, D-mannitol, crystalline cellulose, and lactose (e.g., lactose monohydrate) are used.

[0087] The binder is not particularly limited, but examples include hydroxypropyl cellulose, hydroxypropyl methylcellulose (also called "hypromellose"), povidone, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, copolymers of N-vinylpyrrolidone and vinyl acetate, or combinations thereof, pregelatinized starch, gelatin, agar, and gum arabic. Hydroxypropyl cellulose and hypromellose are preferably used.

[0088] Lubricants are not particularly limited, but examples include inert substances such as talc, kaolin, and titanium dioxide; magnesium stearate, calcium stearate, stearic acid, light anhydrous silicic acid, finely ground silicon dioxide, sodium stearyl fumarate, and glycerin fatty acid esters. Preferably, magnesium stearate and glycerin fatty acid esters are used.

[0089] The disintegrant is not particularly limited, but examples include crospovidone, low-substituted hydroxypropylcellulose, sodium starch glycolate, croscarmellose sodium, carmellose, carmellose calcium, potato starch, etc. Crospovidone is preferably used.

[0090] The coloring agent is not particularly limited, but examples include yellow coloring agents (e.g., yellow iron oxide, yellow iron oxide, food yellow No. 4 aluminum lake, red iron oxide, etc.), red coloring agents (e.g., iron oxide, food red No. 2, food red No. 3, food red No. 102, etc.), black coloring agents (e.g., black iron oxide, carbon black, medicinal charcoal, etc.), blue coloring agents (e.g., blue No. 2 aluminum lake, etc.), caramel, etc. Preferably, iron oxide, yellow iron oxide, and blue No. 2 aluminum lake are used.

[0091] The content of each of the aforementioned additives is not particularly limited and can be appropriately determined by those skilled in the art based on conventionally known techniques.

[0092] In one embodiment of the present invention, the disintegrating particles may comprise a sugar alcohol and organic and inorganic hydrophilic and water-insoluble additives. The organic hydrophilic and water-insoluble additive preferably comprises at least one selected from the group consisting of starch, starch derivatives, and crospovidone. Examples of starch and starch derivatives include corn starch, potato starch, partially pregelatinized starch, and pregelatinized starch. Furthermore, the inorganic hydrophilic and water-insoluble additive preferably comprises light anhydrous silicic acid and / or magnesium aluminometasilicate. Examples of the sugar alcohol include erythritol, xylitol, sorbitol, mannitol, and lactitol.

[0093] In this embodiment, the sugar alcohol content is, for example, 55 to 85% by mass, preferably 65 to 75% by mass, relative to the mass of the disintegrating particles. In this embodiment, the content of the organic hydrophilic and water-insoluble additive is, for example, 10 to 40% by mass, preferably 18 to 32% by mass, relative to the mass of the disintegrating particles. Furthermore, in this embodiment, the content of the inorganic hydrophilic and water-insoluble additive is, for example, 0.3 to 55% by mass, preferably 0.5 to 3% by mass, relative to the mass of the disintegrating particles.

[0094] In one embodiment of the present invention, the particles constituting the orally disintegrating tablet have a core and a coating layer. In this embodiment, the core is covered by the coating layer. That is, the core is located inside the particle and the coating layer is located outside the particle.

[0095] In this embodiment, CNF may be included in the coating layer, in the core, or in both. From the viewpoint of further improving the various physical properties of the orally disintegrating tablet, it is preferable that CNF be included in the coating layer.

[0096] In this embodiment, the core and coating layer may contain the above-mentioned additives in addition to CNF. In one embodiment of the present invention, the core may contain mannitol and light anhydrous silicic acid, and the coating layer may contain corn starch, crospovidone, and CNF. In another embodiment of the present invention, the core may contain mannitol, light anhydrous silicic acid, and CNF, and the coating layer may contain corn starch and crospovidone.

[0097] In one embodiment of the present invention, the coating layer may be a single layer or a multi-layered layer. If the coating layer is a multi-layered layer, each coating layer may have a different function. The function of the coating layer is not particularly limited, but may be, for example, a bitterness masking agent, an enteric coating agent, a sustained-release agent, a moisture-proof agent, a light-resistant agent, a shielding agent, etc.

[0098] (Physical properties) The orally disintegrating tablet has improved compression moldability, disintegration properties, tablet compression problems, tablet hardness after humidification, and abrasion resistance after humidification. In one embodiment of the present invention, it is preferable that the orally disintegrating tablet has improved compression moldability, disintegration properties, tablet compression problems, tablet hardness after humidification, and abrasion resistance after humidification, and it is most preferable that all of them are improved.

[0099] In this specification, "compression moldability" refers to the property of powders or granules bonding together when pressure is applied to them, and means the ability to compress amorphous powders or granules into a specific shape, preferably achieving practical hardness at low pressure. Specifically, compression moldability is measured by the method described in the examples.

[0100] In this specification, "disintegration" refers to the ease with which a tablet disintegrates. Specifically, disintegration is measured by the method described in the examples.

[0101] In this specification, "tableting defect" refers to a malfunction such as sticking that occurs during the tableting process. Specifically, tableting defects are measured by the method described in the examples.

[0102] In this specification, "tablet hardness after humidification" refers to the hardness after storage for 7 days under conditions of 25°C and 75% relative humidity. Specifically, the tablet hardness after humidification is measured by the method described in the examples.

[0103] In this specification, "abrasion after humidification" refers to the abrasion after storage for 7 days under conditions of 25°C and 75% relative humidity. Specifically, the abrasion after humidification is measured by the method described in the examples.

[0104] [8. Decayable Particles] These disintegrating particles are characterized by containing CNF with an average particle diameter of less than 10 μm. By containing CNF with the aforementioned specific average particle diameter, these disintegrating particles have the effect of improving various physical properties of compositions containing these disintegrating particles.

[0105] These disintegrating particles can be used in various applications where disintegration within the oral cavity is required. Examples of applications for these disintegrating particles include pharmaceuticals, foods, and supplements.

[0106] In these disintegrating particles, the terms "particles," "orally disintegrating tablets," and "cellulose nanofiber (CNF)" are as defined in [7. Orally Disintegrating Tablets].

[0107] [9. Method for manufacturing orally disintegrating tablets] This manufacturing method is a method for producing orally disintegrating tablets containing particles, and includes a step of incorporating CNF with an average particle diameter of less than 10 μm into the particles. By incorporating CNF with an average particle diameter of less than 10 μm into the particles constituting the orally disintegrating tablets, the various physical properties of the orally disintegrating tablets can be improved.

[0108] In this manufacturing method, the method for incorporating CNF into the particles constituting the orally disintegrating tablet is not particularly limited, and any method known in the art can be used. In one embodiment of the present invention, the inclusion of CNF into the particles is performed by mixing the CNF with other components constituting the particles in any mixing apparatus.

[0109] In this manufacturing method, the "particles," "orally disintegrating tablets," and "cellulose nanofibers (CNF)" are as defined in [7. Orally Disintegrating Tablets].

[0110] [10. Methods for improving physical properties] This method is a method for improving the physical properties of orally disintegrating tablets containing particles, characterized in that the particles contain CNF with an average particle diameter of less than 10 μm. That is, the method comprises the step of containing CNF with an average particle diameter of less than 10 μm in the particles. The physical properties are at least one of (1) compression moldability, (2) disintegrability, (3) tableting failure, (4) tablet hardness after humidification, and (5) abrasion after humidification. This method can improve at least one of the physical properties (1) to (5) by containing CNF with an average particle diameter of less than 10 μm in the particles constituting the orally disintegrating tablet.

[0111] In this method, the method for incorporating CNF into the particles constituting the orally disintegrating tablet is not particularly limited, and any method known in the art can be used.

[0112] In this method, the terms "particles," "orally disintegrating tablets," and "cellulose nanofiber (CNF)," as well as the various physical properties (physical properties (1) to (5)) described above, are as those described in [7. Orally Disintegrating Tablets].

[0113] The present invention is not limited to the embodiments described above, and various modifications are possible within the scope of the claims. Embodiments obtained by appropriately combining the technical means disclosed in different embodiments are also included in the technical scope of the present invention. [Examples]

[0114] The present invention will be described in more detail below based on examples, but the present invention is not limited to these examples.

[0115] (Invention 1) [Measurement and evaluation methods] The evaluations in the examples and comparative examples were carried out using the following method.

[0116] (Leaching test) The average dissolution rates of particles (overcoat particles, masking particles) and tablets were measured according to the Japanese Pharmacopoeia dissolution test method, paddle method (rotation speed 75 rpm, dissolution test solution 2, 900 mL). For the particle dissolution test, to prevent adhesion and aggregation of particles during the dissolution test, disintegrable particles in an equal proportion to the particles were mixed in advance and placed in the test vessel. The dissolution rate was measured at a measurement wavelength of 288 nm using a fiber probe type ultraviolet-visible spectrophotometer.

[0117] (particle strength) Particle strength was measured using a micro-compression testing machine (MCT-210, manufactured by Shimadzu Corporation).

[0118] [Example 1] (Preparation of drug particles) A mixed powder containing levofloxacin hydrate (0.5 hydrate), hydroxypropyl cellulose (HPC-L (75 μm-106 μm), manufactured by Nippon Soda Co., Ltd.), and low-substituted hydroxypropyl cellulose (LH-31, manufactured by Shin-Etsu Chemical Co., Ltd.) was sprayed with a 50% (w / w) ethanol solution and granulated using a high-speed stirring mixer. The resulting granules were dried using a rolling fluidized bed granulator and then classified using sieves with mesh sizes of 250 μm and 75 μm to prepare drug particles (core particles).

[0119] (Preparation of masking particles) The obtained drug particles were placed in a rolling fluid bed granulator. Aminoalkyl methacrylate copolymer E (Eudragit E, manufactured by Evonik Corporation) was dissolved in a 90% (w / w) ethanol solution, and then talc (Microace P-3, manufactured by Nippon Talc Co., Ltd.) was dispersed in it. By spraying this solution onto the drug particles, Eudragit E and talc were coated, and masking particles (particles in which the core particle is covered with an intermediate layer) were prepared.

[0120] (Preparation of overcoat particles) The obtained masking particles were fed into a rolling fluid bed granulator. A 5% (w / v) aqueous dispersion of cellulose nanofibers (Binfis WFo-100 5%, average fiber diameter approximately 10-50 nm, fiber length approximately 10 μm or less, manufactured by Sugino Machine Co., Ltd.) (5% viscosity: 40,000 mPa·s) was diluted with water to a 1% (w / v) concentration, and then processed using a homogenizer at 10,000 rpm for 20 minutes. By spraying this solution, the masking particles were coated with cellulose nanofibers, and overcoat particles (particles in which the core particles are covered with an intermediate layer and a coating layer) were prepared. The amount of cellulose nanofiber coating was 2% by mass relative to the mass of the masking particles.

[0121] (Preparation of disintegrating particles) 71 parts by mass of D-mannitol (PEARLITOL 50C, manufactured by Rocket Japan Co., Ltd.), 2 parts by mass of ethylcellulose (Etocell Standard FP7CPS Premium, manufactured by DuPont Nutrition & Biosciences Co., Ltd.), and 1 part by mass of light anhydrous silicic acid (Adsolider-101, manufactured by Freund Industrial Co., Ltd.) were placed in a fluid bed granulator. A solution containing 20 parts by mass of corn starch (Corn Starch W, manufactured by Nippon Shokuhin Kako Co., Ltd.) and 6 parts by mass of crospovidone (Polyplasdon INF10, manufactured by ISP Japan Co., Ltd.) dispersed in 80 parts by mass of water was sprayed onto the granulator to granulate the particles. After granulation, the particles were dried and sized to obtain disintegrable particles.

[0122] (Tablet compression) The overcoat particles were mixed with disintegrating particles and magnesium stearate (plant-derived, manufactured by Taihei Chemical Industry Co., Ltd.), and then compressed into tablets at 7 kN using a hand tab. Dissolution tests were performed using the masking particles and the tablets.

[0123] The composition of each component is shown in Table 1.

[0124] [Table 1]

[0125] [Example 2] The preparation of masking particles was carried out using the same method as in Example 1.

[0126] (Preparation of overcoat particles) The obtained masking particles were fed into a rolling fluidized bed granulator. A 5% (w / v) aqueous dispersion of cellulose nanofibers (Binfis AFo-100 5%, average fiber diameter approximately 10-50 nm, fiber length approximately 0.5-1.0 μm, manufactured by Sugino Machine Co., Ltd.) (5% viscosity: 20,000 mPa·s) was diluted with water to a 1% (w / v) concentration, and then processed using a homogenizer at 10,000 rpm for 20 minutes. By spraying this solution, the masking particles were coated with cellulose nanofibers to prepare overcoat particles. The amount of cellulose nanofiber coating was 2% by mass relative to the mass of the masking particles.

[0127] Next, disintegrating particles were prepared and tablets were compressed using the same method as in Example 1. Dissolution tests were performed using the overcoat particles and tablets.

[0128] [Example 3] The preparation of masking particles was carried out using the same method as in Example 1. (Preparation of overcoat particles) The obtained masking particles were fed into a rolling fluidized bed granulator. A solution containing crystalline cellulose nanofiberized to a viscosity of 1000 mPa·s or more in a 2% (w / v) aqueous dispersion was diluted with water to a 1% (w / v) concentration, and then processed using a homogenizer at 10000 rpm for 20 minutes. By spraying this solution, the masking particles were coated with the crystalline cellulose nanofiberized, and overcoat particles were prepared. The amount of crystalline cellulose nanofiberized for coating was 2% by mass relative to the mass of the masking particles.

[0129] Next, disintegrating particles were prepared and tablets were compressed using the same method as in Example 1. Dissolution tests were performed using the overcoat particles and tablets.

[0130] [Comparative Example 1] The preparation of masking particles was carried out using the same method as in Example 1. However, the preparation of overcoat particles was not performed in this case.

[0131] Next, disintegrable particles were prepared using the same method as in Example 1.

[0132] (Tablet compression) Masking particles were mixed with disintegrating particles and magnesium stearate (plant-derived, manufactured by Taihei Chemical Industry Co., Ltd.), and then compressed into tablets at 7 kN using a hand tab. Dissolution tests were performed using the masking particles and tablets.

[0133] [Comparative Example 2] The preparation of masking particles was carried out using the same method as in Example 1.

[0134] (Preparation of overcoat particles) Overcoat particles were prepared by dissolving hydroxypropyl cellulose (HPC-SL, manufactured by Nippon Soda Co., Ltd.) in water to a concentration of 1% (w / v), and then spraying this solution onto masking particles to coat them with HPC-SL. The amount of HPC-SL coating was 2% by mass relative to the mass of the masking particles.

[0135] Next, disintegrating particles were prepared and tablets were compressed using the same method as in Example 1. Dissolution tests (RT-J2000, manufactured by Dainippon Seiki Co., Ltd.) were performed using the overcoat particles and tablets.

[0136] [Comparative Example 3] The preparation of masking particles was carried out using the same method as in Example 1.

[0137] (Preparation of overcoat particles) Ethyl cellulose (Etocel Standard FP7CPS Premium, manufactured by DuPont Nutrition & Biosciences, Inc.) was dissolved in 90% w / w ethanol to a concentration of 1% w / v. This solution was sprayed to coat masking particles with ethyl cellulose, thereby preparing overcoat particles. The amount of ethyl cellulose coating was 2% by mass relative to the mass of the masking particles.

[0138] Next, disintegrating particles were prepared and tablets were compressed using the same method as in Example 1. Dissolution tests were performed using the overcoat particles and tablets.

[0139] [Result-1] Figure 2 shows the results of dissolution tests performed on the particles (overcoat particles and masking particles) and tablets produced in Examples 1-3 and Comparative Examples 1-3 described above.

[0140] Comparing the examples and comparative examples in Figure 2, it can be seen that in Examples 1 to 3, the changes in dissolution behavior between particles and tablets are suppressed compared to Comparative Examples 1 to 3. Here, less change in dissolution behavior between particles and tablets means that cracking of the masking layer (intermediate layer) during tableting is prevented. Therefore, in a particle comprising a core particle, an intermediate layer, and a coating layer, the particle according to one embodiment of the present invention, in which the coating layer contains cellulose nanofibers, is shown to be able to prevent cracking of the intermediate layer during tableting (i.e., the strength of the particle is ensured).

[0141] [Example 4] Using the same method as in Example 1, the particle strength was measured using the obtained overcoat particles.

[0142] [Comparative Example 4] Drug particles were prepared using the same method as in Example 1. The particle strength was measured using the obtained drug particles.

[0143] [Comparative Example 5] The particle strength was measured using the masking particles obtained by the same method as in Comparative Example 1.

[0144] [Comparative Example 6] The particle strength was measured using the overcoat particles obtained by the same method as in Comparative Example 2.

[0145] [Comparative Example 7] The particle strength was measured using the obtained overcoat particles in the same manner as in Comparative Example 3.

[0146] [Example 5] The preparation of drug particles was carried out using the same method as in Example 1.

[0147] (Preparation of masking particles) The obtained drug particles were placed in a rolling fluidized bed granulator. A 5% (w / v) aqueous dispersion of cellulose nanofiber (Binfis WFo-100 5%, manufactured by Sugino Machine Co., Ltd.) was diluted with water to a 1% (w / v) concentration, and then processed using a homogenizer at 10,000 rpm for 20 minutes. By spraying this solution, the drug particles were coated with cellulose nanofiber, and masking particles (particles in which the core particle is covered with a coating layer) were prepared. The amount of cellulose nanofiber coating was 2% by mass relative to the mass of the drug particles.

[0148] The obtained masking particles were used to measure their particle strength.

[0149] [Comparative Example 8] Drug particles were prepared using the same method as in Example 1. The particle strength was measured using the obtained drug particles.

[0150] [Result-2] Figures 3 and 4 show the results of particle strength measurements for the particles (drug particles, masking particles, and overcoat particles) produced in Examples 4 and 5 and Comparative Examples 4 to 8 described above.

[0151] Figure 3 shows that in Example 4, the particle strength is higher compared to Comparative Examples 4 to 7. Therefore, in a particle comprising a core particle, an intermediate layer, and a coating layer, the particle according to one embodiment of the present invention, in which the coating layer contains cellulose nanofibers, is shown to have improved particle strength.

[0152] Furthermore, Figure 4 shows that the particle strength in Example 5 is higher than that of Comparative Example 8. Therefore, it has been shown that the particles according to one embodiment of the present invention, in which the core particles are coated with a coating layer composed of cellulose nanofibers, have improved particle strength.

[0153] [Example 6] The preparation of drug particles was carried out using the same method as in Example 1.

[0154] (Preparation of masking particles) The obtained drug particles were fed into a rolling fluid bed granulator. A 5% (w / v) aqueous dispersion of cellulose nanofibers (Binfis AFo-100 5%, manufactured by Sugino Machine Co., Ltd.) was diluted three-fold with ethanol, and then processed using a homogenizer at 10,000 rpm for 20 minutes to obtain a cellulose nanofiber-containing solution. Next, aminoalkyl methacrylate copolymer E (Eudragit E, manufactured by Evonik Co., Ltd.) was dissolved in an ethanol solution, and the cellulose nanofiber-containing solution was added to finally obtain an 80% (w / w) ethanol solution. By spraying this solution onto the drug particles, Eudragit E and cellulose nanofibers were coated, and masking particles were prepared.

[0155] Next, disintegrating particles were prepared and tablets were compressed using the same method as in Example 1. Dissolution tests were performed using the obtained masking particles and tablets. In addition, particle strength was measured using the obtained masking particles.

[0156] The composition of each component is shown in Table 2.

[0157] [Table 2]

[0158] [Comparative Example 9] The preparation of drug particles was carried out using the same method as in Example 1.

[0159] (Preparation of masking particles) The obtained drug particles were placed in a rolling fluid bed granulator. Aminoalkyl methacrylate copolymer E (Eudragit E, manufactured by Evonik Co., Ltd.) was dissolved in an 80% (w / w) ethanol solution, and then talc (Microace P-3, manufactured by Nippon Talc Co., Ltd.) was dispersed in it. By spraying this solution onto the drug particles, Eudragit E and talc were coated onto them, and masking particles (particles in which the core particle is covered with a coating layer) were prepared.

[0160] Next, disintegrating particles were prepared and tablets were compressed using the same method as in Example 1. Dissolution tests were performed using the obtained masking particles and tablets. In addition, particle strength was measured using the obtained masking particles.

[0161] [Result-3] Figures 5 and 6 show the results of measuring the dissolution rate and particle strength of the particles (masking particles) and tablets produced in Example 6 and Comparative Example 9 described above.

[0162] Figure 5 shows that in Example 6, the change in dissolution behavior between particles and tablets is suppressed compared to Comparative Example 9. Therefore, it has been shown that in a particle comprising a core particle and a coating layer, the particle according to one embodiment of the present invention, in which the coating layer contains cellulose nanofibers, can prevent cracking of the coating layer during tableting.

[0163] Furthermore, Figure 6 shows that the particle strength in Example 6 is higher than that of Comparative Example 9. Therefore, it has been shown that in particles comprising a core particle and a coating layer, the particles according to one embodiment of the present invention, in which the coating layer contains cellulose nanofibers, exhibit improved particle strength.

[0164] [Example 7] The preparation of drug particles was carried out using the same method as in Example 1.

[0165] (Preparation of masking particles) The obtained drug particles were placed in a rolling fluid bed granulator. Ammonioalkyl methacrylate copolymer RL and ammonioalkyl methacrylate copolymer RS ​​(Eudragit RL and RS, manufactured by Evonik Corporation) were dissolved in a 90% (w / w) ethanol solution, and then talc (Microace P-3, manufactured by Nippon Talc Co., Ltd.) was dispersed in the solution. Masking particles (particles in which the core particle is coated with an intermediate layer) were prepared by spraying this solution onto the drug particles.

[0166] (Preparation of overcoat particles) The obtained masking particles were fed into a rolling fluid bed granulator. A 2% (w / v) aqueous dispersion of cellulose nanofiber (Binfis WFo-100 2%, manufactured by Sugino Machine Co., Ltd.) (2% viscosity: 6000 mPa·s) was diluted with water to a 1% (w / v) concentration, and then processed using a homogenizer at 10000 rpm for 20 minutes. Overcoat particles (particles in which the core particles are covered with an intermediate layer and a coating layer) were prepared by spraying this solution. The amount of cellulose nanofiber coating was 2% by mass relative to the mass of the masking particles.

[0167] Next, disintegrating particles were prepared and tablets were compressed (compression pressure 11kN) using the same method as in Example 1. Dissolution tests were performed using the overcoat particles and tablets.

[0168] The composition of each component is shown in Table 3.

[0169] [Table 3]

[0170] [Comparative Example 10] The preparation of masking particles was carried out in the same manner as in Example 7. However, the preparation of overcoat particles was not performed in this case.

[0171] Next, disintegrating particles were prepared and tablets were compressed (compression pressure 11kN) using the same method as in Example 1. Dissolution tests were performed using the masking particles and tablets.

[0172] [Result-4] Figures 7 and 8 show the results of measuring the dissolution rate and particle strength of the particles (overcoat particles) and tablets produced in Example 7 and Comparative Example 10 described above.

[0173] Figure 7 shows that in Example 7, the change in dissolution behavior between particles and tablets is suppressed compared to Comparative Example 10. Therefore, it has been shown that particles according to one embodiment of the present invention, which include a core particle, an intermediate layer, and a coating layer, and in which the coating layer contains cellulose nanofibers, can prevent cracking of the coating layer during tableting.

[0174] Furthermore, Figure 8 shows that the particle strength in Example 7 is higher than that of Comparative Example 10. Therefore, it has been shown that in a particle comprising a core particle, an intermediate layer, and a coating layer, the particle according to one embodiment of the present invention, in which the coating layer contains cellulose nanofibers, exhibits improved particle strength.

[0175] [Example 8] The preparation of drug particles was carried out using the same method as in Example 1.

[0176] (Preparation of masking particles) The obtained drug particles were placed in a rolling fluid bed granulator. Ethyl cellulose (Etocell Standard FP7CPS Premium, manufactured by DuPont Nutrition & Biosciences Co., Ltd.) was dissolved in a 90% (w / w) ethanol solution, and then talc (Microace P-3, manufactured by Nippon Talc Co., Ltd.) and hydrated silicon dioxide (Adsolider-102, manufactured by Freund Industrial Co., Ltd.) were dispersed in it. This solution was sprayed onto the drug particles to prepare masking particles (particles in which the core particle is covered with a coating layer).

[0177] (Preparation of overcoat particles) The obtained masking particles were fed into a rolling fluid bed granulator. A 5% (w / v) aqueous dispersion of cellulose nanofiber (Binfis AFo-100 5%, manufactured by Sugino Machine Co., Ltd.) (5% viscosity: 20,000 mPa·s) was diluted with water to a 1% (w / v) concentration, and then processed using a homogenizer at 10,000 rpm for 20 minutes. Overcoat particles (particles in which the core particle is covered with an intermediate layer and a coating layer) were prepared by spraying this solution onto the masking particles. The amount of cellulose nanofiber coating was 2% by mass relative to the mass of the masking particles.

[0178] Next, disintegrating particles were prepared and tablets were compressed (compression pressure 7kN) using the same method as in Example 1. Dissolution tests were performed using the overcoat particles and tablets.

[0179] The composition of each component is shown in Table 4.

[0180] [Table 4]

[0181] [Comparative Example 11] The preparation of masking particles was carried out in the same manner as in Example 8. However, the preparation of overcoat particles was not performed in this case.

[0182] Next, disintegrating particles were prepared and tablets were compressed (compression pressure 7kN) using the same method as in Example 1. Dissolution tests were performed using the overcoat particles and tablets.

[0183] [Result-5] Figures 9 and 10 show the results of measuring the dissolution rate and particle strength of the particles (overcoat particles) and tablets produced in Example 8 and Comparative Example 11 described above.

[0184] Figure 9 shows that in Example 8, the change in dissolution behavior between particles and tablets is suppressed compared to Comparative Example 11. Therefore, it has been shown that particles according to one embodiment of the present invention, which include a core particle, an intermediate layer, and a coating layer, and in which the coating layer contains cellulose nanofibers, can prevent cracking of the coating layer during tableting.

[0185] Furthermore, Figure 10 shows that the particle strength in Example 8 is higher than that of Comparative Example 11. Therefore, it has been shown that in a particle comprising a core particle, an intermediate layer, and a coating layer, the particle according to one embodiment of the present invention, in which the coating layer contains cellulose nanofibers, exhibits improved particle strength.

[0186] (Invention 2) 〔material〕 (CNF) <CNF used in the examples> CNF-1: Average particle size 2.0 μm, average fiber diameter approximately 10 nm, average fiber length less than 10 μm. Crystalline cellulose (Ceolus® (manufactured by Asahi Kasei Corporation), grade PH-101, average particle size 77 μm, average fiber diameter approximately 50 μm, average fiber length approximately 150 μm) was dispersed in water at a concentration of 2% (w / v), and then processed 30 times in a wet atomization device (Starburst Labo, Sugino Machine Co., Ltd.) to produce an aqueous CNF dispersion. • CNF-2: BiNFi-s (manufactured by Sugino Machine Co., Ltd.), Grade: Short chain, Average particle size: 2.9 μm, Average fiber diameter: approx. 10-50 nm, Average fiber length: 0.5-1.0 μm. • CNF-3: BiNFi-s (manufactured by Sugino Machine Co., Ltd.), Grade: Ultra-short chain, Average particle diameter: 2.5 μm, Average fiber diameter: Approximately 10-50 nm, Average fiber length: Less than 0.5 μm.

[0187] <Cellulose used in the comparative example> • Microfibrillated cellulose: Celish (manufactured by Daicel Corporation), Grade FD200L, average particle size 11.1 μm, average fiber diameter approximately 0.1-1.0 μm, average fiber length over 10 μm. This is the microfibrous cellulose used in the examples of International Publication No. 2015 / 163135. • Crystalline cellulose: Ceolus, Grade PH-101 (manufactured by Asahi Kasei Corporation) • Ethylcellulose: EtCell Standard 7FP Premium (manufactured by DuPont Nutrition & Biosciences Co., Ltd.) [Measurement and evaluation methods] The evaluations in the examples and comparative examples were carried out using the following method.

[0188] (Average particle size) A CNF-containing aqueous dispersion was prepared to have a solid content of 0.125-0.5%. After preparation, the dispersion was treated with an ultrasonic homogenizer (UD-200, manufactured by Tommy Seikou Co., Ltd.) for 5-10 minutes until the fibers were uniformly dispersed. The treated solution was then measured using a laser diffraction particle size analyzer (MS3000, manufactured by Malvern) equipped with a wet dispersion unit (Hydro MV, manufactured by Malvern). The measurement solution was circulated for 30 seconds at a pump speed of 3500 rpm while irradiating with ultrasound, then the ultrasound and pump were stopped, and the average particle size was measured. The measurement solution was circulated again, and the same measurement was performed to obtain the average particle size.

[0189] (Average fiber diameter) A scanning probe microscope was used to observe the morphology of CNF and measure its fiber diameter. As a pretreatment of the observation sample, a sheet of dried CNF aqueous dispersion was fixed to a sample holder. A minute probe was then brought into contact with the sample surface and scanned to observe and analyze the surface microstructure (fiber diameter, etc.) with nano-order resolution.

[0190] (Compression moldability) The hardness of the tablets was measured using a hardness tester (manufactured by ERWEKA), and their compressibility was evaluated.

[0191] (Collapse-like) In accordance with the disintegration test method (immediately disintegrating preparations) of the 18th revised Japanese Pharmacopoeia, a disintegration test was conducted without an auxiliary disc, and the disintegration time when the tablets disintegrated was measured.

[0192] (Tablet hardness after humidification) After storage for 7 days under conditions of 25°C and 75% relative humidity, the tablet hardness was measured using a hardness tester (manufactured by ERWEKA).

[0193] (Degree of wear after humidification) After being stored for 7 days under conditions of 25°C and 75% relative humidity, the degree of abrasion was measured using an abrasion tester (manufactured by Toyama Sangyo Co., Ltd.).

[0194] (Tablet compression disorder) Tablets were continuously compressed using a rotary tablet press, and the appearance of the tablets and any powder residue on the punches and dies were visually inspected. Specifically, after 20 minutes of compression, the punches of the rotary tablet press were visually inspected, and the clouding (powder residue) of the punches was evaluated. The evaluation criteria were as follows:

[0195] (Evaluation Criteria) A: No powder residue. B: A thin layer of powder is attached, resulting in a cloudy appearance (the surface of the pestle lacks its metallic luster). C: The powder adhesion is clearly visible.

[0196] (particle strength) Particle strength was measured using a micro-compression testing machine (MCT-210, manufactured by Shimadzu Corporation).

[0197] [Example 1-1] A mixed powder containing olmesartan medoxomil, hydroxypropyl cellulose (HPC-M, manufactured by Nippon Soda Co., Ltd.), and lactose monohydrate (Fine Powder, manufactured by DFE Pharma Co., Ltd.) was sprayed with purified water and granulated using a high-speed agitator. The resulting granules were dried using a fluidized bed granulator (MP-01, manufactured by Powrec Co., Ltd.), and then classified using sieves with mesh sizes of 250 μm and 75 μm to prepare drug particles.

[0198] Next, 71 parts by mass of D-mannitol (PEARLITOL 50C, manufactured by Rocket Japan Co., Ltd.) and 1 part by mass of light anhydrous silicic acid (Adsolider-101, manufactured by Freund Industrial Co., Ltd.) were added to a fluidized bed granulator. Water was added to CNF-1 to a concentration of 1.25% (w / v) to dilute it, and then it was treated in a homogenizer at 10,000 rpm for 20 minutes (2 parts by mass as CNF). In this liquid, 20 parts by mass of corn starch (Corn Starch W, manufactured by Nippon Shokuhin Kako Co., Ltd.) and 6 parts by mass of crospovidone (Polyplasdone INF10, manufactured by ISP Japan Co., Ltd.) were dispersed in water, and this liquid was sprayed and granulated. After drying, it was classified at 30M to obtain disintegrable particles.

[0199] Subsequently, drug particles, disintegrating particles, aspartame (manufactured by Ajinomoto Co., Inc.), light anhydrous silicic acid (Adsolider-101, manufactured by Freund Industrial Co., Ltd.), and magnesium stearate (plant-derived, manufactured by Taihei Chemical Industry Co., Ltd.) were mixed and compressed using a rotary tablet press to obtain tablets with a diameter of 10 mm (punch: with markings and score lines). The obtained tablets were measured for compression moldability, disintegration, tablet hardness after humidification, abrasion after humidification, and tableting defects.

[0200] The composition of each component is shown in Table 5.

[0201] [Table 5]

[0202] [Example 2-1] Particles and tablets were prepared in the same manner as in Example 1-1, except that the CNF content was changed from 5.28 mg (2% by mass) to 2.64 mg (1% by mass). The resulting tablets were measured for their compressibility, disintegration, hardness after humidification, and abrasion after humidification.

[0203] [Example 3-1] Particles and tablets were prepared in the same manner as in Example 1-1, except that the CNF content was changed from 5.28 mg (2% by mass) to 10.56 mg (4% by mass). The resulting tablets were measured for their compressibility, disintegration, hardness after humidification, and abrasion after humidification.

[0204] [Example 4-1] Tablets were manufactured in the same manner as in Example 1-1, except that the type of CNF was changed from "CNF-1" to "CNF-2". The resulting tablets were measured for their compressibility, disintegration properties, hardness after humidification, abrasion after humidification, and tableting defects.

[0205] [Example 5-1] Tablets were manufactured in the same manner as in Example 1-1, except that the type of CNF was changed from "CNF-1" to "CNF-3". Disintegration properties, tablet hardness after humidification, abrasion degree after humidification, and tableting defects were measured for the obtained tablets.

[0206] [Example 6-1] Tablets were manufactured in the same manner as in Example 1-1, except that the punch was changed from one with markings to one without during tableting using a rotary tablet press. The resulting tablets were measured for their compressibility and disintegration properties.

[0207] [Example 7-1] A mixed powder containing olmesartan medoxomil, hydroxypropyl cellulose (HPC-M, manufactured by Nippon Soda Co., Ltd.), and lactose monohydrate (Fine Powder, manufactured by DFE Pharma Co., Ltd.) was sprayed with purified water and granulated using a high-speed agitator. The resulting granules were dried using a fluidized bed granulator (MP-01, manufactured by Powrec Co., Ltd.), and then classified using sieves with mesh sizes of 250 μm and 75 μm to prepare drug particles.

[0208] Next, 71 parts by mass of D-mannitol (PEARLITOL 50C, manufactured by Rocket Japan Co., Ltd.) and 1 part by mass of light anhydrous silicic acid (Adsolider-101, manufactured by Freund Industrial Co., Ltd.) were placed in a fluidized bed granulator. Water was added to CNF-1 to a concentration of 1.25% (w / v) to dilute it, and then it was treated in a homogenizer at 10,000 rpm for 20 minutes (2 parts by mass as CNF). This liquid was sprayed and granulated, and then dried. 20 parts by mass of corn starch (Corn Starch W, manufactured by Nippon Shokuhin Kako Co., Ltd.) and 6 parts by mass of crospovidone (Polyplasdon INF10, manufactured by ISP Japan Co., Ltd.) were dispersed in water in this granule, and this liquid was sprayed and granulated, then dried, and classified at 30M to obtain disintegrable particles.

[0209] Subsequently, drug particles, disintegrating particles, aspartame (manufactured by Ajinomoto Co., Inc.), light anhydrous silicic acid (Adsolider-101, manufactured by Freund Industrial Co., Ltd.), and magnesium stearate (plant-derived, manufactured by Taihei Chemical Industry Co., Ltd.) were mixed and compressed using a rotary tablet press to obtain tablets with a diameter of 10 mm (punch: no markings, with a score line). The compressibility and disintegration properties of the obtained tablets were measured.

[0210] [Example 8-1] Cilostazol and D-mannitol (PEARLITOL 50C, manufactured by Rocket Japan Co., Ltd.) were placed in a fluidized bed granulator. Water was added to CNF-1 to a concentration of 1.25% (w / v) and diluted, then homogenized at 10,000 rpm for 20 minutes (2 parts by mass as CNF). Corn starch (Corn Starch W, manufactured by Nippon Shokuhin Kako Co., Ltd.) and crospovidone (Polyplasdone INF10, manufactured by ISP Japan Co., Ltd.) were dispersed in water in this solution, and the solution was sprayed and granulated. After drying, it was classified at 30M to obtain drug particles.

[0211] Subsequently, drug particles, crystalline cellulose (PH101, manufactured by Asahi Kasei Corporation), talc (Microace P-3, manufactured by Nippon Talc Co., Ltd.), aspartame (manufactured by Ajinomoto Co., Inc.), light anhydrous silicic acid (Adsolider-101, manufactured by Freund Industrial Co., Ltd.), and magnesium stearate (plant-derived, manufactured by Taihei Chemical Industry Co., Ltd.) were mixed and compressed using a rotary tablet press to obtain tablets with a diameter of 7 mm (punch: with markings and score lines). The compressibility and disintegration properties of the obtained tablets were measured.

[0212] The composition of each component is shown in Table 6.

[0213] [Table 6]

[0214] [Comparative Example 1-1] A mixed powder containing olmesartan medoxomil, hydroxypropyl cellulose (HPC-M, manufactured by Nippon Soda Co., Ltd.), and lactose monohydrate (Fine Powder, manufactured by DFE Pharma Co., Ltd.) was sprayed with purified water and granulated using a high-speed agitator. The resulting granules were dried using a fluidized bed granulator (MP-01, manufactured by Powrec Co., Ltd.), and then classified using sieves with mesh sizes of 250 μm and 75 μm to prepare drug particles.

[0215] Next, 71 parts by mass of D-mannitol (PEARLITOL 50C, manufactured by Rocket Japan Co., Ltd.), 2 parts by mass of ethylcellulose (Etocell Standard FP7CPS Premium, manufactured by DuPont Nutrition & Biosciences Co., Ltd.), and 1 part by mass of light anhydrous silicic acid (Adsolider-101, manufactured by Freund Industrial Co., Ltd.) were added to a fluidized bed granulator. 20 parts by mass of corn starch (Corn Starch W, manufactured by Nippon Shokuhin Kako Co., Ltd.) and 6 parts by mass of crospovidone (Polyplasdon INF10, manufactured by ISP Japan Co., Ltd.) were dispersed in purified water. This liquid was sprayed and granulated, then dried and classified at 30M to obtain disintegrable particles.

[0216] Subsequently, drug particles, disintegrating particles, aspartame (manufactured by Ajinomoto Co., Inc.), light anhydrous silicic acid (Adsolider-101, manufactured by Freund Industrial Co., Ltd.), and magnesium stearate (plant-derived, manufactured by Taihei Chemical Industry Co., Ltd.) were mixed and compressed using a rotary tablet press to obtain tablets with a diameter of 10 mm (punch: with markings and score lines). The obtained tablets were measured for compression moldability, disintegration, tablet hardness after humidification, abrasion after humidification, and tableting defects.

[0217] [Comparative Example 2-1] Tablets were manufactured in the same manner as in Example 1-1, except that the type of CNF was changed from "CNF-1" to "crystalline cellulose". The resulting tablets were measured for particle size distribution, compressibility, disintegration, tablet hardness after humidification, abrasion after humidification, and tableting defects.

[0218] [Comparative Example 3-1] Tablets were manufactured in the same manner as in Example 1-1, except that the type of CNF was changed from "CNF-1" to "microfibrillated cellulose". The resulting tablets were measured for particle size distribution, compressibility, disintegration, tablet hardness after humidification, abrasion after humidification, and tableting defects.

[0219] [Comparative Example 4-1] Tablets were manufactured using the same method as in Comparative Example 1, except that the punch was changed from one with markings to one without, during tableting with a rotary tablet press. The resulting tablets were then measured for compression moldability and disintegration properties.

[0220] [Comparative Example 5-1] Cilostazol, D-mannitol (PEARLITOL 50C, manufactured by Rocket Japan Co., Ltd.), and ethyl cellulose (Ethocel Standard FP7CPS Premium, manufactured by DuPont Nutrition & Biosciences Co., Ltd.) were charged into a fluidized bed granulator. Corn starch (Corn Starch W, manufactured by Nihon Shokuhin Kako Co., Ltd.) and crospovidone (Polyplasdone INF10, manufactured by ISP Japan Co., Ltd.) were dispersed in purified water, this liquid was sprayed to perform granulation, followed by drying, and classification with 30M mesh to obtain drug particles.

[0221] Thereafter, the drug particles, crystalline cellulose (PH101, manufactured by Asahi Kasei Corporation), talc (Microace P-3, manufactured by Nippon Talc Co., Ltd.), aspartame (manufactured by Ajinomoto Co., Inc.), light anhydrous silicic acid (Adsolider 101, manufactured by Freund Corporation), and magnesium stearate (plant-derived, manufactured by Taihei Chemical Industrial Co., Ltd.) were mixed, and the mixture was compressed into tablets with a rotary tableting machine to a practical hardness, to obtain tablets having a diameter of 7 mm (punch: with marking, with score line). The obtained tablets were measured for compressibility, disintegration property, and tableting troubles.

[0222] [Example 9-1] (Preparation of Drug Particles) A CNF aqueous dispersion (CNF-1 described in <CNF Used in Examples>) was sprayed onto a mixed powder containing levofloxacin hydrate (0.5 hydrate), hydroxypropyl cellulose (HPC-L FP (75 µm - 106 µm), manufactured by Nippon Soda Co., Ltd.), and low-substituted hydroxypropyl cellulose (LH-31, manufactured by Shin-Etsu Chemical Co., Ltd.), followed by granulation using a high-speed stirring mixer. The obtained granulated product was dried using a tumbling fluidized bed granulator, and then classified with sieves having openings of 250 µm and 75 µm to prepare drug particles.

[0223] Subsequently, particle strength was measured using the obtained drug particles.

[0224] The composition of each component is shown in Table 7.

[0225] [Table 7]

[0226] [Comparative Example 6-1] Drug particles were prepared in the same manner as in Example 9-1, except that water was used instead of the CNF aqueous dispersion.

[0227] Next, the particle strength was measured using the obtained drug particles.

[0228] [Example 10-1] (Preparation of drug particles) A mixed powder containing levofloxacin hydrate (0.5 hydrate), hydroxypropyl cellulose (HPC-L FP, manufactured by Nippon Soda Co., Ltd.), crystalline cellulose (Ceolus PH101, manufactured by Asahi Kasei Corporation), and carmellose (NS-300, manufactured by Nichirin Chemical Industry Co., Ltd.) was mixed with a CNF aqueous dispersion (CNF-1 as described in <CNF used in the examples>) and granulated using a high-speed stirring mixer. The resulting granules were dried using a rolling fluidized bed granulator and then classified using a sieve with a screen diameter of 1143 mm to sizing the drug particles.

[0229] Subsequently, drug particles, croscarmellose sodium (Ac-Di-Sol, manufactured by DuPont Inc.), and magnesium stearate (plant-derived, manufactured by Taihei Chemical Industry Co., Ltd.) were mixed, and then compressed into tablets using a rotary tablet press with an oval punch (long diameter 8.1 mm, short diameter 4.7 mm) to achieve a practical hardness, thereby obtaining tablets.

[0230] The composition of each component is shown in Table 8.

[0231] [Table 8]

[0232] [Comparative Example 7-1] Drug particles were prepared in the same manner as in Example 10-1, except that water was used instead of a CNF aqueous dispersion. Subsequently, tablets were obtained using the obtained drug particles in the same manner as in Example 10-1. The compressibility, disintegration properties, and tableting defects of the obtained tablets were measured.

[0233] 〔result〕 The results are shown in Figures 11 to 18. As shown in Figure 11, the CNF-1 used in the examples was fine. Here, we attempted to measure the average fiber length of CNF-1 using Valmet FS5 (detection sensitivity of 10 μm or more), which is the successor to FS-200 described in Japanese Patent Publication No. 2009-203559, but it was below the detection limit and could not be measured. Furthermore, from the image data in Figure 11, it was estimated that the average fiber length of CNF-1 was less than 10 μm.

[0234] Figures 12 and 13 show that the examples exhibited superior compression moldability and disintegration properties compared to the comparative examples. Furthermore, the examples were found to be superior to the comparative examples in terms of tablet hardness after humidification and abrasion resistance after humidification. Among the examples, Example 3-1, which had a higher CNF content, showed the shortest disintegration time.

[0235] Figures 14 and 15 show that tablets with shorter average fiber lengths of CNF (especially those less than 10 μm) exhibit superior disintegration, tablet hardness after humidification, and abrasion resistance after humidification.

[0236] Figure 16 shows that Examples 6-1 and 7-1 exhibited superior compression moldability and disintegration properties compared to Comparative Example 4-1. Furthermore, among the examples, Example 6-1, which had a higher proportion of CNF on the particle surface, showed the shortest disintegration time.

[0237] Table 9 shows the results of the evaluation of tableting defects. Sticking (powder adhesion) did not occur in Examples 1-1, 4-1, 5-1, and 8-1, whereas sticking occurred in Comparative Examples 1-1, 2-1, 3-1, and 5-1.

[0238] [Table 9]

[0239] From the above results, it was shown that the present orally disintegrating tablet has improved at least one of compression moldability, disintegration property, tableting trouble, tablet hardness after humidification, and friability after humidification.

[0240] From FIG. 17, it was found that even when the drug particles contain CNF, the examples are superior in disintegration property compared with the comparative examples.

[0241] Further, from FIG. 18, it can be seen that Example 9-1 has higher particle strength than Comparative Example 6-1. Therefore, it was shown that the particle according to one embodiment of the present invention comprising a drug and CNF having an average particle diameter of less than 10 µm has improved particle strength.

[0242] Furthermore, from Table 10 below, it was found that Example 10-1 has comparable hardness, but is superior in disintegration property and tableting trouble compared with Comparative Example 7-1. Therefore, it was found that a tablet comprising the particle according to one embodiment of the present invention comprising a drug and CNF having an average particle diameter of less than 10 µm is excellent in compression moldability, disintegration property, and tableting trouble.

[0243] [Table 10] [Industrial Applicability]

[0244] (Invention 1) Since the strength of the present particles is ensured, they are suitably used in various fields where particles are used, for example, in the fields of medicine, food, cosmetics, and the like.

[0245] (Invention 2) Since various physical properties of the present orally disintegrating tablet are improved, it is suitably used in the fields where orally disintegrating tablets are used, for example, in the fields of medicine and food. [Description of Symbols]

[0246] 1 core particle 2 Coating layer 3. Middle Class

Claims

1. The core particles are covered with a coating layer, The coating layer contains cellulose nanofibers, An intermediate layer is included between the core particles and the coating layer. Particles characterized in that the intermediate layer contains an aminoalkyl methacrylate copolymer, an ammoniaalkyl methacrylate copolymer, or ethylcellulose.

2. The particle according to claim 1, characterized in that the intermediate layer further contains a lubricant.

3. The particle according to claim 1, characterized in that the coating layer does not contain any additives other than the cellulose nanofibers.

4. The particle according to claim 2, wherein the average fiber diameter of the cellulose nanofibers is less than 1 μm.

5. The particle according to claim 1, wherein the average fiber diameter of the cellulose nanofibers is less than 1 μm.

6. A composition comprising the particles described in any one of claims 1 to 5.

7. The composition according to claim 6, wherein the use of the composition is at least one selected from the group consisting of pharmaceuticals, food products, and cosmetics.

8. A method for producing particles in which core particles are covered with a coating layer, and an intermediate layer is placed between the core particles and the coating layer, The process includes coating the core particles with an intermediate layer and coating them with a coating layer containing cellulose nanofibers. A method comprising an aminoalkyl methacrylate copolymer, an ammoniaalkyl methacrylate copolymer, or ethylcellulose in the intermediate layer.

9. A method for ensuring the strength of particles in which a core particle is coated with an intermediate layer and a coating layer, The coating layer comprises a step of incorporating cellulose nanofibers, A method characterized in that the intermediate layer comprises an aminoalkyl methacrylate copolymer, an ammoniaalkyl methacrylate copolymer, or ethylcellulose.

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