Pharmaceutical composition containing relugolix and tablets containing relugolix

Abstract

An embodiment of the present invention provides a pharmaceutical composition containing Relugolix in which generation of related substances of Relugolix is suppressed during a storage period. Alternatively, an embodiment of the present invention provides Relugolix containing tablets that suppress the generation of related substances of Relugolix during the storage period.SOLUTION: A pharmaceutical composition containing Relugolix according to an embodiment of the present invention contains Relugolix or pharmaceutically acceptable salts thereof, and one or more additives selected from stearic acid, hydrogenated oil, carnauba wax, lauromacrogol, and polyoxyethylene hydrogenated castor oil.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] One embodiment of the present invention relates to a pharmaceutical composition containing relugolix, or to a tablet containing relugolix. [Background technology]

[0002] Relugolix (1-(4-{1-(2,6-Difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl}phenyl)-3-methoxyurea) has gonadotropin-releasing hormone (GnRH) antagonistic activity and is an effective drug for the prevention or treatment of, for example, hormone-dependent diseases.

[0003] On the other hand, Patent Document 1 describes that the amount of relugolix-related substances in relugolix-containing tablets increases over time. Patent Document 1 also describes that the degradation of relugolix in tablets over time is suppressed by setting the relugolix content in the tablets to 25% by mass or more. Patent Document 1 also describes that the degradation of relugolix in tablets over time is suppressed by adding a low-melting oil-like substance selected from polyethylene glycol, glycerin monostearate, and triethyl citrate to the tablets. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2016 / 136849 Summary of the Invention [Problem to be solved by the invention]

[0005] One object of one embodiment of the present invention is to provide a relugolix-containing pharmaceutical composition that suppresses the production of relugolix analogs during storage, or one object of one embodiment of the present invention is to provide a relugolix-containing tablet that suppresses the production of relugolix analogs during storage. [Means for solving the problem]

[0006] A relugolix-containing pharmaceutical composition according to one embodiment of the present invention comprises relugolix or a pharmaceutically acceptable salt thereof and one or more additives selected from stearic acid, hydrogenated oil, carnauba wax, lauromacrogol, and polyoxyethylene hydrogenated castor oil.

[0007] One embodiment of the present invention provides a relugolix-containing tablet comprising a core tablet containing relugolix or a pharmaceutically acceptable salt thereof and one or more additives selected from stearic acid, hydrogenated oil, carnauba wax, lauromacrogol, and polyoxyethylene hydrogenated castor oil. [Effects of the Invention]

[0008] According to one embodiment of the present invention, there is provided a pharmaceutical composition containing relugolix that suppresses the production of relugolix analogs during storage, or a tablet containing relugolix that suppresses the production of relugolix analogs during storage. [Brief explanation of the drawings]

[0009] [Figure 1] FIG. 1 shows the change in the amount of relugolix-derived analogues produced during storage in one example of a relugolix-containing tablet. DETAILED DESCRIPTION OF THE INVENTION

[0010] The relugolix-containing pharmaceutical composition and relugolix-containing tablet according to the present invention will be described below with reference to the drawings. The relugolix-containing pharmaceutical composition and relugolix-containing tablet according to the present invention should not be construed as being limited to the description of the following embodiments and examples. In the drawings referred to in the present embodiments and examples below, identical parts or parts having similar functions are designated by the same reference numerals, and repeated description thereof will be omitted.

[0011] As a result of investigations by the present inventors, it has been found that there are additives other than the low-melting-point oily substances described in Patent Document 1 that can suppress the decomposition of relugolix over time. On the other hand, as shown in the Examples described below, it has also been found that some additives generally classified as low-melting-point oily substances cannot suppress the decomposition of relugolix over time. In other words, the present invention has been achieved by first revealing that the decomposition of relugolix over time can be suppressed by using an additive not described in Patent Document 1 that is a low-melting-point oily substance that can suppress the decomposition of relugolix over time.

[0012] [Relugolix-containing pharmaceutical composition] A relugolix-containing pharmaceutical composition according to one embodiment of the present invention comprises relugolix or a pharmaceutically acceptable salt thereof and one or more additives selected from stearic acid, hydrogenated oil, carnauba wax, lauromacrogol, and polyoxyethylene hydrogenated castor oil.

[0013] Pharmaceutically acceptable salts of relugolix can be, for example, salts of inorganic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid, or salts of organic acids selected from the group consisting of formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

[0014] In one embodiment, the relugolix-containing pharmaceutical composition may contain 0.1 to 10% by mass of one or more additives selected from stearic acid, hydrogenated oil, carnauba wax, lauromacrogol, and polyoxyethylene hydrogenated castor oil, relative to 100% by mass of the relugolix-containing pharmaceutical composition. The amount of these additives contained in the relugolix-containing pharmaceutical composition is preferably as small as possible within the range that still allows the effect of inhibiting the formation of relugolix-related substances during storage.

[0015] In one embodiment, the relugolix-containing pharmaceutical composition may further comprise one or more pharmaceutically acceptable additives in addition to one or more additives selected from stearic acid, hydrogenated oil, carnauba wax, lauromacrogol, and polyoxyethylene hydrogenated castor oil. Examples of the pharmaceutically acceptable additives contained in the relugolix-containing pharmaceutical composition include, but are not limited to, excipients, binders, disintegrants, lubricants, colorants, pH adjusters, surfactants, sweeteners, and flavors.

[0016] Examples of excipients contained in the relugolix-containing pharmaceutical composition include D-mannitol; crystalline cellulose; starches such as corn starch, partially pregelatinized starch, pregelatinized starch, and porous starch; anhydrous calcium phosphate; precipitated calcium carbonate; and calcium silicate.

[0017] Examples of binders contained in the relugolix-containing pharmaceutical composition include crystalline cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and copolyvidone. The relugolix-containing pharmaceutical composition may contain a combination of two or more of these binders. The binder may be contained in an amount of 0.5% to 20% by mass relative to 100% by mass of the relugolix-containing pharmaceutical composition.

[0018] Examples of disintegrants contained in the relugolix-containing pharmaceutical composition include cornstarch, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylstarch sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropyl starch, sodium starch glycolate, and magnesium aluminometasilicate. The relugolix-containing pharmaceutical composition may contain a combination of two or more of these disintegrants. The disintegrant may be contained in an amount of 1% by mass to 20% by mass relative to 100% by mass of the relugolix-containing pharmaceutical composition.

[0019] Examples of lubricants contained in the relugolix-containing pharmaceutical composition include magnesium stearate, calcium stearate, talc, sucrose fatty acid esters, and sodium stearyl fumarate. The relugolix-containing pharmaceutical composition may contain a combination of two or more of these lubricants. The lubricant may be contained in an amount of 0.1% by mass to 5% by mass relative to 100% by mass of the relugolix-containing pharmaceutical composition.

[0020] Examples of coloring agents contained in the relugolix-containing pharmaceutical composition include food dyes such as Food Yellow No. 5, Food Red No. 2, and Food Blue No. 2, food lake dye, ferric oxide, and yellow ferric oxide. The relugolix-containing pharmaceutical composition may contain a combination of two or more of these coloring agents.

[0021] Examples of pH adjusters contained in the relugolix-containing pharmaceutical composition include citric acid or a salt thereof, phosphoric acid or a salt thereof, carbonic acid or a salt thereof, tartaric acid or a salt thereof, fumaric acid or a salt thereof, acetic acid or a salt thereof, and amino acids or a salt thereof. The relugolix-containing pharmaceutical composition may contain a combination of two or more of these pH adjusters.

[0022] Examples of surfactants contained in the relugolix-containing pharmaceutical composition include sodium lauryl sulfate, polysorbate 80, and polyoxyethylene (160) polyoxypropylene (30) glycol. The relugolix-containing pharmaceutical composition may contain two or more of these surfactants in combination.

[0023] Examples of sweeteners contained in the relugolix-containing pharmaceutical composition include aspartame (trade name), acesulfame potassium, sucralose, thaumatin, saccharin sodium, and dipotassium glycyrrhizinate. The relugolix-containing pharmaceutical composition may contain two or more of these sweeteners in combination.

[0024] Examples of flavors contained in the relugolix-containing pharmaceutical composition include menthol, peppermint oil, lemon oil, and vanillin. The relugolix-containing pharmaceutical composition may contain two or more of these flavors in combination.

[0025] [Relugolix-containing tablets] In this embodiment, the relugolix-containing formulation is preferably a relugolix-containing tablet obtained by compressing the above-mentioned relugolix-containing pharmaceutical composition. The relugolix-containing tablet according to one embodiment of the present invention comprises a plain tablet containing relugolix or a pharmaceutically acceptable salt thereof and one or more additives selected from stearic acid, hydrogenated oil, carnauba wax, lauromacrogol, and polyoxyethylene hydrogenated castor oil.

[0026] The relugolix-containing tablet further contains one or more pharmaceutically acceptable additives described above in addition to one or more additives selected from stearic acid, hydrogenated oil, carnauba wax, lauromacrogol, and polyoxyethylene hydrogenated castor oil.

[0027] In one embodiment, the relugolix-containing tablet may be a film-coated tablet in which a film is placed on the surface of a plain tablet.

[0028] The film may contain a coating base and a coating additive, and examples of the coating base include a sugar coating base, a water-soluble film coating base, an enteric film coating base, and a sustained-release film coating base.

[0029] Examples of sugar-coating bases contained in the film include sucrose, and in addition to sucrose, one or more selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, and carnauba wax can be used.

[0030] Examples of water-soluble film coating bases contained in the film include cellulose-based polymers such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, and methylhydroxyethyl cellulose; synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E, and polyvinylpyrrolidone; and polysaccharides such as pullulan.

[0031] Examples of enteric film coating bases contained in the film include cellulose-based polymers such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; acrylic acid-based polymers such as methacrylic acid copolymer L, methacrylic acid copolymer LD, and methacrylic acid copolymer S; and natural products such as shellac.

[0032] Examples of sustained-release film coating bases contained in the film include cellulose-based polymers such as ethyl cellulose; and acrylic acid-based polymers such as aminoalkyl methacrylate copolymer RS ​​and ethyl acrylate-methyl methacrylate copolymer suspensions.

[0033] Examples of coating additives contained in the film include light-blocking agents such as titanium oxide, fluidizing agents such as talc, colorants such as ferric oxide and yellow ferric oxide, plasticizers such as polyethylene glycol, triethyl citrate, castor oil and polysorbates, and organic acids such as citric acid, tartaric acid, malic acid and ascorbic acid. The film may also contain a combination of two or more of these coating additives.

[0034] [Method of manufacturing a pharmaceutical composition containing relugolix] The relugolix-containing pharmaceutical composition of this embodiment can be produced by mixing relugolix or a pharmaceutically acceptable salt thereof with one or more additives selected from stearic acid, hydrogenated oil, carnauba wax, lauromacrogol, and polyoxyethylene hydrogenated castor oil. Alternatively, the relugolix-containing pharmaceutical composition may be produced by mixing relugolix or a pharmaceutically acceptable salt thereof with one or more additives selected from stearic acid, hydrogenated oil, carnauba wax, lauromacrogol, and polyoxyethylene hydrogenated castor oil, and one or more of the above-mentioned pharmaceutically acceptable additives.

[0035] Alternatively, the relugolix-containing pharmaceutical composition can be provided as a granule obtained by granulating relugolix or a pharmaceutically acceptable salt thereof with one or more additives selected from stearic acid, hydrogenated oil, carnauba wax, lauromacrogol, and polyoxyethylene hydrogenated castor oil. The relugolix-containing pharmaceutical composition can also be provided as a granule obtained by granulating relugolix or a pharmaceutically acceptable salt thereof with one or more additives selected from stearic acid, hydrogenated oil, carnauba wax, lauromacrogol, and polyoxyethylene hydrogenated castor oil, and one or more of the above-mentioned pharmaceutically acceptable additives. For example, wet granulation can be used as the granulation method.

[0036] Alternatively, the relugolix-containing pharmaceutical composition may be provided as a mixture of the above-mentioned granulated product and one or more of the above-mentioned pharmaceutically acceptable additives.

[0037] [Manufacturing method of relugolix-containing tablets] The relugolix-containing pharmaceutical composition described above can be compressed to produce a relugolix-containing tablet. Specifically, the relugolix-containing tablet according to this embodiment can be produced by a direct compression method in which a relugolix-containing pharmaceutical composition containing relugolix or a pharmaceutically acceptable salt thereof, one or more additives selected from stearic acid, hydrogenated oil, carnauba wax, lauromacrogol, and polyoxyethylene hydrogenated castor oil, and one or more of the above-mentioned pharmaceutically acceptable additives are mixed and compressed. Alternatively, the relugolix-containing tablet according to this embodiment can be produced by granulating a mixture containing relugolix or a pharmaceutically acceptable salt thereof, and one or more additives selected from stearic acid, hydrogenated oil, carnauba wax, lauromacrogol, and polyoxyethylene hydrogenated castor oil, and then further adding and mixing one or more pharmaceutically acceptable additives, followed by compression molding of the resulting mixture.

[0038] Furthermore, film-coated tablets can also be produced by coating the thus obtained uncoated tablets containing relugolix with the above-mentioned film.

[0039] [Stability evaluation] In this specification, the stability of a relugolix-containing pharmaceutical composition or a relugolix-containing tablet is evaluated by quantifying the amount of related substances derived from relugolix using high-performance liquid chromatography (HPLC) and calculating the individual maximum amount of related substances. [Example]

[0040] [Comparative Example 1] 20.0 g of relugolix, 61.0 g of D-mannitol (PEARLITOL® 200SD ROQUETTE), 20.0 g of microcrystalline cellulose (CEOLUS® UF-702, Asahi Kasei Corporation), 3.0 g of hydroxypropyl cellulose (SSL-SFP, Nippon Soda Co., Ltd.), 5.0 g of croscarmellose sodium (Ac-Di-Sol®, DuPont Nutrition Ireland), and 1.0 g of magnesium stearate (plant-based, Taihei Chemical Industry Co., Ltd.) were placed in a plastic bag and mixed. The resulting pharmaceutical composition was tableted using a rotary tableting machine (Kikusui Seisakusho Co., Ltd.) at a tableting pressure of 8 kN to obtain relugolix-containing tablets of Comparative Example 1.

[0041] [Reference example 1] The relugolix-containing tablets of Reference Example 1 were obtained in the same manner as in Comparative Example 1, except that 2.64 g of the pharmaceutical composition of Comparative Example 1 and 0.012 g of Macrogol 6000 (Macrogol 6000 (P), NOF Corporation) were placed in a plastic bag and mixed.

[0042] [Reference example 2] The relugolix-containing tablets of Reference Example 2 were obtained in the same manner as in Reference Example 1, except that the amount of macrogol 6000 was changed to 0.036 g.

[0043] [Reference example 3] The relugolix-containing tablets of Reference Example 3 were obtained in the same manner as in Reference Example 1, except that Macrogol 6000 was changed to 0.012 g of Macrogol 20000 (Macrogol 20000, NOF Corporation).

[0044] [Reference example 4] The relugolix-containing tablets of Reference Example 4 were obtained in the same manner as in Reference Example 3, except that the amount of macrogol 20000 was changed to 0.036 g.

[0045] [Example 1] The relugolix-containing tablets of Example 1 were obtained in the same manner as in Reference Example 2, except that Macrogol 6000 was changed to 0.036 g of hydrogenated oil (Lavriwax (registered trademark) 101, Freund Corporation).

[0046] [Example 2] The relugolix-containing tablets of Example 2 were obtained in the same manner as in Reference Example 2, except that macrogol 6000 was changed to 0.036 g of stearic acid 50 (Kolliwax (registered trademark) S Fine, BASF Japan Ltd.).

[0047] [Example 3] The relugolix-containing tablets of Example 3 were obtained in the same manner as in Reference Example 2, except that macrogol 6000 was changed to 0.036 g of stearic acid 70 (Japanese Pharmacopoeia Stearic Acid 70, Kao Corporation).

[0048] [Example 4] The relugolix-containing tablets of Example 4 were obtained in the same manner as in Reference Example 2, except that macrogol 6000 was changed to 0.036 g of stearic acid 95 (Japanese Pharmacopoeia Stearic Acid NAA (registered trademark)-180P-1, NOF Corporation).

[0049] [Example 5] The relugolix-containing tablets of Example 5 were obtained in the same manner as in Reference Example 2, except that macrogol 6000 was changed to 0.036g of carnauba wax (Nippon Wax Co., Ltd., Polishing Wax 105).

[0050] [Example 6] The relugolix-containing tablets of Example 6 were obtained in the same manner as in Reference Example 2, except that macrogol 6000 was changed to 0.036 g of lauromacrogol (Nippon Surfactant Industry Co., Ltd.).

[0051] [Example 7] The relugolix-containing tablets of Example 7 were obtained in the same manner as in Reference Example 2, except that macrogol 6000 was changed to 0.036 g of polyoxyethylene hydrogenated castor oil 60 (NIKKOL HCO-60, Nikko Chemicals Co., Ltd.).

[0052] Comparative Example 2 Relugolix-containing tablets of Comparative Example 2 were obtained in the same manner as in Reference Example 2, except that macrogol 6000 was changed to 0.036 g of calcium stearate (plant-based, Taihei Chemical Industry Co., Ltd.).

[0053] Comparative Example 3 The relugolix-containing tablets of Comparative Example 3 were obtained in the same manner as in Reference Example 2, except that macrogol 6000 was changed to 0.036 g of magnesium stearate (plant-based, Taihei Chemical Industry Co., Ltd.).

[0054] [Stability evaluation] The relugolix-containing tablets of Comparative Examples 1 to 3, Reference Examples 1 to 4, and Examples 1 to 7 were stored for two weeks under open conditions at 60°C and 60% relative humidity, or for two weeks under sealed conditions at 60°C. The amount of related substances derived from relugolix was measured using each tablet immediately after manufacture (initial) and each tablet after storage. Two tablets were placed in a measuring cylinder, and an appropriate amount of diluted McIlvaine buffer, pH 3.0:acetonitrile (7:3) mixture was added and stirred with a stirrer. Diluted McIlvaine buffer, pH 3.0:acetonitrile (7:3) was added to make a total volume of exactly 100 ml. This solution was filtered through a membrane filter with a pore size of 0.45 μm or less. At least 3 ml of the first filtrate was removed, and the next filtrate was used as the sample solution.

[0055] The amount of related substances was measured by HPLC using an accurate 5 μL aliquot of the sample solution. Using the area percentage method, the sum of the peak areas of relugolix and related substances derived from relugolix obtained on the chromatogram was set to 100, and the maximum amount of related substances derived from relugolix (%) was calculated from the ratio of the peak areas. The measurement results are shown in Figure 1.

[0056] The results in Figure 1 demonstrate that the relugolix-containing tablets of Examples 1 to 7 are able to suppress the production of relugolix-derived analogs during storage to a degree comparable to or greater than that of the relugolix-containing tablets of Reference Examples 1 to 4. In particular, the relugolix-containing tablets of Examples 3, 4, and 6 are able to significantly suppress the production of relugolix-derived analogs during storage. Meanwhile, the relugolix-containing tablets of Comparative Example 2, which contain calcium stearate, generally classified as a low-melting-point oily substance, and Comparative Example 3, which contain magnesium stearate, showed an increase in the amount of analogs over time. Therefore, it became clear that the production of relugolix-derived analogs cannot be suppressed by simply selecting a low-melting-point oily substance, and that specific additives are required.

[0057] [Evaluation of stability when granulated by wet granulation] In order to confirm that the stability-improving effect of specific low-melting oily substances on relugolix is ​​independent of the manufacturing method, relugolix-containing granules were produced using a wet granulation method using a fluidized bed granulator and a high-speed agitator granulator, and the stability when formed into tablets was confirmed.

[0058] Comparative Example 4 64.0 g of relugolix, 195.2 g of D-mannitol (Mannit P, Mitsubishi Corporation Life Sciences), and 32.0 g of microcrystalline cellulose (Ceolus® PH-101, Asahi Kasei Corporation) were mixed in a fluidized-bed granulator (FD-MP-01, Powrex Corporation) and granulated with a granulation solution prepared by dissolving 9.6 g of hydroxypropyl cellulose (L, Nippon Soda Co., Ltd.) in 182.4 g of water. 188 g of the granules were placed in a plastic bag, along with 20.0 g of microcrystalline cellulose (Ceolus® KG-802, Asahi Kasei Corporation), 10.0 g of croscarmellose sodium (Ac-Di-Sol®, DuPont Nutrition Ireland), and 2.0 g of magnesium stearate (plant-based, Taihei Chemical Industry Co., Ltd.). The obtained pharmaceutical composition was tableted at 8 kN using a rotary tableting machine (Kikusui Seisakusho Co., Ltd.) to obtain relugolix-containing tablets of Comparative Example 4.

[0059] [Example 8] The relugolix-containing tablets of Example 8 were obtained in the same manner as in Comparative Example 4, except that the amount of crystalline cellulose to be mixed with the granules was reduced by 3 g and 3 g of stearic acid 95 (Japanese Pharmacopoeia Stearic Acid NAA (registered trademark)-180P-1, NOF Corporation) was added.

[0060] Comparative Example 5 140.0 g of relugolix, 427.0 g of D-mannitol (Mannit P, Mitsubishi Corporation Life Sciences), 70.0 g of microcrystalline cellulose (Ceolas® PH-101, Asahi Kasei Corporation), and 21.0 g of hydroxypropyl cellulose (L-FP, Nippon Soda Co., Ltd.) were mixed in a high-speed agitator granulator, granulated with 92.0 g of water, and dried in a fluidized-bed granulator (FD-MP-01, Powrex Corporation). 188 g of the granulated mixture was placed in a plastic bag and mixed with 20.0 g of microcrystalline cellulose (Ceolas® KG-802, Asahi Kasei Corporation), 10.0 g of croscarmellose sodium (Ac-Di-Sol®, DuPont Nutrition Ireland), and 2.0 g of magnesium stearate (plant-based, Taihei Chemical Industry Co., Ltd.). The obtained pharmaceutical composition was tableted at 8 kN using a rotary tableting machine (Kikusui Seisakusho Co., Ltd.) to obtain relugolix-containing tablets of Comparative Example 5.

[0061] [Example 9] 658.0 g of the granules from Comparative Example 5, 59.5 g of microcrystalline cellulose (CEOLUS® KG-802, Asahi Kasei Corporation), 35.0 g of croscarmellose sodium (Ac-Di-Sol®, DuPont Nutrition Ireland), 10.5 g of stearic acid 95 (JP Stearic Acid NAA®-180P-1, NOF Corporation), and 7.0 g of magnesium stearate (plant-based, Taihei Chemical Industry Co., Ltd.) were placed in a plastic bag and mixed. The resulting pharmaceutical composition was compressed at 8 kN using a rotary tablet press (Kikusui Seisakusho Co., Ltd.) to obtain the relugolix-containing tablets of Example 9.

[0062] Table 1 shows the formulation per tablet of Comparative Examples 4 and 5 and Examples 8 and 9, and the maximum amount of each related substance derived from relugolix immediately after production and after storage for two weeks at 60°C and a relative humidity of 60%. (Table 1) [Table 1]

[0063] The results in Table 1 demonstrate that the relugolix-containing tablets of Examples 8 and 9 can inhibit the production of relugolix-derived analogues regardless of the manufacturing conditions.

[0064] [Confirmation of stability depending on tableting pressure] The inventors of the present application have found that the amount of related substances derived from relugolix increases over time depending on the tableting pressure when forming tablets. We will confirm the effect of tableting pressure on the relugolix-containing tablets of the present patent invention.

[0065] [Reference example 5] The pre-tabletting mixed powder of Comparative Example 1 was used as Reference Example 5.

[0066] [Reference example 6] The pre-tabletting mixed powder of Comparative Example 1 was compressed at 5 kN to prepare a relugolix-containing tablet, which was used as Reference Example 6.

[0067] [Reference example 7] The pre-tabletting mixed powder of Comparative Example 1 was compressed at 11 kN to prepare a relugolix-containing tablet, which was used as Reference Example 7.

[0068] [Example 10] The pre-tabletting mixed powder of Example 9 was compressed at 5 kN to give a tablet containing relugolix, which was designated as Example 10.

[0069] [Example 11] The pre-tabletting mixed powder of Example 9 was compressed at 11 kN to give a tablet containing relugolix, which was designated as Example 11.

[0070] The maximum individual amounts of related substances derived from each relugolix are shown in Table 2. (Table 2) [Table 2]

[0071] The results in Table 2 demonstrate that the relugolix-containing tablets of Examples 9, 10, and 11 can inhibit the production of analogues derived from relugolix, regardless of the tableting pressure.

Claims

1. relugolix or a pharmaceutically acceptable salt thereof; A pharmaceutical composition containing relugolix, comprising one or more additives selected from stearic acid, hydrogenated oil, carnauba wax, lauromacrogol, and polyoxyethylene hydrogenated castor oil.

2. relugolix or a pharmaceutically acceptable salt thereof; A relugolix-containing tablet comprising an uncoated tablet containing one or more excipients selected from stearic acid, hydrogenated oil, carnauba wax, lauromacrogol, and polyoxyethylene hydrogenated castor oil.

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