Granules and preparations using the same

Abstract

To provide granules having high content ratio of a drug substance and high uniformity of grain diameters, and preparation containing the granules.SOLUTION: Provided is a granule 10 including a nuclear material 11, a molten component layer 13 arranged on the surface of the nuclear material, and a drug substance-containing layer 15 arranged on the surface of the molten component layer, where the molten component layer includes a first molten component, the drug substance-containing layer includes a drug substance, a second molten component, or a polymer having compatibility to the first molten component.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to granules containing a high content of active pharmaceutical ingredients and a preparation using the same. [Background technology]

[0002] To improve the manufacturability of pharmaceutical formulations, drug substances are granulated with various additives. Granulation methods are classified into wet granulation and dry granulation depending on whether a solvent is used or not. When granulating a drug substance that is unstable in water, a dry granulation method that does not use a solvent is selected, and among dry granulation methods, a melt granulation method in which an additive is melted by heat and used as a binder is known. For example, Patent Documents 1 to 4 and Non-Patent Document 1 describe core particles in which a layer containing a drug substance is disposed on the surface of a core material using a melt granulation method.

[0003] On the other hand, melt granulation is heavily influenced by the physical properties of the molten components, making it difficult to control the particle size of the granules.In addition, because melt granulation uses molten components instead of solvents, it is difficult to increase the content of the active pharmaceutical ingredient in the granules.As a result, the dosage form inevitably becomes larger, which leads to problems such as reduced medication adherence. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Japanese Patent Application Laid-Open No. 2017-1999 [Patent Document 2] Japanese Patent Application Laid-Open No. 2015-199721 [Patent Document 3] Japanese Patent Application Laid-Open No. 2015-71542 [Patent Document 4] Japanese Patent Application Publication No. 6-256169 [Non-patent literature]

[0005] [Non-Patent Document 1] Chem. Pharm. Bull. 65, 726-731 (2017) Summary of the Invention [Problem to be solved by the invention]

[0006] One object of one embodiment of the present invention is to provide granules having a high content of active pharmaceutical ingredients and a highly uniform particle size by using a melt granulation method, or to provide a formulation containing granules having a high content of active pharmaceutical ingredients and a highly uniform particle size. [Means for solving the problem]

[0007] According to one embodiment of the present invention, a pharmaceutical composition includes a core material, a melt component layer disposed on the surface of the core material, and a drug substance-containing layer disposed on the surface of the melt component layer, wherein the melt component layer contains a first melt component, and the drug substance-containing layer contains a drug substance and a second melt component, or No. and a polymer that is compatible with one of the melt components.

[0008] The second melting component may have a melting point that is lower than the melting point of the first melting component and is 100° C. or less.

[0009] The second melting component may have a melting point that is higher than the melting point of the first melting component and not higher than 100°C.

[0010] When the first melt component is stearic acid or lauromacrogol, the compatible polymer may be selected from the group consisting of aminoalkyl methacrylate copolymer, ammonioalkyl methacrylate copolymer, methacrylic acid copolymer, hypromellose acetate succinate, and polyvinylpyrrolidone.

[0011] The core material is spherical, and the particle size of the core material is the same as the particle size of the drug substance. and It may be larger than the particle size of the second molten component.

[0012] The core material may have pores on the surface, and the molten component layer may have a structure in which the first molten component is also disposed in the pores.

[0013] 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.

[0014] The excipient may be a disintegrant. [Effects of the Invention]

[0015] According to one embodiment of the present invention, granules having a high content of active pharmaceutical ingredients and a highly uniform particle size are provided, or according to one embodiment of the present invention, a formulation containing granules having a high content of active pharmaceutical ingredients and a highly uniform particle size is provided. [Brief explanation of the drawings]

[0016] [Figure 1] 1 is a schematic diagram showing a granule containing a core particle according to one embodiment of the present invention. [Figure 2] 1 is a schematic diagram showing a granule containing a core particle according to one embodiment of the present invention. [Figure 3] FIG. 1 is a flow diagram illustrating a method for producing granules containing core particles according to one embodiment of the present invention. [Figure 4] FIG. 1 is a flow diagram illustrating a method for producing granules containing core particles according to one embodiment of the present invention. [Figure 5] (a) is a scanning electron microscope (SEM) image of granules of Example 1, (b) is an SEM image of granules of Example 2, (c) is an SEM image of granules of Example 3, (d) is an SEM image of granules of Example 4, (e) is an SEM image of granules of Comparative Example 1, and (f) is an SEM image of granules of Comparative Example 2. DETAILED DESCRIPTION OF THE INVENTION

[0017] 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.

[0018] 1 is a schematic diagram (cross-sectional view) showing a granule 10 according to one embodiment of the present invention. Granule 10 includes a core material 11, a molten component layer 13 disposed on the surface of core material 11, and an active pharmaceutical ingredient-containing layer 15 disposed on the surface of molten component layer 13.

[0019] Core material 11 is a carrier for disposing molten component layer 13 and active pharmaceutical ingredient-containing layer 15, and serves as a core material for disposing molten component layer 13 and active pharmaceutical ingredient-containing layer 15 when producing granules 10. To ensure adhesion to molten component layer 13, an adsorbent is used as core material 11. Examples of adsorbents that can be used as core material 11 include 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.

[0020] Core material 11 is preferably spherical in order to uniformly arrange molten component layer 13 and active pharmaceutical ingredient-containing layer 15. Furthermore, from the viewpoint of adhering the active pharmaceutical ingredient, the particle size of core material 11 must be larger than the particle size of the active pharmaceutical ingredient. The particle size of core material 11 is, for example, at least twice the particle size of the active pharmaceutical ingredient, but is not limited to this.

[0021] The melting component layer 13 is a layer disposed between the core material 11 and the active pharmaceutical ingredient-containing layer 15. The melting component layer 13 is a base layer for disposing the active pharmaceutical ingredient-containing layer 15. In the above-mentioned patent documents, the melting component and active pharmaceutical ingredient are disposed directly on the core material. However, if the active pharmaceutical ingredient itself has poor adhesion to the core material or the core material has low ability to support the active pharmaceutical ingredient, it is necessary to blend a large amount of the melting component relative to the active pharmaceutical ingredient, and it has not been possible to obtain a granule containing a high content of active pharmaceutical ingredient. In contrast, in the present invention, by disposing the melting component layer 13 on the surface of the core material 11 in the granule 10, a large amount of active pharmaceutical ingredient can be adhered to the melting component layer 13, and the content of the active pharmaceutical ingredient in the granule 10 can be effectively increased.

[0022] As described above, the melt component (first melt component) constituting the melt component layer 13 is selected from oil-based additives. Because the melt component layer 13 is formed by melt granulation, the first melt component is selected from additives that are solid at room temperature. Considering the temperature range typically used in melt granulation, the first melt component is preferably selected from additives having a melting point of 100°C or lower, and more preferably from additives having a melting point within a temperature range in which the drug substance is not denatured or a significant increase in related substances is not observed. Examples of additives having such properties include, but are not limited to, glyceryl monostearate, macrogol (polyethylene glycol), lauromacrogol, and stearic acid. Furthermore, the first melt component is preferably selected from additives that do not cause the drug substance to be denatured or a significant increase in related substances is not observed upon contact with the drug substance.

[0023] The melting component layer 13 may be disposed on the surface of the core material 11 in an amount that allows the drug substance-containing layer 15 to be disposed, and may be disposed on at least a portion of the surface of the core material 11. It is preferable that the melting component layer 13 covers 90% or more of the surface of the core material 11, and it is preferable that the melting component layer 13 covers the entire surface of the core material 11. twistIt is preferable. The thickness of the melt component layer 13 is not particularly limited, but from the viewpoint of increasing the content of the active pharmaceutical ingredient per granule 10, it is preferable that the thickness of the melt component layer 13 be as thin as possible. In one embodiment, the first melt component constituting the melt component layer 13 is also preferably disposed in the pores on the surface of the core material 11. In one embodiment, the interface between the core material 11 and the melt component layer 13 may have a structure in which the melt component constituting the melt component layer 13 penetrates from the surface of the core material 11. In this case, the core material 11 and the melt component layer 13 do not need to have a clear interface. Disposing the melt 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 imparts an anchoring effect to the melt component layer 13 with respect to the core material 11, thereby improving the adhesion of the melt component layer 13 to the core material 11.

[0024] The drug substance-containing layer is a layer containing a drug substance and a second melt component or polymer, and is disposed on the surface of melt component layer 13. FIG. 1 shows granule 10 in which drug substance-containing layer 15 contains a drug substance and a second melt component. FIG. 2 shows granule 20 in which drug substance-containing layer 25 contains a drug substance and a polymer compatible with the first melt component. The drug substance in granules 10 and 20 is not particularly limited. Since the methods for producing granules 10 and 20 do not use a solvent, particularly water, drug substances that are unstable in water can be suitably used.

[0025] In drug substance-containing layer 15, the second melt component is an additive that binds the drug substances together and also binds the drug substances to the surface of melt component layer 13. To form drug substance-containing layer 15 by melt granulation, the second melt component is selected from additives that are solid at room temperature. Considering the temperature range generally used in melt granulation, the second melt component is preferably selected from additives having a melting point of 100°C or less, and is preferably selected from additives having a melting point within a temperature range in which the drug substance is not denatured or a significant increase in related substances is not observed. Furthermore, when an additive having a melting point lower than that of the first melt component is selected as the second melt component, drug substance-containing layer 15 can be disposed on the surface of melt component layer 13 during formation by melt granulation without significantly affecting or changing the surface structure of melt component layer 13. On the other hand, if an additive having a melting point higher than that of the first molten component is selected as the second molten component, when forming the active ingredient-containing layer 15 by melt granulation, the surface of the molten component layer 13 melts slightly, and the interface between the molten component layer 13 and the active ingredient-containing layer 15 fuses, thereby improving the adhesion of the active ingredient-containing layer 15 to the molten component layer 13.

[0026] 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, and cetyl alcohol. 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. From the perspective of adhering the melt component to core material 11, the particle size of the melt component needs to be smaller than that of core material 11. The melt component (second melt component) contained in drug substance-containing layer 15 may be the same additive as or different from the melt component (first melt component) contained in melt component layer 13.

[0027] In one embodiment, a polymer compatible with the first melt component can be used in granules 20 instead of the second melt component. The phrase "compatible" for a polymer with the first melt component refers to a state in which the first melt component and the polymer do not separate. Alternatively, it refers to a state in which the polymer is dispersed in the first melt component, or a state in which the first melt component is dispersed in the polymer. In one embodiment, the state in which the melt component and the polymer do not separate can be confirmed by an increase in viscosity of the mixture (liquid or flowable semi-solid) when the melt component is mixed with the polymer and melted. By using a polymer compatible with the first melt component, the viscosity of the surface of melt component layer 13 is further improved compared to when the second melt component is used, allowing for more stable adhesion of active pharmaceutical ingredient-containing layer 25. As for combinations of polymers compatible with the first melt component, when the first melt component is stearic acid or lauromacrogol, the polymers preferably used are aminoalkyl methacrylate copolymer, ammonioalkyl methacrylate copolymer, methacrylic acid copolymer, hypromellose acetate succinate, or polyvinylpyrrolidone. More preferably, when the first melt component is stearic acid, the polymers preferably used are aminoalkyl methacrylate copolymer, ammonioalkyl methacrylate copolymer, or polyvinylpyrrolidone. Alternatively, when the first melt component is lauromacrogol, the polymers preferably used are aminoalkyl methacrylate copolymer, ammonioalkyl methacrylate copolymer, methacrylic acid copolymer, or hypromellose acetate succinate.

[0028] When a polymer compatible with the first melt component is used instead of the second melt component, the content of the first melt component is preferably equal to or greater than the content of the polymer in granules 20. For example, the blending ratio of the first melt component to the polymer in granules 20 is preferably 20:1 to 1:1, and more preferably 4:1 to 1:1.

[0029] The active pharmaceutical ingredient-containing layer 15 and the active pharmaceutical ingredient-containing layer 25 contain an active pharmaceutical ingredient as a main component. Drug substance-containing layer 15 and It is preferable that the drug substance contained in drug substance-containing layer 25 is 50% by mass or more of the total mass of the drug substance and the second molten component or polymer. In other words, it is preferable that drug substance-containing layer 15 and drug substance-containing layer 25 contain a small amount of the second molten component or polymer to the extent that drug substance-containing layer 15 or drug substance-containing layer 25 can be formed on the surface of melt component layer 13. This can effectively increase the content of the drug substance in granules 10 and 20.

[0030] [Method of manufacturing granules 10] FIG. 3 is a flow diagram illustrating a method for producing granules containing core particles according to one embodiment of the present invention. Core material 11 and first molten component 131 are mixed (S101), and first molten component 131 is disposed on the surface of core material 11. Furthermore, first molten component 131 is melted by melt granulation to form molten component layer 13 on the surface of core material 11 (S103). At this time, core material 11 and first molten component 131 are heated to a temperature equal to or higher than the melting point of first molten component 131. Considering the temperature range generally used in melt granulation, the heating temperature is 100°C or lower. Furthermore, it is preferable that first molten component 131 be disposed not only on the surface of core material 11 but also in pores connected to the surface of core material 11, thereby imparting an anchoring effect to molten component layer 13 and improving adhesion of molten component layer 13 to core material 11.

[0031] The core material 11 with the melt component layer 13 disposed thereon is mixed with the drug substance 151 and the second melt component 153 (S105), and the drug substance 151 and the second melt component 153 are disposed on the surface of the melt component layer 13. The second melt component 153 is melted by melt granulation to form a drug substance-containing layer 15 on the surface of the melt component layer 13 (S107). At this time, the core material 11 with the melt component layer 13 disposed thereon, the drug substance 151, and the second melt component 153 are heated to a temperature equal to or higher than the melting point of the second melt component 153. Considering the temperature range generally used in melt granulation, the heating temperature is 100°C or lower.

[0032] In one embodiment, when an additive having a melting point lower than that of first melt component 131 is selected as second melt component 153, by heating to a temperature higher than the melting point of second melt component 153 but lower than the melting point of first melt component 131 when forming drug substance-containing layer 15 by melt granulation, drug substance-containing layer 15 can be formed on the surface of melt component layer 13 without significantly affecting or changing the surface structure of melt component layer 13. On the other hand, when an additive having a melting point higher than that of first melt component 131 is selected as second melt component 153, by heating to a temperature higher than the melting point of second melt component 153 when forming drug substance-containing layer 15 by melt granulation, the surface of melt component layer 13 can be slightly melted, and the interface between melt component layer 13 and drug substance-containing layer 15 can be fused, thereby improving the adhesion of drug substance-containing layer 15 to melt component layer 13. It is preferable to carry out melt granulation within a temperature range in which the drug substance 151 is not denatured or a significant increase in related substances is not observed.

[0033] [Method of manufacturing granules 20] As mentioned above, a polymer compatible with the first molten component can be used instead of the second molten component 153. Fig. 4 is a flow diagram illustrating a method for producing a granule 20 containing a core particle according to one embodiment of the present invention. Since the process up to the step of forming a molten component layer 13 on the surface of the core material 11 (S103) is the same as the process for producing the granule 10 described above, a detailed description will be omitted.

[0034] Core material 11 with melt component layer 13 disposed thereon is mixed with drug substance 151 and polymer 253 compatible with the first melt component (S205), and drug substance 151 and polymer 253 are disposed on the surface of melt component layer 13. Furthermore, first melt component 131 is melted by melt granulation to form drug substance-containing layer 25 on the surface of melt component layer 13, in which drug substance 151 and polymer 253 are dispersed in first melt component 131 (S207). At this time, core material 11 with melt component layer 13 disposed thereon, drug substance 151, and polymer 253 are heated to a temperature equal to or higher than the melting point of first melt component 131. Considering the temperature range generally used in melt granulation, the heating temperature is 100°C or lower.

[0035] In this embodiment, first molten component 131 located in the surface layer of molten component layer 13 melts, and drug substance 151 and polymer 253 are dispersed in the surface layer of molten component layer 13, thereby forming drug substance-containing layer 25. In this embodiment, because polymer 253 is compatible with the first molten component, drug substance 151 and polymer 253 can be formed without separating from first molten component 131. In this embodiment, by using a polymer that is compatible with the first molten component, the viscosity of the surface of molten component layer 13 is further improved compared to when the second molten component is used, and drug substance-containing layer 25 can be adhered more stably.

[0036] [formulation] A formulation can be produced using granules 10 or granules 20. For example, granules 10 or granules 20 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. A pharmaceutical composition to which a disintegrant has been added may also be compressed into an orally disintegrating tablet. The pharmaceutical composition may also be encapsulated to form a capsule. [Example]

[0037] [Example 1] Hydrous silicon dioxide (Fuji Silysia Chemical Ltd., Sylopure® P100) was used as the core material, and glycerin monostearate (Riken Vitamin Co., Ltd., Rikemal® S-100P) was used as the first molten component. 300 g of hydrous silicon dioxide and 480 g of glycerin monostearate were mixed in a high-speed agitation granulator ( Fukae Industries Co., Ltd., The mixture was placed in a 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 75.0°C to 79.0°C. At this time, the temperature of the additives was 69.5°C to 73.0°C.

[0038] 195.0 g of the resulting core material with the molten component layer on its surface, 372.2 g of sitagliptin phosphate as the active ingredient, and 27.0 g of stearic acid (NOF Corporation, vegetable) as the second molten component were placed in a high-speed agitation granulator (Fukae Kogyo Co., Ltd., High-Speed ​​Mixer, FS-GS-5J) and granulated for 22 minutes at an agitator rotation speed of 150 rpm to 300 rpm, a chopper rotation speed of 1,500 rpm, and a water temperature of 74.9°C to 75.0°C. The temperature of the excipients was 68.4°C to 70.3°C.

[0039] A scanning electron microscope (SEM) image of the obtained granules is shown in Figure 5(a). The particle size of the granules was also measured using a laser diffraction / scattering method measuring device (Beckman Coulter, Inc., LS 13 320). The measured particle sizes are shown in Table 1.

[0040] [Example 2] In Example 2, melt granulation was carried out using a tumbling granulator using cores having a molten component layer formed on the surface of the cores of Example 1. 97.5 g of the cores having a molten component layer formed on the surface of the cores of Example 1, 186.1 g of sitagliptin phosphate as the active ingredient, and 22.5 g of stearic acid (NOF Corporation, vegetable) as the second molten component were placed in a tumbling granulator (POWREX Corporation, MP-01), and granulation was carried out for 105 minutes at a rotor rotation speed of 200 rpm to 500 rpm, an intake air flow rate of 0.40 L / min to 0.55 L / min, and an intake air temperature of 89.5°C to 90.9°C. The temperature of the additives was 55.4°C to 65.7°C.

[0041] An SEM image of the obtained granules is shown in Figure 5(b). The particle size of the granules of Example 2 is shown in Table 1.

[0042] [Table 1]

[0043] The granules of Examples 1 and 2 had a drug substance content of approximately 60%, demonstrating the feasibility of achieving a high content. Furthermore, the results of Figures 5(a) and 5(b) reveal that the granules of Examples 1 and 2 are round particles, and because they use a core material, the granule particle size is highly uniform. Referring to Figure 5(a), it was confirmed that the granules of Example 1 have uneven surfaces. The granules of Example 1, which have uneven surfaces, are expected to have improved water conductivity. Furthermore, referring to Figure 5(b), the granules of Example 2 have a smooth surface, suggesting that coating may be considered.

[0044] [Nuclear Material Review] In the manufacturing method of Example 1, the core material was changed, and a molten component layer was formed on the surface of the core material. The hydrous silicon dioxide used was Fujisil (registered trademark) manufactured by Fuji Chemical Industry Co., Ltd., the magnesium aluminometasilicate was Neusilin (registered trademark) US2 manufactured by Fuji Chemical Industry Co., Ltd., the crystalline cellulose was Cellupher (registered trademark) CP102 manufactured by Asahi Kasei Corporation, and the mixture of lactose and crystalline cellulose was Nonpareil (registered trademark) 105 manufactured by Freund Corporation. The results of the investigation are shown in Table 2. [Table 2]

[0045] The results in Table 2 show that when hydrous silicon dioxide or magnesium aluminometasilicate was used as the core material, a molten component layer could be formed on the surface because the core material is an adsorbent with fine pores. However, with other core materials, a molten component layer could not be formed on the surface and the material became paste-like, making it difficult to form a molten component layer.

[0046] [Study of the first melt component] In the manufacturing method of Example 1, the first melting component was changed to form a melting component layer on the surface of the core material. As the first melting component, Macrogol 6000 (NOF Corporation, Macrogol 6000(P)), Lauromacrogol (Nippon Surfactant Industry Co., Ltd.), or Stearic Acid (NOF Corporation, Plant) was used. The results of the investigation are shown in Table 3. [Table 3]

[0047] It was revealed that all oily additives that are solid at room temperature are capable of forming a molten component layer.

[0048] [Study of the second melt component] In the manufacturing method of Example 1, the second molten component was changed to form a drug substance-containing layer on the surface of the molten component layer. Stearic acid (NOF Corporation, plant-based), Macrogol 6000 (NOF Corporation, Macrogol 6000(P)), and carnauba wax (Nippon Wax Co., Ltd., Polishing Wax 105) were used as the second molten component. The results of the investigation are shown in Table 4. [Table 4]

[0049] It was revealed that all oily additives that are solid at room temperature are capable of forming a drug substance-containing layer.

[0050] [Consideration of polymers to be used in place of the second melt component] 1 g of the first molten component and 1 g of the polymer were mixed and then heated at 80°C for 2 hours. 2 g of the first molten component was also heated at 80°C for 2 hours in the same manner, and the viscosity of the molten component alone and the molten component mixed with the polymer were evaluated by touch. Lauromacrogol (Nippon Surfactant Industry Co., Ltd.), stearic acid (NOF Corporation), or hardened oil (Freund Corporation) were used as the molten component. Co., Ltd. , Rubriwax). The polymers used were aminoalkyl methacrylate copolymer E (Evonik, Eudragit (registered trademark) EPO), ammonioalkyl methacrylate copolymer RL (Evonik, Eudragit (registered trademark) RLPO), methacrylic acid copolymer L (Evonik, Eudragit (registered trademark) L100-55), hypromellose acetate succinate (Shin-Etsu Chemical Co., Ltd., Shin-Etsu AQOAT (registered trademark) HPMC AS LF), and polyvinylpyrrolidone (BASF, K30).

[0051] The evaluation results are shown 5 Shown below. [Table 5]

[0052] When lauromacrogol was used as the melting component, the viscosity of aminoalkyl methacrylate copolymer, ammonioalkyl methacrylate copolymer, methacrylic acid copolymer, or hypromellose acetate succinate increased, demonstrating compatibility. In particular, methacrylic acid copolymer was found to exhibit excellent compatibility with lauromacrogol. Furthermore, when stearic acid was used as the melting component, the viscosity of aminoalkyl methacrylate copolymer, ammonioalkyl methacrylate copolymer, or polyvinylpyrrolidone increased, demonstrating compatibility. In particular, aminoalkyl methacrylate copolymer and polyvinylpyrrolidone were found to exhibit excellent compatibility with stearic acid. On the other hand, when hydrogenated oil was used as the melting component, none of the polymers exhibited compatibility.

[0053] [Example 3] To the second melt component teenager In addition, we investigated whether granules could be produced by using a polymer compatible with the first molten component. 500.0 g of hydrous silicon dioxide (Sylopure (registered trademark) P100, Fuji Silysia Chemical Ltd.) was used as the core material, and 750.0 g of stearic acid (NOF Corporation, vegetable) was used as the first molten component. Hydrous silicon dioxide and stearic acid were mixed in a high-speed agitation granulator ( Fukae Industries Co., Ltd. The mixture was placed in a high-speed mixer (FS-GS-5J) and granulated for 17 minutes at an agitator rotation speed of 300 rpm, a chopper rotation speed of 500 rpm, and a water temperature of 78.4°C to 82.6°C.

[0054] The resulting core material (160.0 g) with the molten component layer disposed on its surface, 496.4 g of sitagliptin phosphate as the active ingredient, and aminoalkyl methacrylate copolymer E ( Evonik 48.0 g of Eudragit EPO (Powrex Corporation) was placed in a tumbling fluidized bed granulator (Powrex Corporation, MP-01) and the rotor rotation speed was Granulation was carried out for 25 minutes at 400 rpm with an inlet air temperature of 85°C, at which time the temperature of the additives was 62°C.

[0055] A scanning electron microscope (SEM) image of the obtained granules is shown in Figure 5(c). The particle size of the granules was measured using a laser diffraction / scattering method measuring device (Beckman Coulter, Inc., LS 13 320). The measured particle size was D 10 = 165.0 μm, D 50 = 207.0 μm, D 90 =276.0 μm.

[0056] The granules of Example 3 had a content ratio of the active pharmaceutical ingredient of about 60%, which revealed that a high content of the active pharmaceutical ingredient could be achieved.

[0057] [Example 4] drug substance as Sitagliptin phosphate teenager Additionally, it was investigated whether granules could be produced by using fexofenadine hydrochloride. 120.0 g of the core material with the melting component layer on the surface of Example 3, 240.0 g of fexofenadine hydrochloride as the active ingredient, and aminoalkyl methacrylate copolymer E ( Evonik 40.0 g of Eudragit EPO (manufactured by Powrex Corporation) was placed in a tumbling fluidized bed granulator (MP-01, manufactured by Powrex Corporation) and granulated for 45 minutes at a rotor speed of 400 rpm and an inlet air temperature of 80°C. The temperature of the additives during this process was approximately 60°C.

[0058] A scanning electron microscope (SEM) image of the obtained granules is shown in Figure 5(d). The particle size of the granules was measured using a laser diffraction / scattering method measuring device (Beckman Coulter, Inc., LS 13 320). The measured particle size was D 10 = 169.4 μm, D 50 = 215.3 μm, D 90 =320.6 μm.

[0059] [Comparative Example 1] To investigate whether a second melting component is essential for the production of high-drug-load granules, melt granulation was performed without the second melting component. 436 g of hydrous silicon dioxide (Sylopure® P100, Fuji Silysia Chemical Ltd.) was used as the core material, and 654 g of stearic acid (plant-based, NOF Corporation) was used as the first melting 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 15 minutes at an agitator speed of 300 rpm, a chopper speed of 500 rpm, and a water temperature of 75.7°C to 78.5°C. The additive temperature was 69.1°C to 71.9°C.

[0060] 40.0 g of the resulting core material with the molten component layer disposed on its surface and 124.1 g of sitagliptin phosphate as the active ingredient were placed in a tumbling fluidized bed granulator (Powrex Corporation, MP-01) and granulated for 25 minutes at an inlet air temperature of 85.0°C. At this time, the temperature of the excipients was 62°C.

[0061] A scanning electron microscope (SEM) image of the obtained granules is shown in Figure 5(e). Although the molten component layer was placed on the surface of the core material, and some of the active pharmaceutical ingredient adhered to the molten component layer, the absence of a second molten component meant that high-drug-content granules were not obtained.

[0062] Comparative Example 2 To investigate whether the first melt component is essential for the production of high-drug-content granules, melt granulation was carried out without the first melt component. Hydrous silicon dioxide (Fuji Silysia Chemical Ltd., Sylopure® P100) was used as the core material, and aminoalkyl methacrylate copolymer E ( Evonik A 16 g quantity of hydrous silicon dioxide, 12 g of aminoalkyl methacrylate copolymer E, and 124.1 g of sitagliptin phosphate were placed in a tumbling fluidized bed granulator (Powrex Corporation, MP-01) and granulated for 25 minutes at an inlet air temperature of 85.0°C. The temperature of the additives was 62°C.

[0063] A scanning electron microscope (SEM) image of the resulting granules is shown in Figure 5(f). Due to the absence of the first melt component, no drug substance was layered onto the core material. [Explanation of symbols]

[0064] 10 granules, 11 core material, 13 melt component layer, 15 active ingredient-containing layer, 20 granules, 25 active ingredient-containing layer, 131 first melt component, 151 active ingredient, 153 second melt component, 253 polymer

Claims

1. The pharmaceutical composition comprises a core material, a melting component layer disposed on the surface of the core material, and an active pharmaceutical ingredient-containing layer disposed on the surface of the melting component layer, the melt component layer is a base layer containing a first melt component and no active pharmaceutical ingredient; the drug substance-containing layer comprises a drug substance and a second melt component; the first melting component and the second melting component are additives that are solid at room temperature and have a melting point of 100°C or less; the second melt component is a different additive than the first melt component; Granules, wherein the second melting component is one additive selected from the group consisting of stearic acid, glyceryl monostearate, macrogol (polyethylene glycol), carnauba wax, hydrogenated oil, lauromacrogol, palmitic acid, and cetyl alcohol.

2. The granule of claim 1 , wherein the second melting component has a melting point lower than the melting point of the first melting component.

3. The granule of claim 1 , wherein the second melting component has a melting point higher than the melting point of the first melting component.

4. The granule according to claim 1 , wherein the active ingredient-containing layer contains 50% by mass or more of the active ingredient relative to the total mass of the active ingredient and the second molten component.

5. The pharmaceutical composition comprises a core material, a melting component layer disposed on the surface of the core material, and an active pharmaceutical ingredient-containing layer disposed on the surface of the melting component layer, the melt component layer is a base layer containing a first melt component and no active pharmaceutical ingredient; the active pharmaceutical ingredient-containing layer comprises an active pharmaceutical ingredient and a polymer compatible with the first melt component; the first melting component is an additive that is solid at room temperature and has a melting point of 100°C or less; A granule, wherein the polymer compatible with the first melt component is selected from the group consisting of aminoalkyl methacrylate copolymer, ammonioalkyl methacrylate copolymer, methacrylic acid copolymer, hypromellose acetate succinate, and polyvinylpyrrolidone.

6. The granules according to claim 5, wherein the blending ratio of the first molten component to the polymer is 20:1 to 1:

1.

7. The granule according to claim 5 , wherein the active ingredient-containing layer contains 50% by mass or more of the active ingredient relative to the total mass of the active ingredient and the polymer.

8. the core material is spherical; The granule according to claim 1 or 5, wherein the particle size of the core material is larger than the particle size of the active pharmaceutical ingredient.

9. the core material has pores on its surface; The granule according to claim 1 or 5, wherein the molten component layer has a structure in which the first molten component is also disposed in the pores.

10. 6. The granules according to claim 1 or 5, wherein the core material is selected from the group consisting of 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.

11. The granules according to claim 1 or 5, and one or more pharmaceutically acceptable excipients.

12. The formulation of claim 11 , wherein the additive is a disintegrant.

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