Pharmaceutical composition containing relugolix

Abstract

The present invention aims to provide a pharmaceutical composition having excellent elution and stability of the active ingredient relugolix or a salt thereof, a method for producing the same, a method for improving the elution of relugolix or a salt thereof from the pharmaceutical composition, and a method for improving the stability of relugolix or a salt thereof in the pharmaceutical composition. [Solution] The pharmaceutical composition according to the present invention has a cumulative 50% particle size (D) based on volume. 50 The present invention is characterized by containing relugolix or a salt thereof as an active ingredient, wherein the septum is 10 μm or less.

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition having excellent elution properties and stability of the active ingredient relugolix or a salt thereof, a method for producing the same, a method for improving the elution properties of relugolix or a salt thereof from the pharmaceutical composition, and a method for improving the stability of relugolix or a salt thereof in the pharmaceutical composition. [Background technology]

[0002] Relgolyx (chemical name: 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]pyrimidine-6-yl}phenyl)-3-methoxyurea) is a GnRH antagonist that exhibits selective antagonism to human pituitary GnRH receptors, blocking the action of GnRH and thereby inhibiting the secretion of gonadotropins (LH and FSH) from the pituitary gland, and consequently inhibiting the secretion of sex hormones such as estradiol and progesterone from the ovaries. As a result, it improves symptoms such as menorrhagia, lower abdominal pain, lower back pain, and anemia due to uterine fibroids, and also improves pain due to endometriosis (Non-patent Literature 1). Furthermore, in the United States, a formulation containing relugolix is ​​marketed as a treatment for advanced prostate cancer (relugolix 120 mg tablets) (Non-Patent Literature 2).

[0003] As pharmaceutical compositions containing relugolix as an active ingredient, for example, Patent Document 1 discloses a formulation containing relugolix and an organic acid, in which the oral absorption and stability of the active ingredient are improved. Patent Document 2 discloses a tablet containing 25% by mass or more of relugolix and D-mannitol, etc., in which the relugolix is ​​stabilized. [Prior art documents] [Patent Documents]

[0004] [Patent Document 1] International Publication No. 2010 / 026993 Pamphlet [Patent Document 2] International Publication No. 2016 / 136849 Pamphlet [Non-Patent Document]

[0005] [Non-Patent Document 1] Package Insert of "Relumina (Registered Trademark) Tablets 40 mg" [Non-Patent Document 2] Package Insert of "ORGOVYX (Registered Trademark) Tablets 120 mg" [Summary of the Invention] [Problems to be Solved by the Invention]

[0006] As described above, various pharmaceutical compositions containing relugolix as an active ingredient have been developed, and some have improved stability. However, no pharmaceutical composition has been known to improve both the stability and the elution property of relugolix as an active ingredient. Therefore, an object of the present invention is to provide a pharmaceutical composition excellent in the elution property and stability of relugolix or a salt thereof as an active ingredient, a method for producing the same, a method for improving the elution property of relugolix or a salt thereof from the pharmaceutical composition, and a method for improving the stability of relugolix or a salt thereof in the pharmaceutical composition. [Means for Solving the Problems]

[0007] The present inventors have conducted intensive studies to solve the above problems. As a result, by appropriately adjusting the cumulative 50% particle diameter (D 50 ) of relugolix or a salt thereof as an active ingredient, it has been found that both the stability and the elution property of relugolix or a salt thereof are improved, and the present invention has been completed. The present invention is shown below.

[0008] [1] A pharmaceutical composition comprising relugolix or a salt thereof having a volume-based cumulative 50% particle diameter (D 50 ) of 10 μm or less as an active ingredient. [2] The cumulative 50% particle size (D 50 The pharmaceutical composition according to [1], wherein the diameter is 2 μm or more. [3] The pharmaceutical composition according to [1] or [2], comprising granules containing the relgolicus or a salt thereof. [4] A pharmaceutical composition according to any one of the above [1] to [3], containing corn starch. [5] A method for producing a pharmaceutical composition containing relugolix or a salt thereof as an active ingredient, Volume-based cumulative 50% particle size (D 50 A method characterized by comprising the step of granulating relugolix or a salt thereof, wherein the ) is 10 μm or less. [6] A method for improving the dissolution of relugolix or a salt thereof from a pharmaceutical composition containing relugolix or a salt thereof as an active ingredient, The cumulative 50% particle size (D) of the relgolics or salt thereof, based on volume. 50 A method characterized by adjusting the size to 10 μm or less. [7] A method for improving the stability of relugolix or a salt thereof in a pharmaceutical composition containing relugolix or a salt thereof as an active ingredient, The cumulative 50% particle size (D) of the relgolics or salt thereof, based on volume. 50 A method characterized by adjusting the size to 2 μm or larger. [Effects of the Invention]

[0009] The pharmaceutical composition according to the present invention exhibits excellent dissolution properties for the active ingredient relugolix or its salts, and is therefore expected to rapidly release relugolix or its salts after ingestion, thereby exerting its medicinal effect. Furthermore, the pharmaceutical composition according to the present invention also exhibits excellent stability of relugolix or its salts, thus suppressing the decline in medicinal effect due to storage. Therefore, the present invention is industrially superior as one form of formulation containing relugolix or its salts as an active ingredient. [Brief explanation of the drawing]

[0010] [Figure 1] Figure 1 is a graph showing the elution of relugolix from tablets in a pH 5.0 buffer solution. [Figure 2] Figure 2 is a graph showing the elution of relugolix from tablets in a pH 6.8 buffer solution. [Figure 3] Figure 3 is a graph showing the dissolution of relugolix from tablets in buffer solutions at (1) pH 1.2, (2) pH 5.0, and (3) pH 6.8. [Figure 4] Figure 4 is a graph showing the relationship between the storage period and the amount of related substances in relugolix tablets in various packaging forms. [Figure 5] Figure 5 is a graph showing the relationship between the amount of light irradiation and the amount of related substances in uncoated tablets and film-coated tablets containing relugolix as the active ingredient. [Modes for carrying out the invention]

[0011] The pharmaceutical composition according to the present invention has a cumulative 50% particle size (D) based on volume. 50 The active ingredient is relugolix or a salt thereof, with a dendritic function of 10 μm or less. Relugolix has the chemical name 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]pyrimidine-6-yl}phenyl)-3-methoxyurea and is a GnRH antagonist with the following chemical structure. It exhibits selective antagonism to the human pituitary GnRH receptor and inhibits the secretion of gonadotropins (LH and FSH) from the pituitary gland by blocking the action of GnRH, thereby inhibiting the secretion of sex hormones such as estradiol and progesterone from the ovaries. As a result, it improves symptoms such as menorrhagia, lower abdominal pain, lower back pain, and anemia due to uterine fibroids, and also improves pain due to endometriosis.

[0012] [ka]

[0013] D of relugolix or its salt in a pharmaceutical composition 50 Since the crystal diameter of relugolix or its salt hardly changes or does not change during the formulation process, it can be adjusted according to the crystal diameter of the active ingredient of relugolix or its salt. In the present invention, by adjusting D of relugolix or its salt to 10 μm or less, the dissolution property of relugolix or its salt can be improved. Regarding D of relugolix or its salt 50 By adjusting it to 10 μm or less, the dissolution property of relugolix or its salt can be improved. Regarding D of relugolix or its salt 50 Regarding the lower limit of D, 2 μm is preferable from the viewpoint of the stability of relugolix or its salt. As D of relugolix or its salt 50 8 μm or less is preferable, and 5 μm or less or 4 μm or less is more preferable. In the present disclosure, the cumulative 50% particle diameter (D 50 ) is measured on a volume basis by a laser diffraction particle size distribution measuring device.

[0014] As the salt of relugolix, a pharmaceutically acceptable salt is preferable. The pharmaceutically acceptable salt is not particularly limited, and examples thereof include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate; oxalate, malonate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, p-toluenesulfonate, trifluoromethanesulfonate and other organic acid salts; and glutamate, aspartate and other amino acid salts.

[0015] The amount and proportion of relugolix or its salt in the pharmaceutical composition according to the present invention may be adjusted as appropriate within a range in which relugolix or its salt can exert its effects. For example, the amount of relugolix or its salt per tablet can be 10 mg or more and 360 mg or less, preferably 20 mg or more, more preferably 30 mg or more, preferably 240 mg or less, and more preferably 120 mg or less. The proportion of relugolix or its salt per tablet can be 5% by mass or more and 50% by mass or less, preferably 10% by mass or more, more preferably 15% by mass or more, preferably 40% by mass or less, and more preferably 30% by mass or less. For example, the amount of relugolix or its salt per tablet can be 40 ± 5 mg or 120 ± 5 mg.

[0016] The dosage form of the pharmaceutical composition according to the present invention is not particularly limited, but examples include solid preparations such as tablets, capsules, granules, powders, and pills; semi-solid preparations such as oral jellies; and liquid preparations such as elixirs, suspensions, emulsions, and lemonades. From the viewpoint of ease of administration and ease of manufacture, solid preparations are preferred, tablets, capsules, granules, powders, and pills are more preferred, and tablets are even more preferred. Relgolix or a salt thereof may be mixed with general pharmaceutical additives according to the dosage form of the pharmaceutical composition.

[0017] The water content of the pharmaceutical composition according to the present invention is not particularly limited, but is preferably 2% by mass or less, and more preferably 1% by mass or less. The lower limit of the water content is not particularly limited and may be 0% by mass, but the water content can be, for example, 0.2% by mass or more. The water content can be measured, for example, by the Karl Fischer method.

[0018] The method for producing the relugolix-containing pharmaceutical composition according to the present invention will be described step by step below, but the present invention is not limited to the following specific examples.

[0019] 1. Granulation process In this process, the cumulative 50% particle size (D) is determined by volume. 50Granulation is performed on relugolix or a salt thereof, having a particle size of 10 μm or less. This step is optional, and relugolix or salt crystals may be used as is. The granulation method is not particularly limited, and for example, stirring granulation, fluidized bed granulation, rolling fluidized bed granulation, etc., can be used without any particular restriction.

[0020] Granules containing the active ingredient relugolix or a salt thereof may also contain general pharmaceutical additives in addition to relugolix or a salt thereof. For example, relugolix-containing granules may contain general pharmaceutical additives such as excipients, disintegrants, and binders.

[0021] Excipients are additives added to improve the moldability and ease of administration of a formulation by diluting the active ingredient or increasing the volume of the formulation. Examples of excipients include mannitol, corn starch, crystalline cellulose, lactose, ethylcellulose, dextrin, and sucrose. One type of excipient may be used alone, or two or more may be used in combination. The amount and proportion of excipients in relugolix-containing granules may be adjusted as appropriate depending on the dosage form, but for example, it can be 50% by mass or more and 80% by mass or less, preferably 60% by mass or more, and preferably 75% by mass or less.

[0022] According to the inventors' experimental findings, when the pharmaceutical composition according to the present invention disintegrates in a buffer solution, if it contains a relatively large amount of crystalline cellulose as an excipient, the crystalline cellulose remains solid without dissolving, raising concerns about adverse effects on the elution properties of relugolix or its salt. However, if crystalline cellulose is not included, there are concerns about a decrease in the manufacturability of the granules or pharmaceutical composition. On the other hand, when corn starch is used as an excipient, both elution properties and manufacturability can be ensured, so it is preferable to use corn starch or a combination of corn starch and mannitol as the excipient. In this disclosure, manufacturability refers to the characteristic of being able to reproducibly produce formulations with the same dosage form and composition and similar quality.

[0023] Relgolyx or its salt may first be mixed with an excipient to form a diluted powder. Dilution can improve the uniformity of relgolyx or its salt. The proportion of relgolyx or its salt in the diluted powder can be adjusted as appropriate, but for example, the proportion of relgolyx or its salt to the total amount of relgolyx or its salt and the excipient can be 20% by mass or more and 50% by mass or less.

[0024] A disintegrant is an ingredient added to a pharmaceutical composition to absorb moisture and promote its disintegration, thereby facilitating the release of the active pharmaceutical ingredient. While there are no particular limitations on disintegrants, examples include croscarmellose sodium, carmellose, starch, sodium starch glycolate, carmellose sodium, carmellose calcium, light anhydrous silicic acid, and crospovidone. Only one disintegrant may be used, or two or more may be used in combination. The amount and proportion of the disintegrant in relugolix-containing granules can be appropriately adjusted depending on the dosage form, but for example, it can be 1% by mass or more and 20% by mass or less, preferably 2% by mass or more, preferably 15% by mass or less, more preferably 10% by mass or less, and even more preferably 5% by mass or less.

[0025] A binder is an ingredient added to bind the components together and increase the strength of the granules or tablets. While not particularly limited, examples of binders include hydroxypropylcellulose, hypromellose, povidone, vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, polyvinyl alcohol, and ethylcellulose. Only one binder may be used, or two or more may be used in combination. The amount and proportion of the binder in relugolix-containing granules can be adjusted as appropriate depending on the dosage form, but for example, it can be between 0.05% by mass and 20% by mass. Preferably, the proportion is 0.1% by mass or 0.5% by mass or more, more preferably 1% by mass or more, and more preferably 15% by mass or less, more preferably 10% by mass or less, and even more preferably 5% by mass or less.

[0026] In this invention, relugolix-containing granules are produced by granulating relugolix or a salt thereof using a granulation solution containing at least a portion of a binder and / or disintegrant. The granulation solution may contain components other than the binder and disintegrant. For example, a coloring agent may be added to further improve the photostability of the active ingredient, or a fluidizing agent may be added to improve fluidity. As the solvent for the granulation solution, water or a mixed solvent of water and a water-miscible organic solvent can be used. A water-miscible organic solvent is an organic solvent that is unrestrictedly miscible with water, and examples include alcohol solvents such as ethanol and 2-propanol, with ethanol being preferred. The proportion of the water-miscible organic solvent in the mixed solvent is preferably 50% by mass or less or 40% by mass or less, more preferably 20% by mass or less or 10% by mass or less, and even more preferably 5% by mass or less, 2% by mass or less or 1% by mass or less.

[0027] The granulation liquid may be a solution or a dispersion of the binder. A solution is a liquid in which the binder is uniformly dissolved in the solvent, while a dispersion is a liquid in which at least a portion of the binder and / or disintegrant, colorant, and fluidizer are dispersed in the solvent in a solid state.

[0028] The size of the relugolix-containing granules can be adjusted as appropriate. For example, the average particle size (D 50 The particle size can be 30 μm or more and 300 μm or less, and preferably 50 μm or more and 200 μm or less.

[0029] 2. Preparation process for compressed tablet powder In this process, tablet powder is prepared by mixing relugolix, its salt, or relugolix-containing granules with common pharmaceutical additives. Performing this process is optional; for example, if the dosage form is other than tablets, this process does not need to be performed.

[0030] In this process, there are no particular limitations on the general pharmaceutical additives that can be mixed with relugolix, its salts, or relugolix-containing granules, but examples include excipients, disintegrants, and binders, as well as lubricants, fluidizers, sweeteners, and flavorings. Examples of excipients, disintegrants, and binders are the same as those mentioned above.

[0031] Lubricants are components that adhere to the surface of powders, weakening the adhesion between powder particles and increasing the fluidity of the powder, as well as preventing the powder from sticking to the equipment, thereby enabling smooth tableting. Examples of lubricants that can be used include calcium stearate, magnesium stearate, sodium lauryl sulfate, talc, kaolin, titanium dioxide, silicon dioxide, light anhydrous silicic acid, sodium stearyl fumarate, and sucrose fatty acid esters. The proportion of lubricant per 100% by mass of the uncoated tablet can be, for example, 0.1% by mass or more and 2% by mass or less. Cut.

[0032] A fluidizing agent is an additive that improves the fluidity of a powder mixture. Examples of fluidizing agents include light anhydrous silicic acid, hydrated silicon dioxide, magnesium aluminometasilicate, and talc.

[0033] Sweeteners are ingredients that impart sweetness to pharmaceutical compositions, making them easier to consume. Examples include sugars such as glucose, fructose, and isomerized sugar; sugar alcohols such as sorbitol, mannitol, maltitol, and reduced starch syrup; natural sweeteners such as stevia, enzyme-treated stevia, and licorice; and artificial sweeteners such as sucralose, acesulfame potassium, aspartame, and sodium saccharin.

[0034] Fragrances are ingredients that add scent to pharmaceutical compositions to make them easier to ingest. Examples include natural fragrances made from ingredients obtained from nature, such as animals and plants, and artificial or synthetic fragrances created using chemical reactions.

[0035] 3.Tableting process In this step, tablets containing relugolix are obtained by compressing the tablet powder prepared in step 2.

[0036] The compression pressure used when manufacturing tablets is not particularly limited and can be set appropriately depending on the composition and weight of the tablets. For example, the compression pressure can be set to 2kN or more and 20kN or less, preferably 3kN or more, more preferably 5kN or more, preferably 18kN or less, and more preferably 15kN or less.

[0037] The hardness of the relugolix-containing tablets according to the present invention is not particularly limited, but is preferably 25N or more and 300N or less, and more preferably 30N or more and 200N or less. This hardness can be adjusted, for example, by the compression pressure.

[0038] The size of the relugolix-containing tablets according to the present invention can be adjusted as appropriate. For example, the shape of the uncoated tablet can be a disc or lens shape that is easy to swallow orally, with a diameter of 4 mm or more and 20 mm or less, a thickness of 2 mm or more and 7 mm or less, and a weight of 50 mg or more and 360 mg or less per tablet.

[0039] 4. Coating process In this step, the uncoated tablets obtained in step 3 are coated. Performing this step is optional; if coating is not necessary, this step may be omitted. When coating is applied, the tablets before coating are sometimes referred to as uncoated tablets.

[0040] Examples of components of the coating layer include celluloses such as hypromellose, ethylcellulose, hydroxypropylcellulose, cellulose acetate phthalate, and hypromellose phthalate; (meth)acrylic acid copolymers such as polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, methacrylic acid copolymer, methyl methacrylate / butyl methacrylate copolymer, methyl methacrylate / dimethylaminoethyl methacrylate copolymer, and aminoalkyl methacrylate copolymer; other polymers such as polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl alcohol diethylaminoacetate, and polyvinyl alcohol acetate phthalate; and inorganic compounds such as talc, titanium dioxide, and silicic acid. The coating agent may be used alone or in combination of two or more types.

[0041] The coating layer may contain colorants. The colorants may further improve the stability of the active ingredient, relgolics. Examples of colorants include titanium dioxide, yellow iron(III) oxide, red iron(III) oxide, black iron oxide, and tar dyes (red, yellow, or orange).

[0042] The content of the specific coloring agent in the whole tablet of the present invention is not particularly limited as long as it provides a stability-improving effect on relugolix or its salt, for example, but is preferably 0.01% by mass or more and 1% by mass or less.

[0043] When coating the tablets of the present invention, known coating methods can be used. For example, pan coating methods and fluidized bed coating methods can be used. The coating agent can be appropriately selected from pharmaceutically acceptable ones depending on the application of the coating, and may further contain the aforementioned coloring agent.

[0044] For improved identifiability, the surface of the tablets of the present invention may be engraved or printed with the product number, active ingredient name, active ingredient content, dosage form, product number, QR code (registered trademark), and barcode. The engraving or printing may be done directly on the surface of the uncoated or film-coated tablets. Appropriate printing methods can be selected from, for example, ink printing methods using plate transfer printing, gravure printing, offset printing, and inkjet printing, as well as laser printing. The ink used for printing can be selected from edible inks containing dyes and / or pigments, and the ink may be one color or two or more colors from the viewpoint of identifiability.

[0045] The relugolix-containing tablets according to the present invention may be packaged, if necessary, by PTP (Press Through Pack) packaging, bottle filling, aluminum packaging, etc.

[0046] Examples of materials for PTP packaging include resins such as polyvinyl chloride (PVC), polypropylene (PP), polyvinylidene chloride (PVDC), polychlorotrifluoroethylene (PCTFE), polyethylene (PE), polystyrene (PS), and polycarbonate (PC), as well as metals such as aluminum. These materials may be used individually or in combination. Examples of combinations include laminating polyvinyl chloride and polyvinylidene chloride, or laminating polyvinyl chloride and polychlorotrifluoroethylene. The formulation can be placed in a resin sheet formed into a pocket shape using a known method, and then sealed with aluminum foil.

[0047] From the viewpoint of improving photostability, PTP packaging using materials that can block or reduce light of specific wavelengths may be used. Examples of materials for the molded sheet side of PTP packaging include PVC (polyvinyl chloride), PVC / PVDC (polyvinyl chloride + vinylidene chloride coating), PVC / PE / PVDC, and OPA / AL / PVC (biaxially oriented polyamide + aluminum + polyvinyl chloride composite film), with PVC being preferred. Examples of materials for the back sealing material of PTP packaging include aluminum foil and paper / aluminum / PE laminate, with aluminum foil being preferred. Examples of wavelengths of light whose transmittance to the PTP packaging material should be suppressed to 90% or less include 390nm, 480nm, 550nm, 560nm, and 600nm. Examples of material colors include clear (transparent), persimmon, orange, red, and yellow.

[0048] The PTP packaging containing the relugolix-containing tablets according to the present invention may be further packaged in an aluminum pillow or a packaging bag made of a material that can block or reduce light of a specific wavelength, and may also contain a desiccant and an oxygen absorber. Examples of desiccants include calcium chloride, calcium oxide, magnesium oxide, silica gel, or zeolite. Examples of oxygen absorbers include iron-based oxygen absorbers such as iron powder, and organic oxygen absorbers such as ascorbic acid, isoascorbic acid, hydroquinone, or catechol. These desiccants and oxygen absorbers may be used individually, in combination of multiple types, or in combination of a desiccant and an oxygen absorber. An example of a product combining a desiccant and an oxygen absorber is "PharmaKeep®" from Mitsubishi Gas Chemical Company, Inc.

[0049] The dosage of the pharmaceutical composition according to the present invention may be appropriately adjusted depending on the patient's symptoms, severity, age, sex, etc., and the dosage form. For example, when converted to the dosage of relugolix, 1 mg to 100 mg per day may be administered once or twice, up to three times, for one day or more and up to five days.

[0050] The pharmaceutical composition according to the present invention contains D as the active ingredient relugolix or a salt thereof. 50 The appropriate adjustment of the compound improves both the stability and elution properties of relugolix or its salts. [Examples]

[0051] The present invention will be described in more detail below with reference to examples, but the present invention is not limited by the following examples, and it is certainly possible to implement it with appropriate modifications within the scope that is consistent with the spirit of the preceding and following descriptions, and all such modifications are included within the technical scope of the present invention.

[0052] Example 1: Manufacturing of relugolix tablets (1) Granulation of Relgolyx granules Relgolyx crystal (D 90 :134μm,D 50 :48.0μm,D 10 The 7.94 μm particles were ground using a high-speed impact type fine grinder ("Fine Impact Mill 100UPZ," manufactured by Hosokawa Micron Corporation) at disk rotation speeds of 18,000 rpm, 12,000 rpm, or 4,500 rpm. The cumulative 50% particle size (D) of the obtained relgolic crystals was measured by volume. 50 When measured using a laser diffraction particle size distribution analyzer "Mastersizer3000" (manufactured by Malvern Panalytical), the particle sizes were found to be 3.3 μm, 7.8 μm, and 17.9 μm, respectively. Also, relgolic crystals (D 90 :134μm,D 50 :48.0μm,D 10 The 7.94 μm particles were pulverized using a jet mill ("Jet Mill CP-4," manufactured by Seishin Corporation). The volume-based cumulative 50% particle size (D) of the obtained relgolic crystals was measured. 50 When measured using a laser diffraction particle size distribution analyzer "Mastersizer3000" (manufactured by Malvern Panalytical), the particle size was found to be 2.5 μm. Granulation was performed by mixing granulation components other than hydroxypropylcellulose in a fluidized bed granulator (Multiplex FD-MP-01D / SPC / SFP, manufactured by Powrec Co., Ltd.) according to the composition shown in Table 1, spraying a 3% by mass aqueous solution of hydroxypropylcellulose, and then drying at 75°C for 15 to 25 minutes. Note that prescription A is D 50 : Using 7.8 μm relugolix crystals, formulation B uses D 50 : Using relugolix crystals of 2.5 μm, 3.3 μm, and 17.9 μm, formulation C uses D 50 A 3.3 μm relgolic crystal was used.

[0053] (2) Tablet compression Using a container-type powder mixer ("Bohle Container Mixer LM-20" manufactured by Matsubo Co., Ltd.), the granules, croscarmellose sodium, and calcium stearate were mixed according to the formulation shown in Table 1 to prepare compressed tablets. The obtained tablet powder was compressed using a small rotary tablet press for research and development ("VELA5," manufactured by Kikusui Seisakusho Co., Ltd.) or a rotary tablet press ("VIRG0518SS2AZ," manufactured by Kikusui Seisakusho Co., Ltd.) at compression pressures of 7.0kN, 9.0kN, 9.5kN, 11.0kN, or 13.0kN to obtain uncompressed tablets with the shapes shown in Table 2.

[0054] (3) Film coating A film coating (FC) layer was formed on the surface of the obtained uncoated tablets with the composition shown in Table 1. Talc was dispersed in a solution obtained by dissolving hypromellose and hydroxypropylcellulose in purified water. Separately, titanium dioxide, yellow ferric oxide, and ferric oxide were dispersed in purified water. The dispersion of colorants was added to the talc dispersion and mixed to form a film coating solution. Plain tablets were placed in a film coating machine, coated with a film coating solution, and dried at 85°C for 10 to 15 minutes to obtain film-coated tablets.

[0055] [Table 1]

[0056] [Table 2]

[0057] Test Example 1: Dissolution Test 1 Dissolution tests were performed on the tablets of Example 1 in accordance with the dissolution test method described in the Japanese Pharmacopoeia. The tablets were dissolved in a dissolution tester using 900 mL of pH 5.0 buffer or pH 6.8 buffer at 50 rpm using the paddle method. 10 mL of sample was withdrawn at 30 or 60 minutes after the start of the test, filtered through a 0.45 μm pore size membrane filter, and the dissolution rate of the filtrate was calculated by high-performance liquid chromatography. The ultraviolet absorbance of relugolix was measured at 290 nm. The above tests were performed on three tablets (n=3), and the average value (average dissolution rate) was calculated. Figure 1 shows the results for a test solution with a pH of 5.0, and Figure 2 shows the results for a test solution with a pH of 6.8.

[0058] As shown in Figure 1, at pH 5.0, a tendency was observed for better dissolution performance with smaller particle sizes of relugolix crystals. Similar results were also observed at pH 6.8. Therefore, D of the relgolic crystal 50 The pharmaceutical composition according to the present invention, having a particle size of 10 μm or less, has been shown to effectively release relugolix from the stomach to the small intestine, where the pH is 6.8 or less, and to promote the absorption of relugolix in the body.

[0059] Test Example 2: Stability Test 1 Each tablet from Example 1 was packaged in a PVC sheet and an aluminum pillow, stored at 70°C for 9 days without humidity control, and the amount of related substances generated was measured by high-performance liquid chromatography. The results are shown in Table 3.

[0060] [Table 3]

[0061] As shown in Table 3, a tendency was observed for greater stability with increasing particle size of relgolic crystals. However, these results were obtained from accelerated testing under harsh conditions of 70°C, and even when comparing the results 9 days after the start of the test, there was no increase of more than 1% in the amount of related substances. Therefore, D 50 It has become clear that pharmaceutical compositions containing relugolix crystals with a size of 2 μm to 10 μm exhibit excellent dissolution and stability.

[0062] Example 2: Manufacturing of relugolix tablets (1) Granulation of Relgolyx granules Relgolyx crystals were ground using a jet mill ("YPM150-4D-OEB4," manufactured by Taizhou Pudu Machinery Equipment). The cumulative 10% particle size (D) of the obtained relgolyx crystals was measured by volume. 10 ), cumulative 50% particle diameter (D 50 ) and cumulative 90% particle size (D 90 The respective dimensions were 1.09 μm, 3.86 μm, and 10.5 μm. Granulation was performed by mixing granulation components other than hydroxypropylcellulose in a fluidized bed granulator (FD-WSG-5TW, manufactured by Powrec Co., Ltd.) according to the composition shown in Table 4, spraying a 2.8% by mass aqueous solution of hydroxypropylcellulose, and then drying at 75°C for 15 to 25 minutes.

[0063] (2) Tablet compression Using a container-type powder mixer ("Bohle Container Mixer LM-20" manufactured by Matsubo Co., Ltd.), the granules, croscarmellose sodium, and calcium stearate were mixed according to the formulation shown in Table 4 to prepare compressed tablets. The obtained tablet powder was compressed using a rotary tablet press ("VIRG0518SS2AZ," manufactured by Kikusui Seisakusho Co., Ltd.) or a rotary tablet press ("VIRG0518SS2AZ," manufactured by Kikusui Seisakusho Co., Ltd.) at a compression pressure of 7.0 kN to obtain uncoated tablets with the shapes shown in Table 5.

[0064] (3) Film coating A film coating (FC) layer was formed on the surface of the obtained uncoated tablets with the composition shown in Table 4. Talc was dispersed in a solution obtained by dissolving hypromellose and hydroxypropylcellulose in purified water. Separately, titanium dioxide was dispersed in purified water. The titanium dioxide dispersion was added to the talc dispersion and mixed to form a film coating solution. Plain tablets were placed in a film coating machine, coated with a film coating solution, and dried at 85°C for 10 to 15 minutes to obtain film-coated tablets.

[0065] [Table 4]

[0066] [Table 5]

[0067] Test Example 3: Dissolution Test 2 For the tablets of Example 2, the average dissolution rate of relugolix was calculated in the same manner as in Test Example 1, except that buffer solutions with pH 1.2, 5.0, or 6.8 were used. The results are shown in Figure 3. As shown in Figure 3, although the elution rate of relugolix tends to decrease with increasing pH, a sufficient elution rate was observed even at pH 5.0. Therefore, D of the relgolic crystal 50 The pharmaceutical composition according to the present invention, having a particle size of 10 μm or less, has been shown to effectively release relugolix from the stomach to the small intestine, where the pH is approximately 1.0 to 6.8, thereby promoting the absorption of relugolix in the body.

[0068] Test Example 4: Stability Test 2 The tablets from Example 2 were packaged in PTP packaging using a PVC sheet or PCTFE sheet and aluminum foil to obtain PTP packaging. Using a resealable aluminum pillow, the obtained PTP packaging was layered with zeolite or dry mat and then packaged in aluminum pillow packaging to obtain aluminum pillow packaging. The aluminum pillow packaging was stored at 40°C and 75% RH for 6 months, and the amount of related substances produced was measured by high-performance liquid chromatography. The results are shown in Figure 4.

[0069] As shown in Figure 4, packaging with PVC sheets resulted in a lower total amount of relgolics analogs and greater stability compared to packaging with PCTFE sheets. Stability was further improved by packaging the PTP packs in aluminum pillows, and stability was further improved by inserting desiccants such as zeolite or dry mats into the aluminum pillows.

[0070] Test Example 5: Photostability Test For the uncoated tablets and film-coated tablets of Example 2, the amount of related substances and the change in the color tone of the tablet surface upon light irradiation were investigated. Each tablet was placed in a petri dish and irradiated with 1.2 million lx·h of light using a D65 light source. The amount of related substances generated was measured by high-performance liquid chromatography. The results are shown in Figure 5.

[0071] As shown in Figure 5, the photostability of relugolix was significantly improved by using film-coated tablets compared to uncoated tablets.

[0072] Furthermore, the color difference ΔE of the tablets before and after light irradiation was measured using a spectrophotometer. ΔE=[(ΔL * ) 2 +(Δa * ) 2 +(Δb * ) 2 ] 1 / 2 ΔL * Δa * Δb * Each is L * a * b* The lightness L of two object colors in a color system * The difference and the color coordinate Δa * Δb * This is the difference. The color difference measurement results are shown in Table 6.

[0073] [Table 6]

[0074] As shown in Table 6, the uncoated tablets were initially white, but changed to yellow upon exposure to light. In contrast, the film-coated tablets did not show such discoloration and remained almost the same white color as before even after exposure to light. These results clearly demonstrate that film coating can suppress discoloration of relugolix tablets.

Claims

1. Volume-based cumulative 50% particle size (D 50 A pharmaceutical composition characterized by containing relugolix or a salt thereof as an active ingredient, wherein the ) has a size of 10 μm or less.

2. The aforementioned cumulative 50% particle size (D 50 The pharmaceutical composition according to claim 1, wherein the ) is 2 μm or larger.

3. The pharmaceutical composition according to claim 1, which contains granules containing the relgolicus or a salt thereof.

4. The pharmaceutical composition according to claim 1, containing corn starch.

5. A method for producing a pharmaceutical composition containing relugolix or a salt thereof as an active ingredient, Volume-based cumulative 50% particle size (D 50 A method characterized by comprising the step of granulating relgolicus or a salt thereof, wherein the diameter is 10 μm or less.

6. A method for improving the dissolution of relugolix or a salt thereof from a pharmaceutical composition containing relugolix or a salt thereof as an active ingredient, The cumulative 50% particle size (D) of the relgolics or a salt thereof, based on volume. 50 A method characterized by adjusting the size to 10 μm or less.

7. A method for improving the stability of relugolix or a salt thereof in a pharmaceutical composition containing relugolix or a salt thereof as an active ingredient, The cumulative 50% particle size (D) of the relgolics or a salt thereof, based on volume. 50 A method characterized by adjusting the size to 2 μm or larger.

Images