Palbociclib-containing tablets

Abstract

One embodiment of the present invention aims to provide a palbociclib tablet in which the formation of acetyl adducts of palbociclib is suppressed. [Solution] According to one embodiment of the present invention, a palbociclib-containing tablet is provided, comprising a core tablet containing palbociclib or a pharmaceutically acceptable salt thereof, and a film coat layer covering the core tablet, wherein the film coat layer contains an acetyl group-free plasticizer. The acetyl group-free plasticizer may be at least one selected from the group consisting of triethyl citrate, polyvinyl alcohol, polyethylene glycol, and hydroxypropyl cellulose.

Description

Technical Field

[0001] The present invention relates to a palbociclib-containing tablet.

Background Art

[0002] Palbociclib (6-Acetyl-8-cyclopentyl-5-methyl-2-{[5-(1-piperazinyl)-2-pyridinyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one) is an inhibitor selective for cyclin-dependent kinases CDK4 and CDK6 and is clinically used as an anti-cancer drug.

[0003] As a palbociclib-containing preparation, tablets with good elution properties are described, for example, in Patent Document 1, by mixing succinic acid, malic acid, or tartaric acid as a water-soluble acid with a tablet containing palbociclib. Further, as another palbociclib-containing preparation, tablets with reduced generation of impurities during storage are described, for example, in Patent Document 2, by mixing fumaric acid, aspartic acid, or benzoic acid as a water-soluble acid with a tablet containing palbociclib.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0005] Impurities in palbociclib-containing tablets include palbociclib-related substances. While it has been known that the formation of total related substances is suppressed in palbociclib-containing tablets to which certain water-soluble acids are added, the causes of the formation of individual palbociclib-related substances remain unknown.

[0006] One embodiment of the present invention aims to provide a palbociclib tablet in which the formation of acetyl adducts of palbociclib, which are related substances of palbociclib, is suppressed. [Means for solving the problem]

[0007] According to one embodiment of the present invention, a palbociclib-containing tablet is provided, comprising a core tablet containing palbociclib or a pharmaceutically acceptable salt thereof, and a film coating layer covering the core tablet, wherein the film coating layer contains a plasticizer that does not contain an acetyl group.

[0008] The acetyl group-free plasticizer may be at least one selected from the group consisting of triethyl citrate, polyvinyl alcohol, polyethylene glycol, and hydroxypropyl cellulose.

[0009] The film coating layer may contain 1.5% to 30.0% by weight of a plasticizer that does not contain acetyl groups. [Effects of the Invention]

[0010] According to one embodiment of the present invention, a related substance of palbociclib is identified. According to one embodiment of the present invention, a palbociclib-containing tablet is provided in which the formation of acetyl adducts of palbociclib is suppressed. [Modes for carrying out the invention]

[0011] The palbociclib-containing tablets according to the present invention will be described below. In this invention, the term "palbociclib" may include pharmacokinetically acceptable salts. The palbociclib-containing tablets of the present invention are not limited to the embodiments and examples described below.

[0012] The inventors of the present invention diligently investigated substances related to palbociclib in palbociclib-containing tablets and found that one of the substances related to palbociclib is an acetyl adduct of palbociclib. Furthermore, the inventors found that the film coating layer in palbociclib-containing tablets, which does not contain palbociclib, affects the formation of the acetyl adduct of palbociclib.

[0013] Furthermore, as will be shown in the examples described later, the inventors investigated the components constituting the film and found that the cause was an additive having an acetyl group. The inventors found that in a palbociclib-containing formulation, it is possible to suppress the formation of acetyl adducts of palbociclib by incorporating a plasticizer that does not contain an acetyl group into the film coating layer.

[0014] [Palbociclib-containing preparations] A palbociclib-containing tablet according to one embodiment of the present invention is a tablet comprising palbociclib or a pharmaceutically acceptable salt thereof and a film coating layer. The film coating layer contains an acetyl group-free plasticizer.

[0015] In the palbociclib-containing tablets according to this embodiment, palbociclib or a pharmaceutically acceptable salt thereof is the active ingredient of the palbociclib-containing tablets according to the present invention. Examples of palbociclib or a pharmaceutically acceptable salt thereof include the salt described in International Publication No. 2003 / 062236. The amount of palbociclib can be appropriately selected depending on the expected therapeutic effect, but is 25 mg or 125 mg of palbociclib per tablet.

[0016] In the palbociclib-containing tablet according to this embodiment, the film coating layer contains a plasticizer that does not contain acetyl groups. The acetyl group-free plasticizer does not cause the removal of acetyl groups. Therefore, the acetyl group-free plasticizer does not cause acetylation of palbociclib by the removed acetyl groups, and thus does not generate impurities that are acetyl adducts of palbociclib.

[0017] In the palbociclib-containing formulation according to this embodiment, the acetyl group-free plasticizer contained in the film coat layer is preferably at least one selected from the group consisting of triethyl citrate, polyvinyl alcohol, polyethylene glycol (also referred to as macrogol), and hydroxypropyl cellulose. From the viewpoint of suppressing related substances other than acetyl adducts and ease of manufacture, the acetyl group-free plasticizer is more preferably triethyl citrate.

[0018] In the palbociclib-containing tablets according to this embodiment, the acetyl group-free plasticizer is preferably present in an amount of 1.5% to 30.0% by weight relative to the film coating layer, and more preferably in an amount of 8.0% to 20.0% by weight.

[0019] The palbociclib-containing formulation according to the present invention may further contain one or more pharmaceutically acceptable additives in addition to the water-soluble acid described above. Examples of one or more pharmaceutically acceptable additives include disintegrants, binders, lubricants, fluidizers, surfactants, and excipients.

[0020] As a disintegrant, one or more disintegrants selected from known disintegrants can be used, but are not limited to those listed below. For example, one or more disintegrants selected from the group consisting of sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, low-substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate can be used.

[0021] As the binder, it can be selected from known binders. For example, it includes microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic rubbers, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose. In some embodiments, the binder can be one or more binders selected from the group consisting of microcrystalline cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose, but is not limited thereto.

[0022] As the lubricant, it can be selected from known lubricants. For example, one or more lubricants selected from the group consisting of magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, a mixture of magnesium stearate and sodium lauryl sulfate, or a mixture of two or more of these can be used, but is not limited thereto.

[0023] As the fluidizing agent, it can be selected from known fluidizing agents. For example, one or more fluidizing agents selected from the group consisting of silicon dioxide, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc, and light anhydrous silicic acid can be used, but is not limited thereto.

[0024] As the surfactant, it can be selected from known surfactants. For example, at least one surfactant of sodium lauryl sulfate and polysorbate 80 can be used, but is not limited thereto.

[0025] Excipients can be selected from known excipients. For example, one or more excipients selected from the group consisting of D-mannitol, lactose, sucrose, corn starch, calcium phosphate, sorbitol, crystalline cellulose, powdered cellulose, light anhydrous silicic acid, lactose, xylitol, dextrose, sucrose, sorbitol, compressed sugar, starch, pregelatinized starch, dextrates, dextran, dextrin, maltodextrin, calcium carbonate, dicalcium phosphate, tricalcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, poloxamer, polyethylene oxide, hydroxypropyl methylcellulose, and mixtures thereof can be used, but are not limited to these.

[0026] The palbociclib-containing formulation according to the present invention may further contain, in addition to the plasticizer described above, one or more pharmaceutically acceptable additives and bases in the film coating layer. Examples of one or more pharmaceutically acceptable additives and bases include film bases and light-shielding agents.

[0027] The film base can be selected from known film bases. For example, one or more film bases selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose (also called hypromellose), polyvinyl alcohol, and polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer can be used, but are not limited to these.

[0028] As a light-shielding agent, one can be selected from known light-shielding agents. For example, one or more light-shielding agents selected from the group consisting of yellow iron(III) oxide, iron(III) oxide, titanium dioxide, and blue aluminum lake can be used, but are not limited to these.

[0029] The palbociclib-containing tablets according to the present invention can be manufactured into pharmaceutical tablets by packaging as needed. In addition to ordinary PTP packaging, the palbociclib-containing tablets according to the present invention can also be stored in highly moisture-resistant packaging that does not allow moisture to pass through, such as high moisture-proof PTP, double-sided aluminum PTP, or SP packaging. After being packaged in any of the above forms, it is also possible to store them in pillow packaging. For example, aluminum pillows can be used for pillow packaging. A desiccant can also be placed inside the pillow packaging.

[0030] As described above, the palbociclib-containing tablets according to the present invention can suppress the formation of impurities in which acetyl groups are attached to palbociclib by using a plasticizer that does not contain acetyl groups in the film coating layer that covers the uncoated tablet.

[0031] [Manufacturing method for palbociclib-containing preparations] There are no particular limitations on the method for producing the palbociclib-containing tablets according to the present invention, and known manufacturing methods can be used. However, it is preferable to use the following manufacturing method for producing the palbociclib-containing tablets.

[0032] The palbociclib-containing tablets according to the present invention are A) A process in which palbociclib is mixed with various additives such as excipients, disintegrants, and lubricants as needed, granulated by a wet granulation method or a dry granulation method, and after the resulting granules are sized, a post-additive containing a water-soluble acid is added and mixed. B) The process of compressing the mixture obtained by the above mixing into tablets using a rotary tablet press, and C) It can be manufactured by stirring, dissolving, and dispersing an acetyl group-free plasticizer, film base, and light-shielding agent in a solvent to prepare a film coating solution, and then coating the tablets obtained by the above-mentioned tableting with the film coating solution.

[0033] The palbociclib-containing tablets according to the present invention may be manufactured by the following manufacturing method.

[0034] The palbociclib-containing tablets according to the present invention are A) A step of mixing palbociclib with various additives such as excipients, disintegrants, lubricants, and water-soluble acids as needed, and compressing it, and B) The tablets can be manufactured by stirring and dissolving an acetyl group-free plasticizer, a film base, and a light-shielding agent in a solvent to prepare a film coating solution, and then coating the tablets obtained by the above-mentioned tableting process with the film coating solution. [Examples]

[0035] [Comparative Example 1] Tablets containing palbociclib were manufactured. The amounts of palbociclib and each excipient used are given per tablet. Specifically, 125.0 mg of palbociclib, 245.0 mg of crystalline cellulose (Ceolus® PH-102), 19.0 mg of crospovidone (Kollidon® CL-SF, BASF), 2.1 mg of magnesium stearate (Shokubutsu, Taihei Chemical Industry Co., Ltd.), and 6.1 mg of light anhydrous silicic acid (Adsolider 101, FREUND) were mixed. The resulting mixture was placed in a dry granulator (TF-MINI, Freund Industrial Co., Ltd.) and granulated. The resulting granules were combed through a No. 22 comb to sizing. The obtained whole granules were mixed with 133.7 mg of crystalline cellulose (Ceolus® PH-102), 19.0 mg of crospovidone (Kollidon® CL-SF, BASF), 27.0 mg of succinic acid (Tokyo Chemical Industries, Ltd.), 35.6 mg of adipic acid (Fujifilm Wako Pure Chemical Industries, Ltd.), and 12.5 mg of magnesium stearate (Shokubutsu, Taihei Chemical Industry Co., Ltd.). The resulting mixture was compressed into tablets using a rotary tablet press (Ichihashi Seiki Co., Ltd.) to obtain palbociclib-containing tablets weighing 625.0 mg per tablet. A film coating solution was prepared by stirring, dissolving, and dispersing 15.0 mg of hypromellose (TC-5®, Shin-Etsu Chemical Co., Ltd.), 7.38 mg of titanium dioxide (NA61, Toho Titanium Co., Ltd.), 2.0 mg of triacetin (Nacalai Tesque Co., Ltd.), 0.48 mg of Blue No. 2 aluminum lake (Sanei Gen F.F.I. Co., Ltd.), and 0.15 mg of ferric oxide (Kishi Kasei Co., Ltd.) in purified water using a mixer. The above-mentioned uncoated tablets were coated with the film coating solution until the mass per tablet increased by approximately 25 mg, thereby producing palbociclib-containing tablets of Comparative Example 1. Details of the film are shown in Table 1.

[0036] [Comparative Example 2] A palbociclib-containing tablet of Comparative Example 2 was obtained using the same manufacturing method as Comparative Example 1, except that the amount of triacetin (Nacalai Tesque Co., Ltd.) added was increased to 3.0 mg and the amount of hypromellose (TC-5®, Shin-Etsu Chemical Co., Ltd.) added was decreased to 14.0 mg. Details of the film coating layer are shown in Table 1.

[0037] [Comparative Example 3] Comparative Example 3, a palbociclib-containing tablet, was obtained using the same manufacturing method as Comparative Example 1, except that the amount of triacetin (Nacalai Tesque Co., Ltd.) added was increased to 4.0 mg and the amount of hypromellose (TC-5®, Shin-Etsu Chemical Co., Ltd.) added was decreased to 13.0 mg. Details of the film coating layer are shown in Table 1.

[0038] [Table 1]

[0039] [Evaluation of the generation of related substances] Palbociclib-containing tablets of Comparative Examples 1 to 3 were measured using high-performance liquid chromatography (HPLC) after being stored for 2 weeks (2W) and 4 weeks (4W) at 60°C, 60% relative humidity, and open conditions. From the HPLC measurement results, multiple peaks were observed on the HPLC chromatogram at positions different from those of palbociclib. Using the area percentage method, the sum of the peak areas of palbociclib and each of the above-mentioned multiple peaks on the chromatogram was set to 100, and the total amount (%) of the substance with the largest peak among the multiple peaks was calculated from the peak area ratio. The evaluation results are shown in Table 2.

[0040] [Table 2]

[0041] The molecular structure of the largest peak was estimated using a mass spectrometer. Based on the difference in molecular weight of palbociclib, the molecular structure of the largest peak was estimated to be an acetyl adduct, a related substance of palbociclib.

[0042] Next, nuclear magnetic resonance spectroscopy was performed on the acetyl adduct of palbociclib. 1The molecular structure and molecular weight of the acetyl adduct of palbociclib were confirmed by measurement using 1H-NMR and mass spectrometry. A standard solution was prepared using a sample of the acetyl adduct of palbociclib, and when the standard solution was measured using HPLC, the relative retention time (RRT) of the acetyl adduct of palbociclib was consistent with that of a related substance suspected to be the acetyl adduct of palbociclib. Based on these results, the related substance suspected to be the acetyl adduct of palbociclib was identified as the acetyl adduct of palbociclib.

[0043] Furthermore, as shown in Table 2, the amount of the most significant peak tends to increase with increasing triacetin addition, which suggests that triacetin, which contains an acetyl group, is responsible for the formation of the acetyl adduct of palbociclib.

[0044] [Example 1] The palbociclib-containing tablets of Example 1 were obtained by the same manufacturing method as in Comparative Example 1, except that 2.0 mg of triethyl citrate (CITROFLEX2 (SC-60), Morimura Shoji Co., Ltd.) was used instead of triacetin. Details of the film coating layer are shown in Table 3.

[0045] [Example 2] Palbociclib-containing tablets of Example 2 were obtained using the same manufacturing method as in Comparative Example 1, except that 2.0 mg of polyvinyl alcohol (PVA) was used instead of triacetin. Details of the film coating layer are shown in Table 3.

[0046] [Example 3] The palbociclib-containing tablets of Example 3 were obtained using the same manufacturing method as in Comparative Example 1, except that 2.0 mg of macrogol 6000 (NOF Co., Ltd.) was used instead of triacetin. Details of the film coating layer are shown in Table 3.

[0047] [Table 3]

[0048] [Evaluation of acetyl adduct formation 1] The amount of acetyl adducts of palbociclib, an impurity of palbociclib, was measured in palbociclib-containing tablets of Examples 1 to 3 after storage for 2 weeks (2W) and 4 weeks (4W) at 60°C, 60% relative humidity, and open conditions, and the formation of acetyl adducts was evaluated. The total amount of acetyl adducts was calculated using the area percentage method, where the sum of all peak areas detected by high-performance liquid chromatography was set to 100, and the total amount of palbociclib acetyl adducts (%) was calculated from the peak area ratio. The evaluation results are shown in Table 4. The results were below the detection limit (ND).

[0049] [Table 4]

[0050] The results in Table 4 show that in the palbociclib-containing tablets of Examples 1 to 3, the acetyl adducts remained below the detection limit even after 4 weeks of storage at 60°C and 60% RH.

[0051] [Example 4] The palbociclib-containing tablets of Example 4 were obtained using the same manufacturing method as Comparative Example 1, except that 5.0 mg of triethyl citrate (CITROFLEX2 (SC-60), Morimura Shoji Co., Ltd.) was used instead of triacetin, and 12.0 mg of hypromellose was used. Details of the film coating layer are shown in Table 5.

[0052] [Example 5] The palbociclib-containing tablets of Example 5 were obtained using the same manufacturing method as in Comparative Example 1, except that 2.0 mg of hydroxypropylcellulose (L, Nippon Soda Co., Ltd.) was used instead of triacetin. Details of the film coating layer are shown in Table 5.

[0053] [Example 6] The palbociclib-containing tablets of Example 6 were obtained using the same manufacturing method as in Comparative Example 1, except that 2.0 mg of macrogol 400 (NOF Co., Ltd.) was used instead of triacetin. Details of the film coating layer are shown in Table 5.

[0054] [Table 5]

[0055] [Evaluation of acetyl adduct formation 2] The amount of acetyl adducts, which are impurities of palbociclib, was measured in the palbociclib-containing tablets of Examples 4 to 6 after storage for 2 weeks (2W) and 4 weeks (4W) at 60°C, 60% relative humidity, and open conditions. The formation of acetyl adducts was evaluated in the same manner as in the acetyl adduct formation evaluation 1 described above. The evaluation results are shown in Table 6. The results were below the detection limit (ND).

[0056] [Table 6]

[0057] The results in Table 6 show that in the palbociclib-containing tablets of Examples 4 to 6, the acetyl adducts remained below the detection limit even after 4 weeks of storage at 60°C and 60% RH.

Claims

1. A plain tablet containing palbociclib or a pharmaceutically acceptable salt thereof, The aforementioned tablet comprises a film coating layer, The aforementioned film coating layer contains a palbociclib-containing tablet that includes a plasticizer that does not contain an acetyl group.

2. The acetyl group-free plasticizer is selected from the group consisting of triethyl citrate, polyvinyl alcohol, polyethylene glycol, and hydroxypropyl cellulose. A palbociclib-containing tablet according to claim 1, wherein at least one of these tablets is present.

3. The palbociclib-containing tablet according to claim 1, comprising 1.5% to 30.0% by weight of the acetyl group-free plasticizer in the film coating layer.

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