Macitentan-containing preparation

Abstract

To inhibit delayed dissolution of a macitentan-containing preparation after being kept under open conditions prone to humidity, and to suppress the formation of macitentan analogues.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 contain at least one kind of a disintegrant selected from the group consisting of low-substituted hydroxypropyl cellulose, croscarmellose sodium, carmellose, and calcium carmellose.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, carboxymethylcellulose, poloxamer, or a mixture thereof) and at least one pharmaceutically acceptable excipient (Patent Document 3).

[0005] However, heretofore, there has been no disclosure of a masitinib-containing preparation in which elution delay is suppressed and formation of related substances is suppressed even after storage under open conditions that are susceptible to the influence of humidity. In the development of a preparation containing masitinib as an active ingredient, as an effort to improve quality, a preparation in which elution delay is suppressed and further formation of related substances is suppressed even after storage under open conditions that are susceptible to the influence of humidity is desired.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Patent Document 2

Patent Document 3

Summary of the Invention

Problems to be Solved by the Invention

[0007] One object of the present invention is to solve the above problems and suppress elution delay and formation of related substances in a masitinib-containing preparation after storage under open conditions that are susceptible to the influence of humidity.

Means for Solving the Problems

[0008] According to one embodiment of the present invention, there is provided a masitinib-containing preparation including a granule containing masitinib and an additive other than the granule, wherein the granule contains at least one disintegrant selected from the group consisting of low-substituted hydroxypropyl cellulose, croscarmellose sodium, carmellose, and calcium carmellose.

[0009] The granule may further contain crystalline cellulose.

[0010] At least one disintegrant may be low-substituted hydroxypropyl cellulose or calcium carboxymethyl cellulose.

[0011] The granulated product further contains crystalline cellulose, and at least one disintegrant may be low-substituted hydroxypropyl cellulose or calcium carboxymethyl cellulose.

[0012] 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.

[0013] The additive may contain at least one of a disintegrant and a lubricant.

Advantages of the Invention

[0014] According to one embodiment of the present invention, there is provided a masitinib-containing preparation in which elution delay is suppressed and generation of related substances is suppressed after storage under open conditions that are susceptible to the influence of humidity.

Modes for Carrying Out the Invention

[0015] 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 following embodiments and examples.

[0016] As a result of the study by the present inventors, as will also be described in the examples below, it was found that a 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. In addition, even if the preparation is exposed to severe conditions such as high humidity during the distribution period of the preparation or storage until administration, it is desired to develop a preparation that can ensure quality without causing elution delay. Therefore, in order to suppress the elution delay, the inventors examined disintegrants, and it was revealed that the elution delay is suppressed by including the disintegrant selected in the present invention in the granulated product containing masitinib. Furthermore, surprisingly, it was revealed that by including the disintegrant selected in the present invention, not only the suppression of elution delay but also the production of related substances can be suppressed.

[0017] [Masitinib-containing preparation] The masitinib-containing preparation according to one embodiment of the present invention includes a granulated product containing masitinib and additives other than the granulated product, and the granulated product contains at least one disintegrant selected from the group consisting of low-substituted hydroxypropyl cellulose, croscarmellose sodium, carmellose, and calcium carmellose. 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. By containing at least one of the above disintegrants in the granulated product, the masitinib-containing preparation according to the present invention suppresses elution delay and further suppresses the production of related substances compared to conventional preparations even after storage under open conditions that are susceptible to the influence of humidity.

[0018] In one embodiment, it is preferable that at least one disintegrant is low-substituted hydroxypropyl cellulose or calcium carboxymethyl cellulose. Since at least one disintegrant is low-substituted hydroxypropyl cellulose or calcium carboxymethyl cellulose, the masitinib-containing preparation according to the present invention can suppress elution delay and significantly suppress the generation of related substances even after storage under open conditions that are susceptible to humidity, as compared with conventional preparations.

[0019] 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 1.8% by mass to 12.8% by mass based on the mass of the granulated product.

[0020] The masitinib-containing preparation of the present embodiment can further contain a disintegrant, an excipient, a binder, a surfactant, a fluidizing agent, and the like in the granulated product.

[0021] As the disintegrant, for example, it can be selected from, but is not limited to, low-substituted hydroxypropyl cellulose, croscarmellose sodium, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium starch glycolate, crospovidone, corn starch, and pregelatinized starch.

[0022] As the excipient, for example, it can be selected from, but is 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 aluminate metasilicate, and talc.

[0023] In one embodiment, the granulated product can further contain crystalline cellulose. Further, the granulated product may further contain lactose.

[0024] Examples of the binder include, but are not limited to, hydroxypropyl cellulose, hypromellose, povidone, copovidone, methyl cellulose, polyvinyl alcohol, sodium carboxymethyl cellulose, hydroxyethyl cellulose, pregelatinized starch, sugars such as lactose and sucrose, alginic acid, sodium alginate, gelatin, gum arabic, pullulan, dextrin, xanthan gum, and carrageenan.

[0025] Examples of the surfactant include, but are not limited to, sodium lauryl sulfate, polysorbate, polyethylene polyoxypropylene polymer, polyoxyl ethylene stearate, sodium dioctyl sulfosuccinate, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene C 1-4 -alkyl ether, sucrose monoester, lanolin ester, and lanolin ether.

[0026] Examples of the fluidizing agent include, but are not limited to, silica, powdered cellulose, starch, talc, light anhydrous silicic acid, hydrous silicon dioxide, magnesium aluminometasilicate.

[0027] The machiten-tan-containing preparation of this embodiment can contain, as additives other than the granulated product, a disintegrant, an excipient, a fluidizing agent, a lubricant, and the like. For the disintegrant, excipient, and fluidizing agent, the above-described disintegrant, excipient, and fluidizing agent can be used.

[0028] Examples of the lubricant 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.

[0029] In one embodiment, the additives other than the granulated product preferably contain 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 disintegrated more easily. In addition, 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.

[0030] In one embodiment, the additives other than the granulated product preferably further contain 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.

[0031] In one embodiment, the preparation containing machitenitan may be in the form of a tablet.

[0032] In one embodiment, the masitinib-containing formulation 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 is not limited thereto. As the plasticizer, for example, propylene glycol, triacetin, dibutyl phthalate, dibutyl sebacate, polyethylene glycol, triethyl citrate can be used, but is not limited thereto. As the surfactant, for example, sodium lauryl sulfate or polysorbate can be used, but is not limited thereto. As the lubricant and / or fluidizing agent, the lubricants and fluidizing agents described above can be used, but are not limited thereto. As the colorant, for example, iron(II) oxide, iron(III) oxide or titanium oxide can also be used, but is not limited thereto.

[0033] As described above, the masitinib-containing formulation according to the present invention includes a granulated product containing masitinib and additives other than the granulated product, and by including a disintegrant selected in the present invention in the granulated product, it is possible to suppress elution delay and suppress the generation of related substances even after storage under open conditions that are easily affected by humidity.

[0034] [Method for producing masitinib-containing formulation] In one embodiment, the masitinib-containing formulation according to one embodiment of the present invention can be produced by a known production method. For example, as the production method of the masitinib-containing formulation, a wet granulation method can be used, and it is preferable to use a kneading method (also referred to as a stirring granulation method).

[0035] In one embodiment, a method for manufacturing a macitentan-containing formulation includes mixing a granule containing macitentan and an additive other than the granule, and the granule can contain at least one disintegrant selected from the group consisting of low-substituted hydroxypropyl cellulose, croscarmellose sodium, carmellose, and calcium carmellose.

[0036] In one embodiment, a method for manufacturing a macitentan-containing formulation can further include adding purified water to a mixture of macitentan and a disintegrant and granulating to obtain a granule. 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 can be added to the mixture containing macitentan and kneaded to obtain a kneaded product containing macitentan. The obtained kneaded product can be dried and sized to obtain a granule containing macitentan. Further, in one embodiment, the granule contains crystalline cellulose. By including the disintegrant selected in the present invention in the granule containing macitentan, even after storage under open conditions that are susceptible to humidity, the elution delay of the macitentan-containing formulation containing crystalline cellulose can be suppressed, and further the generation of related substances can be suppressed.

[0037] In one embodiment, it is preferable that the at least one disintegrant is low-substituted hydroxypropyl cellulose or calcium carmellose. In one embodiment, the at least one disintegrant can 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. In one embodiment, preferably, it can be contained in the granule at a ratio of 1.8% by mass to 12.8% by mass based on the mass of the granule.

[0038] In one embodiment, the additive other than the granule may include at least one of a disintegrant and a lubricant.

[0039] In one embodiment, a mixture obtained by mixing a granulated product with additives other than the granulated product can be tabletted. In one embodiment, the tablets obtained by tabletting the mixture can be film-coated with a film coating agent.

Examples

[0040] In a preparation containing machitentan, the disintegrant in the granulated product containing machitentan was examined.

[0041] [Comparative Example 1] In Comparative Example 1, machitentan, lactose hydrate (DFE Pharma Co., Ltd., Phamatose, 200M), crystalline cellulose (Asahi Kasei Corporation, Ceolus (registered trademark), PH-101), povidone (Daiichi Kogyo Seiyaku Co., Ltd., K30), sodium starch glycolate (DFE Pharma Co., Ltd., Primogel (registered trademark)), polysorbate 80 (Nippon Surfactant Industry Co., Ltd., TO-10MV) were mixed to obtain a mixture containing machitentan. Then, purified water was used as a granulating liquid and kneaded using a mortar. After drying the kneaded product with a mini jet dryer (Toyama Sangyo Co., Ltd., MO-921), sieving was performed using a sieve (No. 22 sieve) to obtain a granulated product. The obtained granulated product was mixed with crystalline cellulose (Asahi Kasei Corporation, Ceolus (registered trademark), PH-101), sodium starch glycolate (DFE Pharma Co., Ltd., Primogel), 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 agent (FC agent) containing hypromellose (Shin-Etsu Chemical Co., Ltd., TC-5M), macrogol 6000 (NOF Corporation), talc (Fuji Talc Industry Co., Ltd.), titanium oxide (Toho Titanium Co., Ltd., NA61) to obtain a machitentan-containing preparation. The content of each additive in the preparation is shown in Table 1.

[0042] [Comparative Example 2] In Comparative Example 2, a mixture containing marciteitan further mixed with crospovidone (BASF, Kollidon (registered trademark), CL-F) as a disintegrant was obtained, the lactose hydrate in the granulated product was reduced, and carnauba wax (Nippon Wax Co., Ltd., Polishing Wax 105) was added after coating for glazing. A marciteitan-containing formulation was obtained by the same production method as in Comparative Example 1, except for the above. The contents of each additive in the formulation are shown in Table 1.

[0043] [Comparative Example 3] In Comparative Example 3, a mixture containing marciteitan further mixed with corn starch (Nippon Shokuhin Kako Co., Ltd., xx16) as a disintegrant was obtained, the lactose hydrate in the granulated product was reduced, and carnauba wax (Nippon Wax Co., Ltd., Polishing Wax 105) was added after coating for glazing. A marciteitan-containing formulation was obtained by the same production method as in Comparative Example 1, except for the above. The contents of each additive in the formulation are shown in Table 1.

[0044] [Example 1] In Example 1, a mixture containing marciteitan further mixed with low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd., L-HPC (registered trademark), LH-21) as a disintegrant was obtained, the lactose hydrate in the granulated product was reduced, and carnauba wax (Nippon Wax Co., Ltd., Polishing Wax 105) was added after coating for glazing. A marciteitan-containing formulation was obtained by the same production method as in Comparative Example 1, except for the above. The contents of each additive in the formulation are shown in Table 1.

[0045] [Example 2] In Example 2, a mixture containing machitentan further mixed with croscarmellose sodium (Nichirin Chemical Industry Co., Ltd., Kikkolatte (registered trademark), ND-2HS) as a disintegrant was obtained, the lactose hydrate in the granulated product was reduced, and carnauba wax (Nippon Wax Co., Ltd., Polishing Wax 105) was added after coating for glazing. Except for these, a machitentan-containing preparation was obtained by the same production method as in Comparative Example 1. The contents of each additive in the preparation are shown in Table 1.

[0046] [Example 3] In Example 3, a mixture containing machitentan further mixed with carmellose (Nichirin Chemical Industry Co., Ltd., NS-300) as a disintegrant was obtained, the lactose hydrate in the granulated product was reduced, and carnauba wax (Nippon Wax Co., Ltd., Polishing Wax 105) was added after coating for glazing. Except for these, a machitentan-containing preparation was obtained by the same production method as in Comparative Example 1. The contents of each additive in the preparation are shown in Table 1.

[0047] [Example 4] In Example 4, a mixture containing machitentan further mixed with calcium carmellose (Nichirin Chemical Industry Co., Ltd., ND-2HS) as a disintegrant was obtained, the lactose hydrate in the granulated product was reduced, and carnauba wax (Nippon Wax Co., Ltd., Polishing Wax 105) was added after coating for glazing. Except for these, a machitentan-containing preparation was obtained by the same production method as in Comparative Example 1. The contents of each additive in the preparation are shown in Table 1.

[0048]

Table 1

[0049] For the machitentan-containing preparations of Examples 1 to 4 and Comparative Examples 1 to 3, the elution property and the amount of related substances were evaluated.

[0050] [Evaluation of Elution Property] The machitenatant-containing preparations of Examples 1 to 4 and Comparative Examples 1 to 3 were stored for 1 week under open conditions at 25°C and 90% RH. For the machitenatant-containing preparations before and after 1-week storage, using an elution tester (Toyama Sangyo Co., Ltd., NTR-6600A), in accordance with the paddle method of the dissolution test method of the 18th revised Japanese Pharmacopoeia, the dissolution rate at 30 minutes of elution time was evaluated. As the test solution, 900 mL of diluted McIlvaine buffer (pH 6.0) containing 0.1% cetyltrimethylammonium bromide (CTAB) was used. The rotation speed of the paddle was 75 rpm.

[0051] Table 2 shows the evaluation results of the dissolution properties of the machitenatant-containing preparations of Examples 1 to 4 and Comparative Examples 1 to 3. The dissolution delay rate (%) described in Table 2 was calculated using the following formula (1).

[0052] Dissolution delay rate (%) = (dissolution rate after storage / initial dissolution rate) × 100 (1)

[0053] In this embodiment, if the dissolution delay rate calculated from the above formula (1) is 85% or more, it is determined that there is an effect in suppressing dissolution delay.

[0054] [Evaluation of the amount of related substances] The machitenatant-containing preparations of Examples 1 to 4 and Comparative Examples 1 to 3 were stored for 2 weeks under open conditions at 60°C and 60% RH. For the machitenatant-containing preparations after 2-week storage, the amount of related substances was evaluated using liquid chromatography (Shimadzu Corporation, Prominence-i).

[0055] Table 2 shows the evaluation results of the amounts of related substances in the macitentan-containing formulations of Examples 1 to 4 and Comparative Examples 1 to 3. The related substances (%) described in Table 2 were calculated from the ratio of the peak area of the hydrolyzate, which is a related substance derived from macitentan, to the total peak area obtained on the chromatogram, with the total peak area set to 100. The above hydrolyzate is 5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinamine, also known as ACT-080803 and Despropylaminosulfonyl Macitentan.

[0056] In consideration of the fact that, according to the ICH guidelines, the threshold value for which safety confirmation is required is 0.5%, in this embodiment, if the amount of related substances is less than 0.5%, it is determined that there is an effect in suppressing the generation of related substances.

[0057]

Table 2

[0058] From the results in Table 2, in Comparative Example 1, which contained crystalline cellulose in the granulated product and did not contain the disintegrant selected in the present invention, elution delay was observed after storage, and furthermore, a large amount of generation of related substances was also observed. Also, in Comparative Examples 2 and 3, which contained crystalline cellulose in the granulated product and further contained crospovidone and corn starch, respectively, as the disintegrant, only one of the effects of suppressing elution delay or suppressing the generation of related substances was obtained.

[0059] On the other hand, in Examples 1 to 4 in which the disintegrant described above was included together with crystalline cellulose in the granulated product, suppression of elution delay and suppression of generation of related substances were also observed. In particular, the amount of related substances in Example 1 using low-substituted hydroxypropyl cellulose as the disintegrant and Example 4 using calcium carboxymethyl cellulose was reduced to less than half compared to Comparative Example 1 and Comparative Example 2, and a remarkable suppressing effect was observed. From these results, it became clear that in a machitentan-containing preparation containing crystalline cellulose, inclusion of the disintegrant selected in the present invention is effective not only in suppressing elution delay of the machitentan-containing preparation but also in suppressing generation of related substances.

[0060] Next, further examination was carried out using low-substituted hydroxypropyl cellulose, which showed a remarkable suppressing effect, as the disintegrant.

[0061] [Example 5] In Example 5, a machitentan-containing preparation was obtained by the same production method as in Example 1, except that the addition amount of crystalline cellulose in the granulated product was decreased and the addition amount of lactose hydrate was increased. The content of each additive in the preparation is shown in Table 3.

[0062] [Example 6] In Example 6, a machitentan-containing preparation was obtained by the same production method as in Example 1, except that the addition amount of crystalline cellulose in the granulated product was increased and the addition amount of lactose hydrate was decreased. The content of each additive in the preparation is shown in Table 3.

[0063] [Example 7] In Example 7, a machitentan-containing preparation was obtained by the same production method as in Example 1, except that the addition amounts of crystalline cellulose and low-substituted hydroxypropyl cellulose in the granulated product were increased and the addition amount of lactose hydrate was decreased. The content of each additive in the preparation is shown in Table 3.

[0064] [Example 8] In Example 8, a preparation containing masitinib was obtained by the same production method as in Example 1, except that the amounts of crystalline cellulose and hydroxypropyl cellulose with a low degree of substitution in the granulated product were decreased and the amount of lactose hydrate added was increased. The contents of the respective additives in the preparation are shown in Table 3.

[0065] [Example 9] In Example 9, a preparation containing masitinib was obtained by the same production method as in Example 1, except that the amount of hydroxypropyl cellulose with a low degree of substitution in the granulated product was decreased and the amount of lactose hydrate added was increased. The contents of the respective additives in the preparation are shown in Table 3.

[0066] [Example 10] In Example 10, a preparation containing masitinib was obtained by the same production method as in Example 1, except that the amount of hydroxypropyl cellulose with a low degree of substitution in the granulated product was increased and the amount of lactose hydrate added was decreased. The contents of the respective additives in the preparation are shown in Table 3.

[0067] [Example 11] In Example 11, a preparation containing masitinib was obtained by the same production method as in Example 1, except that the variety of hydroxypropyl cellulose with a low degree of substitution in the granulated product was changed from LH-21 to NBD-020. The contents of the respective additives in the preparation are shown in Table 3.

[0068] [Table 3]

[0069] For the masitinib-containing preparations of Examples 5 to 11, the elution property and the amount of related substances were evaluated by the above-described method. The results are shown in Table 4 (the results of Example 1 are reproduced).

[0070] [Table 4]

[0071] In Example 5 or Example 6, the addition amount of crystalline cellulose in the granulated product was increased or decreased compared with Example 1. In Example 9 or Example 10, the addition amount of hydroxypropyl cellulose with a low degree of substitution in the granulated product was increased or decreased compared with Example 1. Further, in Example 7 or Example 8, the addition amounts of crystalline cellulose and hydroxypropyl cellulose with a low degree of substitution in the granulated product were increased or decreased compared with Example 1. However, as shown in the results of Table 4, in all cases, similar to Example 1, suppression of elution delay and suppression of generation of related substances were observed. In Example 11, hydroxypropyl cellulose with a variety different from the variety of hydroxypropyl cellulose with a low degree of substitution used in the granulated product used in Example 1 was used, but similar to Example 1, suppression of elution delay and suppression of generation of related substances were observed.

[0072] From these results, it was clarified that in the masitinib-containing preparation containing crystalline cellulose, by including hydroxypropyl cellulose with a low degree of substitution, not only the effect of suppressing the elution delay of the masitinib-containing preparation but also the effect of suppressing the generation of related substances can be obtained regardless of the addition amount of crystalline cellulose in the granulated product. Further, it was clarified that the hydroxypropyl cellulose with a low degree of substitution in the granulated product in the masitinib-containing preparation of the present embodiment suppresses the elution delay of the masitinib-containing preparation and further suppresses the generation of related substances regardless of its addition amount and variety.

Claims

1. A granulated product containing maritenatane and additives other than the granulated product, wherein the granulated product contains at least one disintegrant selected from the group consisting of low-substituted hydroxypropyl cellulose, croscarmellose sodium, carmellose, and carmellose calcium, A maritenatane-containing preparation.

2. The granulated product further contains crystalline cellulose, The maritenatane-containing preparation according to Claim 1.

3. The at least one disintegrant is low-substituted hydroxypropyl cellulose or carmellose calcium, The maritenatane-containing preparation according to Claim 1.

4. The granulated product further contains crystalline cellulose, The at least one disintegrant is low-substituted hydroxypropyl cellulose or carmellose calcium, The maritenatane-containing preparation according to Claim 1.

5. The at least one disintegrant is 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, The maritenatane-containing preparation according to any one of Claims 1 to 4.

6. The additive contains at least one of a disintegrant and a lubricant, The maritenatane-containing preparation according to Claim 1.

Images