Tablet, method for producing tablet, and method for suppressing formation of analog of palbociclib or pharmaceutically acceptable salt thereof

Abstract

To provide a tablet or the like comprising palbociclib or a pharmaceutically acceptable salt thereof together with an organic acid or a salt thereof, ensuring that the stability of palbociclib or the pharmaceutically acceptable salt thereof is maintained even when the content of palbociclib or the pharmaceutically acceptable salt thereof is high.SOLUTION: The tablet of the present disclosure comprises granules containing palbociclib or a pharmaceutically acceptable salt thereof together with an organic acid or a salt thereof. The content of palbociclib or the pharmaceutically acceptable salt thereof in the tablet is 35 mass% or more. The particle diameter (D50) of the organic acid or the salt thereof is 180 μm or more.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a tablet containing palbociclib or a pharmaceutically acceptable salt thereof. The present invention also relates to a method for producing the tablet and a method for inhibiting the production of analogs of palbociclib or a pharmaceutically acceptable salt thereof. [Background technology]

[0002] Palbociclib is a small molecule compound with the chemical name 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one. Palbociclib has inhibitory activity against cyclin-dependent kinases (CDKs) 4 and 6 and is used as an anti-cancer drug under the name Ibrance®.

[0003] Palbociclib is a basic compound with pH-dependent solubility and is known to have variable pharmacokinetic properties depending on the subject, and therefore, there is a need for improved formulations containing palbociclib. For example, Patent Document 1 discloses that a solid dosage form containing palbociclib and a water-soluble acid selected from the group consisting of succinic acid, malic acid, and tartaric acid enables substantially pH-independent delivery of palbociclib. It also discloses that a solid formulation containing palbociclib and a water-soluble acid selected from the group consisting of succinic acid, malic acid, and tartaric acid exhibits good storage stability. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Japanese Patent Application Publication No. 2017-2034 Summary of the Invention [Problem to be solved by the invention]

[0005] In a formulation containing palbociclib or a pharmaceutically acceptable salt thereof, a specific amount of organic acid, such as succinic acid, must be added to the formulation to achieve a targeted delivery profile. However, there is a problem that organic acids, such as succinic acid, react with palbociclib or its pharmaceutically acceptable salt to produce impurities. Therefore, if the content of palbociclib or its pharmaceutically acceptable salt is increased in a tablet containing a specific amount of organic acid, the contact area between palbociclib or its pharmaceutically acceptable salt and the organic acid increases, raising concerns that the stability of palbociclib or its pharmaceutically acceptable salt may be impaired. On the other hand, in a pharmaceutical product for administering a predetermined amount of active ingredient, decreasing the content of palbociclib or its pharmaceutically acceptable salt requires increasing the amount of excipients other than palbociclib or its pharmaceutically acceptable salt, which results in a tablet size that exceeds the range that is easy for patients to take. Therefore, with regard to tablets containing palbociclib or a pharmaceutically acceptable salt thereof and an organic acid, further improvements are required when the content of palbociclib or a pharmaceutically acceptable salt thereof in the tablet is increased.

[0006] Therefore, one aspect of the present invention aims to provide a tablet or the like containing palbociclib or a pharmaceutically acceptable salt thereof and an organic acid or a salt thereof, in which the stability of palbociclib or a pharmaceutically acceptable salt thereof is maintained even when the content of palbociclib or a pharmaceutically acceptable salt thereof is high. [Means for solving the problem]

[0007] The present inventors conducted extensive research to solve the above-mentioned problems. As a result, they found that tablets containing palbociclib or a pharmaceutically acceptable salt thereof and an organic acid or a salt thereof having a particle size distribution within a specific range reduce the production of impurities such as analogs of palbociclib or a pharmaceutically acceptable salt thereof, even when the content of palbociclib or a pharmaceutically acceptable salt thereof is high. They also found that the stability of palbociclib or a pharmaceutically acceptable salt thereof in the tablets is improved, leading to the completion of the present invention.

[0008] That is, one aspect of the present invention includes the following configuration. <1> A tablet comprising a granule containing palbociclib or a pharmaceutically acceptable salt thereof and an organic acid or a salt thereof, wherein the content of palbociclib or a pharmaceutically acceptable salt thereof in the tablet is 35% by mass or more, and the particle size (D 50 ) is 180 μm or more, tablet. <2> The organic acid or its salt is succinic acid. <1> The tablet described in <3> The particle diameter of the granulated material (D 50 ) is 90 μm or more, <1> or <2> The tablet described in <4> The content of the organic acid or its salt in the tablet is 10% by mass or more. <1> ~ <3> A tablet according to any one of the following: <5> A method for producing a tablet containing a granule containing palbociclib or a pharmaceutically acceptable salt thereof and an organic acid or a salt thereof, the method comprising: 50 a granulation step of obtaining a granule containing palbociclib or a pharmaceutically acceptable salt thereof; and a tableting step of mixing the granule with the organic acid or a salt thereof and tableting the mixture. <6> A method for suppressing the production of analogues of palbociclib or a pharmaceutically acceptable salt thereof in a tablet containing palbociclib or a pharmaceutically acceptable salt thereof and an organic acid or a salt thereof, the method comprising: 50 ) of 180 μm or more with a granulated product of palbociclib or a pharmaceutically acceptable salt thereof, thereby inhibiting the production of the related substances. [Effects of the Invention]

[0009] According to one aspect of the present invention, it is possible to provide a tablet or the like containing palbociclib or a pharmaceutically acceptable salt thereof and an organic acid or a salt thereof, in which the stability of palbociclib or a pharmaceutically acceptable salt thereof is maintained even when the content of palbociclib or a pharmaceutically acceptable salt thereof is high. DETAILED DESCRIPTION OF THE INVENTION

[0010] An embodiment of the present invention will be described in detail below. Unless otherwise specified in this specification, "A to B" representing a numerical range means "A or more and B or less."

[0011] [1. Tablets] A tablet according to one embodiment of the present invention (hereinafter sometimes referred to as "the tablet") comprises a granulation containing palbociclib or a pharmaceutically acceptable salt thereof, and an organic acid or a salt thereof. Hereinafter, "palbociclib or a pharmaceutically acceptable salt thereof" may be referred to as the "active ingredient," and "a granulation containing palbociclib or a pharmaceutically acceptable salt thereof" may be referred to as the "active ingredient granulation."

[0012] (Main drug granules) Palbociclib is a compound with the chemical name 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one. Palbociclib or a pharmaceutically acceptable salt thereof is the active ingredient in the tablet.

[0013] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is medically suitable for use in contact with the tissues of humans or other mammals without causing excessive toxicity, irritation, allergic reactions, etc.

[0014] Pharmaceutically acceptable salts of palbociclib are well known in the art, and any can be used. Examples of pharmaceutically acceptable salts of palbociclib include inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, and phosphate; organic acid salts such as acetate, oxalate, maleate, fumarate, citrate, benzoate, and methanesulfonate; and addition salts of lysine, glycine, phenylalanine, aspartic acid, glutamic acid, and the like.

[0015] The particle size of the active ingredient in this tablet (D 50 ) is 1 to 18 μm, particle diameter (D 90 In this specification, the particle diameter (D 50 ) or particle size (D 90 ) are the cumulative 50% particle size or cumulative 90% particle size in volume-based measurement, respectively.

[0016] The specific surface area of ​​the active ingredient in this tablet is 2.5m 2 / g or more is preferable, and 3m 2 / g or more is more preferable, and 3 to 10m 2 / g, and more preferably 4 to 8m 2 When the specific surface area of ​​the active ingredient is in the above range, the dissolution property of the preparation is improved.

[0017] It is known that the stability of the active ingredient in the tablet deteriorates as the specific surface area of ​​the active ingredient increases. However, in this tablet, the particle diameter (D 50 Since the organic acid or its salt has a specific surface area of ​​180 μm or more, the stability of the main ingredient can be maintained even if the main ingredient has a specific surface area within the above range. The organic acid or its salt will be described later.

[0018] The content of the active ingredient in the tablet is 35% by mass or more, based on the mass of the tablet. The content of the active ingredient in the tablet is preferably in the range of 40 to 95% by mass, more preferably 40 to 70% by mass.

[0019] The content of the active ingredient in the tablet is adjusted appropriately depending on the therapeutic purpose, but is, for example, 10 to 200 mg (e.g., 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg or 200 mg), preferably 20 to 150 mg, and more preferably 25 to 125 mg.

[0020] The active ingredient granules may contain, in addition to the active ingredient, additives such as excipients, binders, lubricants, disintegrants, surfactants, plasticizers, and colorants.

[0021] The excipient is not particularly limited, but examples thereof include D-mannitol, lactose (e.g., lactose hydrate), sucrose, cornstarch, calcium phosphate, sorbitol, crystalline cellulose, and light anhydrous silicic acid.

[0022] Examples of crystalline cellulose include Ceolus KG-1000, Ceolus UF-702, and Ceolus PH-101 (all manufactured by Asahi Kasei Corporation).

[0023] Examples of light anhydrous silicic acid include AEROSIL (registered trademark) 200 (manufactured by Nippon Aerosil Co., Ltd.) and Adsolider (registered trademark) 101 (manufactured by Freund Corporation).

[0024] Examples of binders include, but are not limited to, hydroxypropyl cellulose, hydroxypropylmethyl cellulose (also known as "hypromellose"), povidone, methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, polyvinylpyrrolidone, a copolymer of N-vinylpyrrolidone and vinyl acetate, or a combination of these polymers, pregelatinized starch, gelatin, agar, gum arabic, and the like.

[0025] The lubricant is not particularly limited, but examples thereof include inactive substances such as talc, kaolin, and titanium dioxide, magnesium stearate, calcium stearate, stearic acid, light anhydrous silicic acid, finely ground silicon dioxide, sodium stearyl fumarate, and glycerin fatty acid esters.

[0026] The magnesium stearate may be either regular or light.

[0027] The disintegrant is not particularly limited, but examples thereof include crospovidone, low-substituted hydroxypropyl cellulose, sodium starch glycolate, croscarmellose sodium, carmellose, carmellose calcium, potato starch, and the like.

[0028] Examples of crospovidone include Kollidon CL-F (manufactured by BASF Japan Ltd.), Polyplasdone INF-10 (manufactured by ISP), and Polyplasdone XL-10 (manufactured by ISP).

[0029] The surfactant is not particularly limited, but examples thereof include macrogols such as polyethylene glycol having 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 oils such as polyoxyethylene hydrogenated castor oil; 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; and sodium lauryl sulfate.

[0030] The plasticizer is not particularly limited, but examples thereof include hydrophilic plasticizers such as ethylene glycol, propylene glycol, and glycerin; and fat-soluble plasticizers such as triacetin, triethyl citrate, diethyl phthalate, dioctyl adipate, lauric acid, stearyl alcohol, and cetanol.

[0031] The coloring agent is not particularly limited, but examples thereof include yellow coloring agents (e.g., yellow ferric oxide, yellow iron oxide, Food Yellow No. 4 Aluminum Lake, red iron oxide, etc.), red coloring agents (e.g., ferric oxide, Food Red No. 2, Food Red No. 3, Food Red No. 102, etc.), black coloring agents (e.g., black iron oxide, carbon black, medicinal charcoal, etc.), blue coloring agents (e.g., Blue No. 2 Aluminum Lake, etc.), caramel, etc.

[0032] The content of the additive in the active ingredient granules is not particularly limited and can be appropriately set based on conventionally known techniques.

[0033] The particle size of the active ingredient granules (D 50 ) is preferably 90 μm or more, more preferably 150 μm or more, and even more preferably 250 μm or more.

[0034] Examples of the impurities include analogs of palbociclib. The analogs of palbociclib may be all analogs of palbociclib or specific analogs of palbociclib. Examples of specific analogs of palbociclib include amide, N-formyl, and N-acetyl analogs of palbociclib.

[0035] The particle size of the active ingredient granules (D 10 ) is preferably 40 μm or more, more preferably 60 μm or more, and even more preferably 80 μm or more. 10 ) is the cumulative 10% particle size measured by volume.

[0036] The particle size of the active ingredient granules (D 90) is preferably 300 μm or more, more preferably 400 μm or more, and even more preferably 500 μm or more.

[0037] Particle diameter (D 10 , D 50 , or D 90 ) can be measured by a known measuring device capable of measuring the volume-based cumulative particle diameter.

[0038] In order to further reduce the generation of impurities in the active ingredient in the tablet, the proportion of the active ingredient granules that pass through a sieve with a mesh size of 75 μm is preferably 40% or less, more preferably 30% or less, and even more preferably 20% or less. In this specification, the sieve is a sieve conforming to JIS Z8801-1.

[0039] The active ingredient granules may be dry granulated. When the active ingredient granules are dry granulated, the generation of active ingredient impurities in the tablet is further reduced. Alternatively, the active ingredient granules may be wet granulated. When the active ingredient granules are wet granulated, the dissolution of the active ingredient is further improved. The dry granulated and wet granulated products can be prepared by methods known in the art.

[0040] (organic acid or its salt) Examples of organic acids contained in the present tablet include ascorbic acid, citric acid, tartaric acid, fumaric acid, succinic acid, malic acid, maleic acid, etc. The organic acid is preferably succinic acid, as this makes it easier for the active ingredient in the tablet to dissolve. The organic acid or its salt contained in the present tablet may be one type or two or more types.

[0041] The salt of an organic acid is not particularly limited as long as it is a pharmaceutically acceptable salt. Examples of the salt include alkali metal salts such as sodium salts or potassium salts; alkaline earth metal salts such as calcium salts or magnesium salts; and the like.

[0042] The particle size (D 50 ) is 180 μm or more.50 ) organic acid or its salt has a particle diameter (D 50 ) or a salt thereof may be an organic acid or a salt thereof that passes through the sieve openings of a sieve having a mesh size of more than 180 μm (e.g., 355 μm) but does not pass through the sieve openings of a sieve having a mesh size of 180 μm.

[0043] This tablet has a particle size (D 50 By including an organic acid or its salt having a particle size of 180 μm or more, the contact area between the active ingredient and the organic acid or its salt is reduced, reducing the generation of impurities. This improves the stability (e.g., storage stability) of the tablet.

[0044] The particle size (D 50 ) is preferably 200 μm or more, more preferably 250 μm or more, and even more preferably 350 μm or more.

[0045] The content of the organic acid or its salt in the tablet is preferably 10 to 40% by mass, more preferably 15 to 30% by mass, and even more preferably 20 to 25% by mass, based on the mass of the tablet. When the content of the organic acid or its salt is within the above range, the active ingredient in the tablet is more easily dissolved.

[0046] The content of the organic acid or its salt in the tablet is adjusted appropriately according to the content of the active ingredient and the desired delivery profile, but is, for example, 1 to 90 mg, preferably 5 to 80 mg, and more preferably 10 to 70 mg.

[0047] When the tablet contains 25 mg of the active ingredient, the organic acid or its salt may be 1 to 25 mg, 5 to 20 mg, or 10 to 15 mg. When the tablet contains 125 mg of the active ingredient, the organic acid or its salt may be 50 to 75 mg, 55 to 70 mg, or 60 to 65 mg.

[0048] The tablet may contain additives other than the active ingredient granules and the organic acid or its salt. Examples of additives are the same as those that may be contained in the active ingredient granules.

[0049] (Type of tablet) The present tablet may be a layered tablet such as a single-layer tablet or a multi-layer tablet, or a press-coated tablet. From the viewpoints of ease of production, dissolution of the active ingredient, bioequivalence, etc., the present tablet is preferably a single-layer tablet.

[0050] (Tablet shape) The shape of the tablet is not particularly limited and any shape can be adopted, such as a circle, an oval, a sphere, a rod, a doughnut, etc.

[0051] The hardness of the present tablet is preferably 30 to 300 N. In the case of a round tablet, its thickness (tablet thickness) is, for example, 1 to 10 mm, preferably 4 to 8 mm, and its diameter is not particularly limited, but from the viewpoint of handleability, it is, for example, 4 to 20 mm, preferably 5 to 16 mm. In the case of an oval tablet, its thickness (tablet thickness) is, for example, 1 to 10 mm, preferably 2 to 8 mm, and its major axis is not particularly limited, but from the viewpoint of handleability, it is, for example, 5 to 20 mm, preferably 6 to 16 mm, and its minor axis is not particularly limited, but from the viewpoint of handleability, it is, for example, 3 to 12 mm, preferably 4 to 10 mm.

[0052] The water content of the tablet is not particularly limited, but is preferably 5% by mass or less, and more preferably 3% by mass or less. The water content can be measured, for example, by the Karl Fischer method.

[0053] The mass of the tablet is adjusted appropriately 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 are easy to take. Even with a mass within the above range, the contact area between the active ingredient and the organic acid or its salt does not increase, and the stability of the active ingredient is maintained.

[0054] When the tablet contains 25 mg of the active ingredient, the tablet mass may be 30 to 100 mg, 40 to 85 mg, or 50 to 70 mg. When the tablet contains 125 mg of the active ingredient, the tablet mass may be 130 to 600 mg, 150 to 500 mg, or 200 to 400 mg.

[0055] (tablet coating) The tablet may be further coated as needed. The coating agent used for coating the tablet is not particularly limited, but examples include hydroxypropyl cellulose, hydroxypropyl methylcellulose (also known as "hypromellose"), polyvinyl alcohol, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer. Light-blocking agents and plasticizers may also be added to the coating as appropriate. Examples of light-blocking agents include yellow ferric oxide, ferric oxide, titanium oxide, and aluminum lake blue No. 2. Examples of plasticizers include triacetin, macrogol, hydroxypropyl cellulose, propylene glycol, and triethyl citrate.

[0056] It is more preferable that the coating agent used to coat the tablets does not contain triacetin, as this further reduces the production of impurities of the active ingredient in the tablets (particularly the N-acetylated active ingredient).

[0057] The amount of coating agent used to coat the present tablet may be increased or decreased as appropriate, but for example, the amount is in the range of 1 to 10% by mass relative to the tablet mass.

[0058] To improve identifiability, the surface of the tablet of the present invention may be engraved or printed with a product number, the name of the active ingredient, the content of the active ingredient, the dosage form, the product number, a QR code, a bar code, etc. Engraving or printing may be performed directly on the surface of the plain tablet or film-coated tablet. An appropriate printing method can be selected from ink printing methods using plate-type transfer printing, gravure printing, offset printing, and inkjet printing, laser printing, etc. The ink used for printing can be selected from edible inks containing dyes and / or pigments, and the ink color may be one color or two or more colors from the viewpoint of identifiability, etc.

[0059] Furthermore, the present tablets may be packaged in PTP packaging, bottles, aluminum packaging, etc., as needed.

[0060] Examples of materials for PTP packaging include resins such as polyvinyl chloride, polypropylene, polyvinylidene chloride, polychlorotrifluoroethylene, polyethylene, polystyrene, and polycarbonate, and metals such as aluminum. These materials may be used alone or in combination. Examples of combinations include laminating polyvinyl chloride and polyvinylidene chloride, or laminating polyvinyl chloride and polychlorotrifluoroethylene. The above resins are molded using a known method into a resin sheet, and the tablet is placed in a molded pocket, which is then covered with aluminum foil to complete the packaging.

[0061] The PTP package containing the tablet may be further packaged in an aluminum pillow. This aluminum pillow may further contain a desiccant and an oxygen scavenger. Examples of desiccant include calcium chloride, calcium oxide, magnesium oxide, silica gel, and zeolite. Examples of oxygen scavenger include iron-based oxygen scavengers such as iron powder, and organic oxygen scavengers such as ascorbic acid, isoascorbic acid, hydroquinone, and catechol. These desiccant and oxygen scavengers may be used alone or in combination, or a combination of a desiccant and an oxygen scavenger may be used. An example of a product combining a desiccant and an oxygen scavenger is "PharmaKeep (registered trademark)" from Mitsubishi Gas Chemical Company, Inc.

[0062] 2. Tablet manufacturing method A tablet manufacturing method according to one embodiment of the present invention (hereinafter sometimes referred to as "this manufacturing method") includes a preparation step, a granulation step, and a tableting step. In this manufacturing method, the explanations of each component (e.g., "active ingredient (palbociclib or a pharmaceutically acceptable salt thereof)," "active ingredient granules," and "organic acid or its salt") are as described in [1. Tablets].

[0063] (Preparation process) The above preparation step is carried out to obtain a particle diameter (D 50 For example, a sieve with a mesh size of 180 μm and a sieve with a mesh size of more than 180 μm (e.g., 355 μm) are used to classify an organic acid or a salt thereof that passes through the mesh of the sieve with a mesh size of more than 180 μm but does not pass through the mesh of the sieve with a mesh size of 180 μm, thereby adjusting the particle size (D 50 ) can be prepared to have a particle size of 180 μm or more.

[0064] (granulation process) The granulation step is a step of obtaining a granulated active ingredient containing palbociclib or a pharmaceutically acceptable salt thereof. Granulation can be performed by a conventional method, and may be dry granulation or wet granulation.

[0065] The moisture content of the active ingredient granules is not particularly limited, but is preferably 3% by mass or less, and more preferably 1% by mass or less. The moisture content can be measured, for example, by the Karl Fischer method.

[0066] In order to further reduce the generation of impurities of the active ingredient in the present tablet, it is preferable to control the particle size distribution of the active ingredient granules in the granulation process. 50 It is more preferable to adjust the particle size to 90 μm or more. The particle size distribution of the active ingredient granules can be controlled by adjusting the type and amount of additives used for granulation.

[0067] (tableting process) The tableting step involves mixing a granulated active ingredient with an organic acid or its salt and tableting the mixture. The granulated active ingredient may be mixed with a mixture of an organic acid or its salt and an additive. The mixture may be subjected to granulation such as dry granulation or sizing.

[0068] The tableting pressure in this production method can be appropriately adjusted depending on the formulation, type, shape, etc. of the tablet, but is preferably in the range of 1 to 20 kN, for example.

[0069] In this manufacturing method, in addition to the preparation step, granulation step, and tableting step, any step carried out in tablet manufacturing may be performed. An example of such an optional step is a step of coating the tablets with a coating agent. The description of the coating agent is as described in [1. Tablets].

[0070] For example, a coating liquid containing a coating agent can be sprayed onto a tablet and dried to form a coating layer containing the coating agent on the surface of the tablet, thereby coating the tablet. The spraying and drying conditions can be appropriately set depending on the composition or viscosity of the coating liquid, etc.

[0071] 3. Method for suppressing the analogues of the active ingredient in tablets Another aspect of the present invention is a method for suppressing the production of analogues of palbociclib or its pharmaceutically acceptable salt in a tablet containing palbociclib or its pharmaceutically acceptable salt and an organic acid or its salt (hereinafter, this may be referred to as the "inhibition method"). The inhibition method involves reducing the particle diameter (D 50 The production of analogs of palbociclib or its pharmaceutically acceptable salt is suppressed by mixing an organic acid or its salt having a particle size of 180 μm or more with a granule of palbociclib or its pharmaceutically acceptable salt. In this suppression method, the explanation of each component (e.g., "principal drug (palbociclib or its pharmaceutically acceptable salt)," "principal drug granules," and "organic acid or its salt") is as described in [1. Tablets].

[0072] As mentioned above, this suppression method is based on the particle diameter (D 50 By including an organic acid or its salt having a particle size of 180 μm or more, the contact area between the active ingredient and the organic acid or its salt is reduced, thereby reducing the production of impurities related to the active ingredient. This improves the stability (e.g., storage stability) of the tablet. Therefore, this inhibition method is extremely useful in designing tablets containing palbociclib or a pharmaceutically acceptable salt thereof with improved stability.

[0073] The amount of impurities in the tablet can be measured, for example, by HPLC (high performance liquid chromatography).

[0074] The present invention is not limited to the above-described embodiments, 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. [Example]

[0075] In the following examples, % means % by mass unless otherwise specified.

[0076] Particle size of the active ingredient granules (D 10 , D 50 , or D90 ) were measured using a micro-type electromagnetic vibrating sieve (Tsutsui Scientific Instruments Co., Ltd.).

[0077] [Formulation Example 1] Preparation of tablets Tablets were prepared according to Procedures 1 and 2 below.

[0078] (Step 1) Preparation of palbociclib granules Palbociclib (drug substance), crystalline cellulose (Ceolas UF-702, manufactured by Asahi Kasei Corporation), light anhydrous silicic acid (AEROSIL® 200, manufactured by Nippon Aerosil Co., Ltd.), and crospovidone (Kollidon CL-F, manufactured by BASF Japan Ltd.) were charged into a stirring granulator and mixed in the amounts shown in Table 1. Next, hydroxypropyl cellulose (HPC-L) was dissolved in purified water to obtain a granulation liquid. The mixed powder was sprayed with the granulation liquid to granulate, and the resulting granules were charged into a fluidized bed granulation dryer and dried. The resulting dried powder was then sized to obtain a palbociclib granulated powder.

[0079] The particle size (D 10 , D 50 , D 90 ) and the percentage of particles that passed through the sieve with a sieve opening of 75 μm (percentage of 75 μm pass products) are shown in Table 1.

[0080] (Step 2) Tableting The palbociclib granulated powder obtained in step 1, the succinic acid fraction, microcrystalline cellulose (Ceolas UF-702), crospovidone (Kollidon CL-F), and magnesium stearate (general grade) were mixed in the amounts shown in Table 1.

[0081] The succinic acid fraction was a fraction of 106 μm to 355 μm. This succinic acid fraction passed through the sieve with a mesh size of 355 μm, but did not pass through the sieve with a mesh size of 106 μm.

[0082] The mixture obtained by the above mixing was compressed (compression pressure: 7 kN) to obtain single-layer tablets.

[0083] [Formulation Example 2] Preparation of tablets Tablets were prepared in the same manner as in Formulation Example 1, except that in Step 2, the 180 μm to 355 μm fraction was used as the succinic acid fraction. The 180 μm to 355 μm fraction is succinic acid that passed through the sieve with a 355 μm mesh opening but did not pass through the sieve with a 180 μm mesh opening.

[0084] Palbociclib granulated powder particle size (D 10 , D 50 , D 90 ) and the percentage of particles that passed through the sieve with a sieve opening of 75 μm (percentage of 75 μm pass products) are shown in Table 1.

[0085] [Formulation Example 3] Preparation of tablets Tablets were prepared according to Procedures 1 and 2 below.

[0086] (Step 1) Preparation of palbociclib granules Palbociclib (the same drug substance as in Formulation Example 1), microcrystalline cellulose (Ceolas UF-702, manufactured by Asahi Kasei Corporation), and crospovidone (Kollidon CL-F, manufactured by BASF Japan Ltd.) were charged into a stirring granulator and mixed in the amounts shown in Table 1. Next, hydroxypropyl cellulose (HPC-L) was dissolved in purified water to obtain a granulation liquid. The mixed powder was sprayed with the granulation liquid to granulate, and the resulting granules were charged into a fluidized bed granulation dryer and dried. The resulting dried powder was then sized to obtain a palbociclib granulated powder.

[0087] The particle size (D 10 , D 50 , D 90 ) and the percentage of particles that passed through the sieve with a sieve opening of 75 μm (percentage of 75 μm pass products) are shown in Table 1.

[0088] (Step 2) Tableting The palbociclib granules obtained in step 1, the succinic acid fraction (fraction of 180 μm to 355 μm), microcrystalline cellulose (Ceolas UF-702), crospovidone (Kollidon CL-F), and magnesium stearate (general grade) were mixed in the amounts shown in Table 1. The mixture obtained by this mixing was compressed (compression pressure: 7 kN) to obtain single-layer tablets. The obtained tablets were circular tablets with a hardness of 110 N, a diameter of 9.5 mm, and a thickness of 4.0 mm, and a disintegration time of 2580 seconds (Disintegration Test Method according to the 18th Edition of the Japanese Pharmacopoeia). [Table 1]

[0089] The palbociclib granulated powders prepared in Formulation Examples 1 to 3 are granulated powders obtained by wet granulation.

[0090] [Prescription Example 4] Tablets were prepared according to Procedures 1 and 2 below.

[0091] (Step 1) Preparation of palbociclib granules Palbociclib (the same drug substance as in Formulation Examples 1 to 3), microcrystalline cellulose (Ceolus UF-702, manufactured by Asahi Kasei Corporation), crospovidone (Kollidon CL-F, manufactured by BASF Japan Ltd.), and light anhydrous silicic acid (AEROSIL® 200, manufactured by Nippon Aerosil Co., Ltd.) were roughly mixed in the amounts shown in Table 2, sieved, and then mixed to obtain a double-pulverized powder. Next, the double-pulverized powder and magnesium stearate (general grade) were mixed in the amounts shown in Table 2 to obtain a lubricated mixed powder. The obtained lubricated mixed powder was dry granulated and then sized to obtain a palbociclib granulated powder.

[0092] The particle size (D 10 , D 50 , D 90 ) and the percentage of particles that passed through the sieve with a sieve opening of 75 μm (percentage of 75 μm pass products) are shown in Table 2.

[0093] (Step 2) Tableting The palbociclib granules obtained in step 1, succinic acid fraction (180 μm to 355 μm fraction), microcrystalline cellulose (Ceolas UF-702), crospovidone (Kollidon CL-F), and magnesium stearate (general grade) were mixed in the amounts shown in Table 2. The mixture obtained by this mixing was compressed (compression pressure: 7 kN) to obtain single-layer tablets. The obtained tablets were circular tablets with a hardness of 60 N, a diameter of 9.5 mm, and a thickness of 4.0 mm, and had a moisture content of 2.1% by mass and a disintegration time of 1,800 seconds (Disintegration Test Method according to the 18th Edition of the Japanese Pharmacopoeia).

[0094] [Table 2]

[0095] [Evaluation Example 1] Evaluation of the specific surface area of ​​palbociclib The specific surface area of ​​palbociclib (active drug substance) used in Formulation Examples 1 to 4 was measured according to the specific surface area measurement method in accordance with JIS Z8830:2013. The measurement conditions for the specific surface area are shown in Table 3.

[0096] [Table 3]

[0097] As a result of the measurement, the specific surface area of ​​palbociclib (active ingredient) used in Formulation Examples 1 to 4 was 2.6 m 2 / g.

[0098] [Evaluation Example 2] Evaluation of storage stability of palbociclib The storage stability of palbociclib was evaluated for the tablets of Formulation Examples 1 to 4 when stored under the following conditions 1 or 2, respectively. Condition 1: Stored at 70°C for 9 days in double-sided aluminum (hereinafter referred to as "AL") packaging. Condition 2: Stored at 40°C and 75% RH for one month in double-sided AL packaging

[0099] The amounts of each of the related substances of palbociclib (succinic acid amide, N-formyl, and N-acetyl) in each of the tablets stored under the above conditions 1 and 2 were measured by HPLC.

[0100] (Preparation of sample solution for HPLC) Each test composition was placed in a brown measuring flask, and a 100 mL volumetric flask was used.

[0101] 50 mL of phosphoric acid diluted 100 times with water was added to the brown measuring flask containing the test composition.

[0102] After sonication, the solution was diluted to volume with acetonitrile. The diluted solution was centrifuged at 3000 rpm at 10°C for 5 minutes, and the supernatant was collected. 5 mL of the collected supernatant was placed in a 20 mL brown volumetric flask. The diluent was then diluted to volume to prepare a sample solution with a palbociclib concentration of approximately 0.3 mg / mL. The diluent used was a 1:1 mixture of phosphoric acid diluted 100-fold with water and acetonitrile.

[0103] (Measurement of each related substance by HPLC) Each related substance was measured by HPLC under the conditions shown below. HPLC: Shimadzu Corporation LC-20A Detector: UV spectrophotometer ·Measurement wavelength: 364nm Column: YMC-Triart PEP, 4.6 mm x 150 mm, 3 μm Column temperature: constant temperature around 40°C Mobile phase A: 2.72 g of calcium dihydrogen phosphate dissolved in 1000 mL of water, and adjusted to pH 2.5 by adding phosphoric acid. Mobile phase B: Acetonitrile ·Flow rate: approx. 1.0mL / min Injection volume (sample solution): 10 μL Sample cooler temperature: 10℃ The gradients of mobile phases A and B used in the above HPLC measurements are shown in Table 6. The values ​​for mobile phases A and B in Table 6 indicate the proportions (%) of mobile phases A and B contained in the mobile phase (eluent).

[0104] [Table 4]

[0105] For Formulation Examples 1 to 4, the measurement results for the succinamide form of palbociclib are shown in Table 5, and the measurement results for the N-formyl form of palbociclib are shown in Table 6. In the tables, "initial" indicates the test results for tablets before the start of stability evaluation. "ND" indicates that measurement was not performed.

[0106] [Table 5]

[0107] [Table 6]

[0108] As shown in Tables 5 and 6, the increase in the succinamide and N-formyl forms of palbociclib was suppressed in all of the tablets of Formulation Examples 2 to 4 compared to the tablets of Formulation Example 1. These results demonstrate that the use of succinic acid in the 180 to 355 μm fraction suppresses the production of palbociclib analogs.

[0109] Furthermore, the increase in the succinamide and N-formyl forms of palbociclib in the tablets of Formulation Example 3 was suppressed compared to the tablets of Formulation Example 2. From these results, it can be seen that the particle diameter (D 50 It was found that when a palbociclib granulated powder with a larger particle size is used, the contact area between succinic acid and palbociclib becomes even smaller, thereby further suppressing the production of palbociclib-related substances.

[0110] [Prescription Example 5] Tablets were prepared according to the following steps 1 to 3.

[0111] (Step 1) Preparation of palbociclib granules Palbociclib (the same drug substance as in Formulation Examples 1 to 4), crystalline cellulose (Ceolas UF-702, manufactured by Asahi Kasei Corporation), crospovidone (Kollidon CL-F, manufactured by BASF Japan Ltd.), and light anhydrous silicic acid (AEROSIL® 200, manufactured by Nippon Aerosil Co., Ltd.) were coarsely mixed in the amounts shown in Table 7, sieved, and then mixed to obtain a double-pulverized powder. Next, the double-pulverized powder and magnesium stearate (general grade) were mixed in the amounts shown in Table 7 to obtain a lubricated mixed powder. The obtained lubricated mixed powder was dry granulated and then sized to obtain a palbociclib granulated powder.

[0112] (Step 2) Tableting The palbociclib granulated powder obtained in step 1, succinic acid fraction (180 μm to 355 μm fraction), microcrystalline cellulose (Ceolas UF-702), crospovidone (Kollidon CL-F), and magnesium stearate (general grade) were mixed in the amounts shown in Table 7. The mixture obtained by this mixing was compressed (compression pressure: 7 kN) to obtain uncoated single-layer tablets.

[0113] (Step 3) Coating the plain tablets OPADRY® PURPLE (Colorcon) was used as the coating agent. An aqueous solution containing the amount of coating agent shown in Table 7 was spray-coated onto the plain tablets, followed by drying to obtain tablets with a coating layer. The resulting tablets were circular tablets with a hardness of 80 N, a diameter of 9.5 mm, and a thickness of 4.1 mm, a moisture content of 1.4% by mass, and a disintegration time of 90 seconds (Disintegration Test Method in the 18th Edition of the Japanese Pharmacopoeia).

[0114] [Prescription Example 6] Tablets having a coating layer were prepared in the same manner as in Formulation Example 5, except that POVACOAT (Daido Chemical Industry Co., Ltd.) was used as the coating agent, and a coating liquid obtained by mixing POVACOAT, titanium oxide, talc, and a pigment in the amounts shown in Table 7 with purified water was spray-coated onto the tablets.

[0115] [Table 7]

[0116] OPADRY® PURPLE is a premix containing triacetin. The numbers in parentheses in Table 7 represent the mass (mg) of triacetin contained in OPADRY® PURPLE.

[0117] [Evaluation Example 3] Evaluation of storage stability of palbociclib The storage stability of palbociclib was evaluated for the tablets of Formulation Examples 5 and 6 using an evaluation test similar to that under Condition 1 of Evaluation Example 2. The measurement results for the succinamide form of palbociclib are shown in Table 8, the measurement results for the N-formyl form of palbociclib are shown in Table 9, and the measurement results for the N-acetyl form of palbociclib are shown in Table 10. In the tables, "initial" indicates the test results for the tablets before the start of stability evaluation.

[0118] [Table 8]

[0119] [Table 9]

[0120] [Table 10]

[0121] As shown in Table 10, the tablets of Formulation Example 5, which contained triacetin in the coating layer, showed a higher increase in the amount of N-acetylated palbociclib compared to the tablets of Formulation Example 6. These results demonstrated that when forming a coating layer on the surface of tablets, it is preferable to use a coating agent that does not contain triacetin. [Industrial Applicability]

[0122] The present invention can improve the stability of tablets containing palbociclib or a pharmaceutically acceptable salt thereof, and can be suitably used in the treatment of malignant tumors, etc.

Claims

1. A tablet comprising a granule containing palbociclib or a pharmaceutically acceptable salt thereof, and an organic acid or a salt thereof, the content of palbociclib or a pharmaceutically acceptable salt thereof in the tablet is 35% by mass or more; The particle diameter (D ５０ ) is 180 μm or more.

2. 2. The tablet of claim 1, wherein the organic acid or salt thereof is succinic acid.

3. The particle diameter of the granulated product (D ５０ 2. The tablet according to claim 1, wherein the particle size is 90 μm or more.

4. The tablet according to claim 1, wherein the content of the organic acid or its salt in the tablet is 10% by mass or more.

5. A method for producing a tablet containing a granule comprising palbociclib or a pharmaceutically acceptable salt thereof and an organic acid or a salt thereof, comprising: The particle diameter (D ５０ a preparation step of adjusting the particle size to 180 μm or more; a granulation step to obtain a granulation product containing palbociclib or a pharmaceutically acceptable salt thereof; A method for producing tablets, comprising a tableting step of mixing the granulated product with the organic acid or a salt thereof and tableting the mixture.

6. A method for inhibiting production of an analogue of palbociclib or a pharmaceutically acceptable salt thereof in a tablet containing palbociclib or a pharmaceutically acceptable salt thereof, and an organic acid or a salt thereof, comprising: Particle diameter (D ５０ ) is 180 μm or more, and a granule of palbociclib or a pharmaceutically acceptable salt thereof is mixed with the organic acid or a salt thereof, and the production of the related substance is inhibited by the method.

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