Particle and use thereof

Abstract

To provide a particle in which the strength of a core particle coated with a coating layer is secured. In addition, the present invention provides an orally disintegrating tablet or the like having improved physical properties (particularly, compression moldability, disintegratability, tableting difficulty, tablet hardness after humidification, and abrasion loss after humidification).SOLUTION: In the particles according to the present disclosure, a core particle is coated with a coating layer, and the coating layer contains cellulose nanofibers. The orally disintegrating tablet according to the present disclosure has particles containing cellulose nanofibers having an average particle size of less than 10 μm.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] (Invention 1) The present invention relates to particles 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 particles in which core particles are covered with a coating layer.

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

[0003] (Invention 1) Core particles have problems such as the possibility of bitterness depending on the type of active ingredient contained therein, and the fact that they may not be stable enough on their own. Therefore, functional coating technology for coating core particles is being developed with the aim of improving the bitterness and stability of the active ingredient.

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

[0005] (Invention 2) Tablets can be difficult to take for elderly and pediatric patients who have difficulty swallowing, as well as for patients on fluid restrictions. Orally disintegrating tablets (also called "orally disintegrating preparations: OD tablets") are applicable to such patients and are therefore useful for formulating various active ingredients.

[0006] Orally disintegrating tablets have different properties from ordinary tablets, and technical development is being carried out from different perspectives than ordinary tablets (e.g., compression moldability, disintegrability in the oral cavity, etc.). For example, Patent Document 2 describes a disintegrating particle composition used in orally disintegrating tablets, which contains 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 Summary of the Invention [Problem to be solved by the invention]

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

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

[0010] (Invention 2) However, the orally disintegrating tablet described in Patent Document 1 has room for improvement in terms of its physical properties, particularly compression moldability, disintegrability, tableting trouble, tablet hardness after humidification, and friability after humidification.

[0011] Therefore, an object of one aspect of the present invention is to provide an orally disintegrating tablet having improved physical properties, and disintegrating particles used in the orally disintegrating tablet, etc. Another object of the present invention is to provide a method for producing an orally disintegrating tablet having 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 extensive research to solve the above problems, the inventors discovered for the first time that the strength of core particles can be ensured by coating the core particles with a coating layer containing cellulose nanofibers, and thus completed the present invention. That is, one aspect of the present invention includes the following configuration. <1> The core particles are coated with a coating layer, The particles, wherein the coating layer contains cellulose nanofibers. <2> An intermediate layer is included between the core particle and the coating layer. <1> The particle according to claim 1. <3> The coating layer does not contain any additives other than the cellulose nanofibers. <1> or <2> The particle according to claim 1. <4> The average fiber diameter of the cellulose nanofibers is less than 1 μm. <1> ~ <3> 1. The particle according to any one of the preceding items. <5> <1> ~ <4> A composition comprising the particles according to any one of the preceding items. <6> The composition is used for at least one purpose selected from the group consisting of medicine, food, and cosmetics. <5> The composition described in <7> A method for producing particles in which a core particle is covered with a coating layer, comprising the steps of: The method comprises a step of coating the core particles with a coating layer comprising cellulose nanofibers. <8> A method for ensuring the strength of a particle in which a core particle is covered with a coating layer, comprising the steps of: A method comprising a step of incorporating cellulose nanofibers into the coating layer.

[0013] (Invention 2) As a result of extensive research to solve the above problems, the present inventors discovered for the first time that the physical properties of orally disintegrating tablets (particularly compression moldability, disintegrability, tableting trouble, tablet hardness after humidification, and friability after humidification) are improved by incorporating cellulose nanofibers (hereinafter also referred to as "CNF") having an average particle size of less than 10 μm into the particles that make up the orally disintegrating tablet, and have thus completed the present invention. That is, one aspect of the present invention encompasses the following configuration. <9> An orally disintegrating tablet characterized by having particles containing cellulose nanofibers with an average particle size of less than 10 μm. <10> The particles are disintegrating particles. <9> The orally disintegrating tablet according to claim 1. <11> The cellulose nanofibers have an average fiber diameter of 0.001 to 1 μm. <9> or <10> The orally disintegrating tablet according to claim 1. <12> the particle has a core and a coating layer; The cellulose nanofibers are contained in the coating layer. <9> or <10> The orally disintegrating tablet according to claim 1. <13> the disintegrating particles contain a sugar alcohol and organic and inorganic hydrophilic and water-insoluble additives; the 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 comprises light anhydrous silicic acid and / or magnesium aluminometasilicate. <10> The orally disintegrating tablet according to claim 1. <14> An orally disintegrating tablet comprising cellulose nanofibers having an average fiber length of less than 10 μm. <15> Disintegrable particles, characterized by containing cellulose nanofibers having an average particle diameter of less than 10 μm. <16> Particles comprising a drug and cellulose nanofibers with an average particle size of less than 10 μm. <17> 1. A method for producing an orally disintegrating tablet comprising the steps of: The production method includes a step of making the particles contain cellulose nanofibers having an average particle diameter of less than 10 μm. <18> 1. A method for improving the physical properties of an orally disintegrating tablet comprising particles, The method is characterized by including a step of making the particles contain cellulose nanofibers having an average particle diameter of less than 10 μm, wherein the physical property is at least one of the following physical properties: (1) Compression moldability, (2) Collapsibility, (3) Tableting disorders, (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, it is possible to provide a particle having a core particle coated with a coating layer and having ensured strength. Also, according to another aspect of the present invention, it is possible to provide a method for ensuring the strength of a particle having a core particle coated with a coating layer.

[0015] (Invention 2) According to one aspect of the present invention, it is possible to provide an orally disintegrating tablet having improved physical properties (particularly, compression moldability, disintegrability, tableting trouble, tablet hardness after humidification, and friability after humidification), as well as disintegrating particles used in the orally disintegrating tablet, etc. Furthermore, according to another aspect of the present invention, it is possible to provide a method for producing an orally disintegrating tablet having the above-mentioned physical properties, and a method for improving the above-mentioned physical properties in an orally disintegrating tablet. [Brief explanation of the drawings]

[0016] [Figure 1] FIG. 1 is a schematic diagram showing a particle according to one embodiment of the present invention in (Invention 1). [Figure 2] FIG. 1 shows the results of dissolution tests using particles and tablets in Examples 1 to 3 and Comparative Examples 1 to 3. [Figure 3] FIG. 1 is a graph showing the results of measuring particle strength using particles in Example 4 and Comparative Examples 4 to 7. [Figure 4] FIG. 10 is a graph showing the results of measuring particle strength using particles in Example 5 and Comparative Example 8. [Figure 5] FIG. 1 shows the results of dissolution tests using particles and tablets in Example 6 and Comparative Example 9. [Figure 6] FIG. 10 is a graph showing the results of measuring particle strength using particles in Example 6 and Comparative Example 9. [Figure 7] FIG. 1 shows the results of dissolution tests using particles and tablets in Example 7 and Comparative Example 10. [Figure 8] FIG. 10 is a graph showing the results of measuring particle strength using particles in Example 7 and Comparative Example 10. [Figure 9] FIG. 1 shows the results of dissolution tests using particles and tablets in Example 8 and Comparative Example 11. [Figure 10] FIG. 10 is a graph showing the results of measuring particle strength using particles in Example 8 and Comparative Example 11. [Figure 11] These are photographs of the CNF (CNF-1) used in the examples of (Invention 2) taken with a scanning electron microscope (JSM-IT200, top two rows) and a scanning probe microscope (SPM-Nanoa, bottom row). [Figure 12] FIG. 1 is a diagram showing the relationship between tableting pressure and tablet hardness (compression moldability), and the relationship between tablet hardness and disintegration time (disintegrability) in Examples 1-1 to 3-1 and Comparative Examples 1-1 to 2-1. [Figure 13] FIG. 1 is a graph showing tablet hardness after humidification and friability after humidification in Examples 1-1 to 3-1 and Comparative Examples 1-1 to 2-1. [Figure 14] FIG. 1 is a graph showing the relationship between tablet hardness and disintegration time (disintegrability) in Examples 1-1, 4-1, and 5-1, and Comparative Examples 1-1 and 3-1. [Figure 15] FIG. 1 shows the tablet hardness after humidification and the friability after humidification in Examples 1-1, 4-1, and 5-1, and Comparative Examples 1-1 and 3-1. [Figure 16]FIG. 1 is a graph showing the relationship between tableting 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] FIG. 1 is a graph showing the relationship between tablet hardness and disintegration time (disintegrability) in Example 8-1 and Comparative Example 5-1. [Figure 18] FIG. 1 is a diagram showing the results of measuring particle strength using particles in Example 9-1 and Comparative Example 6-1. DETAILED DESCRIPTION OF THE INVENTION

[0017] An embodiment of the present invention will be described in detail below. In this specification, unless otherwise specified, "A to B" representing a numerical range means "A or more and B or less."

[0018] (Invention 1) 1. Overview of the 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 present composition") is characterized by containing the present 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 particles in which core particles are 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 such as those described in Patent Document 1 have traditionally had the problem of film cracking of the functional coating layer due to tableting stress, resulting in 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 have room for improvement in terms of strength.

[0023] Therefore, the present inventors have conducted extensive research from the viewpoint of ensuring the strength of particles in which core particles are covered with a coating layer, and as a result have succeeded in making the following findings. - The strength of the particles can be improved by covering the core particles with a coating layer containing cellulose nanofibers. In particles that include a core particle, an intermediate layer, and a coating layer, by including cellulose nanofibers in the coating layer, the strength of the particles can be improved and cracking of the intermediate layer during tableting can be prevented.

[0024] Until now, it was not known that cellulose nanofibers contribute to particle strength. Therefore, it is surprising that the inventors focused on cellulose nanofibers to ensure particle strength, and by applying them to a coating layer inside the particles, they were able to improve particle strength and prevent cracking of the intermediate layer during tableting. Furthermore, in the present particles, the strength of the particles can be ensured by incorporating cellulose nanofibers into the outer layer (e.g., coating layer) of the core particles without adding cellulose nanofibers to the core particles.

[0025] As described above, the present particles exhibit advantageous effects based on the above findings, and can therefore be used extremely advantageously in various fields in which particles having a coating layer are used as raw materials.

[0026] [2. Particles] The present particles have a core particle covered with a coating layer, and the coating layer contains cellulose nanofibers. The presence of the cellulose nanofibers in the coating layer of the present particles has the effect of ensuring the strength of the particles.

[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] Hereinafter, embodiments of the present invention will be described with reference to Fig. 1. Note that the embodiments described below are merely examples of the present invention, and the present invention is not limited to these embodiments.

[0029] The present particles can be used for various purposes including medicine, food, and cosmetics, and the following describes the use of the present particles for medicine as an example, although it goes without saying that the use of the present particles is not limited to medicine.

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

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

[0032] Coating layer 2 is located on the exterior of intermediate layer 3. In embodiments in which the particle does not include intermediate layer 3, coating layer 2 is located on the exterior of core particle 1.

[0033] The coating layer 2 contains cellulose nanofibers. In this specification, the term "cellulose nanofibers" refers to cellulose fibers with nano-sized fiber diameters that are 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 especially preferably 100 nm or less. When the average fiber diameter of the cellulose nanofibers is less than 1 μm, coating can be performed appropriately. Furthermore, the particle size after coating can be maintained at an appropriate level. The average fiber diameter of the cellulose nanofibers refers to the average value of fiber diameters measured for 10 or more cellulose nanofibers selected from an image obtained 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. When the cellulose nanofiber has a fiber length of 0.001 to 100 μm, coating can be performed appropriately. Furthermore, the particle size after coating can be maintained at an appropriate level. The fiber length of the cellulose nanofiber is measured by image analysis.

[0036] The content of the cellulose nanofibers is, for example, 0.1 to 10.0 mass%, preferably 0.4 to 9.0 mass%, more preferably 0.6 to 8.0 mass%, and even more preferably 0.8 to 7.0 mass%, relative to the total mass of the core particle 1 and the intermediate layer 3. When the content of the cellulose nanofibers is 0.1 to 10.0 mass%, relative to the total mass of the core particle 1 and the intermediate layer 3, the effect 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 particle 1, and examples thereof include a layer containing a bitterness-masking agent, an enteric base, a sustained-release base, a moisture-proof base, a light-resistant base, a shielding base, etc.

[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 be composed only of cellulose nanofibers.

[0039] The intermediate layer 3 is located between the core particle 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, the description of (Coating layer) is incorporated herein by reference.

[0040] The intermediate layer 3 may be a single layer or multiple layers. When the intermediate layer 3 is multiple layers, the number of layers is not particularly limited, and may be, for example, two, three, four, five, etc. When the intermediate layer 3 is multiple layers, each layer may be the same functional coating layer or different functional coating layers. Preferably, each layer is a different functional coating layer.

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

[0042] The excipient is not particularly limited, but examples thereof include D-mannitol, lactose (e.g., lactose hydrate), sucrose, cornstarch, calcium phosphate, sorbitol, crystalline cellulose, light anhydrous silicic acid, etc. Preferably, crystalline cellulose and lactose (e.g., lactose hydrate) are used.

[0043] The binder is not particularly limited, but examples thereof include hydroxypropyl cellulose, hydroxypropylmethyl cellulose (also called "hypromellose"), povidone, methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, polyvinylpyrrolidone, a copolymer of N-vinylpyrrolidone and vinyl acetate, or a combination of these polymers, pregelatinized starch, gelatin, agar, gum arabic, etc. Preferably, hypromellose is used.

[0044] The lubricant is not particularly limited, but examples thereof 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 thereof include crospovidone, low-substituted hydroxypropyl cellulose, sodium starch glycolate, croscarmellose sodium, carmellose, carmellose calcium, potato starch, etc. Crospovidone is preferably used.

[0046] The colorant is not particularly limited, but examples thereof include yellow colorants (e.g., yellow ferric oxide, yellow iron oxide, Food Yellow No. 4 Aluminum Lake, red iron oxide, etc.), red colorants (e.g., ferric oxide, Food Red No. 2, Food Red No. 3, Food Red No. 102, etc.), black colorants (e.g., black iron oxide, carbon black, medicinal charcoal, etc.), blue colorants (e.g., Blue No. 2 Aluminum Lake, etc.), caramel, etc. Preferably, yellow ferric oxide and Blue No. 2 Aluminum Lake are used.

[0047] The content of each of the additives is not particularly limited and can be appropriately determined by a person 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 bitter-masking functional coating layer (coating layer 2) containing cellulose nanofibers.

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

[0050] In embodiment 2, the particle does not contain an intermediate layer 3. In this case, the content of the cellulose nanofiber is, for example, 0.1 to 10.0 mass%, preferably 0.4 to 9.0 mass%, more preferably 0.6 to 8.0 mass%, and even more preferably 0.8 to 7.0 mass%, relative to the mass of the core particle 1. When the content of the cellulose nanofiber is 0.1 to 10.0 mass%, relative to the mass of the core particle 1, the effect 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, such as those described in <embodiment 1>.

[0052] In addition, in the second embodiment, the "core particle" is the same as that described in the first embodiment.

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

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

[0055] In the third embodiment, the "core particle" is the same as that described in the first embodiment.

[0056] [3. Composition] The present composition contains the particles described in [2. Particles] (i.e., the present particles). Because the present composition contains particles with ensured strength, the active ingredient contained in the core particle can be utilized more effectively.

[0057] The present composition can be used for various purposes based on the active ingredient contained in the core particle of the present particle. The uses of the present composition are not particularly limited, but may be, for example, medicines, foods (e.g., functional foods, supplements), cosmetics, etc.

[0058] In addition to the particles, the composition may contain various additives depending on the intended use. When the intended use is a pharmaceutical, for example, the additives described in the section <Embodiment 1> may be used.

[0059] 4. Particle Manufacturing Method The present production method is a method for producing particles in which core particles are coated with a coating layer, and includes a step of coating the core particles with a coating layer containing cellulose nanofibers. By coating the core particles with a coating layer containing cellulose nanofibers, the present production method can ensure the strength of the particles.

[0060] In the present production method, the method for covering the core particles with the 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 method includes coating the core particles with an intermediate layer.

[0062] In another embodiment of the present invention, the production method is a method for producing particles in which core particles are coated with a coating layer, the method 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 terms "core particle," "coating layer," "cellulose nanofiber," and "intermediate layer" are defined in [2. Particles].

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

[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 terms "core particle," "coating layer," and "cellulose nanofiber" are defined in [2. Particles].

[0067] The present invention is not limited to the above-described embodiments, 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. Overview of the Invention An orally disintegrating tablet according to one embodiment of the present invention (hereinafter referred to as "the present orally disintegrating tablet") is characterized by having particles containing cellulose nanofibers with an average particle size of less than 10 μm.

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

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

[0071] Additionally, 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 "this method") is characterized in that the particles contain cellulose nanofibers having an average particle diameter of less than 10 μm, and the physical property is at least one of the following: (1) compression moldability, (2) disintegrability, (3) tableting trouble, (4) tablet hardness after humidification, and (5) friability after humidification.

[0072] As described above, the orally disintegrating tablet described in Patent Document 1 has room for improvement in terms of its physical properties, particularly compression moldability, disintegrability, tableting trouble, tablet hardness after humidification, and friability after humidification.

[0073] Therefore, the present inventors conducted extensive research and succeeded in obtaining the following findings. By incorporating CNF with an average particle size of less than 10 μm into the particles that make up the orally disintegrating tablet, the physical properties of the orally disintegrating tablet (particularly, compression moldability, disintegration, tableting problems, tablet hardness after humidification, and friability after humidification) are improved. The particles containing CNF may be disintegrating particles or drug particles, but disintegrating particles are preferred. When the particles have a core and a coating layer, the CNF is preferably contained in the coating layer.

[0074] It has not been known until now that CNF is involved in various physical properties of orally disintegrating tablets containing particles thereof (particularly, compression moldability, disintegrability, tableting trouble, tablet hardness after humidification, and friability after humidification). Therefore, it is surprising that the present inventors focused on CNF in order to improve the various physical properties of the orally disintegrating tablets, and were able to improve the various physical properties of the orally disintegrating tablets by incorporating the CNF into the particles that constitute the orally disintegrating tablets.

[0075] As described above, the present orally disintegrating tablet exhibits advantageous effects based on the above findings, and is therefore applicable to various active ingredients in orally disintegrating applications.

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

[0077] [7. Orally disintegrating tablets] The 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 specific average particle size, the orally disintegrating tablet has the effect of improving various physical properties of the orally disintegrating tablet.

[0078] (CNF) The particles constituting the orally disintegrating tablet contain CNF. As used herein, "cellulose nanofiber (CNF)" refers to cellulose fibers with nano-sized fiber diameters that are prepared by mechanically treating cellulose.

[0079] The average particle size of the 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. Having an average particle size of the CNF less than 10 μm can improve various physical properties of the orally disintegrating tablet. The lower limit of the average particle size of the CNF is not particularly limited as long as the effects of the present invention are achieved, but is, for example, 1.0 μm or more, preferably 2.0 μm or more. The average particle size of the CNF refers to the volume-based average particle size measured using a laser diffraction particle size distribution analyzer.

[0080] The average fiber diameter of the 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 especially preferably 0.01 to 0.05 μm. When the average fiber diameter of the CNF is 0.001 to 1 μm, various physical properties of the orally disintegrating tablet can be improved. The average fiber diameter of the CNF means the average fiber diameter of fiber measured for any 10 or more cellulose nanofibers in an image obtained by a scanning probe microscope.

[0081] The average fiber length of the CNF is preferably less than 10 μm, more preferably 5 μm or less, and even more preferably 2 μm or less. By having an average fiber length of the CNF less than 10 μm, various physical properties of the orally disintegrating tablet can be improved. The lower limit of the average fiber length of the CNF is not particularly limited as long as the effects of the present invention are exhibited, but is, for example, 0.5 μm or more, preferably 1.0 μm or more. The average fiber length of the 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 CNF-containing particles (when the particles include a core and a coating layer, the total mass of the core and coating layer, as described below). When the CNF content is 0.1 to 10.0% by mass relative to the mass of the CNF-containing particles, various physical properties of the orally disintegrating tablet can be improved.

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

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

[0085] The particles constituting the present orally disintegrating tablet may contain additives such as excipients, binders, lubricants, disintegrants, surfactants, plasticizers, and colorants in addition to CNF.

[0086] The excipient is not particularly limited, but examples thereof include D-mannitol, lactose (e.g., lactose hydrate), sucrose, cornstarch, calcium phosphate, sorbitol, crystalline cellulose, light anhydrous silicic acid, etc. Preferably, D-mannitol, crystalline cellulose, and lactose (e.g., lactose hydrate) are used.

[0087] The binder is not particularly limited, but examples thereof include hydroxypropyl cellulose, hydroxypropylmethyl cellulose (also called "hypromellose"), povidone, methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, polyvinylpyrrolidone, a copolymer of N-vinylpyrrolidone and vinyl acetate, or a combination of these polymers, pregelatinized starch, gelatin, agar, gum arabic, etc. Hydroxypropyl cellulose and hypromellose are preferably used.

[0088] The lubricant is not particularly limited, but examples thereof include inactive 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. Magnesium stearate and glycerin fatty acid esters are preferably used.

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

[0090] The colorant is not particularly limited, but examples thereof include yellow colorants (e.g., yellow ferric oxide, yellow iron oxide, Food Yellow No. 4 Aluminum Lake, red iron oxide, etc.), red colorants (e.g., iron sesquioxide, Food Red No. 2, Food Red No. 3, Food Red No. 102, etc.), black colorants (e.g., black iron oxide, carbon black, medicinal charcoal, etc.), blue colorants (e.g., Blue No. 2 Aluminum Lake, etc.), caramel, etc. Preferably, iron sesquioxide, yellow ferric oxide, and Blue No. 2 Aluminum Lake are used.

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

[0092] In one embodiment of the present invention, the disintegrating particles may contain a sugar alcohol and organic and inorganic hydrophilic and water-insoluble additives. The organic hydrophilic and water-insoluble additive preferably contains 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 contains 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 content of the sugar alcohol is, for example, 55 to 85% by mass, and preferably 65 to 75% by mass, relative to the mass of the disintegrating particles. Furthermore, in this embodiment, the content of the organic hydrophilic, water-insoluble additive is, for example, 10 to 40% by mass, and preferably 18 to 32% by mass, relative to the mass of the disintegrating particles. Furthermore, in this embodiment, the content of the inorganic hydrophilic, water-insoluble additive is, for example, 0.3 to 55% by mass, and 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 with 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, the CNF may be contained in the coating layer, the core, or both. From the viewpoint of further improving various physical properties of the orally disintegrating tablet, the CNF is preferably contained in the coating layer.

[0096] In this embodiment, the core and the 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 multiple layers. When the coating layer is multiple layers, each coating layer may have a different function. The function of the coating layer is not particularly limited, and may be, for example, bitterness masking, an enteric base, a sustained-release base, a moisture-proof base, a light-resistant base, a shielding base, etc.

[0098] (Physical Properties) The orally disintegrating tablet has improved at least one of compression moldability, disintegrability, tableting trouble, tablet hardness after humidification, and friability after humidification. In one embodiment of the present invention, the orally disintegrating tablet preferably has improved multiple of compression moldability, disintegrability, tableting trouble, tablet hardness after humidification, and friability after humidification, and most preferably has improved all of them.

[0099] In this specification, "compression moldability" refers to the property of powder or granules bonding together when pressure is applied to the powder or granules, and means the property of being able to compress amorphous powder or granules into a specific shape, and preferably means that a practical hardness can be obtained at a low pressure. Specifically, compression moldability is measured by the method described in the Examples.

[0100] As used herein, "disintegrability" refers to the ease with which a tablet disintegrates. Specifically, disintegrability is measured by the method described in the Examples.

[0101] In this specification, the term "tabletting trouble" refers to problems such as sticking that occur during the tabletting process. Specifically, the tabletting trouble is measured by the method described in the Examples.

[0102] As used herein, "tablet hardness after humidification" refers to the hardness after storage for 7 days under conditions of a temperature of 25°C and a relative humidity of 75%. Specifically, the tablet hardness after humidification is measured by the method described in the Examples.

[0103] In this specification, "friability after humidification" means the friability after storage for 7 days under conditions of a temperature of 25°C and a relative humidity of 75%. Specifically, the friability after humidification is measured by the method described in the Examples.

[0104] [8. Collapsible Particles] The present disintegrating particles are characterized by containing CNFs with an average particle size of less than 10 μm. By containing CNFs with the specific average particle size, the present disintegrating particles have the effect of improving various physical properties of a composition containing the present disintegrating particles.

[0105] The present disintegrating particles can be used in a variety of applications requiring disintegration in the oral cavity, such as medicines, foods, and supplements.

[0106] In the present disintegrating particles, the terms "particles," "orally disintegrating tablets," and "cellulose nanofibers (CNF)" are the same as those described in [7. Orally disintegrating tablets].

[0107] 9. Manufacturing method of orally disintegrating tablets This manufacturing method is a method for producing an orally disintegrating tablet containing particles, and includes a step of incorporating CNF having an average particle size of less than 10 μm into the particles. By incorporating CNF having an average particle size of less than 10 μm into the particles that constitute the orally disintegrating tablet, various physical properties of the orally disintegrating tablet 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 incorporation of CNF into the particles is carried out by mixing CNF with other components constituting the particles in any mixing device.

[0109] In this manufacturing method, the terms "particles," "orally disintegrating tablets," and "cellulose nanofibers (CNF)" are the same as those described in [7. Orally disintegrating tablets].

[0110] 10. Methods for improving physical properties This method is a method for improving the physical properties of an orally disintegrating tablet containing particles, and is characterized by incorporating CNFs having an average particle size of less than 10 μm into the particles. That is, the method includes a step of incorporating CNFs having an average particle size of less than 10 μm into 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) friability after humidification. This method can improve at least one of the physical properties (1) to (5) by incorporating CNFs having an average particle size of less than 10 μm into the particles constituting the orally disintegrating tablet.

[0111] In this method, the method for incorporating CNF into the particles that constitute 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 nanofibers (CNF)," as well as the various physical properties (physical properties (1) to (5)) described above, are those described in [7. Orally disintegrating tablets].

[0113] The present invention is not limited to the above-described embodiments, 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. [Example]

[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 by the following methods.

[0116] (Dissolution test) The average dissolution rates of particles (overcoated particles, masked particles) and tablets were measured according to the Japanese Pharmacopoeia dissolution test paddle method (rotation speed 75 rpm, dissolution test second fluid 900 mL). For particle dissolution tests, to prevent adhesion and aggregation of particles during the dissolution test, the particles were mixed with disintegrating particles in equal parts beforehand and then placed in the test vessel. The dissolution rate was measured using a fiber probe UV-visible spectrophotometer at a measurement wavelength of 288 nm.

[0117] (particle strength) The particle strength was measured using a microcompression tester (MCT-210, manufactured by Shimadzu Corporation).

[0118] Example 1 (Preparation of Drug Particles) A 50% (w / w) ethanol solution was sprayed onto a powder mixture 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.), and the mixture was granulated using a high-speed agitator mixer. The resulting granules were dried using a tumbling fluidized bed granulator and then classified using sieves with 250 μm and 75 μm openings to prepare drug particles (core particles).

[0119] (Preparation of Masking Particles) The resulting drug particles were placed in a tumbling fluidized bed granulator. Aminoalkyl methacrylate copolymer E (Eudragit E, manufactured by Evonik Co., Ltd.) was dissolved in a 90% (w / w) ethanol solution, and talc (Microace P-3, manufactured by Nippon Talc Co., Ltd.) was dispersed in the solution. The drug particles were sprayed with this solution to coat them with Eudragit E and talc, producing masked particles (particles in which a core particle is coated with an intermediate layer).

[0120] (Preparation of Overcoated Particles) The resulting masked particles were placed in a tumbling fluidized bed granulator. A 5% (w / v) aqueous dispersion (5% viscosity: 40,000 mPa·s) 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.) was diluted with water to a 1% (w / v) concentration and then homogenized at 10,000 rpm for 20 minutes. The masked particles were coated with cellulose nanofibers by spraying this solution, producing overcoated particles (core particles coated with an intermediate layer and a coating layer). The amount of cellulose nanofiber coating was 2% by mass of the masked particles.

[0121] (Preparation of disintegrating particles) 71 parts by mass of D-mannitol (PEARLITOL 50C, manufactured by Roquette Japan Co., Ltd.), 2 parts by mass of ethyl cellulose (Ethocel 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 Corporation) were placed in a fluidized bed granulator, and a liquid prepared by dispersing 20 parts by mass of corn starch (Corn Starch W, manufactured by Nihon Shokuhin Kako Co., Ltd.) and 6 parts by mass of crospovidone (Polyplasdone INF10, manufactured by ISP Japan Inc.) in 80 parts by mass of water was sprayed onto the mixture to granulate, followed by drying and sizing to obtain disintegrating particles.

[0122] (Tablet compression) The overcoated particles were mixed with disintegrating particles and magnesium stearate (vegetable-based, manufactured by Taihei Chemical Industry Co., Ltd.), and then tableted at 7 kN using a hand tub. A dissolution test was conducted using the masked particles and tablets.

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

[0124] [Table 1]

[0125] Example 2 The same method as in Example 1 was used up to the preparation of masked particles.

[0126] (Preparation of Overcoated Particles) The resulting masked particles were placed in a tumbling fluidized bed granulator. A 5% (w / v) aqueous dispersion (5% viscosity: 20,000 mPa·s) 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.) was diluted with water to a 1% (w / v) concentration and then homogenized at 10,000 rpm for 20 minutes. The resulting solution was sprayed onto the masked particles to coat them with cellulose nanofibers, producing overcoated particles. The amount of cellulose nanofiber coating was 2% by mass relative to the mass of the masked particles.

[0127] Subsequently, disintegrating particles were prepared and tablets were formed in the same manner as in Example 1. A dissolution test was carried out using the overcoated particles and tablets.

[0128] Example 3 The preparation of masked particles was carried out in the same manner as in Example 1. (Preparation of Overcoated Particles) The resulting masked particles were placed in a tumbling fluidized bed granulator. A 2% (w / v) aqueous dispersion of crystalline cellulose converted into cellulose nanofibers with a viscosity of 1000 mPa·s or greater was diluted with water to 1% (w / v), and the mixture was processed at 10,000 rpm for 20 minutes using a homogenizer. The masked particles were coated with the cellulose nanofiber converted crystalline cellulose by spraying this solution, producing overcoated particles. The coating amount of the cellulose nanofiber converted crystalline cellulose was 2% by mass relative to the mass of the masked particles.

[0129] Subsequently, disintegrating particles were prepared and tablets were formed in the same manner as in Example 1. A dissolution test was carried out using the overcoated particles and tablets.

[0130] Comparative Example 1 The preparation of masked particles was carried out in the same manner as in Example 1. In this case, the preparation of overcoated particles was not carried out.

[0131] Subsequently, disintegrable particles were prepared in the same manner as in Example 1.

[0132] (Tablet compression) The masked particles were mixed with disintegrating particles and magnesium stearate (vegetable-based, manufactured by Taihei Chemical Industry Co., Ltd.), and then tableted at 7 kN using a hand tub. A dissolution test was conducted using the masked particles and tablets.

[0133] Comparative Example 2 The same method as in Example 1 was used up to the preparation of masked particles.

[0134] (Preparation of Overcoated Particles) Hydroxypropyl cellulose (HPC-SL, manufactured by Nippon Soda Co., Ltd.) was dissolved in water to a concentration of 1% (w / v), and the solution was sprayed onto the masked particles to coat them with HPC-SL, thereby preparing overcoated particles. The coating amount of HPC-SL was 2% by mass relative to the mass of the masked particles.

[0135] Subsequently, disintegrating particles were prepared and tableted in the same manner as in Example 1. A dissolution test (RT-J2000, manufactured by Dai-Nippon Seiki Co., Ltd.) was carried out using the overcoated particles and tablets.

[0136] Comparative Example 3 The same method as in Example 1 was used up to the preparation of masked particles.

[0137] (Preparation of Overcoated Particles) Ethyl cellulose (Ethocel Standard FP7CPS Premium, manufactured by DuPont Nutrition & Biosciences Co., Ltd.) was dissolved in 90% (w / w) ethanol to a concentration of 1% (w / v). The solution was sprayed onto the masked particles to coat them with ethyl cellulose, preparing overcoated particles. The coating amount of ethyl cellulose was 2% by mass relative to the mass of the masked particles.

[0138] Subsequently, disintegrating particles were prepared and tablets were formed in the same manner as in Example 1. A dissolution test was carried out using the overcoated particles and tablets.

[0139] [Result-1] The particles (overcoated particles and masked particles) and tablets produced in Examples 1 to 3 and Comparative Examples 1 to 3 above were subjected to dissolution tests, and the results are shown in FIG.

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

[0141] Example 4 Using the obtained overcoated particles, the particle strength was measured in the same manner as in Example 1.

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

[0143] Comparative Example 5 Using the same method as in Comparative Example 1, the particle strength of the obtained masked particles was measured.

[0144] Comparative Example 6 Using the same method as in Comparative Example 2, the particle strength of the obtained overcoated particles was measured.

[0145] Comparative Example 7 Using the same method as in Comparative Example 3, the particle strength of the obtained overcoated particles was measured.

[0146] Example 5 The same method as in Example 1 was used up to the preparation of drug particles.

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

[0148] The resulting masked particles were used to measure particle strength.

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

[0150] [Result-2] The particle strength of the particles (drug particles, masked particles, and overcoated particles) produced in Examples 4 and 5 and Comparative Examples 4 to 8 was measured, and the results are shown in FIGS.

[0151] 3 shows that Example 4 has higher particle strength than Comparative Examples 4 to 7. This indicates that, among particles including a core particle, an intermediate layer, and a coating layer, particles according to one embodiment of the present invention in which the coating layer contains cellulose nanofibers have improved particle strength.

[0152] 4 also shows that Example 5 has higher particle strength than Comparative Example 8. This indicates that particles according to one embodiment of the present invention, in which core particles are coated with a coating layer made of cellulose nanofibers, have improved particle strength.

[0153] Example 6 The same method as in Example 1 was used up to the preparation of drug particles.

[0154] (Preparation of Masking Particles) The resulting drug particles were placed in a tumbling fluidized 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 homogenized at 10,000 rpm for 20 minutes to produce a cellulose nanofiber-containing solution. Next, aminoalkyl methacrylate copolymer E (Eudragit E, manufactured by Evonik Co., Ltd.) was dissolved in the ethanol solution, and the cellulose nanofiber-containing solution was added to a final concentration of 80% (w / w) ethanol. This solution was sprayed onto the drug particles to coat them with Eudragit E and cellulose nanofibers, producing masked particles.

[0155] Subsequently, disintegrating particles were prepared and tableted in the same manner as in Example 1. A dissolution test was performed using the obtained masked particles and tablets. In addition, particle strength was measured using the obtained masked particles.

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

[0157] [Table 2]

[0158] Comparative Example 9 The same method as in Example 1 was used up to the preparation of drug particles.

[0159] (Preparation of Masking Particles) The resulting drug particles were placed in a tumbling fluidized bed granulator. Aminoalkyl methacrylate copolymer E (Eudragit E, manufactured by Evonik Co., Ltd.) was dissolved in an 80% (w / w) ethanol solution, and talc (Microace P-3, manufactured by Nippon Talc Co., Ltd.) was dispersed in the solution. The drug particles were sprayed with this solution to coat them with Eudragit E and talc, producing masked particles (particles in which the core particle is covered with a coating layer).

[0160] Subsequently, disintegrating particles were prepared and tableted in the same manner as in Example 1. A dissolution test was performed using the obtained masked particles and tablets. In addition, particle strength was measured using the obtained masked particles.

[0161] [Result-3] The particles (masked particles) and tablets produced in Example 6 and Comparative Example 9 were subjected to measurement of dissolution rate and particle strength, and the results are shown in FIGS.

[0162] 5 shows that the change in dissolution behavior between the particles and the tablets is suppressed in Example 6 compared to Comparative Example 9. Therefore, it was demonstrated that, in particles comprising a core particle and a coating layer, particles 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] 6 also shows that Example 6 has higher particle strength than Comparative Example 9. This indicates that, among particles comprising a core particle and a coating layer, particles according to one embodiment of the present invention in which the coating layer contains cellulose nanofibers have improved particle strength.

[0164] Example 7 The same method as in Example 1 was used up to the preparation of drug particles.

[0165] (Preparation of Masking Particles) The resulting drug particles were placed in a tumbling fluidized bed granulator. Aminoalkyl methacrylate copolymer RL and aminoalkyl methacrylate copolymer RS ​​(Eudragit RL and RS, Evonik Corporation) were dissolved in a 90% (w / w) ethanol solution, followed by dispersion of talc (Microace P-3, Nippon Talc Co., Ltd.). Masked particles (particles with a core particle coated with an intermediate layer) were prepared by spraying the solution onto the drug particles.

[0166] (Preparation of Overcoated Particles) The resulting masked particles were placed in a tumbling fluidized bed granulator. A 2% (w / v) aqueous dispersion (2% viscosity: 6000 mPa·s) of cellulose nanofibers (Binfis WFo-100 2%, manufactured by Sugino Machine Co., Ltd.) was diluted with water to 1% (w / v) and then homogenized at 10,000 rpm for 20 minutes. Overcoated particles (core particles coated 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 masked particles.

[0167] Subsequently, disintegrating particles were prepared and tablets were formed (tabletting pressure 11 kN) in the same manner as in Example 1. A dissolution test was carried out using the overcoated particles and tablets.

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

[0169] [Table 3]

[0170] Comparative Example 10 The preparation of masked particles was carried out in the same manner as in Example 7. In this case, the preparation of overcoated particles was not carried out.

[0171] Subsequently, disintegrating particles were prepared and tablets were formed (tabletting pressure 11 kN) in the same manner as in Example 1. A dissolution test was carried out using the masked particles and tablets.

[0172] [Result-4] The dissolution rate and particle strength of the particles (overcoated particles) and tablets produced in Example 7 and Comparative Example 10 were measured, and the results are shown in FIGS.

[0173] 7 shows that the change in dissolution behavior between the particles and the tablets is suppressed in Example 7 compared to Comparative Example 10. Therefore, it was demonstrated that, in particles comprising a core particle, an intermediate layer, and a coating layer, particles 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.

[0174] 8 also shows that Example 7 has higher particle strength than Comparative Example 10. This indicates that, in particles comprising a core particle, an intermediate layer, and a coating layer, particles according to one embodiment of the present invention, in which the coating layer contains cellulose nanofibers, have improved particle strength.

[0175] Example 8 The same method as in Example 1 was used up to the preparation of drug particles.

[0176] (Preparation of Masking Particles) The resulting drug particles were placed in a tumbling fluidized bed granulator. Ethyl cellulose (Ethocel Standard FP7CPS Premium, DuPont Nutrition & Biosciences) was dissolved in a 90% (w / w) ethanol solution, followed by dispersion of talc (Microace P-3, Nippon Talc Co., Ltd.) and hydrous silicon dioxide (Adsolider-102, Freund Corporation). This solution was sprayed onto the drug particles to prepare masked particles (particles with a core particle covered with a coating layer).

[0177] (Preparation of Overcoated Particles) The resulting masked particles were placed in a tumbling fluidized bed granulator. A 5% (w / v) aqueous dispersion (5% viscosity: 20,000 mPa·s) of cellulose nanofibers (Binfis AFo-100 5%, manufactured by Sugino Machine Co., Ltd.) was diluted with water to a 1% (w / v) concentration and then homogenized at 10,000 rpm for 20 minutes. This solution was sprayed onto the masked particles to prepare overcoated particles (particles in which the core particles are coated with an intermediate layer and a coating layer). The amount of cellulose nanofiber coating was 2% by mass of the masked particles.

[0178] Subsequently, disintegrating particles were prepared and tablets were formed (tabletting pressure 7 kN) in the same manner as in Example 1. A dissolution test was carried out using the overcoated particles and tablets.

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

[0180] [Table 4]

[0181] Comparative Example 11 The preparation of masked particles was carried out in the same manner as in Example 8. In this case, the preparation of overcoated particles was not carried out.

[0182] Subsequently, disintegrating particles were prepared and tablets were formed (tabletting pressure 7 kN) in the same manner as in Example 1. A dissolution test was carried out using the overcoated particles and tablets.

[0183] [Result-5] The dissolution rate and particle strength of the particles (overcoated particles) and tablets produced in Example 8 and Comparative Example 11 were measured, and the results are shown in FIGS.

[0184] 9 shows that the change in dissolution behavior between the particles and the tablets is suppressed in Example 8 compared to Comparative Example 11. Therefore, it was demonstrated that, in particles comprising a core particle, an intermediate layer, and a coating layer, particles 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.

[0185] 10 also shows that Example 8 had higher particle strength than Comparative Example 11. This indicates 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, have 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. Microcrystalline cellulose (CEOLUS® (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 to a concentration of 2% (w / v), and then processed 30 times in a wet micronization device (Starburst Labo, Sugino Machine Co., Ltd.) to produce a CNF aqueous dispersion. CNF-2: BiNFi-s (manufactured by Sugino Machine Co., Ltd.), grade short chain, average particle size 2.9 μm, average fiber diameter approximately 10 to 50 nm, average fiber length 0.5 to 1.0 μm. CNF-3: BiNFi-s (manufactured by Sugino Machine Co., Ltd.), grade: very short chain, average particle size: 2.5 μm, average fiber diameter: approximately 10 to 50 nm, average fiber length: less than 0.5 μm.

[0187] <Cellulose used in the comparative examples> Microfibrillated cellulose: Celish (manufactured by Daicel Corporation), grade FD200L, average particle size 11.1 μm, average fiber diameter approximately 0.1 to 1.0 μm, average fiber length greater than 10 μm. This microfibrillated cellulose was used in the examples of WO 2015 / 163135. Crystalline cellulose: Ceolus, Grade PH-101 (Asahi Kasei Corporation) Ethylcellulose: Ethocel Standard 7FP Premium (DuPont Nutrition & Biosciences) [Measurement and evaluation methods] The evaluations in the examples and comparative examples were carried out by the following methods.

[0188] (Average particle size) A CNF-containing aqueous dispersion was prepared to a solids content of 0.125-0.5%. After preparation, the dispersion was processed using an ultrasonic homogenizer (UD-200, manufactured by Tomy Seiko Co., Ltd.) for 5-10 minutes until the fibers were uniformly dispersed. The processed 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). While irradiating with ultrasonic waves, the measurement solution was circulated at a pump speed of 3500 rpm for 30 seconds, after which the ultrasonic waves and pump were stopped and the average particle size was measured. The measurement solution was circulated again and measured in the same manner to obtain the average particle size.

[0189] (average fiber diameter) A scanning probe microscope was used to observe the morphology of the CNFs and measure their fiber diameter. As a pretreatment for the observation sample, a sheet of dried CNF aqueous dispersion was fixed to a sample holder, and then a tiny probe was 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) Tablet hardness was measured using a hardness tester (manufactured by ERWEKA) to evaluate compression moldability.

[0191] (Disintegration) A disintegration test was carried out without an auxiliary disc in accordance with the disintegration test method (rapidly disintegrating preparations) of the 18th edition of the Japanese Pharmacopoeia, and the disintegration time when the tablet disintegrated was measured.

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

[0193] (Friability after humidification) After storage for 7 days under conditions of a temperature of 25°C and a relative humidity of 75%, the degree of friability was measured using a friability tester (manufactured by Toyama Sangyo Co., Ltd.).

[0194] (Tableting problems) Tablets were continuously compressed using a rotary tablet press, and the tablets were visually inspected for any poor appearance and powder adhesion to the punches and dies. Specifically, after 20 minutes of tableting, the punches of the rotary tablet press were visually inspected and evaluated for cloudiness (powder adhesion) of the punches. The evaluation criteria were as follows:

[0195] (Evaluation criteria) A: No powder adhesion. B: A thin layer of powder adheres to the punch, making it cloudy (no metallic luster on the punch surface). C: The adhesion of powder is clearly visible.

[0196] (particle strength) The particle strength was measured using a microcompression tester (MCT-210, manufactured by Shimadzu Corporation).

[0197] Example 1-1 Purified water was sprayed onto a powder mixture containing olmesartan medoxomil, hydroxypropyl cellulose (HPC-M, Nippon Soda Co., Ltd.), and lactose hydrate (Fine Powder, DFE Pharma Co., Ltd.), and the mixture was granulated using a high-speed agitator mixer. The resulting granules were dried using a fluidized bed granulator (MP-01, Powrex Corporation), and then classified using sieves with 250 μm and 75 μm openings to prepare drug particles.

[0198] Next, 71 parts by weight of D-mannitol (PEARLITOL 50C, manufactured by ROCKET JAPAN CO., LTD.) and 1 part by weight of light anhydrous silicic acid (Adsolider-101, manufactured by Freund Corporation) were added to a fluidized bed granulator. CNF-1 was diluted with water to a concentration of 1.25% (w / v), and then processed with a homogenizer at 10,000 rpm for 20 minutes (2 parts by weight as CNF). 20 parts by weight of corn starch (Corn Starch W, manufactured by Nihon Shokuhin Kako Co., Ltd.) and 6 parts by weight of crospovidone (Polyplasdone INF10, manufactured by ISP Japan Inc.) were dispersed in water, and the resulting solution was sprayed to granulate. The mixture was then dried and classified at 30M to obtain disintegrating particles.

[0199] Thereafter, the drug particles, disintegrating particles, aspartame (Ajinomoto Co., Inc.), light anhydrous silicic acid (Adsolider-101, Freund Corporation), and magnesium stearate (vegetable-based, Taihei Chemical Industry Co., Ltd.) were mixed and compressed using a rotary tablet press to a practical hardness, yielding tablets with a diameter of 10 mm (punches: engraved and scored). The obtained tablets were measured for compression moldability, disintegrability, tablet hardness after humidification, friability after humidification, and tableting trouble.

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

[0201] [Table 5]

[0202] Example 2-1 Particles and tablets were produced 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 obtained tablets were measured for compression moldability, disintegration property, tablet hardness after humidification, and friability after humidification.

[0203] Example 3-1 Particles and tablets were produced 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 obtained tablets were measured for compression moldability, disintegration property, tablet hardness after humidification, and friability after humidification.

[0204] Example 4-1 Tablets were produced in the same manner as in Example 1-1, except that the type of CNF was changed from "CNF-1" to "CNF-2." The obtained tablets were measured for compression moldability, disintegration property, tablet hardness after humidification, friability after humidification, and tableting trouble.

[0205] Example 5-1 Tablets were produced in the same manner as in Example 1-1, except that the type of CNF was changed from "CNF-1" to "CNF-3." The resulting tablets were measured for disintegration, tablet hardness after humidification, friability after humidification, and tableting trouble.

[0206] Example 6-1 Tablets were produced in the same manner as in Example 1-1, except that the punches used in the rotary tablet press were changed from "engraved" to "unengraved." The compression moldability and disintegration properties of the obtained tablets were measured.

[0207] Example 7-1 Purified water was sprayed onto a powder mixture containing olmesartan medoxomil, hydroxypropyl cellulose (HPC-M, Nippon Soda Co., Ltd.), and lactose hydrate (Fine Powder, DFE Pharma Co., Ltd.), and the mixture was granulated using a high-speed agitator mixer. The resulting granules were dried using a fluidized bed granulator (MP-01, Powrex Corporation), and then classified using sieves with 250 μm and 75 μm openings to prepare drug particles.

[0208] Next, 71 parts by weight of D-mannitol (PEARLITOL 50C, manufactured by ROCKET JAPAN CO., LTD.) and 1 part by weight of light anhydrous silicic acid (Adsolider-101, manufactured by Freund Corporation) were added to a fluidized bed granulator. CNF-1 was diluted with water to a concentration of 1.25% (w / v), and then processed with a homogenizer at 10,000 rpm for 20 minutes (2 parts by weight as CNF). This solution was sprayed onto the granules, granulated, and then dried. 20 parts by weight of corn starch (Corn Starch W, manufactured by Nihon Shokuhin Kako Co., Ltd.) and 6 parts by weight of crospovidone (Polyplasdone INF10, manufactured by ISP Japan Inc.) were dispersed in water, and the resulting solution was sprayed onto the granules, granulated, dried, and classified at 30M to obtain disintegrating particles.

[0209] Thereafter, the drug particles, disintegrating particles, aspartame (Ajinomoto Co., Inc.), light anhydrous silicic acid (Adsolider-101, Freund Corporation), and magnesium stearate (vegetable-based, Taihei Chemical Industry Co., Ltd.) were mixed, and the mixture was compressed using a rotary tablet press to a practical hardness to obtain tablets with a diameter of 10 mm (punch: no markings, with a score line). The compression moldability and disintegrability of the obtained tablets were measured.

[0210] Example 8-1 Cilostazol and D-mannitol (PEARLITOL 50C, manufactured by ROCKET JAPAN) were placed in a fluidized bed granulator. CNF-1 was diluted with water to a concentration of 1.25% (w / v), and then homogenized at 10,000 rpm for 20 minutes (2 parts by mass as CNF). Cornstarch (Cornstarch W, manufactured by Nihon Shokuhin Kako Co., Ltd.) and crospovidone (Polyplasdone INF10, manufactured by ISP Japan Inc.) were dispersed in water, and the resulting solution was sprayed to granulate the mixture. The mixture was then dried and classified at 30M to obtain drug particles.

[0211] The drug particles, crystalline cellulose (PH101, Asahi Kasei Corporation), talc (Microace P-3, Nippon Talc Co., Ltd.), aspartame (Ajinomoto Co., Inc.), light anhydrous silicic acid (Adsolider-101, Freund Corporation), and magnesium stearate (vegetable-based, Taihei Chemical Industry Co., Ltd.) were then mixed and compressed using a rotary tablet press to a practical hardness, yielding tablets with a diameter of 7 mm (punch: engraved and scored). The compression moldability and disintegration properties of the resulting tablets were measured.

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

[0213] [Table 6]

[0214] Comparative Example 1-1 Purified water was sprayed onto a powder mixture containing olmesartan medoxomil, hydroxypropyl cellulose (HPC-M, Nippon Soda Co., Ltd.), and lactose hydrate (Fine Powder, DFE Pharma Co., Ltd.), and the mixture was granulated using a high-speed agitator mixer. The resulting granules were dried using a fluidized bed granulator (MP-01, Powrex Corporation), and then classified using sieves with 250 μm and 75 μm openings to prepare drug particles.

[0215] Next, 71 parts by mass of D-mannitol (PEARLITOL 50C, manufactured by Roquette Japan Co., Ltd.), 2 parts by mass of ethyl cellulose (Ethocel 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 Corporation) were added to a fluidized bed granulator. 20 parts by mass of corn starch (Corn Starch W, manufactured by Nihon Shokuhin Kako Co., Ltd.) and 6 parts by mass of crospovidone (Polyplasdone INF10, manufactured by ISP Japan Co., Ltd.) were dispersed in purified water, and the resulting solution was sprayed to granulate, then dried and classified at 30M to obtain disintegrating particles.

[0216] Thereafter, the drug particles, disintegrating particles, aspartame (Ajinomoto Co., Inc.), light anhydrous silicic acid (Adsolider-101, Freund Corporation), and magnesium stearate (vegetable-based, Taihei Chemical Industry Co., Ltd.) were mixed and compressed using a rotary tablet press to a practical hardness, yielding tablets with a diameter of 10 mm (punches: engraved and scored). The obtained tablets were measured for compression moldability, disintegrability, tablet hardness after humidification, friability after humidification, and tableting trouble.

[0217] Comparative Example 2-1 Tablets were produced 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, compression moldability, disintegration, tablet hardness after humidification, friability after humidification, and tableting trouble.

[0218] Comparative Example 3-1 Tablets were produced 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, compression moldability, disintegration, tablet hardness after humidification, friability after humidification, and tableting trouble.

[0219] Comparative Example 4-1 Tablets were produced in the same manner as in Comparative Example 1, except that the punches used in tableting with the rotary tablet press were changed from "engraved" to "unengraved." The compression moldability and disintegration properties of the obtained tablets were measured.

[0220] Comparative Example 5-1 Cilostazol, D-mannitol (PEARLITOL 50C, manufactured by Roquette Japan Co., Ltd.), and ethyl cellulose (Ethocel Standard FP7CPS Premium, manufactured by DuPont Nutrition & Biosciences Co., Ltd.) were placed in 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, and the resulting solution was sprayed to granulate the particles, which were then dried and classified at 30M to obtain drug particles.

[0221] The drug particles, crystalline cellulose (PH101, Asahi Kasei Corporation), talc (Microace P-3, Nippon Talc Co., Ltd.), aspartame (Ajinomoto Co., Inc.), light anhydrous silicic acid (Adsolider-101, Freund Corporation), and magnesium stearate (vegetable-based, Taihei Chemical Industry Co., Ltd.) were then mixed and compressed using a rotary tablet press to a practical hardness, yielding tablets with a diameter of 7 mm (punches: engraved and scored). The resulting tablets were then evaluated for compression moldability, disintegration, and tableting failure.

[0222] Example 9-1 (Preparation of Drug Particles) A CNF aqueous dispersion (CNF-1 described in <CNFs used in the Examples>) was sprayed onto a powder mixture 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.), and the mixture was granulated using a high-speed agitator mixer. The resulting granules were dried using a tumbling fluidized bed granulator and then classified using sieves with 250 μm and 75 μm openings to prepare drug particles.

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

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

[0228] Example 10-1 (Preparation of Drug Particles) A CNF aqueous dispersion (CNF-1 described in <CNFs used in the Examples>) was added to a powder mixture containing levofloxacin hydrate (0.5 hydrate), hydroxypropyl cellulose (HPC-L FP, Nippon Soda Co., Ltd.), microcrystalline cellulose (Ceolas PH101, Asahi Kasei Corporation), and carmellose (NS-300, Nichirin Chemical Industry Co., Ltd.), and the mixture was granulated using a high-speed agitator mixer. The resulting granules were dried using a tumbling fluidized bed granulator and then classified using a sieve with a screen diameter of 1143 mm to size the drug particles.

[0229] The drug particles, croscarmellose sodium (Ac-Di-Sol, manufactured by DuPont Co., Ltd.), and magnesium stearate (vegetable-based, manufactured by Taihei Chemical Industry Co., Ltd.) were then mixed together, and the mixture was compressed into tablets with an oval punch (major axis 8.1 mm, minor axis 4.7 mm) in a rotary tablet press to a practical hardness, yielding 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 the CNF aqueous dispersion. Subsequently, tablets were obtained using the obtained drug particles in the same manner as in Example 10-1. The obtained tablets were measured for compression moldability, disintegration property, and tableting trouble.

[0233] 〔result〕 The results are shown in Figures 11 to 18. As shown in Figure 11, the CNF-1 used in the examples was very fine. Here, when an attempt was made to measure the average fiber length of the CNF-1 using a Valmet FS5 (detection sensitivity 10 µm or more), a successor to the FS-200 described in Japanese Patent Application Laid-Open No. 2009-203559, 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 the CNF-1 was less than 10 µm.

[0234] 12 and 13, it was found that the Examples were superior to the Comparative Examples in compression moldability and disintegration properties. It was also found that the Examples were superior to the Comparative Examples in tablet hardness after humidification and friability after humidification. Furthermore, among the Examples, Example 3-1, which had the highest CNF content, showed the shortest disintegration time.

[0235] 14 and 15, it was found that tablets containing CNF with a shorter average fiber length (especially less than 10 μm) had better disintegration properties, tablet hardness after humidification, and friability after humidification.

[0236] 16, it was found that Examples 6-1 and 7-1 were superior in compression moldability and disintegrability compared to Comparative Example 4-1. Furthermore, among the Examples, Example 6-1, which had a high proportion of CNF on the particle surface, showed the shortest disintegration time.

[0237] The results of evaluation of tableting troubles are shown in Table 9. In Examples 1-1, 4-1, 5-1 and 8-1, sticking (powder adhesion) did not occur, whereas in Comparative Examples 1-1, 2-1, 3-1 and 5-1, sticking occurred.

[0238] [Table 9]

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

[0240] From FIG. 17, it was found that even when CNF was contained in the drug particles, the Examples had superior disintegration properties compared to the Comparative Examples.

[0241] 18 also shows that Example 9-1 has a higher particle strength than Comparative Example 6-1. This indicates that particles according to one embodiment of the present invention, which contain a drug and CNFs with an average particle size of less than 10 μm, have improved particle strength.

[0242] Furthermore, from Table 10 below, it was found that Example 10-1 had superior disintegration properties and reduced tableting trouble compared to Comparative Example 7-1, despite having similar hardness. Therefore, it was found that a tablet containing particles according to one embodiment of the present invention, which contain a drug and CNFs with an average particle size of less than 10 μm, has excellent compression moldability, disintegration properties, and reduced tableting trouble.

[0243] [Table 10] [Industrial Applicability]

[0244] (Invention 1) The particles have sufficient strength and are therefore suitable for use in a variety of fields where particles are used, such as medicine, food, and cosmetics.

[0245] (Invention 2) The orally disintegrating tablet of the present invention has various improved physical properties and is therefore suitable for use in fields where orally disintegrating tablets are used, such as the pharmaceutical and food fields. [Explanation of symbols]

[0246] 1. Core particle 2 coating layers 3. Middle class

Claims

1. The particle contains cellulose nanofibers with an average particle size of less than 10 μm, the particles are disintegrating particles, the disintegrating particles contain a sugar alcohol and organic and inorganic hydrophilic and water-insoluble additives; the organic hydrophilic and water-insoluble additive comprises at least one selected from the group consisting of starch, starch derivatives, and crospovidone; An orally disintegrating tablet, characterized in that the inorganic hydrophilic and water-insoluble additive comprises light anhydrous silicic acid and / or magnesium aluminometasilicate.

2. The orally disintegrating tablet according to claim 1, characterized in that the cellulose nanofibers have an average fiber diameter of 0.001 to 1 μm.

3. the particle has a core and a coating layer; The orally disintegrating tablet according to claim 1 or 2, wherein the cellulose nanofibers are contained in the coating layer.

4. The particle contains cellulose nanofibers having an average fiber length of less than 10 μm, the particles are disintegrating particles, the disintegrating particles contain a sugar alcohol and organic and inorganic hydrophilic and water-insoluble additives; the organic hydrophilic and water-insoluble additive comprises at least one selected from the group consisting of starch, starch derivatives, and crospovidone; An orally disintegrating tablet, characterized in that the inorganic hydrophilic and water-insoluble additive comprises light anhydrous silicic acid and / or magnesium aluminometasilicate.

5. The composition comprises cellulose nanofibers having an average particle size of less than 10 μm, a sugar alcohol, and organic and inorganic hydrophilic and water-insoluble additives, the organic hydrophilic and water-insoluble additive comprises at least one selected from the group consisting of starch, starch derivatives, and crospovidone; Disintegrable particles, characterized in that the inorganic hydrophilic and water-insoluble additive comprises light anhydrous silicic acid and / or magnesium aluminometasilicate.

6. 1. A method for producing an orally disintegrating tablet comprising the steps of: The production method includes a step of making the particles contain cellulose nanofibers having an average particle diameter of less than 10 μm, the particles are disintegrating particles, the disintegrating particles contain a sugar alcohol and organic and inorganic hydrophilic and water-insoluble additives; the organic hydrophilic and water-insoluble additive comprises at least one selected from the group consisting of starch, starch derivatives, and crospovidone; The method for producing the present invention, wherein the inorganic hydrophilic and water-insoluble additive comprises light anhydrous silicic acid and / or magnesium aluminometasilicate.

7. 1. A method for improving the physical properties of an orally disintegrating tablet comprising particles, The method includes a step of making the particles contain cellulose nanofibers having an average particle diameter of less than 10 μm, the particles are disintegrating particles, the disintegrating particles contain a sugar alcohol and organic and inorganic hydrophilic and water-insoluble additives; the 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 comprises light anhydrous silicic acid and / or magnesium aluminometasilicate; wherein the physical property is at least one of the following physical properties: (1) Compression moldability, (2) Collapsibility, (3) Tableting problems, (4) tablet hardness after humidification, and (5) Friability after humidification.

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