JP7808937B2 - Granules, preparations containing granules, method for producing granules, and method for producing preparations containing granules - Google Patents

Description

One embodiment of the present invention relates to granules in which the bitter taste of a drug substance is masked, or to a formulation containing the granules. Alternatively, one embodiment of the present invention relates to a method for producing granules in which the bitter taste of a drug substance is masked, or to a method for producing a formulation containing the granules.

Many active pharmaceutical ingredients are known to have a bitter taste, and when released in the oral cavity, they can cause strong discomfort to patients and significantly reduce medication compliance. It is necessary to inhibit the release of active pharmaceutical ingredients from the drug, at least while the drug is present in the oral cavity.

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

Patent Document 2 also describes pharmaceutical composition particles that, with the aim 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.

In Patent Documents 1 and 2, the bitterness is masked by coating the active pharmaceutical ingredient-containing composition, but in the case of an active pharmaceutical ingredient with a strong bitter taste, the coating layer must be made thick. In this case, the coated pharmaceutical composition particles become larger, which causes a problem of 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 produced that is easy to take while masking the bitterness.

WO 02/096392 International Publication No. 2017/146052

One of the objectives of one embodiment of the present invention is to provide granules capable of adequately masking bitterness. Alternatively, one of the objectives of one embodiment of the present invention is to provide a formulation containing granules capable of adequately masking bitterness. Alternatively, one of the objectives of one embodiment of the present invention is to provide a method for producing granules capable of adequately masking bitterness. Alternatively, one of the objectives of one embodiment of the present invention is to provide a method for producing a formulation containing granules capable of adequately masking bitterness.

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.

The device may further include a melt component layer disposed on the surface of the core material and containing the melt component, and a drug substance-containing layer containing the melt component and the drug substance may be disposed on the surface of the melt component layer.

It may further include an overcoat layer disposed on the surface of the hydrophobic polymer-containing layer.

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

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.

The hydrophobic polymer-containing layer may contain 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 diethylamino acetate.

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.

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

According to one embodiment of the present invention, a method for producing granules is provided, 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 of the melting component and the active pharmaceutical ingredient 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.

A melt component layer containing the melt component may be further formed on the surface of the core material, and a drug substance-containing layer containing the melt component and the drug substance may be formed on the surface of the melt component layer.

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

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

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.

The hydrophobic polymer-containing layer may contain 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 diethylamino acetate.

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.

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.

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.

1 is a schematic diagram showing the cross-sectional structure of a granule 10 according to one embodiment of the present invention. FIG. 2 is a schematic diagram showing the cross-sectional structure of a granule 90 of a comparative example. FIG. 1 is a graph showing the dissolution rate of sitagliptin phosphate in a preparation according to an example of the present invention.

The granules of the present invention and formulations using the same will be described below with reference to the drawings. The granules of the present invention and formulations using the same should not be construed as being limited to the contents of the following embodiments and examples. In the drawings referred to in the present embodiments and examples below, identical parts or parts with similar functions are designated by the same reference numerals, and repeated explanations will be omitted.

Figure 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.

The core material 11 is a carrier for disposing the melting component layer 12, the active pharmaceutical ingredient-containing layer 13, the gelling substance-containing layer 15, the hydrophobic polymer-containing layer 17, and the overcoat layer 19. Furthermore, the core material 11 is a material that serves as a core for disposing the melting component layer 12, the active pharmaceutical ingredient-containing layer 13, the gelling substance-containing layer 15, the hydrophobic polymer-containing layer 17, and the overcoat layer 19 when manufacturing the granules 10. To ensure adhesion with the melting component layer 12, an adsorbent is used as the core material 11. 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 granules, bentonite, polyethylene fiber, magnesium aluminometasilicate, and medicinal charcoal.

The core material 11 is preferably spherical in shape to ensure uniform arrangement of 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.

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 adhesion to the core material, or if the core material has a high capacity to support the active pharmaceutical ingredient, the melting component and active pharmaceutical ingredient may be disposed directly on the core material. On the other hand, by disposing a melting component layer 12 composed of a melting component that has high adhesion to the core material 11 on the surface of the core material 11, more active pharmaceutical ingredient can be adhered to the melting component layer 12, effectively increasing the active pharmaceutical ingredient content in the granules 10.

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 active pharmaceutical ingredient or significantly increase the amount of related substances upon contact with the active pharmaceutical ingredient. The melt component layer 12 is preferably formed by melt deposition, and the first melt component may be selected from additives that are solid at room temperature. Considering the temperature range typically used in melt deposition, the first melt component is preferably selected from additives with a melting point of 100°C or below, and preferably from additives with a melting point within a temperature range where the active pharmaceutical ingredient does not denature or significantly increase the amount of related substances. Examples of additives with such properties include, but are not limited to, glyceryl monostearate, macrogol (polyethylene glycol), lauromacrogol, and stearic acid.

The melt component layer 12 may be disposed on the surface of the core material 11 in an amount sufficient to accommodate the active pharmaceutical ingredient-containing layer 13, 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 perspective of increasing the active pharmaceutical ingredient 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. By disposing the molten component 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, improving the adhesion of the molten component layer 12 to the core material 11.

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. There are no particular limitations on the active pharmaceutical ingredient in the granules 10.

When the melt component layer 12 is disposed on the surface of the core material 11, the drug substance-containing layer 13 contains a second melt component to bond the drug substances together and to bond the drug substances to the surface of the melt component layer 12. The second 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. Since the 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 commonly used in melt layering, the second melt component is preferably selected from additives with a melting point of 100°C or below or a glass transition point of 120°C or below, and is preferably selected from additives with a melting point or glass transition point within a temperature range in which the drug substance does not denature or significantly increase the amount of related substances. Furthermore, 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, when forming the drug substance-containing layer 13 by melt lamination, the drug substance-containing layer 13 can be disposed on the surface of the melting component layer 12 without significantly affecting or changing the surface structure of the 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, when forming the drug substance-containing layer 13 by melt lamination, the surface of the melting component layer 12 melts slightly, causing the interface between the melting component layer 12 and the drug substance-containing layer 13 to fuse, thereby improving the adhesion of the drug substance-containing layer 13 to the melting component layer 12.

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 (second melt component) contained in active ingredient-containing layer 13 may contain the same additive as the melt component (first melt component) contained in melt component layer 12, or it may contain a different additive.

The active pharmaceutical ingredient-containing layer 13 contains the active pharmaceutical ingredient as the main component. It is preferable that the active pharmaceutical ingredient-containing layer 13 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, it is preferable that the active pharmaceutical ingredient-containing layer 13 contain a small amount of the second melt component to the extent that the active pharmaceutical ingredient-containing layer 13 can be formed on the surface of the melt component layer 12. This effectively increases the active pharmaceutical ingredient content in the granules 10.

The gelling substance-containing layer 15 functions to adjust the elution of the active pharmaceutical ingredient from the active pharmaceutical ingredient-containing layer 13. As described below, the hydrophobic polymer-containing layer 17 prevents moisture (saliva) from the oral cavity from flowing into the active pharmaceutical ingredient-containing layer 13, while the gelling substance contained in the gelling substance-containing layer 15 absorbs moisture that has seeped in from the hydrophobic polymer-containing layer 17 and gels to form a gel layer. This gel layer prevents moisture from flowing into the active pharmaceutical ingredient-containing layer 13 in the oral cavity, preventing the elution of the active pharmaceutical ingredient from the active pharmaceutical ingredient-containing layer 13. Furthermore, because the large amount of moisture in gastric juice dissolves the gel layer, the gelling substance-containing layer 15 can achieve rapid elution of the active pharmaceutical ingredient from the active pharmaceutical ingredient-containing layer 13 in the stomach.

In this embodiment, a gelling substance having a viscosity of 10 mPa·s or greater 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. One or a combination of two or more gelling substances can be used.

The hydrophobic polymer-containing layer 17 functions to prevent moisture in the oral cavity from flowing into the active pharmaceutical 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 water-insoluble substances include 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.

In the granules 10 according to the embodiment, the inclusion of the gelling substance-containing layer 15 sufficiently prevents moisture in the oral cavity from flowing into the active pharmaceutical ingredient-containing layer 13, allowing the hydrophobic polymer-containing layer 17 to be made thinner. By making the hydrophobic polymer-containing layer 17 thinner, 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, allowing the time required to arrange the gelling substance-containing layer 15 to be significantly reduced compared to conventional methods.

The overcoat layer 19, disposed on the surface of the hydrophobic polymer-containing layer 17, improves swallowability and suppresses delayed dissolution of the active pharmaceutical ingredient. The overcoat layer 19 can be made of one or a combination of two or more selected from the following: 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.

[Method of producing granules]
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 typically used in melt deposition modeling, the heating temperature is 100°C or lower. Preferably, the first molten component is 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 molten component layer 12 and improving adhesion of the molten component layer 12 to the core material 11.

The core material 11 with the molten component layer 12 disposed thereon is mixed with the active pharmaceutical ingredient and the second molten component, and the active pharmaceutical ingredient and the second molten component are disposed on the surface of the molten component layer 12. The second molten component is then melted using melt deposition to form an active pharmaceutical ingredient-containing layer 13 on the surface of the molten component layer 12. At this time, the core material 11 with the molten component layer 12 disposed thereon, the active pharmaceutical ingredient, and the second molten component are heated to a temperature equal to or higher than the melting point of the second molten component. Considering the temperature range typically used in melt deposition, the heating temperature is 100°C or lower.

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, the drug substance-containing layer 13 can be formed on the surface of the melting component layer 12 by heating to a temperature higher than the melting point or glass transition point of the second melting component but lower than the melting point of the first melting component when forming the drug substance-containing layer 13 by melt lamination, without significantly affecting or changing the surface structure of the 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, the drug substance-containing layer 13 can be formed on the surface of the melting component layer 12 by heating to a temperature higher than the melting point or glass transition point of the second melting component when forming the drug substance-containing layer 13 by melt lamination, whereby the surface of the melting component layer 12 slightly melts, the interface between the melting component layer 12 and the drug substance-containing layer 13 fuses, and the adhesion of the drug substance-containing layer 13 to the melting component layer 12 can be improved. It is preferable to perform melt lamination within a temperature range that does not result in denaturation of the active pharmaceutical ingredient or a significant increase in related substances.

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 deposition.

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 hydrophilic organic solvents include, for example, ethanol and isopropanol. It is also preferable to use a mixed solvent with a water:organic solvent ratio in the range of 1:2 to 1:100.

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.

In this embodiment, the gelling substance-containing layer 15 is formed between the active pharmaceutical ingredient-containing layer 13 and the hydrophobic polymer-containing layer 17, allowing the hydrophobic polymer-containing layer 17 to be made thinner. By making the hydrophobic polymer-containing layer 17 thinner, 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 disposed by melt lamination deposition, allowing the time required to dispose the gelling substance-containing layer 15 to be significantly reduced compared to conventional methods.

[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.

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

[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 charged into 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.

80.0 g of core material with a molten component layer 12 disposed on its 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 80.0-85.0°C and a rotor rotation speed of 400 rpm. The temperature of the additives was approximately 60°C.

352.12 g of core material with an active ingredient-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. Co., Ltd., 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 at this time was approximately 60°C. CARBOPOL® 971P NF has a viscosity of 4000-11000 mPa·s as a 0.5% aqueous solution.

A coating solution was prepared by dispersing 48.0 g of dried methacrylic acid copolymer LD (Evonik Röhm, EUDRAGIT® L100-55), 1.44 g of hypromellose (Shin-Etsu Chemical Co., Ltd., TC-5® E), 14.4 g of talc (Fuji Talc Co., Ltd., ML115), and 4.8 g of light anhydrous silicic acid (Freund Corporation, Adsolider® 101) in 560 g of ethanol and 96.0 g of purified water. 390.12 g of core material with a gelling substance-containing layer 15 disposed 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.

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 material with a hydrophobic polymer-containing layer 17 disposed on its surface was placed in a tumbling fluidized bed granulator (Powrex Corporation, Model: MP-01), and the coating agent was sprayed to form an overcoat layer 19, yielding the particles of Example 1.

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 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 1, 34.62 mg of D-mannitol (Freund Corporation, Granutol® F), and silicic acid-treated crystalline cellulose (JRS PHARMA, PROSOLV® SMCC50). 20.0 mg, crospovidone (BASF, Kollidon® CL-F) 16.0 mg, magnesium aluminometasilicate (Fuji Chemical Industry Co., Ltd., Neusilin® UFL-2) 10.0 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.

[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 disposed on the surface of active pharmaceutical ingredient-containing layer 13 instead of gelling substance-containing layer 15.

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 core materials 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.

A coating solution was prepared by dispersing 80.0 g of dried methacrylic acid copolymer LD (Evonik Röhm, EUDRAGIT® L100-55), 3.2 g of hypromellose (Shin-Etsu Chemical Co., Ltd., TC-5® E), 24.0 g of talc (Fuji Talc Co., Ltd., ML115), and 8.0 g of light anhydrous silicic acid (Freund Corporation, Adsolider® 101) in 1,000 g of ethanol and 200.0 g of purified water. 390.12 g of core material with an undercoat layer 95 disposed 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.

An overcoat layer 19 was formed in the same manner as in Example 1 to obtain particles for Comparative Example 1.

Each tablet contains 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), 138.68 mg of granules consisting of 2.56 mg of crospovidone (CL-F) and 2.56 mg of crospovidone (CL-M), 278.46 mg of particles from Comparative Example 1, 35.54 mg of D-mannitol (Granutol® 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 ingredients were mixed in a plastic bag to make a total weight of 16.0 mg, and the mixed powder was compressed into tablets using a rotary tablet press (Kikusui Seisakusho, VELA5) at a tableting pressure of 13.2 kN.

[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.

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

[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 charged into 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.

80.0 g of core material with a molten component layer 12 disposed on its 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 80.0-85.0°C and a rotor rotation speed of 400 rpm. The temperature of the additives was approximately 60°C.

352.12 g of core material with an active ingredient-containing layer 13 disposed on the 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. Co., Ltd., 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 at this time was approximately 60°C. The viscosity of a 0.5% aqueous solution of the carboxyvinyl polymer was 4,000-11,000 mPa·s.

A coating solution was prepared by dispersing 48.0 g of dried methacrylic acid copolymer LD (Evonik Röhm, EUDRAGIT® L100-55), 1.44 g of hypromellose (Shin-Etsu Chemical Co., Ltd., TC-5® E), 14.4 g of talc (Fuji Talc Co., Ltd., ML115), and 4.8 g of light anhydrous silicic acid (Freund Corporation, Adsolider® 101) in 560 g of ethanol and 96.0 g of purified water. 390.12 g of core material with a gelling substance-containing layer 15 disposed 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.

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 material with a hydrophobic polymer-containing layer 17 disposed on its surface was placed in a tumbling fluidized bed granulator (Powrex Corporation, Model: MP-01), and the coating agent was sprayed to form an overcoat layer 19, yielding the particles of Example 2.

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 D-mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, and 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 from Example 2, 34.62 mg of D-mannitol (Freund Corporation, Granutol® F), and silicic acid-treated crystalline cellulose (JRS 20.0 mg of crospovidone (BASF, PROSOLV® SMCC50), 10.0 mg of crospovidone (BASF, Kollidon® CL-F), 16.0 mg of magnesium aluminometasilicate (Fuji Chemical Industry Co., Ltd., Neusilin® UFL-2), and 12.0 mg of sodium stearyl fumarate (Rettenmeyer Japan Co., Ltd., PRUV®) 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.

[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 amount of carboxyvinyl polymer was changed to 24.0 g and the amount of sucralose was changed to 6.2 g.

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

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 (San-Ei Gen F.F.I. Co., Ltd., P) was changed to 4.8 g, thereby obtaining the particles of Example 3.

Each tablet contains 160 mg of D-mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, and crospovidone granules, 243.98 mg of the particles of Example 3, 29.22 mg of D-mannitol (Freund Corporation, Granutol® F), 16.0 mg of silicic acid-treated crystalline cellulose (JRS PHARMA, PROSOLV® SMCC50), 10.0 mg of crospovidone (BASF, Kollidon® CL-F), 16.0 mg of magnesium aluminometasilicate (Fuji Chemical Industry Co., Ltd., Neusilin® UFL-2), and sodium stearyl fumarate (Rettenmeyer Japan Co., Ltd., PRUV®). The ingredients were mixed in a plastic bag so that the total weight was 4.8 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.

[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).

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

The overcoat layer 19 of Example 3 was formed in the same manner as in Example 2, obtaining the particles of Example 4, using 454.6 g of core material with a hydrophobic polymer-containing layer 17 disposed on the surface, and changing the amount of sucralose (San-Ei Gen F.F.I. Co., Ltd., P) to 8.0 g.

The following ingredients were mixed in a plastic bag so that each tablet contained 176 mg of D-mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, and crospovidone granules, 247.26 mg of the particles from Example 4, 10.74 mg of D-mannitol (Freund Corporation, Granutol® F), 10.0 mg of crospovidone (BASF, Kollidon® CL-F), 24.0 mg of magnesium aluminometasilicate (Fuji Chemical Industry Co., Ltd., Neusilin® UFL-2), and 12.0 mg of sodium stearyl fumarate (Rettenmeyer Japan Co., Ltd., PRUV®). The mixed powder was compressed into tablets using a rotary tablet press (Kikusui Seisakusho, VELA5) at a compression pressure of 11.3 kN.

[Example 5]
A 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.

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 material with a gelling substance-containing layer 15 disposed on its surface was placed in a tumbling fluidized bed granulator (Powrex Corporation, model: MP-01), and the coating agent was sprayed to form the hydrophobic polymer-containing layer 17 of Example 5.

Using 456.2 g of core material with a hydrophobic polymer-containing layer 17 disposed on its surface, an overcoat layer 19 of Example 5 was formed in the same manner as in Example 4, thereby obtaining particles of Example 5.

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

[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).

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

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 from Comparative Example 2 with the active ingredient-containing layer 13 disposed on its 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.

A coating solution was prepared by dispersing 48.0 g of dried methacrylic acid copolymer LD (Evonik Röhm, EUDRAGIT® L100-55), 1.92 g of hypromellose (Shin-Etsu Chemical Co., Ltd., TC-5® E), 14.2 g of talc (Fuji Talc Co., Ltd., ML115), and 4.8 g of light anhydrous silicic acid (Freund Corporation, Adsolider® 101) in 600 g of ethanol and 120.0 g of purified water. 385.72 g of core material with an undercoat layer 95 disposed 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.

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 material with a hydrophobic polymer-containing layer 17 disposed on its surface was placed in a tumbling fluidized bed granulator (Powrex Corporation, Model: MP-01), and the coating agent was sprayed to form an overcoat layer 19, yielding particles of Comparative Example 2.

Each tablet contains 152 mg of D-mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, and crospovidone granules, 255.42 mg of particles from Comparative Example 2, 34.58 mg of D-mannitol (Freund Corporation, Granutol® F), 16.0 mg of silicic acid-treated crystalline cellulose (JRS PHARMA, PROSOLV® SMCC50), 10.0 mg of crospovidone (BASF, Kollidon® CL-F), 16.0 mg of magnesium aluminometasilicate (Fuji Chemical Industry Co., Ltd., Neusilin® UFL-2), and 16.0 mg of sodium stearyl fumarate (Rettenmeyer Japan Co., Ltd., PRUV®). The ingredients were mixed in a plastic bag to make a total weight of 16.0 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.

[Comparative Example 3]
A coating solution was prepared by dispersing 80.0 g of dried methacrylic acid copolymer LD (Evonik Röhm, EUDRAGIT® L100-55), 3.2 g of hypromellose (Shin-Etsu Chemical Co., Ltd., TC-5® E), 24.0 g of talc (Fuji Talc Co., Ltd., ML115), and 8.0 g of light anhydrous silicic acid (Freund Corporation, Adsolider® 101) 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 disposed 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.

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

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

[Evaluation of bitterness suppression effect]
The dissolution properties of sitagliptin phosphate were evaluated for the formulations of Examples 2 to 5 and Comparative Examples 2 and 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 solution. 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 dissolution rate measurements of sitagliptin phosphate are shown in Figure 3. The formulations of Examples 2 to 5, which used the gelling substance Carbopol in the gelling substance-containing layer 15, exhibited reduced dissolution of sitagliptin phosphate compared to the formulations of Comparative Examples 2 to 3, which had an undercoat layer 95 containing hypromellose, demonstrating that Carbopol functions to inhibit dissolution (control bitterness) of sitagliptin phosphate.

In particular, the formulations of Examples 2 to 4 suppressed sitagliptin phosphate elution despite having a lower content of hydrophobic polymer (Eudragid® L100-55) in the hydrophobic polymer-containing layer 17 than the formulation of Comparative Example 3. Furthermore, by including a gelling substance in the gelling substance-containing layer 15, the bitterness of sitagliptin phosphate can be suppressed with a smaller coating amount (reducing the time required to form the gelling substance-containing layer 15). Comparing the formulations of Examples 2 and 5, the formulation of Example 2 exhibited similar sitagliptin phosphate elution behavior despite the hydrophobic polymer content 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 gelling substance:hydrophobic polymer ratio is in the range of 2:3 to 3:8. From the perspective of shortening manufacturing time, it is preferable to keep the hydrophobic polymer content in the hydrophobic polymer-containing layer 17 as low as possible.

[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 charged into 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.

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

319.70 g of core material with an active ingredient-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. At this time, the temperature of the additive was approximately 60°C. A 2% aqueous solution of polyethylene oxide has a viscosity of 2000-4000 mPa·s.

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 its surface was used.

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 its surface was used.

[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 charged into 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.

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.

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 from Comparative Example 2 with the active ingredient-containing layer 13 disposed on its surface was placed in a tumbling fluidized bed granulator (Powrex Corporation, model: MP-01), and the coating agent was sprayed onto it to form the undercoat layer 95.

A coating solution was prepared by dispersing 76.0 g of dried methacrylic acid copolymer LD (Evonik Röhm, EUDRAGIT® L100-55), 2.4 g of hypromellose (Shin-Etsu Chemical Co., Ltd., TC-5® E), and 14.2 g of titanium oxide (Toho Titanium Co., Ltd., NA61) in 600 g of ethanol and 120.0 g of purified water. 401.32 g of core material with an undercoat layer 95 disposed 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.

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 material with a hydrophobic polymer-containing layer 17 disposed on its surface was placed in a tumbling fluidized bed granulator (Powrex Corporation, Model: MP-01), and the coating agent was sprayed to form an overcoat layer 19, yielding the particles of Comparative Example 4.

[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 evaluated the bitterness suppression effect by placing 300 mg of the granules of Examples 4 and 6 or Comparative Example 4 in their mouths. The evaluation results of the bitterness suppression effect for 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.

The particles of Examples 4 and 6 contain a gelling substance in the gelling substance-containing layer 15. When placed in the mouth, saliva seeping through the gaps in the hydrophobic polymer-containing layer 17 swells the gelling substance, suppressing the bitterness of the active pharmaceutical ingredient. The particles of Comparative Example 4 do 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. Despite containing less hydrophobic polymer than the particles of Comparative Example 4, the particles of Examples 4 and 6 suppressed the bitterness, 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 shorten the manufacturing time for the gelling substance-containing layer 15, but also enable a reduction in the amount of hydrophobic polymer contained in the hydrophobic polymer-containing layer 17 compared to conventional techniques. No difference was observed between the bitterness suppression effect of the particles in Example 4 and that of the particles in 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.

10 Granules, 11 Core material, 12 Melting component layer, 13 Drug substance-containing layer, 15 Gelling substance-containing layer, 17 Hydrophobic polymer-containing layer, 19 Overcoat layer, 90 Granules, 95 Undercoat layer

Claims (10)

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 . The granules of claim 1, further comprising an overcoat layer disposed on the surface of the hydrophobic polymer-containing layer. 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 . The granules of any one of claims 1 to 3, 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. A granule according to any one of claims 1 to 4 ;
and one or more pharmaceutically acceptable excipients. 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;
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 . The method for producing granules according to claim 6 , further comprising forming an overcoat layer on the surface of the hydrophobic polymer-containing layer. 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. 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. Granules produced by the method according to any one of claims 6 to 9 ;
and one or more pharmaceutically acceptable excipients.