Granules, preparations containing granules, method for producing granules, and method for producing preparations containing granules

Abstract

To provide granules bitter taste of which can be sufficiently masked and a preparation including the granules bitter taste of which can be sufficiently masked.SOLUTION: The granules each include: a nucleus material in which a melting component and a bulk drug are arranged; a gelled material containing layer which has the melting component and the bulk drug arranged on the surface; and a hydrophobic polymer containing layer disposed on the surface of the gelled material containing layer.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] One embodiment of the present invention relates to a granule in which the bitter taste of a drug substance is masked or a formulation containing the granule. Alternatively, one embodiment of the present invention relates to a method for producing the granule in which the bitter taste of a drug substance is masked or a method for producing a formulation containing the granule. [Background technology]

[0002] Many drug substances are known to have a bitter taste, and when released in the oral cavity, they can cause strong discomfort to patients and significantly reduce compliance. It is necessary to suppress the release of drug substances from the drug at least while the drug is present in the oral cavity.

[0003] Conventionally, for example, as described in Patent Document 1, bitterness has been masked by covering a drug substance-containing layer with a taste-masking layer containing a water-insoluble polymer.

[0004] Furthermore, Patent Document 2 describes pharmaceutical composition particles that, for the purpose of simultaneously masking unpleasant tastes and improving dissolution, comprise a core particle containing a drug, an intermediate layer containing a water-soluble gelling and swelling substance that coats the outside of the core particle, and an outer layer containing a water-insoluble substance that coats the outside of the intermediate layer.

[0005] In Patent Documents 1 and 2, bitterness is masked by coating a drug substance-containing composition, but in the case of a drug substance with a strong bitter taste, the coating layer must be made thick. In this case, there is a problem that the coated pharmaceutical composition particles become large, impairing the feeling of taking the drug. Furthermore, if the coating layer is made thicker, the coating time becomes longer and production efficiency decreases. Therefore, there is a need for a formulation that can easily be prepared to mask the bitterness and is easy to take. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. 02 / 096392 [Patent Document 2] International Publication No. 2017 / 146052 Summary of the Invention [Problem to be solved by the invention]

[0007] One object of one embodiment of the present invention is to provide granules capable of sufficiently masking bitterness. Alternatively, one object of one embodiment of the present invention is to provide a formulation containing granules capable of sufficiently masking bitterness. Alternatively, one object of one embodiment of the present invention is to provide a method for producing granules capable of sufficiently masking bitterness. Alternatively, one object of one embodiment of the present invention is to provide a method for producing a formulation containing granules capable of sufficiently masking bitterness. [Means for solving the problem]

[0008] According to one embodiment of the present invention, there is provided a granule comprising: a core material having a melting component and an active pharmaceutical ingredient disposed thereon; a gelling substance-containing layer disposed on the surface on which the melting component and the active pharmaceutical ingredient are disposed; and a hydrophobic polymer-containing layer disposed on the surface of the gelling substance-containing layer.

[0009] The core material may further include a melting component layer that is disposed on the surface of the core material and contains the melting component, and a drug substance-containing layer that contains the melting component and the drug substance may be disposed on the surface of the melting component layer.

[0010] The film may further include an overcoat layer disposed on the surface of the hydrophobic polymer-containing layer.

[0011] The gelling substance-containing layer may contain a gelling substance whose viscosity in a 2% aqueous solution is 10 mPa·s or more.

[0012] The gelling substance-containing layer may contain one or more gelling substances selected from the group consisting of sodium carboxymethylcellulose, polyethylene oxide, sodium polyacrylate, sodium alginate, propylene glycol alginate, xanthan gum, carrageenan, guar gum, tara gum, pectin, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxyvinyl polymer, locust bean gum, tamarind seed gum, gum arabic, karaya gum, agar, gelatin, polyvinyl alcohol, and copolymers containing polyvinyl alcohol as a part thereof.

[0013] The hydrophobic polymer-containing layer may comprise one or more hydrophobic polymers selected from ethyl cellulose, acetyl cellulose, cellulose acetate phthalate, carboxymethyl ethyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, dimethylaminoethyl methacrylate-methyl methacrylate copolymer, methyl acrylate-methacrylic acid copolymer, ethyl acrylate-methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer RS, dry methacrylic acid copolymer LD, aminoalkyl methacrylate copolymer E, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, and polyvinyl acetal diethylaminoacetate.

[0014] The content ratio of the gelling substance contained in the gelling substance-containing layer to the hydrophobic polymer contained in the hydrophobic polymer-containing layer may be in the range of 2:3 to 3:8.

[0015] According to one embodiment of the present invention, there is provided a formulation comprising any of the granules described above and one or more pharmaceutically acceptable additives.

[0016] According to one embodiment of the present invention, there is provided a method for producing granules, which comprises disposing a melting component and an active pharmaceutical ingredient on the surface of a core material, disposing a gelling substance on the surface on which the melting component and the active pharmaceutical ingredient are disposed by dry coating to form a gelling substance-containing layer, and disposing a hydrophobic polymer on the surface of the gelling substance-containing layer to form a hydrophobic polymer-containing layer.

[0017] A melt component layer containing the melt component may be further formed on the surface of the core material, and an active ingredient-containing layer containing the melt component and the active ingredient may be formed on the surface of the melt component layer.

[0018] An overcoat layer may be further formed on the surface of the hydrophobic polymer-containing layer.

[0019] The gelling substance-containing layer may contain a gelling substance whose viscosity in a 2% aqueous solution is 10 mPa·s or more.

[0020] The gelling substance-containing layer may contain one or more gelling substances selected from the group consisting of sodium carboxymethylcellulose, polyethylene oxide, sodium polyacrylate, sodium alginate, propylene glycol alginate, xanthan gum, carrageenan, guar gum, tara gum, pectin, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxyvinyl polymer, locust bean gum, tamarind seed gum, gum arabic, karaya gum, agar, gelatin, polyvinyl alcohol, and copolymers containing polyvinyl alcohol as a part thereof.

[0021] The hydrophobic polymer-containing layer may comprise one or more hydrophobic polymers selected from ethyl cellulose, acetyl cellulose, cellulose acetate phthalate, carboxymethyl ethyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, dimethylaminoethyl methacrylate-methyl methacrylate copolymer, methyl acrylate-methacrylic acid copolymer, ethyl acrylate-methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer RS, dry methacrylic acid copolymer LD, aminoalkyl methacrylate copolymer E, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, and polyvinyl acetal diethylaminoacetate.

[0022] The content ratio of the gelling substance contained in the gelling substance-containing layer to the hydrophobic polymer contained in the hydrophobic polymer-containing layer may be in the range of 2:3 to 3:8.

[0023] According to one embodiment of the present invention, there is provided a method for producing a formulation, which comprises mixing granules produced by any of the above-described production methods with one or more pharmaceutically acceptable additives. [Effects of the Invention]

[0024] One embodiment of the present invention can provide granules capable of sufficiently masking bitterness. Alternatively, one embodiment of the present invention can provide a formulation including granules capable of sufficiently masking bitterness. Alternatively, one embodiment of the present invention can provide a method for producing granules capable of sufficiently masking bitterness. Alternatively, one embodiment of the present invention can provide a method for producing a formulation including granules capable of sufficiently masking bitterness. [Brief explanation of the drawings]

[0025] [Figure 1] 1 is a schematic diagram showing the cross-sectional structure of a granule 10 according to one embodiment of the present invention. [Figure 2]FIG. 2 is a schematic diagram showing the cross-sectional structure of a granule 90 of a comparative example. [Figure 3] FIG. 1 is a graph showing the dissolution rate of sitagliptin phosphate in a preparation according to an example of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0026] The granules according to the present invention and a formulation using the same will be described below with reference to the drawings. Note that the granules according to the present invention and a formulation using the same should not be construed as being limited to the description of the following embodiments and examples. Note that in the drawings referred to in the present embodiments and examples described below, the same parts or parts having similar functions are designated by the same reference numerals, and repeated explanations thereof will be omitted.

[0027] FIG. 1 is a schematic diagram (cross-sectional view) showing a granule 10 according to one embodiment of the present invention. Granule 10 comprises a core material 11, a melting component layer 12 disposed on the surface of core material 11, a drug substance-containing layer 13 disposed on the surface of melting component layer 12, a gelling substance-containing layer 15 disposed on the surface of drug substance-containing layer 13, a hydrophobic polymer-containing layer 17 disposed on the surface of gelling substance-containing layer 15, and an overcoat layer 19 disposed on the surface of hydrophobic polymer-containing layer 17. Note that if the adhesion between core material 11 and drug substance-containing layer 13 is good, melting component layer 12 may be omitted. Also, overcoat layer 19 may be omitted.

[0028] Core material 11 is a carrier for arranging melting component layer 12, active pharmaceutical ingredient-containing layer 13, gelling substance-containing layer 15, hydrophobic polymer-containing layer 17, and overcoat layer 19. Core material 11 also serves as a core for arranging melting component layer 12, active pharmaceutical ingredient-containing layer 13, gelling substance-containing layer 15, hydrophobic polymer-containing layer 17, and overcoat layer 19 when producing granules 10. An adsorbent is used as core material 11 to ensure adhesion with melting component layer 12. Examples of the core material 11 that can be used include adsorbents such as Amberlite IRP-64, ion exchange resin, kaolin, carmellose calcium, hydrous 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 potassium aluminum silicate particles, bentonite, polyethylene fiber, magnesium aluminometasilicate, and medicinal charcoal.

[0029] The core material 11 is preferably spherical in shape so that the melting component layer 12, active pharmaceutical ingredient-containing layer 13, gelling substance-containing layer 15, hydrophobic polymer-containing layer 17 and overcoat layer 19 are uniformly arranged.

[0030] The melting component layer 12 is a layer disposed between the core material 11 and the active pharmaceutical ingredient-containing layer 13. The melting component layer 12 is a base layer for disposing the active pharmaceutical ingredient-containing layer 13. If the active pharmaceutical ingredient itself has strong adhesiveness to the core material, or if the core material has a high capacity to support the active pharmaceutical ingredient, the melting component and the active pharmaceutical ingredient may be disposed directly on the core material. On the other hand, by disposing the melting component layer 12 composed of a melting component that has high adhesiveness to the core material 11 on the surface of the core material 11, a larger amount of active pharmaceutical ingredient can be adhered to the melting component layer 12, effectively increasing the content of the active pharmaceutical ingredient in the granule 10.

[0031] The melt component (first melt component) constituting the melt component layer 12 can be selected from oil-based additives. Furthermore, the first melt component is preferably selected from additives that do not denature the drug substance or significantly increase the amount of related substances upon contact with the drug substance. The melt component layer 12 is preferably formed by melt lamination, and the first melt component may be selected from additives that are solid at room temperature. Considering the temperature range typically used in melt lamination, the first melt component is preferably selected from additives with a melting point of 100°C or less, and preferably from additives with a melting point within a temperature range where the drug substance does not denature or where a significant increase in related substances does not occur. Examples of additives with such properties include, but are not limited to, glyceryl monostearate, macrogol (polyethylene glycol), lauromacrogol, and stearic acid.

[0032] The melt component layer 12 may be disposed on the surface of the core material 11 in an amount that allows the drug substance-containing layer 13 to be disposed thereon, and may be disposed on at least a portion of the surface of the core material 11. The melt component layer 12 preferably covers 90% or more of the surface of the core material 11, and preferably covers the entire surface of the core material 11. The thickness of the melt component layer 12 is not particularly limited, but from the viewpoint of increasing the drug substance content per granule 10, it is preferable that the melt component layer 12 be as thin as possible. In one embodiment, the first melt component constituting the melt component layer 12 is preferably also disposed in the pores of the core material 11. In one embodiment, the interface between the core material 11 and the melt component layer 12 may have a structure in which the melt component constituting the melt component layer 12 penetrates from the surface of the core material 11. In this case, the core material 11 and the melt component layer 12 do not need to have a clear interface. Since the molten component is disposed not only on the surface of the core material 11 but also in the pores connected to the surface of the core material 11, the molten component layer 12 is given an anchoring effect to the core material 11, thereby improving the adhesion of the molten component layer 12 to the core material 11.

[0033] The active pharmaceutical ingredient-containing layer 13 is a layer containing an active pharmaceutical ingredient and a melting component, and may be disposed on the surface of the core material 11 or may be disposed via the melting component layer 12. The active pharmaceutical ingredient in the granules 10 is not particularly limited.

[0034] When melt component layer 12 is disposed on the surface of core material 11, drug substance-containing layer 13 contains a second melt component to bind the drug substances together and to bind the drug substances to the surface of melt component layer 12. The second melt component is preferably selected from additives that do not denature the drug substance or cause a significant increase in related substances upon contact with the drug substance. Since drug substance-containing layer 13 is formed by melt layering, the second melt component is selected from additives that are solid at room temperature. Considering the temperature range generally used in melt layering, the second melt component is preferably selected from additives having a melting point of 100°C or lower or a glass transition point of 120°C or lower, and is preferably selected from additives having a melting point or glass transition point within a temperature range in which the drug substance does not denature or cause a significant increase in related substances. Furthermore, when an additive having a melting point or glass transition point lower than that of the first melt component is selected as the second melt component, when forming drug substance-containing layer 13 by melt lamination, drug substance-containing layer 13 can be disposed on the surface of melt component layer 12 without significantly affecting or changing the surface structure of melt component layer 12. On the other hand, when an additive having a melting point or glass transition point higher than that of the first melt component is selected as the second melt component, when forming drug substance-containing layer 13 by melt lamination, the surface of melt component layer 12 melts slightly, and the interface between melt component layer 12 and drug substance-containing layer 13 fuses, thereby improving the adhesion of drug substance-containing layer 13 to melt component layer 12.

[0035] Examples of additives used as the second melt component include, but are not limited to, stearic acid, glycerin monostearate, macrogol (polyethylene glycol), carnauba wax, hydrogenated oil, lauromacrogol, palmitic acid, cetyl alcohol, aminoalkyl methacrylate copolymer E, ammonioalkyl methacrylate copolymer, dry methacrylic acid copolymer, hypromellose acetate succinate, polyvinylpyrrolidone, and polyvinyl acetal diethylaminoacetate. The melt component contained in active ingredient-containing layer 13 (second melt component) may be the same additive as or different from the melt component contained in melt component layer 12 (first melt component).

[0036] The active pharmaceutical ingredient-containing layer 13 contains an active pharmaceutical ingredient as a main component. The active pharmaceutical ingredient-containing layer 13 preferably contains 50% by mass or more of the active pharmaceutical ingredient relative to the total mass of the active pharmaceutical ingredient and the second melt component. In other words, the active pharmaceutical ingredient-containing layer 13 preferably contains a small amount of the second melt component within a range that allows the active pharmaceutical ingredient-containing layer 13 to be formed on the surface of the melt component layer 12. This effectively increases the content of the active pharmaceutical ingredient in the granules 10.

[0037] Gelling substance-containing layer 15 has the function of adjusting the elution of the drug substance from drug substance-containing layer 13. As will be described later, hydrophobic polymer-containing layer 17 inhibits the inflow of moisture (saliva) in the oral cavity into drug substance-containing layer 13, but the gelling substance contained in gelling substance-containing layer 15 absorbs moisture that has seeped in from hydrophobic polymer-containing layer 17 and gels to form a gel layer. This gel layer inhibits the inflow of moisture into drug substance-containing layer 13 in the oral cavity, thereby preventing the elution of the drug substance from drug substance-containing layer 13. Furthermore, because the large amount of moisture in gastric juice dissolves the gel layer, gelling substance-containing layer 15 can achieve rapid elution of the drug substance from drug substance-containing layer 13 in the stomach.

[0038] In this embodiment, a gelling substance having a viscosity of 10 mPa·s or more in a 2% aqueous solution can be used. Examples of gelling substances that can be used include sodium carboxymethylcellulose, polyethylene oxide, sodium polyacrylate, sodium alginate, propylene glycol alginate, xanthan gum, carrageenan, guar gum, tara gum, pectin, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxyvinyl polymer, locust bean gum, tamarind seed gum, gum arabic, karaya gum, agar, gelatin, polyvinyl alcohol, and copolymers containing polyvinyl alcohol as a part thereof, and the like, and a combination of two or more gelling substances can be used.

[0039] The hydrophobic polymer-containing layer 17 has the function of preventing moisture in the oral cavity from flowing into the active ingredient-containing layer 13. The hydrophobic polymer-containing layer 17 is composed of a water-insoluble substance that is poorly or almost insoluble in water. Examples of the water-insoluble substance include one or a combination of two or more hydrophobic polymers selected from the group consisting of ethyl cellulose, acetyl cellulose, cellulose acetate phthalate, carboxymethyl ethyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, dimethylaminoethyl methacrylate-methyl methacrylate copolymer, methyl acrylate-methacrylic acid copolymer, ethyl acrylate-methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer RS, dried methacrylic acid copolymer LD, aminoalkyl methacrylate copolymer E, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, and polyvinyl acetal diethylamino acetate.

[0040] In the granules 10 according to the embodiment, the inclusion of the gelling substance-containing layer 15 can sufficiently prevent moisture in the oral cavity from flowing into the active pharmaceutical ingredient-containing layer 13, and therefore the hydrophobic polymer-containing layer 17 can be made thin. By making the hydrophobic polymer-containing layer 17 thin, the time required to manufacture the granules 10 can be reduced. Furthermore, in the granules 10 according to the embodiment, the gelling substance-containing layer 15 is arranged by melt lamination deposition, and therefore the time required to arrange the gelling substance-containing layer 15 can be significantly reduced compared to conventional methods.

[0041] The overcoat layer 19 improves intake and suppresses delayed dissolution of the active pharmaceutical ingredient by being disposed on the surface of the hydrophobic polymer-containing layer 17. The overcoat layer 19 can be made of one or a combination of two or more selected from, for example, pregelatinized starch, sodium caseinate, carboxyvinyl polymer, sodium carboxymethyl starch, sucrose fatty acid ester, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, pullulan, polyvinylpyrrolidone, copolyvidone, polyoxyethylene-polyoxypropylene glycol, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, macrogol, polyethylene oxide, amino acids such as glycine and alanine, sweeteners such as glycyrrhizic acid, sugars such as dextrin and lactose, sugar alcohols such as mannitol and xylitol, crystalline cellulose, crospovidone, and triethyl citrate.

[0042] [Granule manufacturing method] In one embodiment, the granule 10 according to the present invention can be manufactured as follows: A core material 11 and a first molten component are mixed, and the first molten component is disposed on the surface of the core material 11. The first molten component is then melted by melt deposition modeling to form a molten component layer 12 on the surface of the core material 11. At this time, the core material 11 and the first molten component are heated to a temperature equal to or higher than the melting point of the first molten component. Considering the temperature range generally used in melt deposition modeling, the heating temperature is 100°C or lower. Furthermore, it is preferable that the first molten component be disposed not only on the surface of the core material 11 but also in pores connected to the surface of the core material 11, thereby imparting an anchoring effect to the core material 11 in the molten component layer 12 and improving the adhesion of the molten component layer 12 to the core material 11.

[0043] Core material 11 with melt component layer 12 disposed thereon is mixed with a drug substance and a second melt component, and the drug substance and second melt component are disposed on the surface of melt component layer 12. Furthermore, the second melt component is melted by melt deposition to form a drug substance-containing layer 13 on the surface of melt component layer 12. At this time, core material 11 with melt component layer 12 disposed thereon, the drug substance, and second melt component are heated to a temperature equal to or higher than the melting point of the second melt component. Considering the temperature range generally used in melt deposition deposition, the heating temperature is 100°C or lower.

[0044] In one embodiment, when an additive having a melting point or glass transition point lower than that of the first melting component is selected as the second melting component, by heating to a temperature higher than the melting point or glass transition point of the second melting component and lower than the melting point of the first melting component when forming drug substance-containing layer 13 by melt lamination, drug substance-containing layer 13 can be formed on the surface of melting component layer 12 without significantly affecting or changing the surface structure of melting component layer 12. On the other hand, when an additive having a melting point or glass transition point higher than that of the first melting component is selected as the second melting component, by heating to a temperature higher than the melting point or glass transition point of the second melting component when forming drug substance-containing layer 13 by melt lamination, the surface of melting component layer 12 can be slightly melted, and the interface between melting component layer 12 and drug substance-containing layer 13 can be fused, thereby improving the adhesion of drug substance-containing layer 13 to melting component layer 12. It is preferable to carry out melt lamination within a temperature range in which the drug substance is not denatured or a significant increase in related substances is not observed.

[0045] A gelling substance is disposed on the surface of the active pharmaceutical ingredient-containing layer 13. In this embodiment, the gelling substance-containing layer 15 is formed by dry coating. In one embodiment, the gelling substance-containing layer 15 can be suitably formed by melt lamination.

[0046] A hydrophobic polymer-containing layer 17 is disposed on the surface of the gelling substance-containing layer 15. The hydrophobic polymer-containing layer 17 can be formed by coating the surface of the gelling substance-containing layer 15 with a hydrophobic polymer using a mixed solvent of a hydrophilic organic solvent and water. Suitable examples of the hydrophilic organic solvent include ethanol and isopropanol. It is also preferable to use a mixed solvent in which the water:organic solvent ratio is in the range of 1:2 to 1:100.

[0047] An overcoat layer 19 is disposed on the surface of the hydrophobic polymer-containing layer 17. The overcoat layer 19 can be formed by coating the surface of the hydrophobic polymer-containing layer 17 with the additives described above using an aqueous solvent such as water or a non-aqueous solvent such as alcohol.

[0048] In this embodiment, the gelling substance-containing layer 15 is formed between the drug substance-containing layer 13 and the hydrophobic polymer-containing layer 17, so the hydrophobic polymer-containing layer 17 can be made thin. By making the hydrophobic polymer-containing layer 17 thin, the time required to manufacture the granules 10 can be reduced. Furthermore, in the granules 10 according to this embodiment, the gelling substance-containing layer 15 is arranged by melt lamination deposition, so the time required to arrange the gelling substance-containing layer 15 can be significantly reduced compared to conventional methods.

[0049] [formulation] A formulation can be produced using the granules 10. For example, the granules 10 may be mixed with one or more known pharmaceutically acceptable additives to form a pharmaceutical composition. The pharmaceutical composition may also be compressed into tablets. Alternatively, a pharmaceutical composition containing a disintegrant may be compressed into an orally disintegrating tablet. Alternatively, the pharmaceutical composition may be encapsulated to form a capsule tablet.

[0050] [Evaluation of bitterness suppression effect] The bitterness suppression effect of the granules 10 according to this embodiment can be evaluated by a sensory test. The bitterness suppression effect of the formulation according to this embodiment can also be evaluated in accordance with the dissolution test method (paddle method) of the Japanese Pharmacopoeia, 17th Edition. [Example]

[0051] [Example 1] 256 g of hydrous silicon dioxide (Sylopure® P100, Fuji Silysia Chemical Ltd.) was used as the core material 11, and 384 g of stearic acid (Sakura Fine Powder, NOF Corporation) was used as the first molten component. The hydrous silicon dioxide and stearic acid were placed in a high-speed agitation granulator (Fukae Kogyo Co., Ltd., High-Speed ​​Mixer, FS-GS-5J) and granulated for 11 minutes at an agitator rotation speed of 300 rpm, a chopper rotation speed of 1,500 rpm, and a water temperature of approximately 80°C. The temperature of the additives was approximately 70°C.

[0052] 80.0 g of cores with a molten component layer 12 disposed on the surface, 248.12 g of sitagliptin phosphate as the active ingredient, and 24.0 g of aminoalkyl methacrylate copolymer E (Evonik Röhm, EUDRAGIT® EPO) as the second molten component were placed in a tumbling fluidized bed granulator (Powrex Corporation, Model: MP-01) and granulated at an inlet air temperature of 80.0 to 85.0°C and a rotor rotation speed of 400 rpm. The temperature of the additives was approximately 60°C.

[0053] 352.12 g of core material with a drug substance-containing layer 13 disposed on its surface, 32.0 g of carboxyvinyl polymer (Lubrizol Advanced Materials, Inc., CARBOPOL® 971P NF), and 6.0 g of sucralose (San-Ei Gen F.F.I., P) were placed in a tumbling fluidized bed granulator (Powrex Corporation, Model: MP-01) and dry-coated at an inlet air temperature of 80.0-85.0°C and a rotor rotation speed of 400 rpm. The additive temperature was approximately 60°C. CARBOPOL® 971P NF has a viscosity of 4000-11000 mPa·s as a 0.5% aqueous solution.

[0054] A coating solution was prepared by dispersing 48.0 g of dried methacrylic acid copolymer LD (EUDRAGIT® L100-55, Evonik Röhm), ​​1.44 g of hypromellose (TC-5® E, Shin-Etsu Chemical Co., Ltd.), 14.4 g of talc (ML115, Fuji Talc Co., Ltd.), and 4.8 g of light anhydrous silicic acid (Adsolider® 101, Freund Corporation) in 560 g of ethanol and 96.0 g of purified water. 390.12 g of core materials with gelling substance-containing layers 15 disposed on their surfaces were placed in a tumbling fluidized bed granulator (Powrex Corporation, model: MP-01), and the coating agent was sprayed onto the core materials to form the hydrophobic polymer-containing layer 17.

[0055] A coating solution was prepared by dissolving 32.0 g of D-mannitol (Mannit P, Mitsubishi Corporation Food Tech Co., Ltd.) and 4.0 g of sucralose (P, San-Ei Gen F.F.I. Co., Ltd.) in 280 g of purified water. 458.76 g of core materials with a hydrophobic polymer-containing layer 17 disposed on the surface were placed in a tumbling fluidized bed granulator (Powrex Corporation, model: MP-01), and a coating agent was sprayed onto the core material to form an overcoat layer 19, yielding the particles of Example 1.

[0056] Each tablet contains 113.4 mg of D-mannitol (Mitsubishi Corporation Foodtech Co., Ltd., Mannit P), 14.0 mg of crystalline cellulose (Asahi Kasei Corporation, Ceolus® PH-101), 7.0 mg of low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd., L-HPC® NDB-022), 140 mg of a granule consisting of 2.8 mg of crospovidone (BASF, Kollidon® CL-F) and 2.8 mg of crospovidone (BASF, Kollidon® CL-M), 247.38 mg of the particles of Example 1, 34.62 mg of D-mannitol (Freund Corporation, Granutol® F), 20.0 mg of silicic acid-treated crystalline cellulose (JRS PHARMA, PROSOLV® SMCC50), and crospovidone (BASF, Kollidon® CL-F). The powder was mixed in a plastic bag so that the total weight of the powder was 16.0 mg, magnesium aluminometasilicate (Fuji Chemical Industry Co., Ltd., Neusilin (registered trademark) UFL-2) 10.0 mg, and sodium stearyl fumarate (Rettenmeyer Japan Co., Ltd., PRUV (registered trademark)) 12.0 mg, and the mixed powder was compressed into tablets using a rotary tablet press (Kikusui Seisakusho, VELA5) at a tableting pressure of 11.3 kN.

[0057] [Comparative Example 1] 2 is a schematic diagram showing a cross section of granule 90 of Comparative Example 1. Granule 90 of Comparative Example 1 differs from granule 10 of Example 1 in that an undercoat layer 95 is arranged on the surface of active pharmaceutical ingredient-containing layer 13 instead of gelling substance-containing layer 15.

[0058] A coating solution was prepared by dispersing 32.0 g of hypromellose (Shin-Etsu Chemical Co., Ltd., TC-5®E) and 1.6 g of light anhydrous silicic acid (Freund Corporation, Adsolider® 101) in 640 g of purified water. 352.12 g of cores with active ingredient-containing layers 13 disposed on their surfaces, obtained by a method similar to that of the Examples, were placed in a tumbling fluidized bed granulator (Powrex Corporation, model: MP-01), and the coating agent was sprayed onto them to form an undercoat layer 95.

[0059] A coating solution was prepared by dispersing 80.0 g of dried methacrylic acid copolymer LD (EUDRAGIT® L100-55, Evonik Röhm), ​​3.2 g of hypromellose (TC-5® E, Shin-Etsu Chemical Co., Ltd.), 24.0 g of talc (ML115, Fuji Talc Co., Ltd.), and 8.0 g of light anhydrous silicic acid (Adsolider® 101, Freund Corporation) in 1000 g of ethanol and 200.0 g of purified water. 390.12 g of core materials with an undercoat layer 95 disposed on their surfaces were placed in a tumbling fluidized bed granulator (Powrex Corporation, model: MP-01), and the coating agent was sprayed to form a hydrophobic polymer-containing layer 17.

[0060] An overcoat layer 19 was formed in the same manner as in Example 1 to obtain particles of Comparative Example 1.

[0061] Each tablet contained 103.68 mg of D-mannitol (Mannit P), 12.8 mg of microcrystalline cellulose (PH-101), 6.4 mg of low-substituted hydroxypropyl cellulose (NDB-022), 2.56 mg of crospovidone (CL-F), 138.68 mg of granules consisting of 2.56 mg of crospovidone (CL-M), 278.46 mg of the particles of Comparative Example 1, 35.54 mg of D-mannitol (Granutol (registered trademark) F), 16.0 mg of silicic acid-treated microcrystalline cellulose (SMCC50), 10.0 mg of crospovidone (CL-F), 16.0 mg of magnesium aluminometasilicate (UFL-2), and sodium stearyl fumarate (PRUV). The mixture was mixed in a plastic bag so that the total weight was 16.0 mg, and the mixed powder was compressed into tablets using a rotary tablet press (VELA5, Kikusui Seisakusho) at a tableting pressure of 13.2 kN.

[0062] [Evaluation of bitterness suppression effect] To evaluate the bitterness suppression effect, three testers placed 300 mg of the granules of Example 1 and Comparative Example 1 in their mouths and evaluated the bitterness masking effect. Although the granules of Example 1 had a lower hydrophobic polymer content than the granules of Comparative Example 1, they were able to suppress the bitterness.

[0063] In Comparative Example 1, it took about 150 minutes to form the undercoat layer 95, but in Example 1, it took only about 15 minutes to form the gelling substance-containing layer 15. Therefore, it was clear that the granules of Example 1 can significantly reduce the production time.

[0064] [Example 2] 256 g of hydrous silicon dioxide (Sylopure® P100, Fuji Silysia Chemical Ltd.) was used as the core material 11, and 384 g of stearic acid (Sakura Fine Powder, NOF Corporation) was used as the first molten component. The hydrous silicon dioxide and stearic acid were placed in a high-speed agitation granulator (Fukae Kogyo Co., Ltd., High-Speed ​​Mixer, FS-GS-5J) and granulated for 11 minutes at an agitator rotation speed of 300 rpm, a chopper rotation speed of 1,500 rpm, and a water temperature of approximately 80°C. The temperature of the additives was approximately 70°C.

[0065] 80.0 g of cores with a molten component layer 12 disposed on the surface, 248.12 g of sitagliptin phosphate as the active ingredient, and 24.0 g of aminoalkyl methacrylate copolymer E (Evonik Röhm, EUDRAGIT® EPO) as the second molten component were placed in a tumbling fluidized bed granulator (Powrex Corporation, Model: MP-01) and granulated at an inlet air temperature of 80.0 to 85.0°C and a rotor rotation speed of 400 rpm. The temperature of the additives was approximately 60°C.

[0066] 352.12 g of core material with a drug substance-containing layer 13 disposed on its surface, 32.0 g of carboxyvinyl polymer (Lubrizol Advanced Materials, Inc., CARBOPOL® 971P NF), and 6.0 g of sucralose (Sanei Gen F.F.I., P) were placed in a tumbling fluidized bed granulator (Powrex Corporation, Model: MP-01) and dry-coated at an inlet air temperature of 80.0-85.0°C and a rotor rotation speed of 400 rpm. The additive temperature was approximately 60°C. The viscosity of a 0.5% aqueous solution of the carboxyvinyl polymer was 4000-11000 mPa·s.

[0067] A coating solution was prepared by dispersing 48.0 g of dried methacrylic acid copolymer LD (EUDRAGIT® L100-55, Evonik Röhm), ​​1.44 g of hypromellose (TC-5® E, Shin-Etsu Chemical Co., Ltd.), 14.4 g of talc (ML115, Fuji Talc Co., Ltd.), and 4.8 g of light anhydrous silicic acid (Adsolider® 101, Freund Corporation) in 560 g of ethanol and 96.0 g of purified water. 390.12 g of core materials with gelling substance-containing layers 15 disposed on their surfaces were placed in a tumbling fluidized bed granulator (Powrex Corporation, model: MP-01), and the coating agent was sprayed onto the core materials to form the hydrophobic polymer-containing layer 17.

[0068] A coating solution was prepared by dissolving 32.0 g of D-mannitol (Mannit P, Mitsubishi Corporation Food Tech Co., Ltd.) and 4.0 g of sucralose (P, San-Ei Gen F.F.I. Co., Ltd.) in 280 g of purified water. 458.76 g of core materials with a hydrophobic polymer-containing layer 17 disposed on the surface were placed in a tumbling fluidized bed granulator (Powrex Corporation, model: MP-01), and a coating agent was sprayed onto the core material to form an overcoat layer 19, yielding particles of Example 2.

[0069] Each tablet contained 113.4 mg of D-mannitol (Mitsubishi Corporation Foodtech Co., Ltd., Mannit P), 14.0 mg of microcrystalline cellulose (Asahi Kasei Corporation, Ceolus® PH-101), 7.0 mg of low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd., L-HPC® NDB-022), 140 mg of D-mannitol-microcrystalline cellulose-low-substituted hydroxypropyl cellulose-crospovidone granules consisting of 2.8 mg of crospovidone (BASF, Kollidon® CL-F) and 2.8 mg of crospovidone (BASF, Kollidon® CL-M), 247.38 mg of the particles of Example 2, 34.62 mg of D-mannitol (Freund Corporation, Granutol® F), and silicic acid-treated microcrystalline cellulose (JRS PHARMA, PROSOLV® SMCC50). 20.0 mg of crospovidone (BASF, Kollidon® CL-F) 10.0 mg, magnesium aluminometasilicate (Fuji Chemical Industry Co., Ltd., Neusilin® UFL-2) 16.0 mg, and sodium stearyl fumarate (Rettenmeyer Japan Co., Ltd., PRUV®) 12.0 mg were mixed in a plastic bag, and the mixed powder was compressed into tablets using a rotary tablet press (Kikusui Seisakusho, VELA5) at a tableting pressure of 11.3 kN.

[0070] [Example 3] A gelling substance-containing layer 15 of Example 3 was formed in the same manner as in Example 2, except that 352.12 g of the core material having the active pharmaceutical ingredient-containing layer 13 of Example 2 disposed on the surface was used, and the amounts of carboxyvinyl polymer and sucralose were changed to 24.0 g and 6.2 g, respectively.

[0071] The hydrophobic polymer-containing layer 17 of Example 3 was formed in the same manner as in Example 2 using 382.52 g of the core material having the gelling substance-containing layer 15 disposed on the surface thereof.

[0072] The overcoat layer 19 of Example 3 was formed in the same manner as in Example 2, except that 451.2 g of core material having a hydrophobic polymer-containing layer 17 disposed on the surface was used and the amount of sucralose (Sanei Gen F.F.I. Co., Ltd., P) was changed to 4.8 g, thereby obtaining the particles of Example 3.

[0073] The D-mannitol-crystalline cellulose-low-substituted hydroxypropyl cellulose-crospovidone granules (160 mg), the particles of Example 3 (243.98 mg), D-mannitol (Granutol® F, Freund Corporation), 29.22 mg, silicic acid-treated crystalline cellulose (PROSOLV® SMCC50, JRS PHARMA), 16.0 mg, crospovidone (Kollidon® CL-F, BASF), 10.0 mg, magnesium aluminometasilicate (Neusilin® UFL-2, Fuji Chemical Industry Co., Ltd.), and sodium stearyl fumarate (PRUV®, Rettenmeyer Japan Co., Ltd.) (4.8 mg) were mixed in a plastic bag so that each tablet contained 160 mg of the D-mannitol-crystalline cellulose-low-substituted hydroxypropyl cellulose-crospovidone granules, 243.98 mg of the particles of Example 3, 29.22 mg of D-mannitol (Granutol® F, Freund Corporation), 16.0 mg of silicic acid-treated crystalline cellulose (PROSOLV® SMCC50, JRS PHARMA), 10.0 mg of crospovidone (Kollidon® CL-F, BASF), 16.0 mg of magnesium aluminometasilicate (Neusilin® UFL-2, Fuji Chemical Industry Co., Ltd.), and 4.8 mg of sodium stearyl fumarate (PRUV®, Rettenmeyer Japan Co., Ltd.) and the mixed powder was compressed into tablets using a rotary tablet press (VELA5, Kikusui Seisakusho) at a tableting pressure of 11.3 kN.

[0074] [Example 4] A gelling substance-containing layer 15 of Example 4 was formed in the same manner as in Example 2, except that 352.12 g of the core material having the active pharmaceutical ingredient-containing layer 13 of Example 2 disposed on the surface was used, and the amount of carboxyvinyl polymer was changed to 24.0 g, and the sucralose was changed to 4.0 g of hydrous silicon dioxide (Evonik, Carplex (registered trademark) #80).

[0075] A coating solution was prepared by dispersing 62.0 g of dry methacrylic acid copolymer LD (EUDRAGIT® L100-55, Evonik Röhm), ​​2.4 g of hypromellose (TC-5® E, Shin-Etsu Chemical Co., Ltd.), and 8.0 g of hydrous silicon dioxide (Carplex® #80, Evonik) in 640 g of ethanol and 160 g of purified water. 380.12 g of core materials with gelling substance-containing layers 15 disposed on their surfaces were placed in a tumbling fluidized bed granulator (Powrex Corporation, model: MP-01), and the coating agent was sprayed onto the core materials to form the hydrophobic polymer-containing layer 17 of Example 4.

[0076] The overcoat layer 19 of Example 3 was formed in the same manner as in Example 2, except that 454.6 g of core material having a hydrophobic polymer-containing layer 17 disposed on the surface was used and the amount of sucralose (Sanei Gen F.F.I. Co., Ltd., P) was changed to 8.0 g, thereby obtaining the particles of Example 4.

[0077] Each tablet contained 176 mg of D-mannitol-crystalline cellulose-low-substituted hydroxypropyl cellulose-crospovidone granules, 247.26 mg of the particles of Example 4, 10.74 mg of D-mannitol (Granutol® F, Freund Corporation), 10.0 mg of crospovidone (Kollidon® CL-F, BASF), 24.0 mg of magnesium aluminometasilicate (Neusilin® UFL-2, Fuji Chemical Industry Co., Ltd.), and 12.0 mg of sodium stearyl fumarate (PRUV®, Rettenmeyer Japan Co., Ltd.). The resulting powder mixture was compressed into tablets using a rotary tablet press (VELA5, Kikusui Seisakusho) at a tableting pressure of 11.3 kN.

[0078] [Example 5] The gelling substance-containing layer 15 of Example 5 was formed in the same manner as in Example 2, except that 352.12 g of the core material having the active pharmaceutical ingredient-containing layer 13 of Example 2 disposed on the surface was used, the amount of carboxyvinyl polymer was changed to 24.0 g, and sucralose was not added.

[0079] A coating solution was prepared by dispersing 80.0 g of dry methacrylic acid copolymer LD (Evonik Röhm, EUDRAGIT® RSPO) in 400 g of ethanol and 100.0 g of purified water. 376.12 g of core materials with gelling substance-containing layers 15 disposed on their surfaces were placed in a tumbling fluidized bed granulator (Powrex Corporation, model: MP-01), and the coating agent was sprayed onto the core materials to form the hydrophobic polymer-containing layer 17 of Example 5.

[0080] Using 456.2 g of the core material having the hydrophobic polymer-containing layer 17 disposed on the surface thereof, the overcoat layer 19 of Example 5 was formed in the same manner as in Example 4, thereby obtaining particles of Example 5.

[0081] The D-mannitol-crystalline cellulose-low-substituted hydroxypropyl cellulose-crospovidone granules (160 mg), the particles of Example 5 (248.06 mg), D-mannitol (Granutol® F, Freund Corporation), silicic acid-treated crystalline cellulose (PROSOLV® SMCC50, JRS PHARMA), crospovidone (Kollidon® CL-F, BASF), 24.0 mg, magnesium aluminometasilicate (Neusilin® UFL-2, Fuji Chemical Industry Co., Ltd.), and magnesium stearate (Taihei Chemical Industry Co., Ltd.) were mixed in a plastic bag so that each tablet contained 160 mg of the D-mannitol-crystalline cellulose-low-substituted hydroxypropyl cellulose-crospovidone granules, 248.06 mg of the particles of Example 5, 17.14 mg of D-mannitol (Granutol® F, Freund Corporation), 17.14 mg of silicic acid-treated crystalline cellulose (PROSOLV® SMCC50, JRS PHARMA), 10.0 mg of crospovidone (Kollidon® CL-F, BASF), 24.0 mg of magnesium aluminometasilicate (Neusilin® UFL-2, Fuji Chemical Industry Co., Ltd.), and 4.8 mg of magnesium stearate (Taihei Chemical Industry Co., Ltd.), and the mixed powder was compressed into tablets using a rotary tablet press (VELA5, Kikusui Seisakusho) at a tableting pressure of 11.3 kN.

[0082] Comparative Example 2 A core material having a molten component layer 12 disposed on its surface was obtained in the same manner as in Example 2, except that stearic acid (NOF Corporation, cherry blossom fine powder) was changed to stearic acid (NOF Corporation, vegetable-based).

[0083] A core material having a drug substance-containing layer 13 of Comparative Example 2 disposed on its surface was obtained in the same manner as in Example 2, except that a core material having a molten component layer 12 of Comparative Example 2 disposed on its surface was used.

[0084] A coating solution was prepared by dispersing 32.0 g of hypromellose (Shin-Etsu Chemical Co., Ltd., TC-5®E) and 1.6 g of light anhydrous silicic acid (Freund Corporation, Adsolider® 101) in 640 g of purified water. 352.12 g of the core material having the active ingredient-containing layer 13 on its surface from Comparative Example 2 was placed in a tumbling fluidized bed granulator (Powrex Corporation, model: MP-01), and the coating agent was sprayed onto it to form an undercoat layer 95.

[0085] A coating solution was prepared by dispersing 48.0 g of dried methacrylic acid copolymer LD (EUDRAGIT® L100-55, Evonik Röhm), ​​1.92 g of hypromellose (TC-5® E, Shin-Etsu Chemical Co., Ltd.), 14.2 g of talc (ML115, Fuji Talc Co., Ltd.), and 4.8 g of light anhydrous silicic acid (Adsolider® 101, Freund Corporation) in 600 g of ethanol and 120.0 g of purified water. 385.72 g of core materials with an undercoat layer 95 disposed on the surface were placed in a tumbling fluidized bed granulator (Powrex Corporation, model: MP-01), and the coating agent was sprayed to form a hydrophobic polymer-containing layer 17.

[0086] A coating solution was prepared by dissolving 48.0 g of D-mannitol (Mannit P, Mitsubishi Corporation Food Tech Co., Ltd.) and 8.0 g of sucralose (P, San-Ei Gen F.F.I. Co., Ltd.) in 400 g of purified water. 454.84 g of core materials with a hydrophobic polymer-containing layer 17 disposed on the surface were placed in a tumbling fluidized bed granulator (Powrex Corporation, model: MP-01), and a coating agent was sprayed onto them to form an overcoat layer 19, yielding particles of Comparative Example 2.

[0087] The D-mannitol-crystalline cellulose-low-substituted hydroxypropyl cellulose-crospovidone granules (152 mg), the particles of Comparative Example 2 (255.42 mg), D-mannitol (Granutol® F, Freund Corporation), 34.58 mg, silicic acid-treated crystalline cellulose (PROSOLV® SMCC50, JRS PHARMA), 16.0 mg, crospovidone (Kollidon® CL-F, BASF), 10.0 mg, magnesium aluminometasilicate (Neusilin® UFL-2, Fuji Chemical Industry Co., Ltd.), and sodium stearyl fumarate (PRUV®, Rettenmeyer Japan Co., Ltd.) were mixed in a plastic bag so that each tablet contained 152 mg of the D-mannitol-crystalline cellulose-low-substituted hydroxypropyl cellulose-crospovidone granules, 255.42 mg of the particles of Comparative Example 2, 34.58 mg, silicic acid-treated crystalline cellulose (PROSOLV® SMCC50, JRS PHARMA), 16.0 mg, crospovidone (Kollidon® CL-F, BASF), 16.0 mg, magnesium aluminometasilicate (Neusilin® UFL-2, Fuji Chemical Industry Co., Ltd.), and 16.0 mg, respectively. The mixed powder was compressed into tablets using a rotary tablet press (VELA5, Kikusui Seisakusho) at a tableting pressure of 11.3 kN.

[0088] Comparative Example 3 A coating solution was prepared by dispersing 80.0 g of dried methacrylic acid copolymer LD (EUDRAGIT® L100-55, Evonik Röhm), ​​3.2 g of hypromellose (TC-5® E, Shin-Etsu Chemical Co., Ltd.), 24.0 g of talc (ML115, Fuji Talc Co., Ltd.), and 8.0 g of light anhydrous silicic acid (Adsolider® 101, Freund Corporation) in 1000 g of ethanol and 200.0 g of purified water. 385.72 g of the core material having the undercoat layer 95 of Comparative Example 2 on its surface was placed in a tumbling fluidized bed granulator (Powrex Corporation, model: MP-01), and the coating agent was sprayed to form a hydrophobic polymer-containing layer 17.

[0089] Using 500.92 g of the core material of Comparative Example 3 on the surface of which the hydrophobic polymer-containing layer 17 was disposed, an overcoat layer 19 was formed in the same manner as in Comparative Example 2, thereby obtaining particles of Comparative Example 3.

[0090] The formulation of Comparative Example 3 was obtained in the same manner as in Comparative Example 2, except that the amount of D-mannitol-crystalline cellulose-low-substituted hydroxypropyl cellulose-crospovidone granules per tablet was changed to 128 mg, the particles of Comparative Example 3 were changed to 278.46 mg, and D-mannitol (Freund Corporation, Granutol (registered trademark) F) was changed to 35.54 mg.

[0091] [Evaluation of bitterness suppression effect] The dissolution properties of sitagliptin phosphate were evaluated for the preparations of Examples 2 to 5 and Comparative Examples 2 to 3 according to the dissolution test method (paddle method) of the Seventeenth Edition of the Japanese Pharmacopoeia. 900 ml of water was used as the test liquid. The paddle rotation speed was 50 rpm. The dissolution rates of sitagliptin phosphate were measured 5, 10, 15, and 30 minutes after the start of the test. The results of the measurement of the dissolution rates of sitagliptin phosphate are shown in Figure 3. The preparations of Examples 2 to 5, which used the gelling substance Carbopol in the gelling substance-containing layer 15, showed reduced dissolution of sitagliptin phosphate compared to the preparations of Comparative Examples 2 to 3, which had an undercoat layer 95 containing hypromellose, demonstrating that Carbopol functions to suppress the dissolution of sitagliptin phosphate (control bitterness).

[0092] In particular, the formulations of Examples 2 to 4 suppressed the release of sitagliptin phosphate despite the fact that the content of hydrophobic polymer (Eudragid® L100-55) in the hydrophobic polymer-containing layer 17 was lower than that of the formulation of Comparative Example 3. Furthermore, by including a gelling substance in the gelling substance-containing layer 15, the bitterness of sitagliptin phosphate could be suppressed with a small coating amount (reducing the time required to form the gelling substance-containing layer 15). Comparing the formulation of Example 2 with the formulation of Example 5, the formulation of Example 2 exhibited a similar release behavior of sitagliptin phosphate despite the content of the hydrophobic polymer in the hydrophobic polymer-containing layer 17 being reduced to 60% by weight. These results demonstrate that suppression of bitterness can be achieved in the formulations of the present invention when the ratio of gelling substance to hydrophobic polymer is in the range of 2:3 to 3:8. From the perspective of shortening production time, it is preferable to minimize the content of hydrophobic polymer in the hydrophobic polymer-containing layer 17.

[0093] [Example 6] 256 g of hydrous silicon dioxide (Sylopure® P100, Fuji Silysia Chemical Ltd.) was used as the core material 11, and 384 g of stearic acid (Sakura Fine Powder, NOF Corporation) was used as the first molten component. The hydrous silicon dioxide and stearic acid were placed in a high-speed agitation granulator (Fukae Kogyo Co., Ltd., High-Speed ​​Mixer, FS-GS-5J) and granulated for 11 minutes at an agitator rotation speed of 300 rpm, a chopper rotation speed of 1,500 rpm, and a water temperature of approximately 80°C. The temperature of the additives was approximately 70°C.

[0094] Using 80.0 g of the core material having a molten component layer 12 disposed on the surface, a core material having a drug substance-containing layer 13 disposed on the surface was obtained in the same manner as in Example 2.

[0095] 319.70 g of core material with a drug substance-containing layer 13 disposed on its surface and 20.4 g of polyethylene oxide (Dow Chemical, POLYOX® WSR N-60K) were placed in a tumbling fluidized bed granulator (Powrex Corporation, Model: MP-01) and dry-coated at an inlet air temperature of 80.0-85.0°C and a rotor rotation speed of 400 rpm. The temperature of the additive was approximately 60°C. The viscosity of a 2% aqueous solution of polyethylene oxide was 2000-4000 mPa·s.

[0096] The hydrophobic polymer-containing layer 17 of Example 6 was formed in the same manner as in Example 4, except that 390.12 g of the core material having the gelling substance-containing layer 15 of Example 6 disposed on the surface thereof was used.

[0097] The particles of Example 6 were obtained in the same manner as in Example 4, except that 458.76 g of the core material having the hydrophobic polymer-containing layer 17 of Example 6 disposed on the surface thereof was used.

[0098] Comparative Example 4 256 g of hydrous silicon dioxide (Fuji Silysia Chemical Ltd., Sylopure® P100) was used as the core material 11, and 153.6 g of stearic acid (NOF Corporation, vegetable-based) and 204.8 g of stearic acid (BASF Pharma, Kolliwax® S Fine) were used as the first molten component. The hydrous silicon dioxide and stearic acid were placed in a high-speed agitation granulator (Fukae Kogyo Co., Ltd., High-Speed ​​Mixer, FS-GS-5J) and granulated for 11 minutes at an agitator rotation speed of 300 rpm, a chopper rotation speed of 1,500 rpm, and a water temperature of approximately 80°C. The temperature of the additives was approximately 70°C.

[0099] 80.0 g of core material with a molten component layer 12 disposed on its surface, 210.9 g of sitagliptin phosphate as the active ingredient, and 27.2 g of aminoalkyl methacrylate copolymer E (Evonik Röhm, EUDRAGIT® EPO) as the second molten component were placed in a tumbling fluidized bed granulator (Powrex Corporation, Model: MP-01) and granulated at an inlet air temperature of 80.0-85.0°C and a rotor rotation speed of 400 rpm. The temperature of the additives was approximately 60°C.

[0100] A coating solution was prepared by dispersing 24.0 g of hypromellose (Shin-Etsu Chemical Co., Ltd., TC-5®E) and 1.2 g of hydrous silicon dioxide (Evonik, Carplex® #80) in 360 g of purified water. 376.12 g of the core material having the active ingredient-containing layer 13 of Comparative Example 2 disposed on the surface was placed in a tumbling fluidized bed granulator (Powrex Corporation, model: MP-01), and the coating agent was sprayed onto it to form an undercoat layer 95.

[0101] A coating solution was prepared by dispersing 76.0 g of dry methacrylic acid copolymer LD (EUDRAGIT® L100-55, Evonik Röhm), ​​2.4 g of hypromellose (TC-5® E, Shin-Etsu Chemical Co., Ltd.), and 14.2 g of titanium oxide (NA61, Toho Titanium Co., Ltd.) in 600 g of ethanol and 120.0 g of purified water. 401.32 g of core materials with an undercoat layer 95 on the surface were placed in a tumbling fluidized bed granulator (Powrex Corporation, model: MP-01), and the coating agent was sprayed onto the core material to form a hydrophobic polymer-containing layer 17.

[0102] A coating solution was prepared by dissolving 32.0 g of D-mannitol (Mannit P, Mitsubishi Corporation Food Tech Co., Ltd.) and 12.0 g of sucralose (P, San-Ei Gen F.F.I. Co., Ltd.) in 280 g of purified water. 494.12 g of core materials with a hydrophobic polymer-containing layer 17 disposed on the surface were placed in a tumbling fluidized bed granulator (Powrex Corporation, model: MP-01), and a coating agent was sprayed onto them to form an overcoat layer 19, yielding particles of Comparative Example 4.

[0103] [Evaluation of bitterness suppression effect] The bitterness suppression effect was evaluated for the particles of Examples 4 and 6 and Comparative Example 4. Specifically, two testers placed 300 mg of the granules of Examples 4 and 6 or Comparative Example 4 in their mouths to evaluate the bitterness suppression effect. The evaluation results of the bitterness suppression effect of the particles of Examples 4 and 6 and Comparative Example 4, and the formation times of the gelling substance-containing layer 15 and the undercoat layer 95 are shown in Table 1. [Table 1]

[0104] The particles of Examples 4 and 6 contained a gelling substance in the gelling substance-containing layer 15. When placed in the mouth, saliva seeped through the gaps in the hydrophobic polymer-containing layer 17 swelled the gelling substance, suppressing the bitterness of the active pharmaceutical ingredient. The particles of Comparative Example 4 did not contain a gelling substance in the undercoat layer 95, and therefore were unable to suppress the bitterness. Comparing the amounts of hydrophobic polymer (Eudragit® L100-55) contained in the hydrophobic polymer-containing layer 17 of the particles of Examples 4, 6, and Comparative Example 4, the amounts were 32 mg and 38 mg, respectively. The particles of Examples 4 and 6 suppressed the bitterness despite containing less hydrophobic polymer than the particles of Comparative Example 4, demonstrating that the gelling substance contributes to the suppression of bitterness. The evaluation results of the bitterness suppression effect showed that the particles of the present invention not only shortened the production time for the gelling substance-containing layer 15, but also reduced the amount of hydrophobic polymer contained in the hydrophobic polymer-containing layer 17 compared to the prior art. No difference was observed between the bitterness-suppressing effect of the particles of Example 4 and that of the particles of Example 6, demonstrating that, in principle, any additive that is generally treated as a gelling substance and can be dry-coated can be applied to the particles of the present invention. [Explanation of symbols]

[0105] 10 granules, 11 core material, 12 melting component layer, 13 active ingredient-containing layer, 15 gelling substance-containing layer, 17 hydrophobic polymer-containing layer, 19 overcoat layer, 90 granules, 95 undercoat layer

Claims

1. a molten component layer disposed on the surface of the core material and including a first molten component; a drug substance-containing layer disposed on the surface of the melt component layer and containing a second melt component and a drug substance; a gelling substance-containing layer disposed on the surface of the drug substance-containing layer; a hydrophobic polymer-containing layer disposed on the surface of the gelling substance-containing layer, the first melt component is selected from the group consisting of glyceryl monostearate, macrogol (polyethylene glycol), lauromacrogol, and stearic acid; the second melt component is selected from the group consisting of stearic acid, glyceryl monostearate, macrogol (polyethylene glycol), carnauba wax, hydrogenated oil, lauromacrogol, palmitic acid, cetyl alcohol, aminoalkyl methacrylate copolymer E, ammonioalkyl methacrylate copolymer, dry methacrylic acid copolymer, hypromellose acetate succinate, polyvinylpyrrolidone, and polyvinyl acetal diethylaminoacetate; the second melt component is a different additive than the first melt component; the gelling substance-containing layer contains a gelling substance having a viscosity of 10 mPa·s or more in a 2% aqueous solution, Granules, wherein the content ratio of the gelling substance contained in the gelling substance-containing layer to the hydrophobic polymer contained in the hydrophobic polymer-containing layer is in the range of 2:3 to 3:

8.

2. The granule of claim 1 , further comprising an overcoat layer disposed on the surface of the hydrophobic polymer-containing layer.

3. 2. The granule of claim 1, wherein the gelling substance-containing layer comprises one or more gelling substances selected from the group consisting of sodium carboxymethylcellulose, polyethylene oxide, sodium polyacrylate, sodium alginate, propylene glycol alginate, xanthan gum, carrageenan, guar gum, tara gum, pectin, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxyvinyl polymer, locust bean gum, tamarind seed gum, gum arabic, karaya gum, agar, gelatin, polyvinyl alcohol, and copolymers containing polyvinyl alcohol as a part thereof.

4. 4. The granule of claim 1, wherein the hydrophobic polymer-containing layer comprises one or more hydrophobic polymers selected from ethyl cellulose, acetyl cellulose, cellulose acetate phthalate, carboxymethyl ethyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, dimethylaminoethyl methacrylate-methyl methacrylate copolymer, methyl acrylate-methacrylic acid copolymer, ethyl acrylate-methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer RS, dry methacrylic acid copolymer LD, aminoalkyl methacrylate copolymer E, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, and polyvinyl acetal diethylaminoacetate.

5. A granule according to any one of claims 1 to 4; and one or more pharmaceutically acceptable excipients.

6. forming a molten component layer disposed on the surface of the core material and including the first molten component; a drug substance-containing layer containing a second molten component and a drug substance is formed on the surface of the molten component layer; a gelling substance is disposed on the surface of the drug substance-containing layer by dry coating to form a gelling substance-containing layer; and disposing a hydrophobic polymer on the surface of the gelling substance-containing layer to form a hydrophobic polymer-containing layer; the first melt component is selected from the group consisting of glyceryl monostearate, macrogol (polyethylene glycol), lauromacrogol, and stearic acid; the second melt component is selected from the group consisting of stearic acid, glyceryl monostearate, macrogol (polyethylene glycol), carnauba wax, hydrogenated oil, lauromacrogol, palmitic acid, cetyl alcohol, aminoalkyl methacrylate copolymer E, ammonioalkyl methacrylate copolymer, dry methacrylic acid copolymer, hypromellose acetate succinate, polyvinylpyrrolidone, and polyvinyl acetal diethylaminoacetate; the second melt component is a different additive than the first melt component; the gelling substance-containing layer contains a gelling substance having a viscosity of 10 mPa·s or more in a 2% aqueous solution, A method for producing granules, wherein the content ratio of the gelling substance contained in the gelling substance-containing layer to the hydrophobic polymer contained in the hydrophobic polymer-containing layer is in the range of 2:3 to 3:

8.

7. The method for producing granules according to claim 6, further comprising forming an overcoat layer on the surface of the hydrophobic polymer-containing layer.

8. 7. The method for producing granules according to claim 6, wherein the gelling substance-containing layer contains one or more gelling substances selected from the group consisting of sodium carboxymethylcellulose, polyethylene oxide, sodium polyacrylate, sodium alginate, propylene glycol alginate, xanthan gum, carrageenan, guar gum, tara gum, pectin, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxyvinyl polymer, locust bean gum, tamarind seed gum, gum arabic, karaya gum, agar, gelatin, polyvinyl alcohol, and copolymers containing polyvinyl alcohol as a part thereof.

9. 9. The method for producing granules according to claim 6, wherein the hydrophobic polymer-containing layer comprises one or more hydrophobic polymers selected from ethyl cellulose, acetyl cellulose, cellulose acetate phthalate, carboxymethylethyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, dimethylaminoethyl methacrylate-methyl methacrylate copolymer, methyl acrylate-methacrylic acid copolymer, ethyl acrylate-methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer RS, dry methacrylic acid copolymer LD, aminoalkyl methacrylate copolymer E, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, and polyvinyl acetal diethylaminoacetate.

10. Granules produced by the method according to any one of claims 6 to 9; and one or more pharmaceutically acceptable excipients.

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