Palbociclib-containing tablets

Abstract

One embodiment of the present invention aims to provide a highly stable palbociclib tablet with improved dissolution properties and suppressed generation of related substances after storage under open conditions susceptible to humidity. [Solution] According to one embodiment of the present invention, a palbociclib-containing tablet is provided, comprising palbociclib or a pharmaceutically acceptable salt thereof, and at least one water-soluble acid, adipic acid, and ascorbic acid. The palbociclib-containing tablet may further contain succinic acid.

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 anticancer drug.

[0003] As a palbociclib-containing formulation, a solid formulation containing succinic acid, malic acid, or tartaric acid as a water-soluble acid is described in, for example, Patent Document 1. Although the palbociclib-containing formulation described in Patent Document 1 has been confirmed to have improved elution properties by using the above water-soluble acid, it has been shown in examples that the formulations using these water-soluble acids have low stability. In addition, although Patent Document 1 describes highly stable palbociclib-containing formulations containing water-soluble acids other than the above, such as benzoic acid and benzenesulfonic acid, it has been confirmed that their elution behavior is low.

[0004] Furthermore, as a palbociclib-containing formulation, a solid formulation containing fumaric acid, aspartic acid, or benzoic acid as a water-soluble acid is described in, for example, Patent Document 2. The palbociclib-containing formulation described in Patent Document 2 has shown high stability by using the above water-soluble acid, but there is no description about elution properties.

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Patent Document 2

[0006] One of the objectives of one embodiment of the present invention is to provide a palbociclib tablet in which dissolution is improved and the generation of related substances is suppressed. [Means for solving the problem]

[0007] According to one embodiment of the present invention, a palbociclib-containing tablet is provided, comprising palbociclib or a pharmaceutically acceptable salt thereof, and at least one water-soluble acid, adipic acid, and ascorbic acid.

[0008] Palbociclib-containing tablets may further contain succinic acid.

[0009] In palbociclib-containing tablets, the content of at least one water-soluble acid, such as adipic acid and ascorbic acid, may be 5% to 25% by weight.

[0010] In palbociclib-containing tablets, the succinic acid content may be less than 5% by weight. [Effects of the Invention]

[0011] According to one embodiment of the present invention, a palbociclib-containing tablet is provided in which dissolution properties are improved and the generation of related substances is suppressed. [Brief explanation of the drawing]

[0012] [Figure 1] This figure shows the evaluation results of the dissolution properties of palbociclib-containing tablets of Example 1, Example 2, and Comparative Example 1 of the present invention. [Modes for carrying out the invention]

[0013] 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.

[0014] As a result of diligent research by the inventors, it has been newly discovered that by combining palbociclib with at least one of adipic acid and ascorbic acid, it is possible to improve both the dissolution properties and the stability.

[0015] [Palbociclib-containing preparations] A palbociclib-containing tablet according to one embodiment of the present invention comprises palbociclib or a pharmaceutically acceptable salt thereof, and at least one water-soluble acid, adipic acid, and ascorbic acid. The palbociclib-containing tablet may further contain palbociclib or a pharmaceutically acceptable salt thereof, at least one water-soluble acid, adipic acid, and ascorbic acid, and a different water-soluble acid. The palbociclib-containing tablet may be coated with a film coating layer.

[0016] In the palbociclib-containing tablets according to this embodiment, palbociclib or a pharmaceutically acceptable salt thereof is the active ingredient of the palbociclib-containing formulation 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 formulation.

[0017] In the palbociclib-containing tablets according to this embodiment, at least one of adipic acid and ascorbic acid is used as the water-soluble acid, with adipic acid being particularly preferred. By using a specific water-soluble acid, dissolution is improved and the formation of related substances is suppressed. In the palbociclib-containing tablets according to this embodiment, the formation of related substances can be suppressed by using a specific water-soluble acid. In this specification, open conditions susceptible to humidity refer to, for example, open conditions at 25°C, 75% relative humidity for one month.

[0018] In one embodiment, the content of water-soluble acid in the palbociclib-containing tablet of the present invention is preferably 5% to 25% by weight, and more preferably 5% to 10% by weight. Note that, in the case of a film-coated tablet, the content of water-soluble acid in the palbociclib-containing tablet of the present invention refers to the content relative to the uncoated tablet portion excluding the film coating layer. Note that if multiple types of water-soluble acid are included, the water-soluble acid in the palbociclib-containing tablet of the present invention includes multiple types of water-soluble acid.

[0019] In one embodiment, the palbociclib-containing tablets of the present invention may further contain a water-soluble acid different from the water-soluble acid described above. Examples of water-soluble acids that may further be included are glutamic acid, erythorbic acid, sorbic acid, tannic acid, acetic acid, phosphoric acid, and the water-soluble acids described in Patent Documents 1 and 2, and it is particularly preferable to further use succinic acid.

[0020] In one embodiment, the succinic acid content in the palbociclib-containing tablets of the present invention is preferably less than 5% by weight. Note that, if the palbociclib-containing tablets of the present invention are film-coated tablets, the succinic acid content refers to the content relative to the uncoated tablet portion excluding the film coating layer.

[0021] The palbociclib-containing tablets according to the present invention can further contain one or more pharmaceutically acceptable additives in addition to the water-soluble acids described above. Examples of the one or more pharmaceutically acceptable additives include disintegrants, binders, lubricants, fluidizing agents, surfactants, excipients, and the like.

[0022] As the disintegrant, it can be selected from known disintegrants. For example, one or more disintegrants selected from the group consisting of sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate can be used, but it is not limited thereto.

[0023] As the binder, it can be selected from known binders. For example, it includes microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic rubbers, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. In some embodiments, the binder can be one or more binders selected from the group consisting of microcrystalline cellulose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose, but it is not limited thereto.

[0024] 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 thereof can be used, but it is not limited thereto.

[0025] As the fluidizing agent, one or more known fluidizing agents can be selected. 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 are not limited to these.

[0026] The surfactant can be selected from known surfactants. For example, at least one surfactant from sodium lauryl sulfate and polysorbate 80 can be used, but is not limited to these.

[0027] 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, dextrose, 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.

[0028] A film coating polymer can be used for the film coating layer. The film coating polymer can be selected from known film coating polymers. For example, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, and polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer can be used. The film coating layer may also contain a light-shielding agent and a plasticizer. 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.

[0029] As described above, the palbociclib-containing tablets according to the present invention contain palbociclib or a pharmaceutically acceptable salt thereof, and at least one water-soluble acid, such as adipic acid and ascorbic acid, thereby improving not only dissolution but also the formation of related substances and enhancing stability.

[0030] [Manufacturing method for palbociclib-containing tablets] 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.

[0031] 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 dry granulation or wet granulation, and after the resulting granules are sized, a post-additive containing a water-soluble acid is added and mixed. and B) A step of compressing the mixture obtained by the above mixing into tablets using a rotary tablet press. It can be manufactured by a process that includes the above. Alternatively, the palbociclib-containing tablets manufactured by the above process may be coated with a film coating layer to produce coated tablets.

[0032] Alternatively, the palbociclib-containing tablets according to the present invention may be manufactured by the following manufacturing method.

[0033] The palbociclib-containing tablets according to the present invention are A) A process of mixing palbociclib with various additives such as excipients, disintegrants, lubricants, and water-soluble acids as needed, and then compressing it. and B) The palbociclib-containing tablets manufactured by the above process may be coated with a film coating layer to form coated tablets. [Examples]

[0034] [Comparative Example 1] Tablets containing palbociclib, known as a method to improve the dissolution of the active pharmaceutical ingredient, were manufactured. The amounts of palbociclib and each excipient used are given as the content 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 6.3 mg of light anhydrous silicic acid (Adsolider 101, FREUND) were mixed, and the resulting mixture was placed in a dry granulator (TF-MINI, Freund Industrial Co., Ltd.) and granulated. The resulting granules were then sized using a granulator (screen diameter 1.0 mm, Dalton Co., Ltd.). The obtained whole granules were mixed with 133.6 mg of crystalline cellulose (Ceolus® PH-102), 19.0 mg of crospovidone (Kollidon® CL-SF, BASF), 62.5 mg of succinic acid (Tokyo Chemical Industries, Ltd.), and 12.5 mg of magnesium stearate (plant-derived, 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 triethyl citrate (CITROFLEX2 (SC-60), Morimura Shoji 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.

[0035] [Example 1] The palbociclib-containing tablets of Example 1 were obtained by the same manufacturing method as in Comparative Example 1, except that 62.5 mg of adipic acid (Fujifilm Wako Pure Chemical Industries, Ltd.) was used instead of succinic acid.

[0036] [Example 2] The palbociclib-containing tablets of Example 2 were obtained by the same manufacturing method as in Comparative Example 1, except that 62.5 mg of ascorbic acid (Kyowa Pharma Chemical Co., Ltd., Ascorbic Acid 100M) was used instead of succinic acid.

[0037] [Example 3] The palbociclib-containing tablets of Example 3 were obtained by the same manufacturing method as in Comparative Example 1, except that 35.6 mg of adipic acid was used in combination with 27.0 mg of succinic acid.

[0038] [Dissolution test] Dissolution tests were conducted on palbociclib-containing tablets of Examples 1-3 and Comparative Example 1 using a dissolution tester (manufactured by Toyama Sangyo Co., Ltd.) in accordance with Dissolution Test Method 2 (paddle method, 50 revolutions per minute) of the 17th edition of the Japanese Pharmacopoeia, using 900 ml of purified water as the test solution. The dissolution rates of the palbociclib-containing tablets of Examples 1-3 and Comparative Example 1 are shown in Figure 1.

[0039] As shown in Figure 1, there was no significant difference in the final dissolution rate among the palbociclib-containing tablets in Examples 1-3 and Comparative Example 1. Therefore, it became clear that dissolution was improved not only with succinic acid, which was known to improve dissolution, but also with adipic acid, ascorbic acid, and a combination of succinic acid and adipic acid.

[0040] [Stability Assessment] The stability of palbociclib-containing tablets from Example 1, Example 2, and Comparative Example 1 was evaluated by measuring the mass of related substances (hydrolyzates) at the initial value (INT) before storage and after storage for one month at 25°C, 75% relative humidity, and open conditions. The total amount of related substances is expressed as the ratio of the total peak area of ​​palbociclib-derived related substances to the total peak area of ​​all peak areas detected by measurement using high-performance liquid chromatography. The evaluation results are shown in Table 1.

[0041] [Table 1]

[0042] Table 1 shows that the palbociclib-containing tablets of Comparative Example 1 showed an increase in related substances. On the other hand, the palbociclib-containing tablets of Example 1 and Example 2 showed suppressed generation of related substances compared to the palbociclib-containing tablets of Comparative Example 1. Dissolution tests and stability evaluations revealed that Examples 1 and 2, which contain at least one water-soluble acid, adipic acid and ascorbic acid, exhibited improved dissolution and high stability.

Claims

1. A palbociclib-containing tablet comprising palbociclib or a pharmaceutically acceptable salt thereof, and at least one water-soluble acid, adipic acid, and ascorbic acid.

2. A palbociclib-containing tablet according to claim 1, further comprising succinic acid.

3. The palbociclib-containing tablet according to claim 1, wherein the content of the at least one water-soluble acid is 5% to 25% by weight.

4. The palbociclib-containing tablet according to claim 2, wherein the succinic acid content is less than 5% by weight.

Images