Macitentan-containing preparation

Abstract

To inhibit delayed dissolution of a macitentan-containing preparation after being kept under open conditions prone to humidity.SOLUTION: According to one embodiment of the present invention, there is provided a macitentan-containing preparation comprising granules containing macitentan and an additive other than the granules, wherein the granules are free from crystalline cellulose. The granules may further contain at least one kind of a disintegrant selected from the group consisting of low-substituted hydroxypropyl cellulose, sodium starch glycolate, croscarmellose sodium, crospovidone, carmellose, calcium carmellose, and corn starch.SELECTED DRAWING: None

Description

Technical Field

[0001] One embodiment of the present invention relates to a macitentan-containing formulation.

Background Art

[0002] Macitentan is an endothelin receptor antagonist and has been recognized as useful in the initial drug treatment for patients with pulmonary arterial hypertension (PAH). As a formulation containing macitentan as an active ingredient, "Opsumit (registered trademark) tablets 10 mg" is sold and is used to suppress vasoconstriction and reduce pulmonary arterial pressure.

[0003] So far, as a formulation containing macitentan as an active ingredient, a stable pharmaceutical composition containing a filler composed of microcrystalline cellulose and lactose, a disintegrant composed of a combination of sodium starch glycolate and polyvinylpyrrolidone, a surfactant composed of polysorbate, a lubricant composed of magnesium stearate, and macitentan has been reported (Patent Document 1).

[0004] Furthermore, as a formulation containing macitentan as an active ingredient, a solid oral pharmaceutical composition showing improved stability and appropriate dissolution profile by containing a sugar alcohol diluent and a surfactant has been reported (Patent Document 2). Also, as a formulation containing macitentan as an active ingredient, there is a report of a macitentan-containing tablet composition having appropriate disintegration characteristics by containing at least one disintegrant (selected from the group including croscarmellose sodium, crospovidone, carboxymethyl cellulose, poloxamer, or a mixture thereof) and at least one pharmaceutically acceptable excipient (Patent Document 3).

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Patent Document 2

Patent Document 3

Summary of the Invention

Problems to be Solved by the Invention

[0006] One object of the present invention is to suppress the elution delay of a masitinib-containing preparation after storage under open conditions that are easily affected by humidity.

Means for Solving the Problems

[0007] According to one embodiment of the present invention, there is provided a masitinib-containing preparation comprising a granule containing masitinib and an additive other than the granule, wherein the granule does not contain crystalline cellulose.

[0008] The granule may further contain at least one disintegrant selected from the group consisting of low-substituted hydroxypropyl cellulose, sodium starch glycolate, croscarmellose sodium, crospovidone, carmellose, carmellose calcium, and corn starch.

[0009] The at least one disintegrant may be selected from the group consisting of low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, carmellose, and carmellose calcium.

[0010] The at least one disintegrant may be contained in the granule at a ratio of 0.05% by mass to 30.0% by mass based on the mass of the granule.

[0011] The additive may contain at least one of a disintegrant and a lubricant.

Effects of the Invention

[0012] According to one embodiment of the present invention, there is provided a masitinib-containing preparation with suppressed elution delay after storage under open conditions that are easily affected by humidity.

Mode for Carrying Out the Invention

[0013] Hereinafter, the masitinib-containing preparation according to the present invention will be described in detail. However, the masitinib-containing preparation of the present invention is not construed as being limited to the descriptions of the embodiments and examples shown below.

[0014] As a result of the study by the present inventors, as will also be described in the examples below, it was found that the masitinib-containing preparation containing crystalline cellulose causes elution delay after storage under open conditions that are susceptible to the influence of humidity. Elution delay is a problem to be improved because it raises concerns that the expected blood concentration and therapeutic effect cannot be obtained. Also, even if the preparation is exposed to harsh conditions such as high humidity during the distribution period of the preparation or storage until administration, it is desired to develop a preparation that does not cause elution delay and can ensure quality. Therefore, in order to suppress the elution delay, the inventors examined additives for the granulated product containing masitinib and additives other than the granulated product, and found that the elution delay of the masitinib-containing preparation is due to crystalline cellulose in the granulated product containing masitinib. Based on this finding, the inventors completed the masitinib-containing preparation according to the present invention.

[0015] [Masitinib-containing preparation] The masitinib-containing preparation according to one embodiment of the present invention includes a granulated product containing masitinib and an additive other than the granulated product, and the granulated product does not contain crystalline cellulose. The content of masitinib in this embodiment can be appropriately selected according to the expected therapeutic effect. For example, it can contain 10 mg in one tablet of the masitinib-containing preparation. Since the granulated product does not contain crystalline cellulose, the masitinib-containing preparation according to the present invention suppresses elution delay compared to conventional preparations even after storage under open conditions that are susceptible to the influence of humidity.

[0016] In one embodiment, the granulated product may further contain at least one disintegrant selected from the group consisting of hydroxypropylcellulose with a low degree of substitution, sodium starch glycolate, croscarmellose sodium, crospovidone, carmellose, carmellose calcium, and corn starch. By containing at least one of the disintegrants without containing crystalline cellulose, the machitentan-containing preparation according to the present invention can suppress elution delay as compared with conventional preparations even after storage under open conditions that are susceptible to the influence of humidity.

[0017] In one embodiment, it is preferable that at least one disintegrant is selected from the group consisting of hydroxypropylcellulose with a low degree of substitution, croscarmellose sodium, crospovidone, carmellose, and carmellose calcium. Thereby, the machitentan-containing preparation according to the present invention can significantly suppress elution delay as compared with conventional preparations even after storage under open conditions that are susceptible to the influence of humidity.

[0018] In one embodiment, at least one disintegrant may be contained in the granulated product at a ratio of 0.05% by mass to 30.0% by mass based on the mass of the granulated product. In one embodiment, preferably, it may be contained in the granulated product at a ratio of 5.2% by mass to 15.0% by mass based on the mass of the granulated product.

[0019] The machitentan-containing preparation of the present embodiment can further contain an excipient, a disintegrant, a binder, a surfactant, a fluidizing agent, etc. in the granulated product.

[0020] Examples of the excipient include, but are not limited to, saccharides such as lactose and sucrose, starches such as corn starch and pregelatinized starch, sugar alcohols such as mannitol, erythritol, xylitol, and sorbitol, crystalline cellulose, maltodextrin, dicalcium phosphate dihydrate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate hydrate, calcium carbonate, magnesium carbonate, magnesium oxide, light anhydrous silicic acid, magnesium aluminometasilicate, and talc.

[0021] Examples of the disintegrant include, but are not limited to, low-substituted hydroxypropyl cellulose, croscarmellose sodium, carmellose, carmellose calcium, sodium starch glycolate, crospovidone, corn starch, and pregelatinized starch.

[0022] Examples of the binder include, but are not limited to, at least one selected from the group consisting of hydroxypropyl cellulose, hypromellose, povidone, copovidone, methyl cellulose, polyvinyl alcohol, carmellose sodium, hydroxyethyl cellulose, pregelatinized starch, saccharides such as lactose and sucrose, alginic acid, sodium alginate, gelatin, gum arabic, pullulan, dextrin, xanthan gum, and carrageenan.

[0023] Examples of the surfactant include, but are not limited to, sodium lauryl sulfate, polysorbate, polyethylene polyoxypropylene polymer, polyoxyl ethylene stearate, dioctyl sodium sulfosuccinate, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene C 1-4 -alkyl ether, sucrose monoester, lanolin ester, and ether.

[0024] Examples of the glidant include, but are not limited to, silica, powdered cellulose, starch, talc, light anhydrous silicic acid, hydrous silicon dioxide, magnesium aluminometasilicate.

[0025] The machiten-tan-containing preparation of this embodiment can contain excipients, disintegrants, glidants, lubricants, and the like as additives other than the granulated product. As the disintegrant, excipient, and glidant, the above-mentioned disintegrant, excipient, and glidant can be used.

[0026] Examples of the lubricant may include, but are not limited to, magnesium stearate, calcium stearate, aluminum stearate, stearic acid, sodium stearyl fumarate, talc, sodium benzoate, glyceryl monofatty acid, glyceryl dibehenate, glyceryl palmitate-stearate, polyethylene glycol, hydrogenated cottonseed oil, castor oil, sucrose ester, glycerin fatty acid ester, and L-leucine.

[0027] In one embodiment, the additives other than the granulated product preferably include at least one of a disintegrant and a lubricant. By including a disintegrant in the additives other than the granulated product, the tablet can be more easily disintegrated. Further, by including a lubricant in the additives other than the granulated product, it is possible to prevent tableting failures that may occur when tableting the powder containing the granulated product.

[0028] In one embodiment, the additives other than the granulated product preferably further include an excipient. By including an excipient in the additives other than the granulated product, the moldability of the tablet containing the granulated product and the additives other than the granulated product can be improved.

[0029] In one embodiment, the preparation containing machitenitan may be in the form of a tablet.

[0030] In one embodiment, the masitinib-containing preparation may be in the form of tablets coated with a film coating agent. The film coating agent may include a film base, a plasticizer, a surfactant, a lubricant and / or a fluidizing agent, and optionally one or more colorants. As the film base, for example, a low water vapor permeability polymer (polyvinyl alcohol), dimethylaminoethyl methacrylate, hypromellose can be used, but it is not limited thereto. As the plasticizer, for example, propylene glycol, triacetin, dibutyl phthalate, dibutyl sebacate, polyethylene glycol, triethyl citrate can be used, but it is not limited thereto. As the surfactant, for example, sodium lauryl sulfate or polysorbate can be used, but it is not limited thereto. As the lubricant and / or fluidizing agent, the lubricants and fluidizing agents described above can be used, but it is not limited thereto. As the colorant, for example, iron(II) oxide, iron(III) oxide or titanium oxide can also be used, but it is not limited thereto.

[0031] As described above, the masitinib-containing preparation according to the present invention includes a granulated product containing masitinib and additives other than the granulated product. Since the granulated product containing masitinib does not contain crystalline cellulose, elution delay can be suppressed even after storage under open conditions that are easily affected by humidity. Further, in the masitinib-containing preparation according to the present invention, the granulated product containing masitinib does not contain crystalline cellulose and contains at least one disintegrant selected from the group consisting of low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, carmellose, and calcium carmellose, whereby elution delay can be significantly suppressed even after storage under open conditions that are easily affected by humidity.

[0032] [Method for Producing Masitinib-Containing Preparation] In one embodiment, the macitentan-containing formulation according to one embodiment of the present invention can be manufactured by a known manufacturing method. For example, a wet granulation method can be used for the manufacturing method of the macitentan-containing formulation, and it is preferable to use a kneading method (also referred to as a stirring granulation method).

[0033] In one embodiment, the manufacturing method of the macitentan-containing formulation includes mixing a granulated product containing macitentan and additives other than the granulated product, and the granulated product does not contain crystalline cellulose. In one embodiment, the granulated product containing macitentan can be manufactured by adding purified water to a mixture of macitentan and a disintegrant and granulating. For example, macitentan, an excipient, a disintegrant, a binder, and a surfactant can be mixed to obtain a mixture containing macitentan. Next, a granulating liquid is added to and kneaded with the mixture containing macitentan to obtain a kneaded product containing macitentan. The obtained kneaded product is dried and sized to obtain a granulated product containing macitentan. Since the granulated product containing macitentan does not contain crystalline cellulose, it is possible to suppress the elution delay of the macitentan-containing formulation even after storage under open conditions that are easily affected by humidity.

[0034] In one embodiment, the disintegrant to be mixed with masitinib is at least one selected from the group consisting of low-substituted hydroxypropyl cellulose, sodium starch glycolate, croscarmellose sodium, crospovidone, carmellose, calcium carmellose, and corn starch. Further, in one embodiment, it is preferable that at least one disintegrant is selected from the group consisting of low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, carmellose, and calcium carmellose. Furthermore, in one embodiment, at least one disintegrant can be contained in the granulated product at a ratio of 0.05% by mass to 30.0% by mass based on the mass of the granulated product. In one embodiment, preferably, it can be contained in the granulated product at a ratio of 5.2% by mass to 15.0% by mass based on the mass of the granulated product. By using at least one disintegrant selected from the group consisting of low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, carmellose, and calcium carmellose as the disintegrant to be mixed with masitinib in a granulated product containing no crystalline cellulose, the elution delay of the masitinib-containing preparation can be significantly suppressed even after storage under open conditions that are susceptible to the influence of humidity.

[0035] In one embodiment, additives other than the granulated product can be mixed with the granulated product containing masitinib to obtain a mixture. Further, in one embodiment, the additives other than the granulated product can include at least one of a disintegrant and a lubricant. In one embodiment, the obtained mixture can be tabletted to obtain tablets. In one embodiment, the obtained tablets can be film-coated with a film coating agent.

Examples

[0036] The influence of additives in the granulated product containing masitinib on the elution property in the masitinib-containing preparation was examined.

[0037] [Comparative Example 1] In Comparative Example 1, masitinib, lactose hydrate (DFE Pharma, Phamatose, 200M), crystalline cellulose (Asahi Kasei Corporation, Ceolus (registered trademark), PH-101), sodium starch glycolate (DFE Pharma, Primojel (registered trademark)), povidone (Daiichi Kogyo Seiyaku Co., Ltd., K30), and polysorbate 80 (Nippon Surfactant Industry Co., Ltd., TO-10MV) were mixed to obtain a mixture containing masitinib. Then, purified water was used as a granulating liquid and kneaded using a mortar. After drying the kneaded mixture with a mini jet dryer (Toyama Sangyo Co., Ltd., MO-921), it was sized using a sieve (No. 22 sieve) to obtain granules. The obtained granules were mixed with crystalline cellulose (Asahi Kasei Corporation, Ceolus (registered trademark), PH-101), sodium starch glycolate (DFE Pharma, Primojel), and calcium stearate (NOF Corporation) and tabletted using a rotary tableting machine (Kikusui Seisakusho Co., Ltd., VELA5). The obtained tablets were coated with a film coating liquid containing Opadry amb (Nippon Karakon, Opadry (registered trademark), 80W480004), which is a film coating agent (FC agent), to obtain a masitinib-containing formulation. The contents of each additive in the formulation are shown in Table 1.

[0038] [Comparative Example 2] In Comparative Example 2, a masitinib-containing formulation was obtained by the same production method as in Comparative Example 1, except that a film coating agent containing hypromellose (Shin-Etsu Chemical Co., Ltd., TC-5M), macrogol 6000 (NOF Corporation), talc (Fuji Talc Industry Co., Ltd.), and titanium oxide (Toho Titanium Co., Ltd., NA61) was used instead of Opadry amb (Nippon Karakon, Opadry (registered trademark), 80W480004). The contents of each additive in the formulation are shown in Table 1.

[0039] [Example 1] In Example 1, instead of crystalline cellulose in the granulated product, low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd., L-HPC (registered trademark), LH-21) was used. After the obtained tablets were coated with a film coating agent, carnauba wax (Nippon Wax Co., Ltd., Polishing Wax 105) was added to polish the tablets. A machiten-tan-containing preparation was obtained by the same production method as in Comparative Example 2, except for the above. The content of each additive in the preparation is shown in Table 1.

[0040] [Example 2] In Example 2, a machiten-tan-containing preparation was obtained by the same production method as in Comparative Example 1, except that low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd., L-HPC (registered trademark), LH-21) was used instead of crystalline cellulose in the granulated product. The content of each additive in the preparation is shown in Table 1.

[0041] [Example 3] In Example 3, instead of crystalline cellulose in the granulated product, low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd., L-HPC (registered trademark), LH-21) was used. Instead of sodium starch glycolate in the granulated product and sodium starch glycolate mixed with the granulated product, croscarmellose sodium (Nichirin Chemical Industry Co., Ltd., ND-2HS) was used respectively. After the obtained tablets were coated with a film coating agent, carnauba wax (Nippon Wax Co., Ltd., Polishing Wax 105) was added to polish the tablets. A machiten-tan-containing preparation was obtained by the same production method as in Comparative Example 2, except for the above. The content of each additive in the preparation is shown in Table 1.

[0042] [Example 4] In Example 4, low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd., L-HPC (registered trademark), LH-21) was used instead of crystalline cellulose in the granulated product, and sodium croscarmellose (Nichirin Chemical Industry Co., Ltd., ND-2HS) was used instead of sodium starch glycolate in the granulated product and the sodium starch glycolate mixed with the granulated product. A machiten-titanium-containing preparation was obtained by the same production method as in Comparative Example 1, except for the above. The content of each additive in the preparation is shown in Table 1.

[0043] [Example 5] In Example 5, low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd., L-HPC (registered trademark), LH-21) was used instead of crystalline cellulose in the granulated product, and sodium croscarmellose was used only for mixing with the granulated product instead of sodium starch glycolate in the granulated product and the sodium starch glycolate mixed with the granulated product. After the obtained tablets were coated with a film coating agent, carnauba wax (Nippon Wax Co., Ltd., Polishing Wax 105) was added to polish the tablets. A machiten-titanium-containing preparation was obtained by the same production method as in Comparative Example 2, except for the above. The content of each additive in the preparation is shown in Table 1.

[0044] [Example 6] In Example 6, low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd., L-HPC (registered trademark), LH-21) was used instead of crystalline cellulose in the granulated product, and sodium croscarmellose was used only for mixing with the granulated product instead of sodium starch glycolate in the granulated product and the sodium starch glycolate mixed with the granulated product. A machiten-titanium-containing preparation was obtained by the same production method as in Comparative Example 1, except for the above. The content of each additive in the preparation is shown in Table 1.

[0045] [Example 7] In Example 7, instead of crystalline cellulose in the granulated product, low-substitution hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd., L-HPC (registered trademark), LH-21) was used. Instead of sodium starch glycolate in the granulated product and sodium starch glycolate mixed with the granulated product, croscarmellose sodium was used only for mixing with the granulated product. Further, except that the lactose hydrate in the granulated product was increased instead of crystalline cellulose mixed with the granulated product, a machitenatant-containing preparation was obtained by the same production method as in Comparative Example 1. The content of each additive in the preparation is shown in Table 1.

[0046] [Table 1]

[0047] [Table 2]

[0048] [Evaluation of Dissolution 1] For the machitenatant-containing preparations of Examples 1 to 7 and Comparative Examples 1 to 2, they were stored for 1 week under open conditions at 25 °C and 90% RH. For the machitenatant-containing preparations at the initial stage and after 1-week storage, using a dissolution tester (Toyama Sangyo Co., Ltd., NTR-6600A), according to the dissolution test method of the eighteenth revised Japanese Pharmacopoeia, paddle method, the dissolution at 30 minutes of dissolution time was evaluated. As the test solution, 900 mL of diluted McIlvaine buffer solution (pH 6.0) containing 0.1% cetyltrimethylammonium bromide (CTAB) was used. The rotation speed of the paddle was 75 rpm.

[0049] The evaluation results of the dissolution of the machitenatant-containing preparations of Examples 1 to 7 and Comparative Examples 1 to 2 are shown in Tables 3 and 4. The dissolution delay rate (%) described in Tables 3 and 4 was calculated using the following formula (1).

[0050] Dissolution delay rate (%) = (dissolution rate after storage / initial dissolution rate) × 100 (1)

[0051] In addition, in the present embodiment, if the elution delay rate calculated from the above formula (1) is 85% or more, it is determined that there is an effect in suppressing the elution delay.

[0052]

Table 3

[0053]

Table 4

[0054] As shown in the results of Table 3 and Table 4, in Comparative Example 1 and Comparative Example 2 containing crystalline cellulose in the granulated product containing masitinib and additives other than the granulated product, elution delay was observed after storage. On the other hand, in Example 7 in which neither the granulated product nor the additives other than the granulated product contained crystalline cellulose, the elution delay was significantly suppressed. Furthermore, in Examples 1 to 6 in which the granulated product containing masitinib did not contain crystalline cellulose and the additives other than the granulated product contained crystalline cellulose, the elution delay was significantly suppressed as in Example 7. Also, in Examples 1 to 6, it was found that the elution delay was suppressed regardless of the composition of the film coating agent. From these results, it was clarified that the elution delay of the masitinib-containing preparation after storage was caused by the crystalline cellulose contained in the granulated product. Therefore, it became clear that in order to suppress the elution delay of the masitinib-containing preparation, it is important not to add or contain crystalline cellulose in the granulated product of the masitinib-containing preparation.

[0055] Next, the type of disintegrant in the granulated product containing masitinib was examined.

[0056] [Example 8] In Example 8, a masitinib-containing preparation was obtained by the same production method as in Example 7, except that sodium starch glycolate (DFE Pharma Co., Ltd., Primogel (registered trademark)) was used instead of low-substituted hydroxypropyl cellulose in the granulated product. The content of each additive in the preparation is shown in Table 5.

[0057] [Example 9] In Example 9, a machitentan-containing preparation was obtained by the same production method as in Example 7, except that sodium croscarmellose (Nichirin Chemical Industry Co., Ltd., ND-2HS) was used instead of low-substituted hydroxypropyl cellulose in the granulated product. The contents of each additive in the preparation are shown in Table 5.

[0058] [Example 10] In Example 10, a machitentan-containing preparation was obtained by the same production method as in Example 7, except that crospovidone (BASF, Kollidon® CL-F) was used instead of low-substituted hydroxypropyl cellulose in the granulated product. The contents of each additive in the preparation are shown in Table 5.

[0059] [Example 11] In Example 11, a machitentan-containing preparation was obtained by the same production method as in Example 7, except that carmellose (Nichirin Chemical Industry Co., Ltd., NS-300) was used instead of low-substituted hydroxypropyl cellulose in the granulated product. The contents of each additive in the preparation are shown in Table 5.

[0060] [Example 12] In Example 12, a machitentan-containing preparation was obtained by the same production method as in Example 7, except that calcium carmellose (Nichirin Chemical Industry Co., Ltd., ND-2HS) was used instead of low-substituted hydroxypropyl cellulose in the granulated product. The contents of each additive in the preparation are shown in Table 5.

[0061] [Example 13] In Example 13, a machitentan-containing preparation was obtained by the same production method as in Example 7, except that corn starch (Nippon Shokuhin Kako Co., Ltd., xx16) was used instead of low-substituted hydroxypropyl cellulose in the granulated product. The contents of each additive in the preparation are shown in Table 5. The contents of each additive in the preparation of Example 7 are reproduced in Table 5.

[0062]

Table 5

[0063] [Evaluation of Dissolution 2] For the macitentan-containing preparations of Examples 8 to 13, they were stored for 10 days under open conditions at 25 °C and 90% RH. For the macitentan-containing preparations at the initial stage and after 10 days of storage, the dissolution was evaluated by the same method as the above-described Evaluation of Dissolution 1.

[0064] The evaluation results of the dissolution of the macitentan-containing preparations of Examples 8 to 13 are shown in Table 6. In addition, the evaluation results of the dissolution of Example 7 described above are re-listed in Table 6.

[0065]

Table 6

[0066] From the results in Table 6, similar to Example 7 in which low-substituted hydroxypropyl cellulose was used as the disintegrant in the granulated product containing macitentan, in Examples 8 to 13 in which sodium starch glycolate, croscarmellose sodium, crospovidone, carmellose, calcium carmellose, or corn starch was used instead of low-substituted hydroxypropyl cellulose as the disintegrant in the granulated product, an effect of suppressing dissolution delay was also observed. From this result, it was found that the effect of suppressing dissolution delay of the macitentan-containing preparation can be obtained without limiting to the type of disintegrant in the granulated product containing macitentan and without adding or including crystalline cellulose in the granulated product of the macitentan-containing preparation.

[0067] Also, in Examples 7 and 9 to 12, since the dissolution delay rate exceeded 98%, it was clarified that by including at least one disintegrant selected from low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, carmellose, and calcium carmellose as the disintegrant in the granulated product containing macitentan, the dissolution delay is more significantly suppressed.

[0068] Furthermore, the content and variety of the disintegrant in the granulated product containing masitinib were examined.

[0069] [Example 14] In Example 14, a masitinib-containing preparation was obtained by the same production method as in Example 7, except that the amount of low-substituted hydroxypropyl cellulose in the granulated product was increased and the amount of lactose hydrate in the granulated product was decreased by the increased amount of low-substituted hydroxypropyl cellulose. The content of each additive in the preparation is shown in Table 7.

[0070] [Example 15] In Example 15, a masitinib-containing preparation was obtained by the same production method as in Example 7, except that the amount of low-substituted hydroxypropyl cellulose in the granulated product was increased, the amount of lactose hydrate in the granulated product was decreased by the increased amount of low-substituted hydroxypropyl cellulose, and instead of Opadry amb (Nippon Karakon, Opadry (registered trademark), 80W480004), it was coated with a film coating agent containing hypromellose (Shin-Etsu Chemical Co., Ltd., TC-5M), macrogol 6000 (NOF Corporation), talc (Fuji Talc Industry Co., Ltd.), and titanium oxide (Toho Titanium Co., Ltd., NA61), and carnauba wax was added for glossing. The content of each additive in the preparation is shown in Table 7.

[0071] [Example 16] In Example 16, a masitinib-containing preparation was obtained by the same production method as in Example 15, except that the variety of low-substituted hydroxypropyl cellulose in the granulated product was changed from LH-21 to NBD-020. The content of each additive in the preparation is shown in Table 7.

[0072]

Table 7

[0073] [Evaluation of Dissolubility 3] The machitentan-containing preparations of Examples 14 to 16 were stored for 1 week under open conditions at 25°C and 90% RH. For the machitentan-containing preparations before and after 1-week storage, the dissolution property was evaluated by the same method as the above-described Dissolution Evaluation 1.

[0074] The evaluation results of the dissolution properties of the machitentan-containing preparations of Examples 14 to 16 are shown in Table 8. In addition, the evaluation results of the dissolution property of Example 7 described above are reproduced in Table 8.

[0075]

Table 8

[0076] In Examples 14 and 15, the content of low-substituted hydroxypropyl cellulose in the granulated product was increased compared with Example 7. However, as shown in Table 8, in both cases, suppression of dissolution delay was observed as in Example 7. In addition, in Example 16, a low-substituted hydroxypropyl cellulose of a variety different from the variety of low-substituted hydroxypropyl cellulose in the granulated product used in Example 7 was used, but suppression of dissolution delay was observed as in Example 7. From these results, it became clear that regardless of the content and variety of low-substituted hydroxypropyl cellulose, the granulated product does not contain crystalline cellulose and contains low-substituted hydroxypropyl cellulose as a disintegrant, whereby the effect of suppressing dissolution delay of the machitentan-containing preparation can be obtained.

Claims

1. A granule containing masitinib, and an additive other than the granule, wherein the granule does not contain crystalline cellulose, a masitinib-containing preparation.

2. The granule further contains at least one disintegrant selected from the group consisting of low-substituted hydroxypropyl cellulose, sodium starch glycolate, croscarmellose sodium, crospovidone, carmellose, calcium carmellose, and corn starch, The masitinib-containing preparation according to claim 1.

3. The at least one disintegrant is selected from the group consisting of low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, carmellose, calcium carmellose, The masitinib-containing preparation according to claim 2.

4. The at least one disintegrant is contained in the granule at a ratio of 0.05% by mass to 30.0% by mass based on the mass of the granule, The masitinib-containing preparation according to claim 2 or claim 3.

5. The additive includes at least one of a disintegrant and a lubricant, The masitinib-containing preparation according to claim 1.

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