Particle and use thereof

Abstract

To provide a particle in which the core particle thereof is enveloped by a coating layer, and which is ensured in the strength thereof.SOLUTION: A particle is provided, in which the core particle thereof is enveloped by a coating layer and the coating layer includes cellulose nanofibers.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to a particle having a coating layer containing cellulose nanofibers. The present invention also relates to a composition containing the particle, and a method for producing the particle. Furthermore, the present invention relates to a method for ensuring the strength of a particle in which a core particle is covered with a coating layer. [Background technology]

[0002] Core particles have problems such as bitterness depending on the type of active ingredient contained in them, and insufficient stability on their own. Therefore, functional coating technology for coating core particles is being developed with the aim of improving the bitterness and stability of active ingredients.

[0003] For example, Patent Document 1 describes a medicinal particle that is formed of a spherical core containing a medicinal ingredient and a coating portion that covers the spherical core and includes a release-controlling layer and an outermost layer containing mannitol. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] JP 2022-024336 A Summary of the Invention [Problem to be solved by the invention]

[0005] However, the medicinal particles described in Patent Document 1 leave room for improvement in terms of particle strength.

[0006] In view of the above, an object of one aspect of the present invention is to provide a particle in which a core particle is covered with a coating layer and the strength of the particle is ensured.An object of another aspect of the present invention is to provide a method for ensuring the strength of a particle in which a core particle is covered with a coating layer. [Means for solving the problem]

[0007] As a result of intensive research to solve the above problems, the inventors discovered for the first time that the strength of the particles can be ensured by covering 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> The present invention is characterized in that 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> 2. The particle according to any one of claims 1 to 11. <5> <1> ~ <4> A composition comprising the particles according to any one of claims 1 to 5. <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 a particle having a core particle covered with a coating layer, comprising the steps of: The method comprises the 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: The method, characterized in that the coating layer comprises cellulose nanofibers. Effect of the Invention

[0008] According to one aspect of the present invention, it is possible to provide a particle having a core particle covered with a coating layer and having ensured strength. Also, according to one aspect of the present invention, it is possible to provide a method for ensuring the strength of a particle having a core particle covered with a coating layer. [Brief description of the drawings]

[0009] [Figure 1] FIG. 1 is a schematic diagram illustrating a particle according to one embodiment of the present invention. [Diagram 2] FIG. 2 is a graph showing the results of dissolution tests using particles and tablets in Examples 1 to 3 and Comparative Examples 1 to 3. [Diagram 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. 13 is a graph showing the results of measuring particle strength using particles in Example 5 and Comparative Example 8. [Diagram 5] FIG. 1 shows the results of dissolution tests using particles and tablets in Example 6 and Comparative Example 9. [Figure 6] FIG. 13 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. 13 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. 13 is a graph showing the results of measuring particle strength using particles in Example 8 and Comparative Example 11. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] 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."

[0011] 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.

[0012] Moreover, a composition according to one embodiment of the present invention (hereinafter referred to as "the present composition") is characterized by containing the present particles.

[0013] Furthermore, a method for producing particles in which core particles are covered 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.

[0014] In addition, the method for ensuring the strength of a core particle 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.

[0015] Particles having a functional coating as described in Patent Document 1 have had problems such as film cracking of the functional coating layer due to tableting stress, which can lead to leakage of active ingredients (e.g., drugs) contained in the core particles. Furthermore, conventional particles in which the core particles are covered with a coating layer have room for improvement in terms of strength.

[0016] Therefore, the present inventors conducted extensive research from the viewpoint of ensuring the strength of particles in which a core particle is covered with a coating layer, and as a result, succeeded in obtaining the following findings. The strength of the particles can be improved by covering the core particles with a coating layer containing cellulose nanofibers. In a particle comprising a core particle, an intermediate layer, and a coating layer, by incorporating cellulose nanofibers in the coating layer, the strength of the particle can be improved and cracking of the intermediate layer during tableting can be prevented.

[0017] It has not been known that cellulose nanofibers contribute to particle strength. Therefore, it is surprising that the present inventors focused on cellulose nanofibers for the purpose of ensuring 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 including cellulose nanofibers in the outer layer (e.g., coating layer) of the core particles without adding cellulose nanofibers to the core particles.

[0018] As described above, the present particles exhibit advantageous effects based on the above findings, and therefore can be used extremely advantageously in various fields in which particles including a coating layer are used as raw materials.

[0019] [2. Particles] In the present particle, a core particle is covered with a coating layer, and the coating layer contains cellulose nanofibers. Since the coating layer contains cellulose nanofibers, the present particle has an effect of ensuring the strength of the particle.

[0020] 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 the strength of the particles.

[0021] Hereinafter, an embodiment 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.

[0022] 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 medical purposes as an example. However, it goes without saying that the use of the present particles is not limited to medicine.

[0023] <Embodiment 1> Embodiment 1 is shown in the upper diagram of Figure 1. In embodiment 1, a core particle 1 is covered with an intermediate layer 3, and the intermediate layer 3 is further covered with a coating layer 2. The coating layer 2 contains cellulose nanofibers. In embodiment 1, the core particle 1 is covered with the intermediate layer 3 and the coating layer 2, which has the effect of improving particle strength. In addition, it has the effect of preventing the intermediate layer from cracking during tableting.

[0024] 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 medicines, food ingredients, nutrients, micronutrients, flavorings, and fragrances.

[0025] Coating layer 2 is located external to intermediate layer 3. In embodiments in which the particle does not include intermediate layer 3, coating layer 2 is located external to core particle 1.

[0026] The coating layer 2 contains cellulose nanofibers. In this specification, the term "cellulose nanofibers" refers to cellulose fibers having a nano-sized fiber diameter that are prepared by subjecting cellulose to a mechanical treatment.

[0027] 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, it is possible to perform appropriate coating. In addition, it is possible to maintain the particle size after coating at an appropriate level. The average fiber diameter of the cellulose nanofibers means the average fiber diameter measured for any 10 or more cellulose nanofibers in an image obtained by a scanning probe microscope.

[0028] 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 fiber length of the cellulose nanofiber is 0.001 to 100 μm, appropriate coating can be performed. In addition, the particle size after coating can be appropriately maintained. The fiber length of the cellulose nanofiber is measured by image analysis.

[0029] 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.

[0030] 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 of the functional coating layer include layers containing bitterness masking agents, enteric bases, sustained-release bases, moisture-proof bases, light-resistant bases, shielding bases, etc.

[0031] 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.

[0032] 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, those described in (Coating layer) are used.

[0033] The intermediate layer 3 may be a single layer or a multilayer. When the intermediate layer 3 is a multilayer, the number of layers is not particularly limited, and may be, for example, two layers, three layers, four layers, five layers, etc. When the intermediate layer 3 is a multilayer, each layer may be the same functional coating layer or different functional coating layers. Preferably, each layer is a different functional coating layer.

[0034] 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.

[0035] 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.

[0036] The binder is not particularly limited, but examples thereof include hydroxypropyl cellulose, hydroxypropyl methylcellulose (also called "hypromellose"), povidone, methylcellulose, 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.

[0037] The lubricant is not particularly limited, but examples thereof include inactive substances such as talc, kaolin, titanium dioxide, magnesium stearate, calcium stearate, stearic acid, light anhydrous silicic acid, finely ground silicon dioxide, sodium stearyl fumarate, glycerin fatty acid esters, etc. Glycerin fatty acid esters are preferably used.

[0038] 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.

[0039] The colorant is not particularly limited, but examples thereof include yellow colorants (e.g., yellow ferric oxide, yellow ferric 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 ferric 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.

[0040] 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.

[0041] In one embodiment of the present invention, the particle is composed of a core particle 1, a shielding layer (middle layer 3), and a bitterness-masking functional coating layer (coating layer 2) containing cellulose nanofibers.

[0042] <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, the core particle 1 is coated with the coating layer 2, which has the effect of improving particle strength.

[0043] In embodiment 2, the particle does not include an intermediate layer 3. In this case, the content of the cellulose nanofiber is, for example, 0.1 to 10.0 mass% relative to the mass of the core particle 1, 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%. 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.

[0044] In the second embodiment, the coating layer 2 only needs to contain cellulose nanofibers, and may contain any other additives. Examples of such additives include those described in the first embodiment.

[0045] In addition, in the second embodiment, the "core particle" is the same as that described in the first embodiment.

[0046] <Embodiment 3> Embodiment 3 is shown in the lower diagram of Figure 1. In embodiment 3, similar to embodiment 2, a core particle 1 is coated with a coating layer 2. The coating layer 2 is composed only of cellulose nanofibers. In embodiment 3, the core particle 1 is coated with the coating layer 2, which has the effect of improving the particle strength.

[0047] In embodiment 3, the particle does not include an intermediate layer 3. In this case, the content of the cellulose nanofiber is, for example, 0.1 to 10.0 mass% relative to the mass of the core particle 1, 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%. 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.

[0048] In the third embodiment, the "core particle" is the same as that described in the first embodiment.

[0049] [3. Composition] The present composition contains the particles described in [2. Particles] (i.e., the present particles). Since the present composition contains particles with ensured strength, the active ingredient contained in the core particle can be utilized more effectively.

[0050] 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.

[0051] In addition to the particles, the composition may contain various additives depending on the application. When the application is a medicine, for example, the additives described in the section of <Embodiment 1> may be used.

[0052] 4. Method for Producing Particles The present production method is a method for producing particles in which a core particle is coated with a coating layer, and includes a step of coating the core particle with a coating layer containing cellulose nanofibers. By coating the core particle with a coating layer containing cellulose nanofibers, the present production method can ensure the strength of the particle.

[0053] In the present production method, the method for covering the core particles with a coating layer is not particularly limited, and any method known in the art can be used.

[0054] In one embodiment of the present invention, the method includes coating the core particles with an intermediate layer.

[0055] In another embodiment of the present invention, the present manufacturing method is a method for manufacturing particles in which a core particle is covered with a coating layer, the method comprising the steps of coating the core particle with an intermediate layer, and coating the intermediate layer with a coating layer containing cellulose nanofibers.

[0056] In this method, the terms "core particle," "coating layer," "cellulose nanofiber," and "intermediate layer" are defined in [2. Particles] by reference.

[0057] 5. How to ensure particle strength This method is a method for ensuring the strength of particles in which core particles are covered with a coating layer, and is characterized in that the coating layer contains cellulose nanofibers. In this method, the strength of the particles can be ensured by including cellulose nanofibers in the coating layer.

[0058] 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.

[0059] In this method, the terms "core particle," "coating layer," and "cellulose nanofiber" are defined in [2. Particles] by way of reference.

[0060] 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. EXAMPLES

[0061] The present invention will be described in more detail below based on examples, but the present invention is not limited to these examples.

[0062] [Measurement and evaluation methods] The evaluations in the examples and comparative examples were carried out by the following methods.

[0063] (Dissolution test) The average dissolution rate of particles (overcoated particles, masking particles) and tablets was measured according to the Japanese Pharmacopoeia dissolution test paddle method (rotation speed 75 rpm, dissolution test second liquid 900 mL). For particle dissolution tests, to prevent adhesion and aggregation of particles during the dissolution test, disintegrative particles were mixed with the particles in equal parts beforehand and placed in the test vessel. The dissolution rate was measured at a measurement wavelength of 288 nm using a fiber probe type ultraviolet-visible spectrophotometer.

[0064] (particle strength) The particle strength was measured using a microcompression tester (MCT-210, manufactured by Shimadzu Corporation).

[0065] Example 1 Preparation of Drug Particles A 50% (w / w) ethanol solution was sprayed onto a mixed powder containing levofloxacin hydrate (0.5 hydrate), hydroxypropyl cellulose (HPC-L (75 μm-106 μm), Nippon Soda Co., Ltd.), and low-substituted hydroxypropyl cellulose (LH-31, Shin-Etsu Chemical Co., Ltd.), and granulated using a high-speed stirring 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).

[0066] (Preparation of Masking Particles) The obtained drug particles were placed in a tumbling fluidized bed granulator. Aminoalkyl methacrylate copolymer E (Eudragit E, Evonik Co., Ltd.) was dissolved in a 90% (w / w) ethanol solution, and then talc (Microace P-3, Nippon Talc Co., Ltd.) was dispersed in the solution. The drug particles were sprayed with this solution to coat the Eudragit E and talc, and masked particles (particles in which the core particles are covered with a coating layer) were prepared.

[0067] (Preparation of Overcoat Particles) The obtained masked particles were put into a rolling fluidized bed granulator. A 5% (w / v) aqueous dispersion (5% viscosity: 40000 mPa·s) of cellulose nanofibers (Binfis WFo-100 5%, average fiber diameter about 10-50 nm, fiber length about 10 μm or less, manufactured by Sugino Machine Co., Ltd.) was diluted with water to 1% (w / v), and then treated at 10000 rpm for 20 minutes using a homogenizer. This solution was sprayed to coat the masked particles with cellulose nanofibers, preparing 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 relative to the mass of the masked particles.

[0068] (Preparation of disintegrating particles) 71 parts by weight of D-mannitol, 2 parts by weight of ethyl cellulose, and 1 part by weight of light anhydrous silicic acid were placed in a fluidized bed granulator, and a liquid prepared by dispersing 20 parts by weight of corn starch and 6 parts by weight of crospovidone in 80 parts by weight of water was sprayed onto the mixture to granulate it, which was then dried and sized to obtain disintegrating particles.

[0069] (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 tab. A dissolution test was performed using the masked particles and tablets.

[0070] The composition of each component is shown in Table 1.

[0071] [Table 1]

[0072] Example 2 The same method as in Example 1 was used up to the preparation of the masked particles.

[0073] (Preparation of Overcoat Particles) The obtained masked particles were put into a rolling fluidized bed granulator. A 5% (w / v) aqueous dispersion (5% viscosity: 20000 mPa·s) of cellulose nanofibers (Binfis AFo-100 5%, average fiber diameter about 10-50 nm, fiber length about 0.5-1.0 μm, manufactured by Sugino Machine Co., Ltd.) was diluted with water to 1% (w / v), and then treated at 10000 rpm for 20 minutes using a homogenizer. This solution was sprayed to coat the masked particles with cellulose nanofibers, preparing overcoated particles. The amount of cellulose nanofiber coated was 2% by mass relative to the mass of the masked particles.

[0074] Subsequently, preparation of disintegrating particles and tableting were carried out in the same manner as in Example 1. A dissolution test was carried out using the overcoated particles and tablets.

[0075] Example 3 The masked particles were prepared in the same manner as in Example 1. (Preparation of Overcoat Particles) The obtained masked particles were placed in a tumbling fluidized bed granulator. A liquid containing crystalline cellulose converted into cellulose nanofibers so that the viscosity of the 2% (w / v) aqueous dispersion was 1000 mPa·s or more was added with water to make it 1% (w / v) and then diluted, and the mixture was treated at 10,000 rpm for 20 minutes using a homogenizer. This solution was sprayed to coat the masked particles with the crystalline cellulose converted into cellulose nanofibers, thereby preparing overcoated particles. The coating amount of the crystalline cellulose converted into cellulose nanofibers was 2% by mass relative to the mass of the masked particles.

[0076] Subsequently, preparation of disintegrating particles and tableting were carried out in the same manner as in Example 1. A dissolution test was carried out using the overcoated particles and tablets.

[0077] 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.

[0078] Next, disintegrative particles were prepared in the same manner as in Example 1.

[0079] (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 tab. A dissolution test was performed using the masked particles and tablets.

[0080] Comparative Example 2 The same method as in Example 1 was used up to the preparation of the masked particles.

[0081] (Preparation of Overcoat Particles) Hydroxypropyl cellulose (HPC-SL, Nippon Soda Co., Ltd.) was dissolved in water to a concentration of 1% (w / v), and the solution was sprayed to coat the masked particles with HPC-SL to prepare overcoated particles. The coating amount of HPC-SL was 2% by mass relative to the mass of the masked particles.

[0082] Subsequently, preparation of disintegrating particles and tableting were carried out in the same manner as in Example 1. Using the overcoated particles and tablets, a dissolution test (RT-J2000, manufactured by Dai-Nippon Seiki Co., Ltd.) was carried out.

[0083] Comparative Example 3 The same method as in Example 1 was used up to the preparation of the masked particles.

[0084] (Preparation of Overcoat Particles) Ethyl cellulose (Ethocel Standard FP7CPS Premium, manufactured by Daw Chemical Co., Ltd.) was dissolved in 90% (w / w) ethanol to a concentration of 1% (w / v). This solution was sprayed to coat the masking particles with ethyl cellulose, preparing overcoated particles. The coating amount of ethyl cellulose was 2% by mass relative to the mass of the masking particles.

[0085] Subsequently, preparation of disintegrating particles and tableting were carried out in the same manner as in Example 1. A dissolution test was carried out using the overcoated particles and tablets.

[0086] [Result-1] The results of the dissolution test carried out on the particles (overcoated particles and masked particles) and tablets produced in the above Examples 1 to 3 and Comparative Examples 1 to 3 are shown in FIG.

[0087] Comparing the Examples and Comparative Examples in FIG. 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 fact that there is little change in dissolution behavior between the particles and the tablets means that cracking of the masking layer (intermediate layer) during tableting can be prevented. Therefore, it was shown that in a particle including a core particle, an intermediate layer, and a coating layer, a particle according to one embodiment of the present invention in which the coating layer includes cellulose nanofibers can prevent cracking of the intermediate layer during tableting (i.e., the strength of the particle can be ensured).

[0088] Example 4 Using the obtained overcoated particles, the particle strength was measured in the same manner as in Example 1.

[0089] 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.

[0090] Comparative Example 5 Using the masked particles thus obtained, the particle strength was measured in the same manner as in Comparative Example 1.

[0091] Comparative Example 6 Using the same method as in Comparative Example 2, the particle strength of the obtained overcoated particles was measured.

[0092] Comparative Example 7 Using the same method as in Comparative Example 3, the particle strength of the obtained overcoated particles was measured.

[0093] Example 5 The procedures up to the preparation of drug particles were the same as those in Example 1.

[0094] (Preparation of Masking Particles) The obtained drug particles were put into 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 solution was sprayed to coat the drug particles with cellulose nanofibers, preparing 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.

[0095] Using the masked particles thus obtained, the particle strength was measured.

[0096] 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.

[0097] [Result-2] The particle strength of the particles (drug particles, masked particles, and overcoated particles) produced in the above Examples 4 and 5 and Comparative Examples 4 to 8 was measured, and the results are shown in FIGS.

[0098] 3, it can be seen that Example 4 has a higher particle strength than Comparative Examples 4 to 7. Therefore, it was demonstrated that, in a particle including a core particle, an intermediate layer, and a coating layer, a particle according to one embodiment of the present invention in which the coating layer includes cellulose nanofibers has improved particle strength.

[0099] 4, it can be seen that the particle strength is higher in Example 5 than in Comparative Example 8. This shows that the particle strength of the particles according to one embodiment of the present invention in which the core particles are covered with a coating layer composed of cellulose nanofibers is improved.

[0100] Example 6 The procedures up to the preparation of drug particles were the same as those in Example 1.

[0101] (Preparation of Masking Particles) The obtained drug particles were put into a rolling fluidized bed granulator. A 5% (w / v) aqueous dispersion of cellulose nanofibers (Binfis AFo-100 5%, manufactured by Sugino Machine Co., Ltd.) was diluted 3-fold with ethanol, and then treated at 10,000 rpm for 20 minutes using a homogenizer to obtain 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 so that the final ethanol solution was 80% (w / w). This liquid was sprayed onto the drug particles to coat the Eudragit E and cellulose nanofibers, and masked particles were prepared.

[0102] Subsequently, disintegrating particles were prepared and tableted in the same manner as in Example 1. The obtained masked particles and tablets were used to carry out a dissolution test. In addition, the obtained masked particles were used to measure particle strength.

[0103] The composition of each component is shown in Table 2.

[0104] [Table 2]

[0105] Comparative Example 9 The procedures up to the preparation of drug particles were the same as those in Example 1.

[0106] (Preparation of Masking Particles) The obtained drug particles were placed in a tumbling fluidized bed granulator. Aminoalkyl methacrylate copolymer E (Eudragit E, Evonik Co., Ltd.) was dissolved in an 80% (w / w) ethanol solution, and then talc (Microace P-3, Nippon Talc Co., Ltd.) was dispersed in the solution. The solution was sprayed onto the drug particles to coat them with Eudragit E and talc, preparing masked particles (particles in which the core particles are covered with a coating layer).

[0107] Subsequently, disintegrating particles were prepared and tableted in the same manner as in Example 1. The obtained masked particles and tablets were used to carry out a dissolution test. In addition, the obtained masked particles were used to measure particle strength.

[0108] [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.

[0109] 5, it can be seen 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 a particle including a core particle and a coating layer, a particle according to one embodiment of the present invention in which the coating layer includes cellulose nanofibers can prevent cracking of the coating layer during tableting.

[0110] 6 also shows that Example 6 has a higher particle strength than Comparative Example 9. This shows that, in particles including a core particle and a coating layer, particles according to one embodiment of the present invention in which the coating layer includes cellulose nanofibers have improved particle strength.

[0111] Example 7 The procedures up to the preparation of drug particles were the same as those in Example 1.

[0112] (Preparation of Masking Particles) The obtained drug particles were placed in a rolling fluidized bed granulator. Aminoalkyl methacrylate copolymer RL and aminoalkyl methacrylate copolymer RS ​​(Eudragit RL and RS, manufactured by Evonik Co., Ltd.) were dissolved in a 90% (w / w) ethanol solution, and then talc (Microace P-3, manufactured by Nippon Talc Co., Ltd.) was dispersed therein. The solution was sprayed onto the drug particles to prepare masked particles (particles in which the core particles are covered with a coating layer).

[0113] (Preparation of Overcoat Particles) The masked particles obtained were placed in a tumbling fluidized bed granulator. A 2% (w / v) aqueous dispersion (2% viscosity: 6000 mPa·s) of cellulose nanofiber (Binfis WFo-100 2%, 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. This solution was sprayed 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 relative to the mass of the masked particles.

[0114] Subsequently, preparation of disintegrating particles and tableting (tabletting pressure 11 kN) were performed in the same manner as in Example 1. A dissolution test was performed using the overcoated particles and tablets.

[0115] The composition of each component is shown in Table 3.

[0116] [Table 3]

[0117] 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.

[0118] Subsequently, preparation of disintegrating particles and tableting (tabletting pressure 11 kN) were performed in the same manner as in Example 1. A dissolution test was performed using the masked particles and tablets.

[0119] [Result-4] The particles (overcoated particles) and tablets produced in Example 7 and Comparative Example 10 were subjected to measurement of dissolution rate and particle strength, and the results are shown in FIGS.

[0120] 7, it can be seen 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 a particle including a core particle, an intermediate layer, and a coating layer, a particle according to one embodiment of the present invention including cellulose nanofibers in the coating layer can prevent cracking of the coating layer during tableting.

[0121] 8, it can be seen that Example 7 has a higher particle strength than Comparative Example 10. Therefore, it was demonstrated that, in a particle including a core particle, an intermediate layer, and a coating layer, a particle according to one embodiment of the present invention in which the coating layer includes cellulose nanofibers has improved particle strength.

[0122] Example 8 The procedures up to the preparation of drug particles were the same as those in Example 1.

[0123] (Preparation of Masking Particles) The obtained drug particles were placed in a tumbling fluidized bed granulator. Ethyl cellulose (Ethocel, Standard FP7CPS Premium, Daw Chemical Co., Ltd.) was dissolved in a 90% (w / w) ethanol solution, and then talc (Microace P-3, Nippon Talc Co., Ltd.) and hydrated silicon dioxide (Adsolider-102, Freund Corporation) were dispersed. This solution was sprayed onto the drug particles to prepare masked particles (particles in which the core particles are covered with a coating layer).

[0124] (Preparation of Overcoat Particles) The masked particles obtained were placed in a tumbling fluidized bed granulator. A 5% (w / v) aqueous dispersion (5% viscosity: 20,000 mPa·s) of cellulose nanofiber (Binfis AFo-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. 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 relative to the mass of the masked particles.

[0125] Subsequently, preparation of disintegrating particles and tableting (tabletting pressure 7 kN) were performed in the same manner as in Example 1. A dissolution test was performed using the overcoated particles and tablets.

[0126] The composition of each component is shown in Table 4.

[0127] [Table 4]

[0128] 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.

[0129] Subsequently, preparation of disintegrating particles and tableting (tabletting pressure 7 kN) were performed in the same manner as in Example 1. A dissolution test was performed using the overcoated particles and tablets.

[0130] [Result-5] The particles (overcoated particles) and tablets produced in Example 8 and Comparative Example 11 were subjected to measurement of dissolution rate and particle strength, and the results are shown in FIGS.

[0131] 9, it can be seen 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 a particle including a core particle, an intermediate layer, and a coating layer, a particle according to one embodiment of the present invention including cellulose nanofibers in the coating layer can prevent cracking of the coating layer during tableting.

[0132] 10, it can be seen that Example 8 has a higher particle strength than Comparative Example 11. Therefore, it was demonstrated that, in a particle including a core particle, an intermediate layer, and a coating layer, a particle according to one embodiment of the present invention in which the coating layer includes cellulose nanofibers has improved particle strength. [Industrial Applicability]

[0133] Since the particles of the present invention have sufficient strength, they are suitable for use in various fields in which particles are used, such as the fields of medicine, food, cosmetics, etc. [Explanation of symbols]

[0134] 1. Core Particle 2 Coating Layer 3. Middle tier

Claims

[Claim 1] Particles as described in the specification.

Images