Osimertinib-containing tablet

Abstract

The osimertinib-containing tablet of the present disclosure comprises 40% by mass or more of osimertinib or a pharmaceutically acceptable salt thereof, and is a direct compression tablet.

Description

Osimertinib-containing tablets

[0001] The present invention relates to osimertinib-containing tablets and a method for producing the same, a method for improving the dissolution of osimertinib or a pharmaceutically acceptable salt thereof from osimertinib-containing tablets, and a method for suppressing sticking in the production of osimertinib-containing tablets.

[0002] Osimertinib is a compound with the chemical name N-(2-{[2-(dimethylamino)ethyl](methyl)amino}-4-methoxy-5-{[4-(1-methyl-1H-indole-3-yl)pyrimidine-2-yl]amino}phenyl)prop-2-enamide. Osimertinib mesylate has an inhibitory effect on the growth of tumors with EGFR gene mutations and is used as an anti-cancer agent under the name Tagrisso®.

[0003] Currently, development is underway to improve pharmaceutical compositions containing osimertinib or a pharmaceutically acceptable salt thereof as an active ingredient. For example, Patent Document 1 discloses a pharmaceutical composition containing osimertinib or a pharmaceutically acceptable salt thereof, in which the solubility properties have been improved under physiologically appropriate conditions.

[0004] Japan Special Table No. 2017-501201

[0005] Pharmaceutical compositions containing osimertinib or a pharmaceutically acceptable salt thereof are primarily administered orally to subjects in the form of tablets. While it is generally preferred that tablets be 8 mm or smaller to facilitate swallowing, no tablets containing osimertinib or a pharmaceutically acceptable salt thereof (hereinafter sometimes referred to as "osimertinib-containing tablets") 8 mm or smaller have been reported.

[0006] One aspect of the present invention aims to realize a miniaturized osimertinib-containing tablet.

[0007] As a result of diligent research to solve the aforementioned problems, the inventors of the present invention have discovered that it is possible to miniaturize osimertinib-containing tablets by a direct compression method that does not involve granulating the active pharmaceutical ingredient, and have completed the present invention.

[0008] In other words, one aspect of the present invention includes the following configuration: <1> An osimertinib-containing tablet comprising 40% by mass or more of osimertinib or a pharmaceutically acceptable salt thereof, and being a direct-compression tablet. <2> The particle size (D) of the osimertinib or a pharmaceutically acceptable salt thereof. ５０ <1> An osimertinib-containing tablet according to <1>, wherein the particle size (D) of the osimertinib or pharmaceutically acceptable salt is 80 μm or larger. <3> An osimertinib-containing tablet according to <1> or <2>, further comprising 3% by mass or more of stearyl sodium fumarate. <4> A method for producing an osimertinib-containing tablet, comprising a tableting step of compressing a mixture containing the osimertinib or a pharmaceutically acceptable salt by direct compression, wherein the content ratio of the osimertinib or a pharmaceutically acceptable salt in the osimertinib-containing tablet is 40% by mass or larger. <5> The particle size (D) of the osimertinib or a pharmaceutically acceptable salt ５０ A method for producing an osimertinib-containing tablet according to <4>, wherein the particle size (D) of the osimertinib-containing tablet is 80 μm or larger. <6> A method for producing an osimertinib-containing tablet according to <4> or <5>, wherein the osimertinib-containing tablet further contains 3% by mass or more of stearyl sodium fumarate. <7> An osimertinib-containing tablet containing 40% by mass or more of osimertinib or a pharmaceutically acceptable salt thereof, wherein the particle size (D) of the osimertinib or a pharmaceutically acceptable salt thereof is 80 μm or larger. ５０ A method for improving the dissolution of osimertinib or a pharmaceutically acceptable salt thereof from osimertinib-containing tablets by adjusting the size of the osimertinib-containing tablet to 80 μm or more. <8> A method for suppressing sticking in the manufacture of osimertinib-containing tablets by including 3% by mass or more of stearyl sodium fumarate in osimertinib-containing tablets containing 40% by mass or more of osimertinib or a pharmaceutically acceptable salt thereof.

[0009] According to one aspect of the present invention, miniaturized osimertinib-containing tablets and the like can be provided.

[0010] This is a diagram showing the results of evaluation example 3. This is a diagram showing the results of evaluation example 5.

[0011] One embodiment of the present invention will be described in detail below. Unless otherwise specified herein, "A to B" representing a numerical range means "A or greater, and B or less."

[0012] [Osimertinib-containing tablets] An osimertinib-containing tablet according to one aspect of the present invention (hereinafter sometimes referred to as "the tablet") contains 40% by mass or more of osimertinib or a pharmaceutically acceptable salt thereof, and is a direct-compression tablet. Hereinafter, osimertinib or a pharmaceutically acceptable salt thereof may be referred to as "active ingredient."

[0013] (Active Pharmaceutical Ingredient) Osimertinib is a compound with the chemical name N-(2-{[2-(dimethylamino)ethyl](methyl)amino}-4-methoxy-5-{[4-(1-methyl-1H-indole-3-yl)pyrimidine-2-yl]amino}phenyl)prop-2-enamide. Osimertinib or a pharmaceutically acceptable salt thereof is the active ingredient in osimertinib-containing tablets.

[0014] In this specification, “pharmaceutically acceptable salt” means a salt that is medically free from excessive toxicity, irritation, allergic reactions, etc., and suitable for use in contact with human or other mammalian tissues.

[0015] The pharmaceutically acceptable salts of osimertinib are well known in the art and any of them can be used. Examples of pharmaceutically acceptable salts of osimertinib include inorganic salts such as hydrochloride, hydrobromide, nitrate, sulfate, and phosphate; organic salts such as formate, acetate, oxalate, maleate, fumarate, citrate, benzoate, mesylate (methanesulfonate), benzenesulfonate, p-toluenesulfonate, trifluoroacetate, succinate, tartrate, lactate, and pyruvate; and addition salts such as lysine, glycine, phenylalanine, aspartic acid, and glutamic acid.

[0016] In terms of improving the dissolution of the active ingredient in this tablet, the particle size (D) of the active ingredient in this tablet is improved. ５０ The particle size (D) of the active pharmaceutical ingredient in this tablet is preferably 80 μm or larger, more preferably 90 μm or larger, and even more preferably 100 μm or larger.５０ When it is 80 µm or more, the gelation of the tablets in water is suppressed, and the dissolution rate of the active ingredient in the tablets is further improved.

[0017] The dissolution property of the active ingredient is evaluated by the dissolution rate determined by the dissolution test method (paddle method, test solution: water) of the 18th revised Japanese Pharmacopoeia.

[0018] Also, when the particle size (D ５０ ) of the active ingredient in the tablets is 100 µm or more, the disintegration time of the tablets can be shortened. In this specification, the disintegration time of the tablets indicates the disintegration time determined by the disintegration test method of the 18th revised Japanese Pharmacopoeia.

[0019] In this specification, the particle size (D １０ ), the particle size (D ５０ ) or the particle size (D ９０ ) is the cumulative 10% particle size, the cumulative 50% particle size or the cumulative 90% particle size in volume-based measurement, respectively. The particle size (D １０ ), the particle size (D ５０ ) or the particle size (D ９０ ) can be measured by a known wet measuring device capable of measuring the volume-based cumulative particle size.

[0020] The content ratio of the active ingredient in the tablets is 40% by mass or more based on the mass of the tablets. The preferable range of the content ratio of the active ingredient in the tablets is 42 - 95% by mass, and the more preferable range is 45 - 70% by mass.

[0021] The content of the active ingredient in the tablets is appropriately adjusted according to its therapeutic purpose. For example, as osimertinib, it is 10 - 200 mg (for example, 10 mg, 20 mg, 25 mg, 40 mg, 50 mg, 75 mg, 80 mg, 100 mg, 125 mg, 150 mg, 175 mg or 200 mg), preferably 20 - 150 mg, and more preferably 25 - 125 mg.

[0022] (Other components) The tablets may contain additives such as excipients, binders, lubricants, disintegrants, surfactants, plasticizers and colorants as components other than osimertinib or its pharmaceutically acceptable salts.

[0023] Excipients are not particularly limited, but examples include D-mannitol, lactose (e.g., lactose monohydrate), sucrose, corn starch, calcium phosphate, sorbitol, and crystalline cellulose.

[0024] Examples of D-mannitol include Parteck M200 (manufactured by Merck).

[0025] Examples of crystalline cellulose include Ceolus KG-1000, Ceolus UF-702, and Ceolus PH-101, PH-102 (all manufactured by Asahi Kasei Corporation).

[0026] The binder is not particularly limited, but examples include hydroxypropylcellulose, hydroxypropylmethylcellulose (also called "hypromellose"), povidone, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, copolymers of N-vinylpyrrolidone and vinyl acetate, or combinations thereof, pregelatinized starch, gelatin, agar, gum arabic, etc.

[0027] Lubricants are not particularly limited, but examples include inert substances such as talc, kaolin, and titanium dioxide, magnesium stearate, calcium stearate, stearic acid, light anhydrous silicic acid, hydrated silicon dioxide, sodium stearyl fumarate, and glycerin fatty acid esters.

[0028] The disintegrants are not particularly limited, but examples include crospovidone, low-substituted hydroxypropylcellulose, sodium starch glycolate, croscarmellose sodium, carmellose, carmellose calcium, and potato starch.

[0029] Examples of low-substituted hydroxypropyl cellulose include LH-31 (manufactured by Shin-Etsu Chemical Co., Ltd.).

[0030] The surfactant is not particularly limited. For example, macrogols such as polyethylene glycol with a weight average molecular weight of 300 to 6000; polyoxyethylene polyoxypropylene glycols such as Pluronic (registered trademark) and poloxamer; polyoxyethylene sorbitan fatty acid esters (polysorbates) such as polysorbate 80; polyoxyethylene hydrogenated castor oil and other polyoxyethylene hydrogenated oils; glycerin fatty acid esters such as glycerin monostearate; sorbitan fatty acid esters such as sorbitan monostearate and sorbitan monolaurate; sucrose fatty acid esters such as sucrose laurate; sodium lauryl sulfate and the like can be mentioned.

[0031] The plasticizer is not particularly limited. For example, hydrophilic plasticizers such as ethylene glycol, propylene glycol, and glycerin; fat-soluble plasticizers such as triacetin, triethyl citrate, diethyl phthalate, dioctyl adipate, lauric acid, stearyl alcohol, and cetyl alcohol can be mentioned.

[0032] The colorant is not particularly limited. For example, colorants that exhibit yellow (e.g., yellow iron sesquioxide, yellow iron oxide, aluminum lake of food yellow No. 4, red iron oxide, etc.), colorants that exhibit red (e.g., iron sesquioxide, food red No. 2, food red No. 3, food red No. 102, etc.), colorants that exhibit black (e.g., black iron oxide, carbon black, medicinal charcoal, etc.), colorants that exhibit blue (e.g., aluminum lake of blue No. 2, etc.), caramel, and the like can be mentioned.

[0033] The content of the additive in this tablet is not particularly limited and can be appropriately set based on conventionally known techniques.

[0034] In terms of suppressing sticking in the production of this tablet, it is preferable that this tablet contains a lubricant, and it is more preferable that it contains sodium stearyl fumarate. In terms of further suppressing sticking in the production of this tablet, the content of sodium stearyl fumarate in this tablet is preferably 3% by mass or more, and more preferably 3.5% by mass or more, based on the mass of this tablet.

[0035] In this specification, "sticking" refers to a tableting defect in which powder, which is a component of the tablet, adheres to the surface of the punch of the tablet press during tableting. If tableting is repeated with powder adhering to the surface of the punch, tablets with an uneven surface are likely to be produced.

[0036] (Type of Tablet) One aspect of the present invention is an osimertinib-containing tablet, which is a direct-compression tablet. In this specification, a direct-compression tablet refers to a tablet obtained by compressing a mixture of the active pharmaceutical ingredient and an additive without granulating the active pharmaceutical ingredient.

[0037] This tablet may be a single-layer tablet, a multilayer tablet, or a core tablet. However, from the viewpoint of ease of manufacture, dissolution of the active pharmaceutical ingredient, and bioequivalence, this tablet is preferably a single-layer tablet.

[0038] (Tablet Shape) The shape of this tablet is not particularly limited, and any shape can be used. For example, it may be round, oval, spherical, rod-shaped, donut-shaped, etc.

[0039] The hardness of the tablets is preferably 30 to 300 N. In the case of round tablets, the thickness (tablet thickness) is, for example, 1 to 10 mm, preferably 2 to 8 mm, and the diameter is not particularly limited, but from the viewpoint of handling, it is, for example, 4 to 20 mm, preferably 5 to 16 mm, and more preferably 6 to 10 mm. In the case of oval tablets, the thickness (tablet thickness) is, for example, 1 to 10 mm, preferably 2 to 8 mm, and the major axis is not particularly limited, but from the viewpoint of handling, it is, for example 5 to 20 mm, preferably 6 to 16 mm, and the minor axis is not particularly limited, but from the viewpoint of handling, it is, for example 3 to 12 mm, preferably 4 to 10 mm.

[0040] The moisture content of these tablets is not particularly limited, but is preferably 5% by mass or less, and more preferably 3% by mass or less. The moisture content can be measured, for example, by the Karl Fischer method.

[0041] The mass of this tablet is adjusted as appropriate depending on the content of the active ingredient, but is preferably 30 to 1000 mg, more preferably 40 to 600 mg, and even more preferably 50 to 350 mg. Tablets with a mass within the above range have the effect of being easy to take.

[0042] If the active ingredient content in this tablet is 40 mg, the mass of the tablet may be 45 to 100 mg, 50 to 100 mg, or 60 to 95 mg. Also, if the active ingredient content in this tablet is 80 mg, the mass of the tablet may be 85 to 200 mg, 100 to 200 mg, or 150 to 190 mg.

[0043] (Tablet Coating) These tablets may be further coated as needed. The coating agent used for coating the tablets is not particularly limited, but examples include hydroxypropyl cellulose, hydroxypropyl methylcellulose (also called "hypromellose"), polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, etc. Light-shielding agents and plasticizers may also be added as appropriate during coating. Examples of light-shielding agents include yellow iron(III) oxide, iron(III) oxide, titanium dioxide, and blue aluminum lake. Examples of plasticizers include triacetin, macrogol, hydroxypropyl cellulose, propylene glycol, and triethyl citrate.

[0044] The amount of coating agent used in the coating of these tablets may be increased or decreased as appropriate, but for example, it is coated in an amount in the range of 1 to 10% by mass relative to the mass of the tablet.

[0045] For improved identifiability, the surface of these tablets may be engraved or printed with the product number, active ingredient name, active ingredient content, dosage form, product number, QR code (registered trademark), barcode, etc. 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 methods such as plate transfer printing, gravure printing, offset printing, inkjet printing, and laser printing. The ink used for printing may be an edible ink containing dyes and / or pigments, and the ink may be a single color or two or more colors from the perspective of identifiability.

[0046] Furthermore, these tablets may be packaged in PTP packaging, bottles, aluminum packaging, or other methods as needed.

[0047] Examples of materials for PTP packaging include resins such as polyvinyl chloride, polypropylene, polyvinylidene chloride, polychlorotrifluoroethylene, polyethylene, polystyrene, or polycarbonate, as well as metals such as aluminum. These materials may be used individually or in combination of multiple types. Examples of combinations include laminating polyvinyl chloride and polyvinylidene chloride, or laminating polyvinyl chloride and polychlorotrifluoroethylene. The tablets can be packaged by placing them in molded pockets of a resin sheet, which is formed from the aforementioned resins using a known method, and then sealing the package with aluminum foil.

[0048] The PTP packaging containing these tablets may be further packaged in an aluminum pillow. This aluminum pillow may further 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] [Method for producing osimertinib-containing tablets] A method for producing osimertinib-containing tablets according to one aspect of the present invention (hereinafter sometimes referred to as "this manufacturing method") is a method for producing osimertinib-containing tablets, comprising a tableting step of compressing a mixture containing the active pharmaceutical ingredient by a direct compression method. This manufacturing method makes it possible to produce miniaturized osimertinib-containing tablets having an active pharmaceutical ingredient content of 40% by mass or more.

[0050] (Tableting process) The tableting process involves compressing a mixture containing the active pharmaceutical ingredient (for example, a mixture of the active pharmaceutical ingredient and an additive) into tablets by direct compression. The active pharmaceutical ingredient is not granulated before the tableting process.

[0051] This manufacturing method improves the dissolution of the active pharmaceutical ingredient in tablets produced by this method, and the particle size (D) of the active pharmaceutical ingredient is also improved. ５０ The thickness of the particle is preferably 80 μm or more.

[0052] In order to suppress the occurrence of sticking in the tableting process, it is preferable to add stearyl fumarate sodium to the mixture containing the active pharmaceutical ingredient such that the content of stearyl fumarate sodium in the tablets produced by this manufacturing method is 3% by mass or more.

[0053] The tablet compression pressure (pressure) in this manufacturing method can be appropriately adjusted depending on the particle size of the active pharmaceutical ingredient, the tablet formulation, type, or shape, but it is preferably in the range of 1 to 30 kN, and more preferably in the range of 4 to 24 kN.

[0054] In this manufacturing method, in addition to the tableting process, any other process performed in the manufacture of tablets may be carried out. An example of an optional process is a process of coating the tablets with a coating agent. The description of the coating agent is as provided in [Osimertinib-containing tablets].

[0055] For example, by spraying a coating solution containing a coating agent onto a tablet and drying it, a coating layer containing the coating agent can be formed on the surface of the tablet, thereby coating the tablet. The spraying and drying conditions can be set appropriately depending on the composition or viscosity of the coating solution.

[0056] [Method for improving the dissolution of active pharmaceutical ingredient in osimertinib-containing tablets] A method for improving the dissolution of active pharmaceutical ingredient in osimertinib-containing tablets according to one aspect of the present invention is to provide an osimertinib-containing tablet containing 40% by mass or more of osimertinib or a pharmaceutically acceptable salt thereof, wherein the particle size (D) of osimertinib or a pharmaceutically acceptable salt thereof is improved. ５０ By adjusting the size to 80 μm or larger, the dissolution of osimertinib or its pharmaceutically acceptable salt from osimertinib-containing tablets is improved.

[0057] To facilitate administration of the tablets by the target population, osimertinib-containing tablets with improved drug dissolution are preferably small in size, and more preferably compressed tablets.

[0058] The dissolution rate of the active pharmaceutical ingredient (API) can be evaluated by the API dissolution rate determined by the dissolution test method (paddle method, test solution: water) of the 18th edition of the Japanese Pharmacopoeia.

[0059] [Method for suppressing sticking in the manufacture of osimertinib-containing tablets] A method for suppressing sticking in the manufacture of osimertinib-containing tablets according to one aspect of the present invention involves suppressing sticking in the manufacture of osimertinib-containing tablets by adding 3% or more by mass of stearyl sodium fumarate to osimertinib-containing tablets containing 40% or more by mass of osimertinib or a pharmaceutically acceptable salt thereof.

[0060] To facilitate the administration of tablets by the target population, osimertinib-containing tablets that suppress sticking are preferably small, and more preferably direct-compression tablets.

[0061] The present invention is not limited to the embodiments described above, and various modifications are possible within the scope of the claims. Embodiments obtained by appropriately combining the technical means disclosed in different embodiments are also included in the technical scope of the present invention.

[0062] In the following examples, unless otherwise specified, % represents mass %.

[0063] [Methods for evaluating the active pharmaceutical ingredient and tablets] (Measurement of particle size of the active pharmaceutical ingredient) Particle size of the active pharmaceutical ingredient (D １０ , D ５０ , or D ９０ Each of these values ​​was measured using a wet measurement method with a Mastersizer 3000 (Malvern).

[0064] (Measurement of tablet thickness) The thickness of the tablets was measured using a thickness gauge. The tablet diameter can be measured using a thickness gauge or calipers, for example.

[0065] (Measurement of tablet hardness) Tablet hardness was measured using a hardness tester (manufactured by ERWEKA).

[0066] (Measurement of tablet disintegration time) The disintegration time of the tablets was measured according to the disintegration test method of the 18th edition of the Japanese Pharmacopoeia.

[0067] [Manufacturing Example 1] Production of miniaturized osimertinib-containing tablets Particle size (D ５０A 90 mg formulation containing 40 mg of osimertinib was obtained by mixing 71.52 g of osimertinib mesylate with a particle size of 122 μm, 24.71 g of D-mannitol ("PARTECK M200," manufactured by MERCK), 25.50 g of crystalline cellulose ("Ceolus UF-702," manufactured by Asahi Kasei Corporation), and 8.550 g of low-substituted hydroxypropyl cellulose ("LH-31," manufactured by Shin-Etsu Chemical Co., Ltd.), then adding and mixing 4.725 g of stearyl fumarate ("NISSO SSF," manufactured by Nippon Soda Co., Ltd.), and compressing the mixture using a rotary tablet press.

[0068] [Manufacturing Example 2] Production of miniaturized osimertinib-containing tablets Particle size (D ５０ A 90 mg formulation containing 40 mg of osimertinib was obtained by mixing 71.52 g of osimertinib mesylate with a particle size of 105 μm, 24.71 g of D-mannitol ("PARTECK M200," manufactured by MERCK), 25.50 g of crystalline cellulose ("Ceolus UF-702," manufactured by Asahi Kasei Corporation), and 8.550 g of low-substituted hydroxypropyl cellulose ("LH-31," manufactured by Shin-Etsu Chemical Co., Ltd.), then adding and mixing 4.725 g of stearyl fumarate ("NISSO SSF," manufactured by Nippon Soda Co., Ltd.), and compressing the mixture using a rotary tablet press.

[0069] [Manufacturing Example 3] Production of miniaturized osimertinib-containing tablets Particle size (D ５０ A 90 mg formulation containing 40 mg of osimertinib was obtained by mixing 71.52 g of osimertinib mesylate with a particle size of 83.9 μm, 24.71 g of D-mannitol ("PARTECK M200," manufactured by MERCK), 25.50 g of crystalline cellulose ("Ceolus UF-702," manufactured by Asahi Kasei Corporation), and 8.550 g of low-substituted hydroxypropyl cellulose ("LH-31," manufactured by Shin-Etsu Chemical Co., Ltd.), then adding and mixing 4.725 g of stearyl fumarate ("NISSO SSF," manufactured by Nippon Soda Co., Ltd.), and compressing the mixture using a rotary tablet press.

[0070] [Manufacturing Example 4] Production of miniaturized osimertinib-containing tablets Particle size (D ５０A 90 mg formulation containing 40 mg of osimertinib was obtained by mixing 166.9 g of osimertinib mesylate with a particle size of 122 μm, 62.37 g of D-mannitol ("PARTECK M200," manufactured by MERCK), 59.50 g of crystalline cellulose ("Ceolus UF-702," manufactured by Asahi Kasei Corporation), and 19.95 g of low-substituted hydroxypropyl cellulose ("LH-31," manufactured by Shin-Etsu Chemical Co., Ltd.), then adding and mixing 6.300 g of stearyl fumarate ("NISSO SSF," manufactured by Nippon Soda Co., Ltd.), and compressing the mixture using a rotary tablet press.

[0071] [Manufacturing Example 5] Production of miniaturized osimertinib-containing tablets Particle size (D ５０ 214.6 g of osimertinib mesylate with a particle size of 122 μm, 76.14 g of D-mannitol ("PARTECK M200," manufactured by MERCK), 76.50 g of crystalline cellulose ("Ceolus UF-702," manufactured by Asahi Kasei Corporation), and 25.65 g of low-substituted hydroxypropyl cellulose ("LH-31," manufactured by Shin-Etsu Chemical Co., Ltd.) were mixed together, and then 12.15 g of stearyl fumarate ("NISSO SSF," manufactured by Nippon Soda Co., Ltd.) was added and mixed. By compressing the mixture using a rotary tablet press, a 90 mg formulation containing 40 mg of osimertinib was obtained.

[0072] [Manufacturing Example 6] Production of miniaturized osimertinib-containing tablets Particle size (D ５０ 143.0 g of osimertinib mesylate with a particle size of 122 μm, 49.41 g of D-mannitol ("PARTECK M200," manufactured by MERCK), 51.00 g of crystalline cellulose ("Ceolus UF-702," manufactured by Asahi Kasei Corporation), and 17.10 g of low-substituted hydroxypropyl cellulose ("LH-31," manufactured by Shin-Etsu Chemical Co., Ltd.) were mixed together, and then 9.450 g of stearyl fumarate ("NISSO SSF," manufactured by Nippon Soda Co., Ltd.) was added and mixed. By compressing the mixture into tablets using a rotary tablet press, a 90 mg formulation containing 40 mg of osimertinib was obtained.

[0073] [Manufacturing Example 7] Production of miniaturized osimertinib-containing tablets Particle size (D ５０143.0 g of osimertinib mesylate with a particle size of 122 μm, 48.06 g of D-mannitol ("PARTECK M200," manufactured by MERCK), 51.00 g of crystalline cellulose ("Ceolus UF-702," manufactured by Asahi Kasei Corporation), and 17.10 g of low-substituted hydroxypropyl cellulose ("LH-31," manufactured by Shin-Etsu Chemical Co., Ltd.) were mixed together. Then, 10.80 g of stearyl fumarate ("NISSO SSF," manufactured by Nippon Soda Co., Ltd.) was added and mixed, and the mixture was compressed into tablets using a rotary tablet press to obtain a 90 mg formulation containing 40 mg of osimertinib.

[0074] [Manufacturing Example 8] Production of miniaturized osimertinib-containing tablets Particle size (D ５０ 143.0 g of osimertinib mesylate with a particle size of 122 μm, 46.71 g of D-mannitol ("PARTECK M200," manufactured by MERCK), 51.00 g of crystalline cellulose ("Ceolus UF-702," manufactured by Asahi Kasei Corporation), and 17.10 g of low-substituted hydroxypropyl cellulose ("LH-31," manufactured by Shin-Etsu Chemical Co., Ltd.) were mixed together, and then 12.15 g of stearyl fumarate ("NISSO SSF," manufactured by Nippon Soda Co., Ltd.) was added and mixed. By compressing the mixture using a rotary tablet press, a 90 mg formulation containing 40 mg of osimertinib was obtained.

[0075] [Comparative Example 1] Particle size (D) of osimertinib-containing tablets ５０ 33.38 g of osimertinib mesylate with a particle size of 122 μm, 91.40 g of D-mannitol ("Parteck M200," manufactured by Merck), 33.08 g of crystalline cellulose ("Ceolus UF-702," manufactured by Asahi Kasei Corporation), and 11.03 g of low-substituted hydroxypropyl cellulose ("LH-31," manufactured by Shin-Etsu Chemical Co., Ltd.) were mixed together, and then 6.125 g of stearyl fumarate ("NISSO SSF," manufactured by Nippon Soda Co., Ltd.) was added and mixed. By compressing the mixture using a rotary tablet press, a 250 mg formulation containing 40 mg of osimertinib was obtained.

[0076] [Evaluation Example 1] Examination of miniaturization of osimertinib-containing tablets Table 1 shows the detailed components of the osimertinib-containing tablets of Manufacturing Example 1 and Comparative Example 1, which were examined in Evaluation Example 1.

[0077]

[0078] (Measurement of the active pharmaceutical ingredient dissolution rate of tablets) The active pharmaceutical ingredient dissolution rate of tablets in Comparative Example 1 and Manufacturing Example 1 was measured according to the dissolution test method (paddle method, test solution: water) of the 18th edition of the Japanese Pharmacopoeia. Details of the measurement method are shown below.

[0079] One tablet of Comparative Example 1 or the manufacturing example was placed in 900 mL of water heated to 37 ± 0.5 °C, and the paddle was rotated at 50 rpm. 20 mL was collected after 5, 10, 15, and 30 minutes and filtered through a membrane filter with a pore size of 0.45 μm. After removing the initial filtrate of 15 mL or more, 5 mL was taken to prepare the stock sample solution. 3 mL of the stock sample solution was measured out, and 3 mL of diluted phosphoric acid (diluted 100 times with water) was added to prepare the sample solution.

[0080] Separately, approximately 66 mg of osimertinib mesylate was precisely weighed and diluted with water (diluted 100-fold) to a total volume of 25 mL. 2 mL of this solution was weighed out and diluted with water (diluted 100-fold) to a total volume of 50 mL to prepare the standard stock solution. 3 mL of the standard stock solution was taken and mixed with 3 mL of water to prepare the standard solution.

[0081] Osimertinib was quantified by analyzing 5 μL each of the sample solution and standard solution using liquid chromatography under the following conditions. <Analysis Conditions> Analyzer: High-performance liquid chromatograph, Shimadzu Corporation, Waters Detector: Ultraviolet spectrophotometer, Shimadzu Corporation, Waters Detection wavelength: 270 nm Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 5 cm was packed with 3 μm octadecylsilylated silica gel for liquid chromatography. (YMC-Triart C18, 4.6 × 50 mm, 3 μm) Flow rate: 0.8 mL / min Sample cooler temperature: Approximately 25°C Column temperature: Approximately 50°C Mobile phase: 1.36 g of potassium dihydrogen phosphate and 1.4 g of sodium perchlorate monohydrate were dissolved in 1000 g of water, and phosphoric acid was added to adjust the pH to 2.0. 700 mL of this solution was mixed with 300 mL of acetonitrile.

[0082] Table 2 shows the active pharmaceutical ingredient particle size, manufacturing conditions, and physical properties of each tablet. VEL-5 in Table 2 refers to a tablet press manufactured by Kikusui Seisakusho. Measurement results in parentheses in Table 2 indicate the "average value of the measurement results for three tablets (minimum measurement value to maximum measurement value)."

[0083]

[0084] Figure 1 shows the measurement results of the dissolution rate for each tablet.

[0085] As shown in Figure 1, the osimertinib-containing tablet of Manufacturing Example 1, which was small in size, had a dissolution rate equal to or better than that of Comparative Example 1.

[0086] [Evaluation Example 2] Examination of active pharmaceutical ingredient particle size in direct compression tablets Table 3 shows the details of the components of the osimertinib-containing tablets examined in Evaluation Example 2. The osimertinib-containing tablets in Manufacturing Examples 1 to 3 were each manufactured by mixing the components and quantities shown in Table 3 and then performing direct compression of the resulting mixture at the tableting pressure (compression pressure) shown in Table 4.

[0087]

[0088] Table 4 shows the active pharmaceutical ingredient particle size, manufacturing conditions, and physical properties of each tablet. Measurement results in parentheses in Table 4 indicate the "average value of the measurement results for three tablets (minimum measurement value to maximum measurement value)."

[0089]

[0090] As shown in Table 4, it was found that the tablets disintegrate more rapidly when the size of the active pharmaceutical ingredient particles increases.

[0091] The dissolution rates of the active pharmaceutical ingredients (APIs) in tablets from manufacturing examples 1 to 3 were measured using the same method as in evaluation example 1. The measurement results for the dissolution rates of the APIs in each tablet are shown in Figure 2.

[0092] From Figures 1 and 2, the active pharmaceutical ingredient particle size D ５０ Small osimertinib-containing tablets with a particle size of 80 μm or more exhibited a dissolution rate equivalent to or better than that of Comparative Example 1.

[0093] (Summary of Evaluation Examples 1-2) From Evaluation Examples 1 and 2, it was found that osimertinib-containing tablets can be miniaturized by preparing them using the direct compression method. Also, the active pharmaceutical ingredient particle size D５０ It was found that osimertinib-containing tablets with a particle size of 80 μm or larger exhibit high dissolution of the active pharmaceutical ingredient.

[0094] [Evaluation Example 3] Examination of Sticking Improvement In the preparation of direct-compression tablets in the evaluation example described above, sticking occurred when 1000 tablets were compressed, with the ingredient powder adhering to the punch. Therefore, the type and amount of lubricant were examined to improve sticking. Table 5 shows the details of the ingredients used in Manufacturing Examples 4 to 8 in Evaluation Example 3.

[0095]

[0096] Table 6 shows the tablet thickness, hardness, and disintegration time for each tablet. In Table 6, for the measurement results of tablet thickness, hardness, and disintegration time, the results without parentheses represent the measurement result for one tablet. For the measurement results with parentheses, the "average value of the measurement results for three tablets (minimum measurement value to maximum measurement value)" is shown.

[0097] Furthermore, the "Static Disintegration Time" in Table 6 indicates the time it took for the tablet to disintegrate while left undisturbed, using a disintegration test machine.

[0098]

[0099] As shown in Table 6, in the direct-compressed tablets of Production Examples 5 to 8, which contained 3% by mass or more of sodium stearyl fumarate as a lubricant, no powder from the tablet components adhered to the punch, and no sticking occurred.

[0100] (Measurement of the dissolution rate of the active pharmaceutical ingredient in tablets) The dissolution rate of the active pharmaceutical ingredient in tablets of manufacturing examples 4 to 8 was measured according to the dissolution test method (paddle method, test solution: water) of the 18th edition of the Japanese Pharmacopoeia. Details of the measurement method are shown below.

[0101] One tablet from each of the manufacturing examples 4-8 was placed in 900 mL of water heated to 37 ± 0.5°C. The paddle was rotated at 50 rpm, and 20 mL was collected after 5, 10, 15, and 30 minutes and filtered through a membrane filter with a pore size of 0.45 μm. Then, the paddle was rotated at 200 rpm, and 20 mL was collected after 10 minutes and filtered through a membrane filter with a pore size of 0.45 μm. After removing the initial filtrate of 15 mL or more, 5 mL was taken to prepare the stock sample solution. 3 mL of the stock sample solution was measured out, and 3 mL of diluted phosphoric acid (diluted 100 times with water) was added to prepare the sample solution.

[0102] Separately, approximately 66 mg of osimertinib mesylate was precisely weighed out, and diluted phosphoric acid (diluted 100-fold with water) was added to accurately prepare a total volume of 25 mL. 2 mL of this solution was weighed out, and diluted phosphoric acid (diluted 100-fold with water) was added to accurately prepare a total volume of 50 mL to prepare the standard stock solution. 3 mL of the standard stock solution was taken and mixed with 3 mL of water to prepare the standard solution.

[0103] Osimertinib was quantified by analyzing 5 μL each of the sample solution and standard solution using liquid chromatography under the following conditions.

[0104] <Analysis Conditions> Analytical instrument: High-performance liquid chromatograph, manufactured by Shimadzu Corporation and Waters Corporation Detector: Ultraviolet spectrophotometer, manufactured by Shimadzu Corporation and Waters Corporation Detection wavelength: 270 nm Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 5 cm was packed with 3 μm octadecylsilylated silica gel for liquid chromatography. (YMC-Triart C18, 4.6 × 50 mm, 3 μm) Flow rate: 0.8 mL / min Sample cooler temperature: Approximately 25°C Column temperature: Approximately 50°C Mobile phase: 1.36 g of potassium dihydrogen phosphate and 1.4 g of sodium perchlorate monohydrate were dissolved in 1000 g of water, and phosphoric acid was added to adjust the pH to 2.0. 300 mL of acetonitrile was added to 700 mL of this solution and mixed.

[0105] Measurement of the active pharmaceutical ingredient dissolution rate of the tablets revealed that the miniaturized tablets of Manufacturing Examples 4-8 had dissolution rates equal to or better than those of Comparative Example 1.

[0106] (Summary of Evaluation Example 3) Evaluation Example 3 also showed that osimertinib-containing tablets can be miniaturized by preparing them using the direct compression method. Furthermore, it was found that sticking does not occur when preparing direct compression tablets containing 3% or more by mass of stearyl sodium fumarate.

[0107] An osimertinib-containing tablet according to one aspect of the present invention can be suitably used in the treatment of malignant tumors and the like.

Claims

1. Osimertinib-containing tablets containing 40% by mass or more of osimertinib or a pharmaceutically acceptable salt thereof, and being in the form of direct-compression tablets.

2. The particle size (D) of osimertinib or a pharmaceutically acceptable salt thereof. ５０ The osimertinib-containing tablet according to claim 1, wherein the diameter of the tablet is 80 μm or larger.

3. An osimertinib-containing tablet according to claim 1 or 2, further comprising 3% by mass or more of sodium stearyl fumarate.

4. A method for producing osimertinib-containing tablets comprising osimertinib or a pharmaceutically acceptable salt thereof, comprising a tableting step of compressing a mixture containing osimertinib or a pharmaceutically acceptable salt thereof by direct compression, wherein the content ratio of osimertinib or a pharmaceutically acceptable salt in the osimertinib-containing tablets is 40% by mass or more.

5. The particle size (D) of osimertinib or a pharmaceutically acceptable salt thereof. ５０ A method for producing osimertinib-containing tablets according to claim 4, wherein the diameter of the tablet is 80 μm or larger.

6. A method for producing an osimertinib-containing tablet according to claim 4 or 5, wherein the osimertinib-containing tablet further contains 3% by mass or more of stearyl fumarate sodium.

7. In an osimertinib-containing tablet containing 40% by mass or more of osimertinib or a pharmaceutically acceptable salt thereof, the particle size (D) of the osimertinib or the pharmaceutically acceptable salt thereof is ５０ A method for improving the dissolution of osimertinib or a pharmaceutically acceptable salt thereof from osimertinib-containing tablets by adjusting the size of the osimertinib to 80 μm or more.

8. A method for suppressing sticking in the manufacture of osimertinib-containing tablets, which contain 40% by mass or more of osimertinib or a pharmaceutically acceptable salt thereof, by including 3% by mass or more of stearyl sodium fumarate.

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