Film-coated granules, formulations containing the same, and methods for producing the same.

Abstract

To provide film-coated granules which have a new film constitution, to provide a pharmaceutical preparation containing the film-coated granules which have a new film constitution, to provide a new dry manufacturing method of the film-coated granules, and to provide a new dry manufacturing method of the pharmaceutical preparation containing the film-coated granules.SOLUTION: According to one embodiment of the present invention, a film-coated granule is provided that comprises a core particle having a melt component, and a film disposed on a surface of the core particle, wherein the film includes a porous substance, a plasticizer and a polymer.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] One embodiment of the present invention relates to film-coated granules. Or, one embodiment of the present invention relates to a pharmaceutical preparation containing film-coated granules. Or, one embodiment of the present invention relates to a method for producing film-coated granules. Or, one embodiment of the present invention relates to a method for producing a pharmaceutical preparation containing film-coated granules.

Background Art

[0002] In pharmaceutical preparations, coating is performed for various purposes such as controlling the dissolution of drugs such as gastric solubility, enteric solubility, and sustained release, and masking the bitterness of drugs. Coating methods are roughly classified into dry methods and wet methods. In the wet method, a huge production time is generally required for spraying and drying the solvent. Also, in the wet method, the solvent may have an adverse effect on the stability of the drug. For this reason, for example, in Patent Document 1, as a method that does not use a solvent, while continuously spraying a mixture of a liquid substance having a contact angle of 10° or less with respect to a polymer coating agent and a plasticizer onto a solid drug, a method of spraying and coating a powdery polymer coating agent is described. However, the method of Patent Document 1 requires special equipment capable of introducing a certain amount of powder into the production apparatus. Also, in the method of Patent Document 1, the granulated product is likely to agglomerate and can only be applied to particles or tablets having a large particle diameter.

[0003] On the other hand, as a dry method, Patent Document 2 describes a method of crushing particles after a layering step of attaching a polymer to particles having a core and a wax layer covering it in a dry manner. However, since many of the existing technologies of the dry method are powder coatings, the formed film may not be dense and there is a possibility that the intended function cannot be obtained. Also, when forming a dense film by the conventional technology, there was a problem that the polymer used for the coating was limited to a polymer having a low minimum film-forming temperature.

Prior Art Documents

Patent Documents

[0004] [Patent Document 1] Patent No. 3417772 [Patent Document 2] Patent No. 6067154 [Overview of the Initiative] [Problems that the invention aims to solve]

[0005] One embodiment of the present invention aims to provide film-coated granules having a novel film structure. Alternatively, one embodiment of the present invention aims to provide a formulation containing film-coated granules having a novel film structure. Alternatively, one embodiment of the present invention aims to provide a novel dry method for producing film-coated granules. Alternatively, one embodiment of the present invention aims to provide a novel dry method for producing a formulation containing film-coated granules. [Means for solving the problem]

[0006] According to one embodiment of the present invention, a film-coated granule is provided, comprising core particles containing a molten component and a film disposed on the surface of the core particles, wherein the film comprises a porous material, a plasticizer, and a polymer.

[0007] The plasticizer may be selected from plasticizers that can be positioned between polymer molecules.

[0008] The plasticizer is one or more selected from the group consisting of triethyl citrate, polyethylene glycol, propylene glycol, triacetin, and tributyl acetyl citrate, and the polymer may be one or more selected from the group consisting of hypromellose acetate succinate, hydroxypropyl cellulose, ethyl cellulose, vinyl acetate, methacrylic acid copolymer L, ammonia alkyl methacrylate copolymer, and methacrylic acid copolymer S.

[0009] The core particle may include a core material, a molten component layer disposed on the surface of the core material, and an active pharmaceutical ingredient (API) containing layer disposed on the surface of the molten component layer.

[0010] The core particle contains the active pharmaceutical ingredient and a molten component, and the active pharmaceutical ingredient and the molten component may be bound together.

[0011] The core particle may further contain a polymer, and the active pharmaceutical ingredient, the molten component, and the polymer may be bound together.

[0012] The film may further contain one or more first additives that are pharmaceutically acceptable.

[0013] According to one embodiment of the present invention, a formulation is provided comprising any of the above-described film-coated granules and one or more pharmaceutically acceptable second additives.

[0014] According to one embodiment of the present invention, a method for producing film-coated granules is provided, which involves adsorbing a plasticizer onto a porous material, adsorbing the porous material with the adsorbed plasticizer onto core particles containing a molten component to obtain first particles, and adsorbing a polymer onto the first particles to form a film on the core particles containing the porous material, the plasticizer, and the polymer.

[0015] A polymer may be adsorbed onto the first particles at a first temperature, and a film may be formed on the core particles at a second temperature higher than the first temperature.

[0016] The plasticizer may be selected from plasticizers that can be positioned between polymer molecules.

[0017] The plasticizer is one or more selected from the group consisting of triethyl citrate, polyethylene glycol, propylene glycol, triacetin, and tributyl acetyl citrate, and the polymer may be one or more selected from the group consisting of hypromellose acetate succinate, hydroxypropyl cellulose, ethyl cellulose, vinyl acetate, methacrylic acid copolymer L, ammonia alkyl methacrylate copolymer, and methacrylic acid copolymer S.

[0018] A molten component may be adsorbed onto a nucleus material to form a molten component layer, and an active pharmaceutical ingredient (API) may be adsorbed onto the molten component to form an API-containing layer containing the molten component and the API, thereby obtaining nucleus particles.

[0019] The molten component and the active pharmaceutical ingredient may be bound together to obtain a core particle containing the molten component and the active pharmaceutical ingredient.

[0020] A molten component, an active pharmaceutical ingredient, and a polymer may be bonded together to obtain particles containing the molten component, the active pharmaceutical ingredient, and the polymer.

[0021] When forming the film on the nucleus particles, one or more pharmaceutically acceptable lubricants may be added.

[0022] According to one embodiment of the present invention, a method for producing a pharmaceutical product is provided, which involves mixing film-coated granules obtained by any of the above-described methods for producing film-coated granules with one or more pharmaceutically acceptable second additives and then compressing the mixture into tablets. [Effects of the Invention]

[0023] According to one embodiment of the present invention, film-coated granules having a novel film structure are provided. Alternatively, according to one embodiment of the present invention, a formulation comprising film-coated granules having a novel film structure is provided. Alternatively, according to one embodiment of the present invention, a novel dry method for producing film-coated granules is provided. Alternatively, according to one embodiment of the present invention, a novel dry method for producing a formulation comprising film-coated granules is provided.

Brief Description of the Drawings

[0024] [Figure 1] It is a schematic diagram (cross-sectional end view) showing a film-coated granule 100 according to an embodiment of the present invention. [Figure 2] It is a schematic diagram (cross-sectional end view) showing a core particle 10 according to an embodiment. [Figure 3] It is a flowchart for explaining a method for manufacturing a core particle 10 according to an embodiment of the present invention. [Figure 4] It is a schematic diagram (cross-sectional end view) showing a core particle 20 according to an embodiment. [Figure 5] It is a flowchart for explaining a method for manufacturing a core particle 20 according to an embodiment. [Figure 6] It is a schematic diagram (cross-sectional end view) showing a film-coated granule 200 according to an embodiment. [Figure 7] (A) is a flowchart for explaining a step of preparing a porous substance 150 adsorbed with a plasticizer according to an embodiment, and (B) is a flowchart for explaining a method for manufacturing a film-coated granule 100 according to an embodiment. [Figure 8] (A) is a scanning electron microscope image of the particles of Example 1 before curing, (B) is a scanning electron microscope image of the particles of Example 1 after curing, (C) is a scanning electron microscope image of the particles of Example 2 before curing, and (D) is a scanning electron microscope image of the particles of Example 2 after curing. [Figure 9] (A) is a scanning electron microscope image of the particles of Comparative Example 2 before curing, and (B) is a scanning electron microscope image of the particles of Comparative Example 2 after curing. [Figure 10] It is a diagram showing the dissolution rate of duloxetine hydrochloride in the film-coated granules of Example 3 and Comparative Example 4.

Modes for Carrying Out the Invention

[0025] The film-coated granules, formulations containing them, and methods for producing them according to the present invention will be described below with reference to the drawings. However, the film-coated granules, formulations containing them, and methods for producing them according to the present invention are not limited to the descriptions of the embodiments and examples shown below. In the drawings referenced in these embodiments and the examples described later, the same parts or parts having similar functions are denoted by the same reference numerals, and repeated descriptions thereof are omitted.

[0026] As mentioned above, when using the dry process, the polymer is attached in powder form, resulting in a low film density. In the dry process, to produce a dense film, it is necessary to soften the polymer by heating it to a temperature above its minimum film-forming temperature to form a film. However, considering the thermal stability of the active pharmaceutical ingredient and the heating limits of the manufacturing equipment, the polymers that can be used are limited to those with low minimum film-forming temperatures. Therefore, when using other polymers, it is necessary to lower the minimum film-forming temperature of the polymer. For example, in the wet process, a technique is known to lower the minimum film-forming temperature of the polymer by adding a plasticizer that lowers the glass transition temperature of the polymer. It is also expected that adding a plasticizer in the dry process will lower the minimum film-forming temperature of the polymer. On the other hand, the polymer and plasticizer react rapidly, causing the polymer to soften rapidly, resulting in the particles sticking together and forming aggregates.

[0027] In this invention, by using a porous material on which a plasticizer has been adsorbed, the plasticizer gradually seeps out from the pores of the porous material. As a result, the rapid softening of the polymer caused by the rapid reaction between the polymer and the plasticizer is avoided, and the above-mentioned problem is resolved.

[0028] [Film-coated granules] Figure 1 is a schematic diagram (cross-sectional end view) showing film-coated granules 100 according to one embodiment of the present invention. The film-coated granules 100 include core particles 10 containing molten components and a film 130 disposed on the surface of the core particles 10. The film 130 includes a porous material 150, a plasticizer, and a polymer. The method for manufacturing the film-coated granules 100 will be described later, but in the film-coated granules 100 according to this embodiment, when forming the film 130, the plasticizer adsorbed on the porous material 150 gradually seeps out from the porous material 150 and mixes with the polymer, thereby lowering the glass transition temperature of the polymer. As a result, the film 130 becomes a dense film.

[0029] In this embodiment, it is not essential that all of the plasticizer seeps out of the porous material 150, and some of the plasticizer may be adsorbed onto the porous material 150. The porous material 150 can be selected from pharmaceutically acceptable porous materials. In one embodiment, "porous material" refers to particles with numerous pores formed on their surface. In one embodiment, the porous material 150 is a particle that satisfies one or more of the following: bulk density of 2 ml / g to 18 ml / g, BET specific surface area of ​​110 m² / g to 700 m² / g, pore volume of 0.4 cm³ / g to 2.1 cm³ / g, or oil absorption of 1 ml / g to 4 ml / g. In one embodiment, the porous material 150 is a pharmaceutically acceptable porous silicate, which can be selected from hydrated silicon dioxide, light anhydrous silicic acid, or magnesium aluminometasilicate. In one embodiment, the plasticizer is adsorbed on the surface and / or inside the pores of the porous material 150. In one embodiment, the film-coated granules 100 may contain 1% to 30% by weight of porous material 150 relative to 100% by weight of film-coated granules.

[0030] In one embodiment, the plasticizer can be selected from plasticizers that can be positioned between polymer molecules. The plasticizer is selected from, for example, the group consisting of triethyl citrate, polyethylene glycol, propylene glycol, triacetin, and tributyl acetylcitrate, but is not limited to these. In one embodiment, the film coating granules 100 may contain 1% to 30% by weight of plasticizer per 100% by weight of film coating granules.

[0031] In one embodiment, the polymer is selected from additives capable of forming a film, and is selected from the group consisting of, for example, hypromellose acetate succinate, hydroxypropyl cellulose, ethyl cellulose, vinyl acetate, methacrylic acid copolymer L, ammonia alkyl methacrylate copolymer, and methacrylic acid copolymer S, but is not limited thereto. In one embodiment, the film coating granules 100 may contain 1% to 30% by weight of the polymer per 100% by weight of the film coating granules.

[0032] In one embodiment, the film may further contain one or more pharmaceutically acceptable additives (first additives). The composition of the core particles 10 and the porous material 150 may be the same as that described above, and a detailed explanation is omitted. The polymer contained in the film 130 can also be selected from the polymers described above. Additives that can be contained in the film 130 are, for example, one or more additives selected from the group consisting of hypromellose, polyvinylpyrrolidone, polyvinyl alcohol, mannitol, erythritol, trehalose, lactose monohydrate, crospovidone, starch, low-substituted hydroxypropyl cellulose, talc, titanium dioxide, stearic acid, magnesium stearate, light anhydrous silicic acid, hydrated silicon dioxide, dibutylhydroxytoluene, aspartame, and sucralose.

[0033] [Nuclear particle] In this embodiment, the core particle 10 contains a molten component at least on its surface. The core particle 10 also contains an active pharmaceutical ingredient. Figure 2(A) is a schematic diagram (cross-sectional end view) showing a core particle 10 according to one embodiment. In one embodiment, the core particle 10 includes a core material 11, a molten component layer 13 disposed on the surface of the core material 11, and an active pharmaceutical ingredient-containing layer 15 disposed on the surface of the molten component layer 13.

[0034] The core material 11 is a carrier for arranging the molten component layer 13 and the active pharmaceutical ingredient-containing layer 15, and is a core material for arranging the molten component layer 13 and the active pharmaceutical ingredient-containing layer 15 when manufacturing core particles 10. The core material 11 can be selected from the group consisting of, for example, amberlite IRP-64, ion exchange resin, kaolin, carmellose calcium, hydrated silicon dioxide, magnesium silicate, light anhydrous silicic acid, light liquid paraffin, diatomaceous earth, synthetic aluminum silicate, aluminum oxide, aluminum hydroxide, absorbent cotton, magnesium carbonate, precipitated calcium carbonate, dextrin, silicon dioxide, composite aluminum potassium silicate granules, bentonite, polyethylene fiber, magnesium aluminometasilicate, medicinal charcoal, calcium silicate, cellulose acetate, anhydrous calcium hydrogen phosphate, crystalline cellulose, mannitol, sucrose, starch, lactose monohydrate, ammonia alkyl methacrylate copolymer, etc. As will be described later, the nuclear material 11 is preferably an adsorbent such as amberlite IRP-64, ion exchange resin, kaolin, carmellose calcium, hydrated silicon dioxide, magnesium silicate, light anhydrous silicic acid, light liquid paraffin, diatomaceous earth, synthetic aluminum silicate, aluminum oxide, aluminum hydroxide, absorbent cotton, magnesium carbonate, precipitated calcium carbonate, dextrin, silicon dioxide, composite aluminum potassium silicate granules, bentonite, polyethylene fiber, magnesium aluminometasilicate, and medicinal charcoal.

[0035] The nuclear material 11 is preferably spherical in shape in order to uniformly distribute the molten component layer 13 and the active pharmaceutical ingredient-containing layer 15.

[0036] The molten component layer 13 is a layer placed between the core material 11 and the active pharmaceutical ingredient (API) containing layer 15. The molten component layer 13 is a base layer for placing the API containing layer 15. In the core particle 10, by placing the molten component layer 13 on the surface of the core material 11, more API can be attached to the molten component layer 13, and the API content in the core particle 10 can be effectively increased.

[0037] A "meltable component" is a component that can be melted by heating. The meltable component constituting the meltable component layer 13 is selected from oily additives. Since the meltable component layer 13 is formed by fused deposition modeling, the meltable component is selected from additives that are solid at room temperature. Considering the temperature range generally used in fused deposition modeling, it is preferable that the meltable component be selected from additives having a melting point of 100°C or lower, and preferably from additives having a melting point within a temperature range in which the active pharmaceutical ingredient (API) does not denature or a significant increase in related substances is observed. Examples of additives having such characteristics include, but are not limited to, glyceryl monostearate, macrogol (polyethylene glycol), lauromacrogol, and stearic acid. Furthermore, it is preferable that the meltable component be selected from additives in which contact with the API does not denature the API or a significant increase in related substances is observed.

[0038] The molten component layer 13 should be positioned on the surface of the nuclear material 11 in an amount that allows for the placement of the active pharmaceutical ingredient (API) layer 15, and should be positioned on at least a portion of the surface of the nuclear material 11. Preferably, the molten component layer 13 covers 90% or more of the surface of the nuclear material 11, and preferably, it covers the entire surface of the nuclear material 11. The thickness of the molten component layer 13 is not particularly limited, but from the viewpoint of increasing the API content per nuclear particle 10, it is preferable that the thickness of the molten component layer 13 be as thin as possible. In one embodiment, when the nuclear material 11 is an adsorbent, it is preferable that the molten components constituting the molten component layer 13 are also positioned in the pores that the nuclear material 11 has on its surface. In one embodiment, when the nuclear material 11 is an adsorbent, the interface between the nuclear material 11 and the molten component layer 13 may have a structure in which the molten components constituting the molten component layer 13 have entered from the surface of the nuclear material 11. In this case, the nuclear material 11 and the molten component layer 13 do not need to have a clear interface. By distributing the molten component not only on the surface of the nuclear material 11 but also in the pores connected to the surface of the nuclear material 11, an anchoring effect is imparted to the molten component layer 13 to the nuclear material 11, thereby improving the adhesion of the molten component layer 13 to the nuclear material 11.

[0039] The active pharmaceutical ingredient (API) containing layer 15 is a layer containing at least the API and is located on the surface of the molten component layer 13.

[0040] The active pharmaceutical ingredient (API) containing layer 15 may further contain molten components or polymers. If an additive having a lower melting point than the molten component contained in the molten component layer 13 is selected as the molten component contained in the API containing layer 15, the API containing layer 15 can be placed on the surface of the molten component layer 13 without significantly affecting or changing the surface structure of the molten component layer 13 when forming the API containing layer 15 by fused deposition modeling. On the other hand, if an additive having a higher melting point than the molten component contained in the molten component layer 13 is selected as the molten component contained in the API containing layer 15, the surface of the molten component layer 13 may slightly melt when forming the API containing layer 15 by fused deposition modeling, causing the interface between the molten component layer 13 and the API containing layer 15 to fuse, thereby improving the adhesion of the API containing layer 15 to the molten component layer 13.

[0041] Examples of additives used as molten components in the active pharmaceutical ingredient (API) containing layer 15 include, but are not limited to, stearic acid, glyceryl monostearate, macrogol (polyethylene glycol), carnauba wax, hydrogenated oil, lauromacrogol, palmitic acid, and cetyl alcohol. It is preferable that the molten components in the API containing layer 15 be selected from additives that do not cause the API to denature or a significant increase in related substances upon contact with the API. Furthermore, from the viewpoint of adhering to the core material 11, the particle size of the molten components must be smaller than the particle size of the core material 11. In addition, the molten components in the API containing layer 15 may be the same as or different from the molten components in the molten component layer 13.

[0042] In one embodiment, the core particles 10 may contain a polymer in the active pharmaceutical ingredient-containing layer 15 that is compatible with the molten component contained in the molten component layer 13. "Compatible with the molten component" means that the polymer and the molten component do not separate. Alternatively, it means that the polymer is dispersed in the molten component, or that the molten component is dispersed in the polymer. In one embodiment, the state of non-separation between the molten component and the polymer can be confirmed by the increase in viscosity of the mixture (liquid or semi-solid with fluidity) when the molten component is melted by mixing the molten component and the polymer. By using a polymer compatible with the molten component contained in the molten component layer 13, the viscosity of the surface of the molten component layer 13 is further improved, allowing the active pharmaceutical ingredient-containing layer 15 to adhere more stably. As for combinations of polymers compatible with the molten component, when the molten component is stearic acid or lauromacrogol, aminoalkyl methacrylate copolymer, ammoniaalkyl methacrylate copolymer, methacrylic acid copolymer, hypromellose acetate succinate, or polyvinylpyrrolidone can be preferably combined as polymers. More preferably, when the molten component is stearic acid, aminoalkyl methacrylate copolymer, ammoniaalkyl methacrylate copolymer, or polyvinylpyrrolidone can be combined as polymers. Alternatively, when the molten component is lauromacrogol, aminoalkyl methacrylate copolymer, ammoniaalkyl methacrylate copolymer, methacrylic acid copolymer, or hypromellose acetate succinate can be preferably combined as polymers.

[0043] When the active pharmaceutical ingredient layer 15 contains a polymer, it is preferable that the content of the molten component in the core particle 10 is equal to or greater than the content of the polymer. For example, in the core particle 10, the mixing ratio of the molten component to the polymer is preferably 20:1 to 1:1, and more preferably 4:1 to 1:1.

[0044] The active pharmaceutical ingredient (API) containing layer 15 contains an API as its main component. The API contained in the API containing layer 15 is not particularly limited as long as it is an API that can form the API containing layer 15 by the fused deposition modeling method. In other words, the API contained in the API containing layer 15 is selected from APIs that do not denature upon contact with molten components or show a significant increase in related substances. Preferably, the API containing layer 15 contains 50% by weight or more of the API based on the total weight of the substances contained in the API containing layer 15. In other words, if the API containing layer 15 contains molten components or polymers, it is preferable that the API containing layer 15 contains a small amount of molten components or polymers on the surface of the molten component layer 13, within a range that allows the API containing layer 15 to be formed. This effectively increases the API content in the core particles 10.

[0045] [Method for manufacturing nuclear particles 10] Figure 3 is a flowchart illustrating a method for manufacturing a nuclear particle 10 according to one embodiment of the present invention. A nuclear material 11 and a molten component 12 are mixed, and the molten component 12 is placed on the surface of the nuclear material 11 (S101). Furthermore, the molten component 12 is melted by a fused deposition modeling method to form a molten component layer 13 on the surface of the nuclear material 11 (S103). At this time, the nuclear material 11 and the molten component 12 are heated to a temperature above the melting point of the molten component 12. Considering the temperature range generally used in fused deposition modeling, the heating temperature is 100°C or lower. In addition, when an adsorbent is used for the nuclear material 11, it is preferable that the molten component 12 is placed not only on the surface of the nuclear material 11 but also in the pores connected to the surface of the nuclear material 11, thereby providing an anchoring effect to the molten component layer 13 on the nuclear material 11 and improving the adhesion of the molten component layer 13 to the nuclear material 11.

[0046] The core material 11 containing the molten component layer 13 is mixed with the active pharmaceutical ingredient 16, and the active pharmaceutical ingredient 16 is placed on the surface of the molten component layer 13 (S105). Furthermore, the surface of the molten component layer 13 is melted by a fused deposition modeling method to form an active pharmaceutical ingredient-containing layer 15 on the surface of the molten component layer 13 (S107).

[0047] In one embodiment, when the active pharmaceutical ingredient (API) containing layer 15 further contains a molten component together with the API 16, the molten component contained in the API containing layer 15 is mixed with the API 16 and the core material 11 on which the molten component layer 13 is arranged. When an additive having a lower melting point than the molten component contained in the molten component layer 13 is selected as the molten component contained in the API containing layer 15, when forming the API containing layer 15 by fused deposition modeling, the API containing layer 15 can be formed on the surface of the molten component layer 13 without significantly affecting or changing the surface structure of the molten component layer 13 by heating to a temperature higher than the melting point of the molten component contained in the API containing layer 15 and lower than the melting point of the molten component contained in the molten component layer 13. On the other hand, when selecting an additive with a higher melting point than the melting point of

[0048] In one embodiment, when the active pharmaceutical ingredient-containing layer 15 further contains a polymer together with the active pharmaceutical ingredient 16, the polymer is mixed together with the active pharmaceutical ingredient 16 with the core material 11 on which the molten component layer 13 is arranged. A polymer that is compatible with the molten component contained in the molten component layer 13 can be used. In this embodiment, by using a polymer that is compatible with the molten component contained in the molten component layer 13, the viscosity of the surface of the molten component layer 13 is further improved, and the active pharmaceutical ingredient-containing layer 15 can be attached more stably.

[0049] [Differential examples of nuclear particles] The core particles described above have a structure in which a molten component layer and an active pharmaceutical ingredient (API)-containing layer are laminated on the surface of a core material, but the core particles according to this embodiment are not limited to these. As a variation of the core particles, core particles that do not contain a core material will be described. Figure 4 is a schematic diagram (cross-sectional end view) showing a core particle 20 according to one embodiment. The core particle 20 contains an API 16, a molten component 12, and optionally a polymer 27. The core particle 20 is a particle formed by binding the API 16 and the molten component 12 together by melt granulation. When polymer 27 is included, the core particle 20 is a particle formed by binding the API 16, the molten component 12, and the polymer 27 together by melt granulation.

[0050] If polymer 27 is included, in the core particle 20, polymer 27 is selected from additives that are compatible with molten component 12 and applicable to melt granulation, in order to bind the molten component 12 and polymer 27. In this embodiment, molten component 12 can be selected from the molten components described for core particle 10. Polymer 27 can also be selected from polymers described for core particle 10 and combined with molten component 12. In this embodiment, the active pharmaceutical ingredient 16 is not particularly limited as long as it is an active pharmaceutical ingredient that can bind to molten component 12 and / or polymer 27 by melt granulation. In other words, the active pharmaceutical ingredient 16 is selected from active pharmaceutical ingredients that do not denature or show a significant increase in related substances upon contact with molten component 12 and / or polymer 27. For this reason, a detailed description of these additives is omitted.

[0051] In the core particle 20, the active pharmaceutical ingredient 16 and the molten component 12 only need to form a core particle, and may be in a structure where the active pharmaceutical ingredient 16 and the molten component 12 are melted and mixed with each other, or may be in a structure where a portion of the active pharmaceutical ingredient 16 and the molten component 12 are melted and bound to each other. In one embodiment, it is preferable that a structure is formed in which a portion of the particles of the active pharmaceutical ingredient 16 and the particles of the molten component 12 are melted and bound to each other.

[0052] If polymer 27 is included, in the core particle 20, the active pharmaceutical ingredient 16, the molten component 12, and the polymer 27 only need to form a core particle, and the structure may be one in which the active pharmaceutical ingredient 16, the molten component 12, and the polymer 27 are melted and mixed with each other, or a structure in which a portion of the active pharmaceutical ingredient 16, the molten component 12, and the polymer 27 are melted and bound to each other. In one embodiment, it is preferable that a structure is formed in which a portion of the particles of the active pharmaceutical ingredient 16, the particles of the molten component 12, and the particles of the polymer 27 are melted and bound to each other.

[0053] The core particles 20 preferably contain the active pharmaceutical ingredient 16 as their main component. The core particles 20 preferably contain 50% by weight or more of the active pharmaceutical ingredient 16 relative to the total weight of the active pharmaceutical ingredient 16 and the molten component 12. In other words, the core particles 20 preferably contain as little molten component 12 as possible within the limits of what is possible to form. This effectively increases the content of the active pharmaceutical ingredient 16 in the core particles 20. Furthermore, the core particles 20 exhibit high uniformity in particle size of the granulated material.

[0054] When polymer 27 is included, it is preferable that the core particles 20 contain 50% by weight or more of the active pharmaceutical ingredient 16 relative to the total weight of the active pharmaceutical ingredient 16, molten component 12, and polymer 27. In other words, it is preferable that the core particles 20 contain as little molten component 12 and polymer 27 as possible within the range that is feasible to form. This effectively increases the content of the active pharmaceutical ingredient 16 in the core particles 20. Furthermore, the core particles 20 exhibit high uniformity in particle size of the granulated material.

[0055] [Method for manufacturing nuclear particles 20] Figure 5 is a flowchart illustrating a method for producing core particles 20 according to one embodiment. The active pharmaceutical ingredient 16 and the molten component 12 are mixed, and the active pharmaceutical ingredient 16 and the molten component 12 are melted and granulated by a melt granulation method to form core particles 20 (S201). At this time, the temperature of these products is heated to a temperature above the melting point of the molten component 12. Considering the temperature range generally used in melt granulation methods, the heating temperature is 100°C or lower. It is preferable to perform melt granulation within a temperature range in which the active pharmaceutical ingredient 16 does not denature or a significant increase in related substances is not observed.

[0056] If the core particles 20 contain polymer 27, the active pharmaceutical ingredient 16, molten component 12, and polymer 27 are mixed, and the active pharmaceutical ingredient 16, molten component 12, and polymer 27 are melted and granulated by a melt granulation method to form the core particles 20 (S201). At this time, the temperature of these products is heated to a temperature above the melting point of the molten component 12 and above the glass transition temperature of the polymer 27. Considering the temperature range generally used in melt granulation methods, the heating temperature is 100°C or lower. It is preferable to perform melt granulation within a temperature range in which the active pharmaceutical ingredient 16 does not denature and no significant increase in related substances is observed.

[0057] By manufacturing the core particles 20 under such temperature control, the active pharmaceutical ingredient 16 and the molten component 12 can bind together to produce the core particles 20. Alternatively, the active pharmaceutical ingredient 16, the molten component 12, and the polymer 27 can bind together to produce the core particles 20. In this way, the core particles 20 can be easily manufactured by the melt granulation method.

[0058] [Variations of film-coated granules] Since the aforementioned core particle 10 or core particle 20 contains a molten component, it can be used as a core particle in the film-coated granules according to this embodiment. Therefore, film-coated granules can be obtained by using core particle 20 instead of core particle 10.

[0059] Figure 6 is a schematic diagram (cross-sectional end view) showing film-coated granules 200 according to one embodiment. The film-coated granules 200 include core particles 20 containing molten components, a porous material 150 on which a plasticizer has been adsorbed and placed on the surface of the core particles 20, and a film 130. The structure of the film 130 is the same as that described above, so a detailed explanation is omitted.

[0060] [Method for manufacturing film-coated granules] A method for manufacturing film-coated granules according to this embodiment will now be described. Figure 7(A) is a flowchart illustrating the process of preparing a porous material 150 on which a plasticizer has been adsorbed according to one embodiment. The plasticizer 153 is adsorbed onto the porous material 151. For example, the porous material 151 and the plasticizer 153 are mixed in a mortar and pestle to adsorb the plasticizer 153 onto the porous material 151 (S301). At this time, it is preferable that the plasticizer 153 is adsorbed not only on the surface of the porous material 151, but also inside the pores that have opened on the surface of the porous material 151.

[0061] The aforementioned core particles are prepared, and porous material 150 with the plasticizer adsorbed onto them is adsorbed onto them. Figure 7(B) is a flowchart illustrating a method for manufacturing film-coated granules 100 according to one embodiment. Figure 7(B) shows an example using core particles 10, but this embodiment is not limited to this, and the aforementioned core particles 20 can be used. The porous material 150 with the plasticizer adsorbed and the core particles 10 containing the molten component are mixed, and the molten component 12 is melted by a melt granulation method to obtain particles (first particles) in which the porous material 150 is adsorbed onto the surface of the core particles 10 (S311). At this time, the core particles 10 and the porous material 150 are heated to a temperature (first temperature) above the melting point of the molten component 12. Considering the temperature range generally used in melt granulation methods, the heating temperature is 100°C or lower.

[0062] Next, the core particles 10 on which the porous material 150 is adsorbed are mixed with the polymer 131, and the molten component 12 is melted by melt granulation to obtain particles (second particles) on which the polymer 131 is adsorbed on the surface of the core particles 10 (S313). At this time, the core particles 10 and the polymer 131 are heated to a temperature above the melting point of the molten component 12 (second temperature). Considering the temperature range generally used in melt granulation, the heating temperature is 100°C or lower. The first temperature when the porous material 150 is adsorbed onto the core particles 10 and the second temperature when the polymer 131 is adsorbed onto the core particles 10 may be the same or different. Furthermore, in one embodiment, one or more pharmaceutically acceptable additives can be mixed with a polymer 131 and a core particle 10 on which a porous material 150 has been adsorbed, and the molten component 12 can be melted by a melt granulation method to obtain particles (second particles) on which one or more pharmaceutically acceptable additives have been adsorbed together with the polymer 131 on the surface of the core particle 10.

[0063] In the curing process, the polymer 131 adsorbed on the core particles 10 is formed into a film (S315). This allows a film 130 containing a porous material 151, a plasticizer 153, and the polymer 131 to be formed on the core particles 10. At this time, the core particles 10 on which the polymer 131 is adsorbed are heated to a temperature of a second temperature or higher (third temperature). In this embodiment, the centrifugal force during curing causes the plasticizer 153 adsorbed on the porous material 151 to gradually seep out, thereby lowering the glass transition temperature of the polymer 131. This lowers the minimum film formation temperature of the film 130, allowing for the formation of a dense film.

[0064] In one embodiment, a lubricant may be added during the curing process. By adding a lubricant, the effect of suppressing soil aggregation during curing can be enhanced.

[0065] Directly adding a plasticizer to the polymer can lower the minimum film-forming temperature. However, during melt granulation, the polymer softens rapidly, causing particles to stick together and form aggregates. In contrast, in this embodiment, during curing, the plasticizer 153 adsorbed on the porous material 151 gradually seeps out, thus suppressing the formation of aggregates caused by the rapid softening of the polymer while lowering the minimum film-forming temperature. Furthermore, the manufacturing method of this embodiment allows for the formation of the film 130 in a shorter time compared to conventional methods.

[0066] In one embodiment, when forming a film from the polymer 131 adsorbed on the core particles 10, a lubricant may be further added. The lubricant can be selected from known additives, and examples include light anhydrous silicic acid, talc, carnauba wax, hydrated silicon dioxide, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, and magnesium aluminometasilicate. Adding a lubricant can enhance the effect of suppressing aggregation during melt granulation.

[0067] In addition to the dry method described above, the curing process may also involve a wet method in which a solvent such as water is sprayed onto the granules while they are in a fluidized bed granulator or similar device, and then heated.

[0068] [formulation] A formulation can be manufactured using film-coated granules 100 or 200. For example, film-coated granules 100 or 200 may be mixed with one or more pharmaceutically acceptable known additives to form a pharmaceutical composition. Alternatively, the pharmaceutical composition may be compressed into tablets. Alternatively, a pharmaceutical composition with a disintegrant added may be compressed into orally disintegrating tablets. Alternatively, the pharmaceutical composition may be encapsulated to form capsules. [Examples]

[0069] [Example 1] 140g of hydrated silicon dioxide (Fuji Silicia Chemical Co., Ltd., Sylopure® P100) as the core material, 84g of stearic acid (NOF Co., Ltd., plant-derived) and 112g of stearic acid (BASF Japan, Kolliwax® S Fine) as the melting components were placed in a high-speed stirring granulator (Earth Technica Co., Ltd., High-Speed ​​Mixer LFS-GS-2J), and adsorption was performed for 13 minutes at a product temperature of 80°C.

[0070] 76.3 g of the molten material obtained, along with 198.3 g of sitagliptin phosphate as the active pharmaceutical ingredient and 25.4 g of aminoalkyl methacrylate copolymer E (Evonik, Eudragit® EPO) as the polymer, were placed in a fluidized bed granulator (Pawrec Co., Ltd., MP01), and granulation was carried out for 30 minutes at a product temperature of 65°C to obtain nucleus particles.

[0071] As a porous material, 12g of light anhydrous silicic acid (Freund Industrial Co., Ltd., Adsolider® 101) and 30g of triethyl citrate (Morimura Trading Co., Ltd., Citroflex® 2) as a plasticizer were mixed in a mortar, and the triethyl citrate was adsorbed onto the light anhydrous silicic acid.

[0072] 300g of core particles and 42g of light anhydrous silicic acid adsorbed with triethyl citrate were placed in a fluidized bed granulator (Powrec Co., Ltd., MP01), and granulation was carried out for 10 minutes at a product temperature of 55°C, causing the light anhydrous silicic acid adsorbed with triethyl citrate to be adsorbed onto the surface of the core particles.

[0073] 342 g of the obtained particles and 100 g of hypromellose acetate succinate (Shin-Etsu Chemical Co., Ltd., Shin-Etsu AQOAT® AS-LF) as a polymer were placed in a fluid bed granulator (Powrec Co., Ltd., MP01), and granulation was carried out for 10 minutes at a product temperature of 55°C to adsorb the hypromellose acetate succinate onto the surface of the core particles, thereby obtaining particles before the curing process.

[0074] As a lubricant, 44.2g of light anhydrous silicic acid (Freund Industrial Co., Ltd., Adsolider® 101) was added, and the mixture was cured for 1 hour at an air supply temperature of 90°C to obtain the film-coated granules of Example 1.

[0075] Figure 8(A) is a scanning electron microscope image of the particles of Example 1 before curing, and Figure 8(B) is a scanning electron microscope image of the particles of Example 1 after curing. In Figure 8(A), particles of hypromellose acetate succinate adsorbed on the surface of the particles were observed, while in Figure 8(B), it was confirmed that a film was formed by curing. This example demonstrates that a film can be formed without the formation of aggregates.

[0076] [Example 2] Film-coated granules were manufactured by changing the active pharmaceutical ingredient (API) of the core particles to lacosamide. 21.6 g of lacosamide was used as the API, 4.0 g of ammonia alkyl methacrylate copolymer (Evonik, Eudragit® RSPO) as the core material, and 2.6 g of glyceryl monostearate (Riken Vitamin Co., Ltd., Rikemar® S-100P) as the molten component. These were placed in a horizontal twin-screw mixer with a constant temperature water circulation jacket (Caleva UK, Mixer Torque Rheometer; MTR), and granulation was carried out for 30 minutes at a product temperature of 72°C to obtain core particles containing the molten component.

[0077] 28.2 g of core particles and 4.0 g of light anhydrous silicic acid adsorbed with triethyl citrate prepared in Example 1 were placed in a horizontal twin-screw mixer with a constant temperature water circulation jacket (Caleva UK, Mixer Torque Rheometer; MTR), and granulation was carried out for 10 minutes at a product temperature of 55°C to adsorb the light anhydrous silicic acid adsorbed with triethyl citrate onto the surface of the core particles.

[0078] 32.2 g of the obtained particles and 9.4 g of hypromellose acetate succinate (Shin-Etsu Chemical Co., Ltd., Shin-Etsu AQOAT® AS-LF) as a polymer were placed in a horizontal twin-screw mixer with a constant temperature water circulation jacket (Caleva UK, Mixer Torque Rheometer; MTR). Granulation was carried out for 10 minutes at a product temperature of 55°C to adsorb the hypromellose acetate succinate onto the surface of the core particles, obtaining particles before the curing process. Subsequently, curing was carried out for 1 hour at a feedwater temperature of 90°C to obtain the film-coated granules of Example 2.

[0079] Figure 8(C) is a scanning electron microscope image of the particles of Example 2 before curing, and Figure 8(D) is a scanning electron microscope image of the particles of Example 2 after curing. In Figure 8(C), particles of hypromellose acetate succinate adsorbed on the surface of the particles were observed, while in Figure 8(D), it was confirmed that a film was formed by curing. This example demonstrates that a film can be formed without the formation of aggregates.

[0080] [Comparative Example 1] As Comparative Example 1, the effect of including molten components in the core particles was investigated. 300g of crystalline cellulose (Asahi Kasei Corporation, Cellphia® CP102) was used as the core particles. 42g of light anhydrous silicic acid, on which triethyl citrate prepared in Example 1 was adsorbed, was placed in a fluidized bed granulator (Powrec Co., Ltd., MP01), and granulation was carried out for 10 minutes at a product temperature of 55°C to adsorb the light anhydrous silicic acid with adsorbed triethyl citrate onto the surface of the core particles.

[0081] 342g of the obtained particles and 100g of hypromellose acetate succinate (Shin-Etsu Chemical Co., Ltd., Shin-Etsu AQOAT® AS-LF) as a polymer were placed in a fluidized bed granulator (Powrec Co., Ltd., MP01), and granulation was carried out for 10 minutes at a product temperature of 55°C to 65°C.

[0082] In Comparative Example 1, under low-temperature conditions of 55°C, hypromellose acetate succinate did not adsorb onto the surface of the particles during the film coating process. Furthermore, aggregates formed under high-temperature conditions of 65°C. Therefore, film-coated granules could not be obtained in Comparative Example 1. The results of Comparative Example 1 indicate that, in order for the porous material with the adsorbed plasticizer and the polymer to adsorb onto the surface of the core particles, the core particles must contain molten components.

[0083] [Comparative Example 2] As Comparative Example 2, the effect of including a porous material with an adsorbed plasticizer was investigated. 300 g of the core particles prepared in Example 1 and 100 g of hypromellose acetate succinate (Shin-Etsu Chemical Co., Ltd., Shin-Etsu AQOAT® AS-LF) as a polymer were placed in a fluid bed granulator (Powrec Co., Ltd., MP01), and granulation was carried out for 10 minutes at a product temperature of 55°C to adsorb the hypromellose acetate succinate onto the surface of the core particles, obtaining particles before the curing process. Subsequently, curing was carried out for 1 hour at an air supply temperature of 90°C.

[0084] Figure 9(A) shows a scanning electron microscope image of the particles of Comparative Example 2 before curing, and Figure 9(B) shows a scanning electron microscope image of the particles of Comparative Example 2 after curing. A comparison of Figure 9(A) and Figure 9(B) confirmed that the polymer adsorbed on the surface of the nucleus particles did not form a film. The results for Comparative Example 2 indicate that, in order for the polymer to form a film, it is necessary to include a porous material on which a plasticizer has been adsorbed.

[0085] [Comparative Example 3] As Comparative Example 3, the effect of a porous material for adsorbing a plasticizer was investigated. Instead of a porous material, 12g of non-porous light anhydrous silicic acid (Aerosil® 200, Nippon Aerosil Co., Ltd.) and 30g of triethyl citrate (Citroflex® 2, Morimura Shoji Co., Ltd.) were mixed in a mortar and pestle to adsorb the triethyl citrate onto the light anhydrous silicic acid.

[0086] 300 g of the core particles prepared in Example 1 and 42 g of light anhydrous silicic acid adsorbed with triethyl citrate from Comparative Example 3 were placed in a fluidized bed granulator (Powrec Co., Ltd., MP01), and granulation was carried out for 10 minutes at a product temperature of 55°C to adsorb the light anhydrous silicic acid adsorbed with triethyl citrate onto the surface of the core particles.

[0087] 342g of the obtained particles and 100g of hypromellose acetate succinate (Shin-Etsu Chemical Co., Ltd., Shin-Etsu AQOAT® AS-LF) as a polymer were placed in a fluid bed granulator (Powrec Co., Ltd., MP01), and granulation was carried out for 10 minutes at a product temperature of 55°C to adsorb the hypromellose acetate succinate onto the surface of the core particles, obtaining particles before the curing process. Subsequently, curing was carried out for 1 hour at an air supply temperature of 90°C.

[0088] In Comparative Example 3, aggregates formed during the film coating process, and film coating granules could not be obtained. From the results of Comparative Example 3, it was considered that because the plasticizer was not adsorbed by the non-porous light anhydrous silicic acid, the polymer and plasticizer reacted all at once when the polymer was added, causing the polymer to soften rapidly and resulting in the formation of aggregates. The results of Comparative Example 3 indicated that a porous material is necessary for the adsorption of plasticizers.

[0089] [Investigation of bitterness suppression effect] A sensory evaluation was conducted to determine whether the bitterness of sitagliptin phosphate could be suppressed in the granules of Example 1 and Comparative Example 2, and in the core particles of Example 1. Five subjects held 50 mg of the granules of Example 1 and Comparative Example 2 in their mouths for 20 seconds and checked for bitterness. In the film-coated granules of Example 1, four subjects did not perceive bitterness, and one subject perceived a slight bitterness. On the other hand, in the granules of Comparative Example 2, where the polymer did not form a film, and in the core particles of Example 1, five subjects perceived a strong bitterness. From these results, it was confirmed that a dense film capable of suppressing bitterness was formed in the film-coated granules of Example 1.

[0090] [Example 3] 430.5g of hydrated silicon dioxide (Fuji Silicia Chemical Co., Ltd.) as the core material and 336.0g of stearic acid (Kao Corporation, Stearic Acid 70) as the melting component were placed in a high-speed stirring granulator (Earth Technica Co., Ltd., High-Speed ​​Mixer FS-GS-5J), and adsorption was performed for 17 minutes at a product temperature of 75°C.

[0091] 186.15 g of the molten component-containing core material (adsorbent particles), 286.45 g of duloxetine hydrochloride as the active pharmaceutical ingredient, and 47.60 g of aminoalkyl methacrylate copolymer E (Evonik, Eudragit® EPO) as the polymer were placed in a high-speed stirring granulator (Earth Technica Co., Ltd., High-Speed ​​Mixer FS-GS-5J), and granulation was carried out for 28 minutes at a product temperature of 65°C to obtain core particles.

[0092] The obtained 520.2g of core particles and 15.3g of talc (Fuji Talc Industry Co., Ltd., ML115) were placed in a high-speed stirring granulator (Earth Technica Co., Ltd., High-Speed ​​Mixer FS-GS-5J), and the mixture was mixed for 1 minute at a product temperature of 65°C to perform an anti-adhesion treatment.

[0093] As a porous material, 24g of light anhydrous silicic acid (Freund Industrial Co., Ltd., Adsolider® 101) and 60g of triethyl citrate (Morimura Trading Co., Ltd., Citroflex® 2) as a plasticizer were mixed in a mortar, and the triethyl citrate was adsorbed onto the light anhydrous silicic acid.

[0094] 126 g of core particles and 25.2 g of light anhydrous silicic acid with adsorbed triethyl citrate were placed in a fluidized bed granulator (Powrec Co., Ltd., MP01), and granulation was carried out for 5 minutes at a product temperature of 65.3°C, causing the light anhydrous silicic acid with adsorbed triethyl citrate to be adsorbed onto the surface of the core particles.

[0095] 151.2 g of the obtained particles, along with 120 g of hypromellose acetate succinate (Shin-Etsu Chemical Co., Ltd., Shin-Etsu AQOAT® AS-LF) as a polymer and 2 g of talc (Fuji Talc Industrial Co., Ltd., ML115) as a lubricant, were placed in a fluidized bed granulator (Powrec Co., Ltd., MP01). Granulation was carried out at a product temperature of 65°C for 15 minutes, allowing the hypromellose acetate succinate to adsorb onto the surface of the core particles, thus obtaining particles before the curing process.

[0096] The film-coated granules of Example 3 were obtained by curing for 90 minutes at an air supply temperature of 90°C.

[0097] [Comparative Example 4] 126 g of the core particles from Example 3, 120 g of hypromellose acetate succinate (Shin-Etsu Chemical Co., Ltd., Shin-Etsu AQOAT® AS-LF) as a polymer, and 2 g of talc (Fuji Talc Industrial Co., Ltd., ML115) as a lubricant were placed in a fluid bed granulator (Powrec Co., Ltd., MP01), and granulation was carried out for 15 minutes at a product temperature of 65°C to adsorb the hypromellose acetate succinate onto the surface of the core particles, obtaining particles before the curing process.

[0098] The air supply temperature was set to 90°C, and curing was performed for 90 minutes to obtain the film-coated granules of Comparative Example 4.

[0099] [Film Evaluation] The dissolution properties of duloxetine hydrochloride were evaluated for the film-coated granules of Example 3 and Comparative Example 4 in accordance with the dissolution test method (paddle method) of the 17th edition of the Japanese Pharmacopoeia. 136.6 g of the film-coated granules of Example 3 and 124 g of the film-coated granules of Comparative Example 4 were each filled into hypromellose capsules to prepare test formulations. 900 ml of dissolution test solution 1 (JP1) was used as the test solution. The paddle rotation speed was set to 50 rpm. The dissolution rate of duloxetine hydrochloride was measured by high-performance liquid chromatography (HPLC) at 60 and 120 minutes after the start of the test. The results of the duloxetine hydrochloride dissolution rate measurement are shown in Figure 10. The film-coated granules of Example 3, which contained a porous material with adsorbed plasticizer, showed suppressed dissolution of duloxetine hydrochloride even 120 minutes after the start of the dissolution test due to the coating with hypromellose acetate succinate, an enteric polymer. On the other hand, the film-coated granules of Comparative Example 4, in which the core particles were directly coated with an enteric-coated polymer, showed significantly greater dissolution of duloxetine hydrochloride compared to Example 3. From these results, it became clear that in Example 3, which contained a porous material with adsorbed plasticizer, the polymer formed a dense film, suppressing the dissolution of duloxetine hydrochloride. [Explanation of Symbols]

[0100] 10 Core particles, 11 Core material, 12 Molten component, 13 Molten component layer, 15 Active pharmaceutical ingredient (API) containing layer, 16 API, 20 Core particles, 27 Polymer, 100 Film-coated granules, 130 Film, 131 Polymer, 150 Porous material with adsorbed plasticizer, 151 Porous material, 153 Plasticizer, 200 Film-coated granules

Claims

1. It comprises core particles containing a molten component and a film disposed on the surface of the core particles, The aforementioned film is a film-coated granule comprising a porous material, a plasticizer, and a polymer.

2. The film coating granules according to claim 1, wherein the plasticizer is selected from plasticizers that can be positioned between the molecules of the polymer.

3. The film-coated granules according to claim 1, wherein the plasticizer is one or more selected from the group consisting of triethyl citrate, polyethylene glycol, propylene glycol, triacetin, and tributyl acetyl citrate, and the polymer is one or more selected from the group consisting of hypromellose acetate succinate, hydroxypropyl cellulose, ethyl cellulose, vinyl acetate, methacrylic acid copolymer L, ammonia alkyl methacrylate copolymer, and methacrylic acid copolymer S.

4. The film-coated granules according to claim 1, wherein the core particles include a core material, a molten component layer disposed on the surface of the core material, and an active pharmaceutical ingredient-containing layer disposed on the surface of the molten component layer.

5. The aforementioned core particle comprises the active pharmaceutical ingredient and a molten component. The film-coated granules according to claim 1, wherein the active pharmaceutical ingredient and the molten component are bound together.

6. The aforementioned nuclear particle further contains a polymer, The film-coated granules according to claim 5, wherein the active pharmaceutical ingredient, the molten component, and the polymer are bound together.

7. The film coating granules according to claim 1, wherein the film further comprises one or more pharmaceutically acceptable first additives.

8. A film-coated granule according to any one of claims 1 to 7, A formulation comprising one or more pharmaceutically acceptable second excipients.

9. By adsorbing a plasticizer onto a porous material, The porous material on which the plasticizer has been adsorbed is adsorbed onto core particles containing molten components to obtain first particles. A method for producing film-coated granules, comprising adsorbing a polymer onto the first particles to form a film on the core particles comprising the porous material, the plasticizer, and the polymer.

10. The polymer is adsorbed onto the first particles at a first temperature. A method for producing film-coated granules according to claim 9, wherein the film is formed on the nucleus particles at a second temperature equal to or higher than the first temperature.

11. The method for producing film-coated granules according to claim 9, wherein the plasticizer is selected from plasticizers that can be positioned between the molecules of the polymer.

12. The method for producing film-coated granules according to claim 9, wherein the plasticizer is one or more selected from the group consisting of triethyl citrate, polyethylene glycol, propylene glycol, triacetin, and tributyl acetyl citrate, and the polymer is one or more selected from the group consisting of hypromellose acetate succinate, hydroxypropyl cellulose, ethyl cellulose, vinyl acetate, methacrylic acid copolymer L, ammonia alkyl methacrylate copolymer, and methacrylic acid copolymer S.

13. The molten component is adsorbed onto the nuclear material to form a molten component layer. The active pharmaceutical ingredient is adsorbed onto the molten component. A method for producing film-coated granules according to claim 9, comprising forming an active pharmaceutical ingredient-containing layer comprising the molten component and the active pharmaceutical ingredient to obtain the core particles.

14. The molten component and the active pharmaceutical ingredient are bound together. A method for producing film-coated granules according to claim 9, comprising obtaining the core particles containing the molten component and the active pharmaceutical ingredient.

15. The molten component, the active pharmaceutical ingredient, and the polymer are bonded together. A method for producing film-coated granules according to claim 9, comprising obtaining the core particles comprising the molten component, the active pharmaceutical ingredient, and the polymer.

16. A method for producing film-coated granules according to claim 9, wherein when forming the film on the nucleus particles, one or more pharmaceutically acceptable lubricants are further added.

17. A method for producing a pharmaceutical product, comprising mixing film-coated granules obtained by the method for producing film-coated granules according to any one of claims 9 to 16 with one or more pharmaceutically acceptable second additives and compressing the mixture into tablets.

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