Palbociclib tablets

Abstract

Palbociclib free base has a pH-dependent solubility, resulting in a problem of significantly reduced dissolution in the neutral pH range of 5.5 or higher compared to dissolution in the acidic range. To address this issue, the use of a water-soluble acid such as succinic acid is known. However, it is also known that palbociclib is decomposed by the water-soluble acid, resulting in the formation of related substances in the formulation. Therefore, there is a need for a pharmaceutical tablet containing palbociclib and a water-soluble acid and having excellent storage stability. In particular, the objective is to provide a pharmaceutical tablet in which the formation of related substances is suppressed after storage. [Solution] By adding adipic acid to pharmaceutical tablets containing palbociclib as an active ingredient, it is possible to prepare pharmaceutical tablets that suppress the production of related substances during storage.

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical tablet composition containing palbociclib or a salt thereof as an active ingredient. [Background technology]

[0002] Palbociclib is a kinase inhibitor that selectively inhibits cyclin-dependent kinases 4 and 6 (CDK4 / 6), and is clinically used as a therapeutic agent for hormone receptor-positive, HER2-negative inoperable or recurrent breast cancer. Palbociclib is available on the market in capsule formulations containing crystalline cellulose, lactose hydrate, sodium starch glycolate, light anhydrous silicic acid, and magnesium stearate, as well as in tablets containing crystalline cellulose, light anhydrous silicic acid, crospovidone, succinic acid, magnesium stearate, etc. (Non-Patent Document 1). Regarding palbociclib tablets, Patent Document 1 describes tablets containing 10-80% palbociclib or a salt thereof, as well as a disintegrant, diluent, lubricant, surfactant, and binder. Patent Document 2 describes pharmaceutical tablets containing palbociclib free base, whose solubility is pH-dependent, as the active ingredient, and formulated with a water-soluble acid such as succinic acid, malic acid, or tartaric acid to provide stable pharmaceutical tablets that are unaffected by food or have no adverse interactions with proton pump inhibitors (PPIs) and enable substantially pH-independent delivery of palbociclib. Patent Document 3 also describes pharmaceutical tablets containing fumaric acid, aspartic acid, or benzoic acid, and Patent Document 4 describes pharmaceutical formulations containing aspartic acid or glutamic acid. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Pharmaceutical Interview Form "Ibrance (registered trademark) Capsules 25 mg 125 mg, Ibrance (registered trademark) Tablets 25 mg 125 mg January 2024 revised edition (13th edition)" [Patent documents]

[0004] [Patent Document 1] Special Publication No. 2017-532347 [Patent Document 2] Japanese Patent Application Publication No. 2017-2034 [Patent Document 3] Japanese Patent Application Publication No. 2023-152768 [Patent Document 4] Japanese Patent Application Publication No. 2024-92942 Summary of the Invention [Problem to be solved by the invention]

[0005] Palbociclib free base has a pH-dependent solubility, resulting in a problem of significantly reduced dissolution in the neutral pH range of 5.5 or higher compared to dissolution in the acidic range. To address this issue, the use of a water-soluble acid such as succinic acid is known. However, it is also known that palbociclib is decomposed by the water-soluble acid, resulting in the formation of related substances in the formulation. Therefore, there is a need for a pharmaceutical tablet containing palbociclib and a water-soluble acid, which exhibits dissolution properties in the neutral range similar to those of existing palbociclib tablets made with succinic acid, and which also has excellent storage stability. In particular, the objective of the present invention is to provide a pharmaceutical tablet in which the formation of related substances is suppressed after storage. [Means for solving the problem]

[0006] [1] A pharmaceutical tablet containing palbociclib, adipic acid or its salts. [2] The pharmaceutical tablet according to [1], wherein the content of palbociclib is 1 part by mass and the content of adipic acid is 0.1 to 1.0 parts by mass. [3] The pharmaceutical tablet according to [1] or [2], comprising 10 to 45 parts by mass of palbociclib, 5 to 30 parts by mass of adipic acid, 40 to 75 parts by mass of an excipient, 3 to 12 parts by mass of a disintegrant, and 0.5 to 4 parts by mass of a lubricant. [4] A method for producing a pharmaceutical tablet containing palbociclib as an active ingredient, comprising: preparing a granulation comprising palbociclib, an excipient, and a disintegrant; mixing the granules with adipic acid or a salt thereof and an excipient; molding the mixture to prepare tablets; A method for producing a pharmaceutical tablet, comprising: [5] The method for producing a pharmaceutical tablet according to [4], wherein the adipic acid is contained in an amount of 0.5 to 1.0 parts by mass per part by mass of palbociclib. [Effects of the Invention]

[0007] The pharmaceutical tablet of the present invention containing palbociclib and adipic acid or a salt thereof exhibits dissolution properties in the neutral range similar to those of existing tablets using succinic acid, and furthermore, the production of related substances is suppressed, making it possible to provide a pharmaceutical tablet with excellent stability. DETAILED DESCRIPTION OF THE INVENTION

[0008] The present invention relates to a pharmaceutical tablet containing palbociclib, adipic acid or a salt thereof, and also includes a method for producing the pharmaceutical tablet containing palbociclib, adipic acid or a salt thereof.

[0009] The pharmaceutical tablet of the present invention contains palbociclib as an active ingredient. Palbociclib has 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 is a dibasic compound and can form salts with various conjugate acids. The present invention uses palbociclib free base as an active ingredient. It is desirable to use palbociclib as a compound of a quality level suitable for use as an active ingredient in pharmaceuticals. Palbociclib is preferably contained in the pharmaceutical tablet at 10% by mass or more and 45% by mass or less, more preferably 15% by mass or more and 40% by mass or less, and more preferably 15% by mass or more and 34% by mass or less.

[0010] The pharmaceutical tablet of the present invention contains adipic acid or a salt thereof. Adipic acid may be used as a free acid or in the form of a salt such as a sodium salt, potassium salt, or ammonium salt. It is preferable to use adipic acid (free acid). The amount of adipic acid or a salt thereof contained in the pharmaceutical tablet is preferably 5% by mass or more and 30% by mass or less, more preferably 5% by mass or more and 25% by mass or less, and more preferably 5% by mass or more and 20% by mass or less, in terms of the amount of adipic acid equivalent to the free acid. Furthermore, since adipic acid improves the dissolution of palbociclib, it is important to apply it in an amount relative to palbociclib. It is preferable to apply 0.1 to 1.0 parts by mass of adipic acid (equivalent to the free acid) per part by mass of palbociclib. Preferably, 0.15 to 0.8 parts by mass of adipic acid (equivalent to the free acid), and more preferably 0.15 to 0.6 parts by mass of adipic acid (equivalent to the free acid), per part by mass of palbociclib.

[0011] The pharmaceutical tablet of the present invention preferably contains an excipient, a disintegrant, and a lubricant. These additives may be appropriately selected from additives commonly used for pharmaceutical tablets.

[0012] Examples of excipients include celluloses such as crystalline cellulose, sugars such as lactose, mannitol, maltose, sucrose, sorbitol, xylitol, and inositol, starches such as corn starch, and inorganic salts such as magnesium aluminometasilicate and anhydrous calcium phosphate. These may be used alone or in combination of two or more. Preferred are crystalline cellulose, lactose, and mannitol, and excipients containing one or more of these. Preferably, crystalline cellulose is used. The excipient content in the pharmaceutical tablet is preferably 40% by mass or more and 75% by mass or less, and more preferably 45% by mass or more and 70% by mass or less.

[0013] Examples of disintegrants include croscarmellose sodium, carboxymethyl starch sodium, crospovidone, carmellose, carmellose calcium, and low-substituted carboxymethyl starch sodium. These may be used alone or in combination of two or more. Preferred are croscarmellose sodium, carboxymethyl starch sodium, and crospovidone. More preferred is crospovidone. When a disintegrant is used, it is preferably used in an amount of 3% by mass to 12% by mass in the pharmaceutical tablet, and more preferably 3% by mass to 10% by mass.

[0014] Examples of lubricants include magnesium stearate, stearic acid, zinc stearate, aluminum stearate, glycerin monostearate, sodium stearyl fumarate, calcium stearate, talc, carnauba wax, etc., and it is preferable to use these alone or in combination of two or more. When a lubricant is used, it is preferably used in an amount of 0.5% by mass to 4% by mass in the pharmaceutical tablet, and more preferably 0.5% by mass to 3% by mass.

[0015] The pharmaceutical tablet of the present invention may contain other formulation additives such as binders, glidants, solubilizers, stabilizers, and the like. Examples of binders include hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, copolyvidone, carmellose sodium, methylcellulose, partially pregelatinized starch, and polyvinyl alcohol, and these may be used alone or in combination of two or more. Preferred are hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, copolyvidone, carmellose sodium, and methylcellulose. When a binder is used, it is preferably used in an amount of 0.5% by mass to 10% by mass in the pharmaceutical tablet, and more preferably 0.5% by mass to 5% by mass.

[0016] Examples of the fluidizing agent include silicic anhydride, talc, and hydrous silicon dioxide. When a fluidizing agent is used, it is preferably used in an amount of 0.1% by mass to 10% by mass in the pharmaceutical tablet, and more preferably 0.1% by mass to 5% by mass. Examples of solubilizers include sodium lauryl sulfate, soybean lecithin, refined soybean lecithin, sorbitan fatty acid ester, soybean oil, lauromacrogol, polyoxyethylene-polyoxypropylene-polyoxyethylene block copolymer, and the like. The solubilizer is preferably used in a pharmaceutical tablet in an amount of 0.5% by mass to 5% by mass, more preferably 1.0% by mass to 5% by mass. Examples of stabilizers include dibutylhydroxytoluene, tocopherol, ascorbic acid, sulfites, and the like. The stabilizer is preferably used in an amount of 0.5% by mass to 5% by mass in the pharmaceutical tablet, and more preferably 1.0% by mass to 5% by mass.

[0017] A preferred embodiment of the palbociclib-containing tablet of the present invention is a pharmaceutical tablet containing 10 to 45 parts by mass of palbociclib, 5 to 30 parts by mass of adipic acid, 40 to 75 parts by mass of an excipient, 3 to 12 parts by mass of a disintegrant, and 0.5 to 4 parts by mass of a lubricant, and more preferably 15 to 40 parts by mass of palbociclib, 5 to 20 parts by mass of adipic acid, 45 to 70 parts by mass of an excipient, 3 to 10 parts by mass of a disintegrant, and 0.5 to 3 parts by mass of a lubricant.

[0018] The tablets containing palbociclib of the present invention are in the form of ordinary tablets, orally disintegrating tablets, etc. They may also be film-coated tablets with a coating film containing a suitable coating agent and any suitable plasticizer, light-blocking agent, colorant, etc.

[0019] Examples of coating agents include hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol (partially saponified), polyvinyl alcohol-polyethylene glycol-graft copolymer, ethyl acrylate-methyl methacrylate copolymer, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc. These are preferably used alone or in combination of two or more. Hydroxypropyl methylcellulose, hydroxypropyl cellulose, or polyvinyl alcohol (partially saponified) is preferred, with polyvinyl alcohol (partially saponified) being more preferred. The coating agent is preferably used in an amount of 0.1% by mass to 10% by mass, and more preferably 0.2% by mass to 5% by mass, based on the total weight of the pharmaceutical tablet.

[0020] Examples of plasticizers include triacetin, triethyl citrate, glycerin, propylene glycol, macrogol, polysorbate, D-sorbitol, and liquid paraffin, and these are preferably used alone or in combination of two or more. Triacetin or macrogol is preferred, and examples of macrogol include Macrogol 4000 and Macrogol 6000. When a plasticizer is used, it is preferably used in an amount of 0.01% by mass or more and 2% by mass or less, more preferably 0.02% by mass or more and 2% by mass or less, based on the total weight of the pharmaceutical tablet.

[0021] Examples of light-blocking agents and colorants include titanium oxide, ferric oxide, talc, yellow iron oxide, yellow iron oxide, black iron oxide, zinc oxide, brown iron oxide, food yellow dyes, food blue dyes, food red dyes, etc. Titanium oxide and ferric oxide are preferred. When a light-shielding agent or coloring agent is used, it is preferable to use it in an amount of 0.001% by mass or more and 2% by mass or less, and more preferably 0.002% by mass or more and 2% by mass or less, based on the total amount of the pharmaceutical tablet.

[0022] The pharmaceutical tablet containing palbociclib of the present invention can be produced by the following steps. (Step A) preparing a granulation containing palbociclib, an excipient, and a disintegrant; (Step B) mixing the granules with adipic acid or a salt thereof and an excipient; (Step C) forming the mixture into tablets; A method for producing a pharmaceutical tablet containing palbociclib as an active ingredient, comprising: Optionally, (Step D) may be added, in which the tablets obtained in Step C are subjected to a coating treatment to prepare film-coated tablets.

[0023] (Step A) is a step of preparing granules by mixing palbociclib, excipients, and a disintegrant, and subjecting the mixture to a mechanical operation such as compression or rolling. This mixture may optionally contain other additives such as a flow agent, a binder, a solubilizer, and a lubricant. Palbociclib is mixed with formulation additives, and then the mixture containing the active ingredient and various additives adheres to itself to form a granular product having a consistent particle size. The granulation process may be dry or wet granulation. Dry granulation is a granulation method in which water is not added during granulation. Wet granulation is a process in which an appropriate amount of an aqueous medium, such as water, an organic solvent (e.g., ethanol, methanol), or a mixture thereof, is added to the mixture, and mechanical pressure, such as a mixing process, is applied to cause the mixture to adhere to itself and granulate into a granular product. Examples of granulation processes include compression granulation, melt granulation, roller compactor granulation, tumbling granulation, fluidized bed granulation, agitation granulation, and extrusion granulation. The granulation process of the present invention can be appropriately selected from these methods to prepare the granules.

[0024] Step B is a step of mixing the granules prepared in Step A with adipic acid or a salt thereof and an excipient. At this time, other additives such as a disintegrant, a flow agent, a solubilizer, a lubricant, etc. may be added.

[0025] (Step C) is a step of preparing tablets by molding the mixture prepared in (Step B). Methods for molding the pharmaceutical tablets include rotary tableting and single-shot tableting, and pharmaceutical tablets are prepared by molding using these methods.

[0026] The resulting tablets may optionally be subjected to a coating treatment (Step D) to prepare film-coated tablets. When coating is performed, the film-coated portion, which is the exterior of the pharmaceutical tablet, can be film-coated by dissolving any additives used in the coating agent in a water-soluble solvent containing water or an organic solvent that can be mixed with water in any ratio, pouring or spraying the solution into a coating pan containing the plain tablets, which are the interior of the tablet, and then blowing hot air onto the tablet surface to remove the solvent from the tablet surface and dry it. The drying step is preferably performed at room temperature to about 80°C. Drying may also be performed under reduced pressure to volatilize the aqueous solvent.

[0027] The pharmaceutical tablet of the present invention has formulation properties that ensure dissolution in the neutral range of pH 5.5 or higher. For example, in a dissolution test according to Method 2 (paddle method) of the Pharmacopoeia Dissolution Test, using 900 mL of water as the test solution, the dissolution rate of the active ingredient of the tablet of the present invention is 50 to 70% at 15 minutes from the start of the test, and 55 to 80% at 30 minutes. Therefore, dissolution in the neutral range can be ensured for pharmaceutical tablets of palbociclib, whose solubility is pH-dependent. [Example]

[0028] The present invention will be described in more detail below with reference to Production Examples and Examples. In the following Examples, % represents % by mass unless otherwise specified.

[0029] [Manufacturing example] Stability test compositions were prepared using the following procedure: 400 mg of palbociclib was mixed with 400 mg of succinic acid (Composition 1) or adipic acid (Composition 2) as a water-soluble acid to prepare a stability test composition.

[0030] [Test Example 1] Compositions 1 and 2 of the Preparation Examples were each placed in an amber vial, sealed, and left to stand at 60°C for 14 days. Palbociclib related substances in each test composition before and after standing were quantitatively analyzed by HPLC, and the maximum content of the related substance was measured by the measurement method shown below.

[0031] <Method for measuring the amount of related substances> (Preparation of sample solution for HPLC) 1.36 g of potassium dihydrogen phosphate was dissolved in 1000 mL of water, and 2 mL of triethylamine was added. After that, phosphoric acid was added to adjust the pH to 2.2, and 700 mL of the solution was mixed with 300 mL of a 4:1 acetonitrile / methanol mixture to prepare a solvent.

[0032] 50 mg of the stability test composition was placed in a 50 mL volumetric flask, 40 mL of the prepared solvent was added, and the mixture was dispersed by ultrasonic treatment, followed by the addition of the prepared solvent to make exactly 50 mL. This solution was filtered through a membrane filter with a pore size of 0.45 μm or less, and the first filtrate (5 mL or more) was removed, and the next filtrate was used as the sample solution.

[0033] (Measurement of total related substances by HPLC) The total related substances were measured by HPLC under the conditions shown below. Column: InertSustain C18, 3.0 μm, 4.6 mm x 150 mm Column temperature: 40℃ Mobile phase A: Dissolve 1.36 g of potassium dihydrogen phosphate in 1000 mL of water, add 2 mL of triethylamine, and then add phosphoric acid to adjust the pH to 2.2. Mobile phase B: Acetonitrile / methanol mixture (4:1) Flow rate: Adjust so that the retention time of palbociclib is approximately 7 minutes. ·Measurement wavelength: 290nm The gradients of mobile phases A and B used in the above HPLC measurements are shown in Table 1.

[0034] [Table 1] TIFF2026044274000001.tif43110

[0035] Table 2 shows the measurement results for the maximum amount of related substances in palbociclib related substances. In Table 2, "Initial" refers to the test result of the formulation before storage under the above conditions. "60°C / 14 days" refers to the test result of the test composition after storage under the above conditions. The maximum amount (%) of related substances at "Initial" and "60°C / 14 days" is the amount of the largest related substance when the amount of the drug substance is taken as 100%. "Increase (%)" is the value obtained by subtracting the maximum amount (%) of related substances at the initial time from the maximum amount (%) of related substances at 60°C / 14 days.

[0036] [Table 2] TIFF2026044274000002.tif25150

[0037] As shown in Table 2, it was found that composition 2 using adipic acid exhibited a significant inhibitory effect on the increase of related substances compared to composition 1 using succinic acid, which is used in commercially available palbociclib formulations.

[0038] [Example] The following procedure was used to form the tablets of Example 1. Microcrystalline cellulose, light anhydrous silicic acid, intragranular crospovidone, and palbociclib were blended and passed through a Comill for homogenization. Next, intragranular magnesium stearate was blended. The mixture was then dry granulated using a roller compactor and a speed mill to prepare granules. The granules were mixed with sieved water-soluble acid, microcrystalline cellulose, and extragranular crospovidone. Then, extragranular magnesium stearate was mixed in as a tableting lubricant. The mixture was formed into tablets using a rotary tablet press with pre-compression. The final composition per tablet is shown in Table 3.

[0039] [Table 3] TIFF2026044274000003.tif8678

[0040] [Example 2] The following procedure was used to form the film-coated tablets according to Example 2. A coating solution was prepared by adding 185.6 g of hydroxypropylmethylcellulose, 75.8 g of titanium oxide, 16.9 g of triacetin, 0.8 g of Blue No. 2 aluminum lake, and 2.3 g of ferric oxide to 2250 g of purified water. The tablets obtained in Example 1 were coated with the coating liquid so that each tablet was coated with 15 mg of coating, to prepare film-coated tablets.

[0041] [Test Example 2] The dissolution rates of the tablets of Examples 1 and 2 were evaluated by the Japanese Pharmacopoeia Dissolution Test, Method 2 (paddle method) using water as a test solution. Ibrance (registered trademark) tablets (125 mg) were used as a control formulation. The control formulation was a tablet containing palbociclib, crystalline cellulose, light anhydrous silicic acid, crospovidone, succinic acid, magnesium stearate, hypromellose, titanium oxide, triacetin, Blue No. 2 aluminum lake, and ferric oxide. The detailed conditions for the dissolution test were set as follows: Dissolution tester: NTR-6400A, manufactured by Toyama Sangyo Co., Ltd. Test volume: 900 mL Test liquid temperature: 37±0.5℃ Paddle rotation speed: 50 rpm

[0042] The dissolution rate was measured by the following method. <Method for measuring dissolution rate> (Preparation of sample solution for HPLC) 1.36 g of potassium dihydrogen phosphate was dissolved in water to make 1000 mL, and 2 mL of triethylamine was added. After that, 700 mL of the solution was adjusted to pH 4.0 by adding diluted phosphoric acid (10-fold dilution), and this solution was mixed with 300 mL of acetonitrile to prepare the solvent.

[0043] At each sampling time, the solution was filtered through a membrane filter with a pore size of 0.45 μm or less, and 2 mL of the filtrate was accurately measured, to which 2 mL of the preparation solvent was added to prepare a sample solution.

[0044] (Measurement of dissolution rate by HPLC) The dissolution rate was measured by HPLC under the following conditions. Column: InertSustain C18, 3.0 μm, 4.6 mm x 150 mm Column temperature: 40℃ Mobile phase A: Dissolve 1.36 g of potassium dihydrogen phosphate in water to make 1000 mL, add 2 mL of triethylamine, and then add diluted phosphoric acid (10 times diluted) to adjust the pH to 4.0. Mobile phase B: Acetonitrile Mobile phase flow: Mobile phase A: Mobile phase B = 72.5:27.5 ·Flow rate: 1.0mL / min ·Measurement wavelength: 290nm

[0045] The results of measuring the dissolution rates of the tablets of Examples 1 and 2 and the control formulation are shown in Table 4.

[0046] [Table 4] TIFF2026044274000004.tif29130

[0047] As shown in Table 4, Examples 1 and 2, which used adipic acid, ensured dissolution in the neutral range in pharmaceutical tablets of palbociclib, whose solubility is pH-dependent, and it was confirmed that the dissolution properties were similar to those of the control formulation.

[0048] As described above, it was demonstrated that a formulation containing adipic acid is effective in ensuring the dissolution of palbociclib, which exhibits pH-dependent solubility, while also ensuring storage stability in tablets.

Claims

1. A pharmaceutical tablet containing palbociclib, adipic acid or a salt thereof.

2. The pharmaceutical tablet according to claim 1, wherein the content of adipic acid is 0.1 to 1.0 parts by mass per part by mass of palbociclib.

3. A pharmaceutical tablet according to claim 1 or 2, comprising 10 to 45 parts by mass of palbociclib, 5 to 30 parts by mass of adipic acid, 40 to 75 parts by mass of an excipient, 3 to 12 parts by mass of a disintegrant, and 0.5 to 4 parts by mass of a lubricant.

4. A method for producing a pharmaceutical tablet containing palbociclib as an active ingredient, comprising: preparing a granulation comprising palbociclib, an excipient, and a disintegrant; mixing the granules with adipic acid or a salt thereof and an excipient; molding the mixture to prepare tablets; A method for producing a pharmaceutical tablet, comprising:

5. The method for producing a pharmaceutical tablet according to claim 4, wherein adipic acid is contained in an amount of 0.1 to 1.0 parts by mass per part by mass of palbociclib.

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