JP2023152768A - Solid preparation, method for producing solid preparation, and method for stabilizing solid preparation - Google Patents

Abstract

To provide a solid preparation or the like, including palbociclib, with improved stability.SOLUTION: A solid preparation includes palbociclib or a pharmaceutically acceptable salt thereof, and a water-soluble acid. The water-soluble acid is at least one water-soluble acid selected from the group consisting of fumaric acid, aspartic acid and benzoic acid.SELECTED DRAWING: None

Description

The present invention relates to a solid formulation containing palbociclib or a pharmaceutically acceptable salt thereof. The present invention also relates to a method for producing the solid preparation and a method for stabilizing the solid preparation.

Palbociclib has the chemical name 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}pyrido[2,3-d]pyrimidine-7 It is a low molecular compound that is (8H)-one. Palbociclib has inhibitory activity against cyclin-dependent kinases (CDK) 4 and 6 and is used as an anti-malignant tumor agent under the name Ibrance (registered trademark).

Palbociclib is a basic compound with pH-dependent solubility, and it is known that its pharmacokinetic properties vary depending on the subject, and there is a need to improve formulations containing palbociclib. For example, U.S. Pat. No. 5,002,201 discloses that a solid dosage form comprising palbociclib and a water-soluble acid selected from the group consisting of succinic acid, malic acid and tartaric acid allows for substantially pH-independent delivery of palbociclib. Disclose.

JP 2017-2034 Publication

On the other hand, in the solid dosage form containing palbociclib disclosed in Patent Document 1, since impurities increase when stored for a certain period of time, there is room for improvement regarding its stability.

Therefore, an object of one embodiment of the present invention is to realize a solid preparation containing palbociclib and the like with improved stability.

As a result of extensive studies to solve the above problems, the present inventors have found that by incorporating a specific water-soluble acid into solid preparations containing palbociclib, the production of impurities such as palbociclib related substances can be reduced. I discovered this for the first time. Then, they discovered for the first time that the stability of palbociclib was improved, leading to the completion of the present invention. That is, one embodiment of the present invention includes the following configuration.
<1> Contains palbociclib or a pharmaceutically acceptable salt thereof and a water-soluble acid,
A solid preparation, wherein the water-soluble acid is at least one water-soluble acid selected from the group consisting of fumaric acid, aspartic acid, and benzoic acid.
<2> Including a manufacturing process of containing palbociclib or a pharmaceutically acceptable salt thereof and a water-soluble acid in a solid preparation,
A method for producing a solid preparation, wherein the water-soluble acid is at least one water-soluble acid selected from the group consisting of fumaric acid, aspartic acid, and benzoic acid.
<3> The method for manufacturing a solid preparation according to <2>, wherein the manufacturing step is any one or more steps selected from the group consisting of the following steps (A) to (D):
(A) mixing the palbociclib or a pharmaceutically acceptable salt thereof and the water-soluble acid and tableting;
(B) a step of laminating the layer containing the palbociclib or a pharmaceutically acceptable salt thereof and the layer containing the water-soluble acid and compressing into a tablet;
(C) disposing an outer layer containing the palbociclib or a pharmaceutically acceptable salt thereof on the inner core containing the water-soluble acid and tableting;
(D) A step of disposing an outer layer containing the water-soluble acid on the inner core containing the palbociclib or a pharmaceutically acceptable salt thereof, and then tableting.
<4> In a solid preparation containing palbociclib or a pharmaceutically acceptable salt thereof,
A method for stabilizing palbociclib or a pharmaceutically acceptable salt thereof in a solid preparation, the method comprising the step of containing at least one water-soluble acid selected from the group consisting of fumaric acid, aspartic acid and benzoic acid.

According to one aspect of the present invention, it is possible to provide a solid preparation containing palbociclib and the like that has improved stability.

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

[1. Solid preparation]
A solid preparation according to one aspect of the present invention (hereinafter sometimes referred to as "this solid preparation") contains palbociclib or a pharmaceutically acceptable salt thereof and a water-soluble acid.

(palbociclib)
Palbociclib has the chemical name 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}pyrido[2,3-d]pyrimidine-7 This is a compound that is (8H)-one. Palbociclib or a pharmaceutically acceptable salt thereof is the active ingredient of the solid formulation.

As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is medically free from excessive toxicity, irritation, allergic reactions, etc., and is suitable for use in contact with human or other mammalian tissue. It means salt.

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

The content of palbociclib or a pharmaceutically acceptable salt thereof in the solid preparation is preferably 5 to 95% by weight, more preferably 10 to 70% by weight, based on the weight of the solid preparation. , more preferably 15 to 45% by mass.

The particle size of palbociclib or a pharmaceutically acceptable salt thereof in the present solid preparation preferably has a D50 of 1 to 18 μm and a D90 of 3 to 24 μm. Further, the specific surface area of palbociclib or a pharmaceutically acceptable salt thereof in the present solid preparation is usually 3 m ² /g or more, preferably 3 to 8 m ² /g.

(water soluble acid)
The water-soluble acid is at least one kind of water-soluble acid selected from the group consisting of fumaric acid, aspartic acid, and benzoic acid. By including the water-soluble acid in place of succinic acid in the present solid preparation, the production of impurities is reduced and the stability (eg, storage stability) of the present solid preparation is improved. Examples of impurities include substances related to palbociclib. The analogs of palbociclib may be all analogs of palbociclib or specific analogs of palbociclib. Examples of specific analogs of palbociclib include amide forms of palbociclib.

In particular, in the case of high-content tablets in which the content of palbociclib or its pharmaceutically acceptable salt is 40% by mass or more based on the mass of the solid preparation, in tablets containing succinic acid as a water-soluble acid, There is concern that the contact area between palbociclib or its pharmaceutically acceptable salt and succinic acid will increase, resulting in increased formation of impurities. Therefore, in high-content tablets, adding at least one water-soluble acid selected from the group consisting of fumaric acid, aspartic acid, and benzoic acid in place of succinic acid is effective in reducing the formation of impurities. is remarkable.

The water-soluble acid is preferably fumaric acid, since the generation of impurities such as palbociclib related substances is further reduced.

The content of the water-soluble acid in the solid preparation is preferably 1 to 40% by mass, more preferably 5 to 30% by mass, even more preferably 7 to 30% by mass, based on the mass of the solid preparation. It is 25% by mass.

(Other ingredients)
This solid preparation contains ingredients other than palbociclib or its pharmaceutically acceptable salt and water-soluble acid, such as excipients, binders, lubricants, disintegrants, surfactants, plasticizers, and colorants. It may also contain an agent.

Excipients include, but are not particularly limited to, D-mannitol, lactose (e.g., lactose hydrate), white sugar, corn starch, calcium phosphate, sorbitol, crystalline cellulose, light anhydrous silicic acid, and the like. .

Examples of the binder include, but are not limited to, hydroxypropylcellulose, hydroxypropylmethylcellulose (also referred to as "hypromellose"), povidone, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, N-vinylpyrrolidone and vinyl acetate. Examples include copolymers or combinations of these polymers, pregelatinized starch, gelatin, agar, gum arabic, and the like.

Examples of lubricants include, but are not limited to, talc, kaolin, inert substances such as titanium dioxide, magnesium stearate, calcium stearate, stearic acid, light silicic anhydride, finely ground silicon dioxide, and sodium stearyl fumarate. , glycerin fatty acid ester, etc.

Examples of the disintegrant include, but are not limited to, crospovidone, low-substituted hydroxypropylcellulose, sodium starch glycolate, croscarmellose sodium, carmellose, carmellose calcium, potato starch, and the like.

The coloring agent is not particularly limited, but includes, for example, a coloring agent that exhibits a yellow color (e.g., yellow iron sesquioxide, yellow iron oxide, food yellow No. 4 aluminum lake, red iron oxide, etc.), a colorant that exhibits a red color (e.g., yellow iron sesquioxide, yellow iron oxide, food yellow No. 4 aluminum lake, red iron oxide, etc.). iron, Food Red No. 2, Food Red No. 3, Food Red No. 102, etc.), colorants that give a black color (e.g., black iron oxide, carbon black, medicinal charcoal, etc.), colorants that give a blue color (e.g., Blue No. 2) (aluminum lake, etc.), caramel, etc.

The content of additives in the present solid preparation is not particularly limited, and can be appropriately set based on conventionally known techniques.

(Dosage form of solid preparation)
The dosage form of the present solid preparation is preferably a preparation shaped to be administered orally. Examples of formulations shaped to be administered orally include tablets (including orally disintegrating tablets), capsules, granules, powders, dry syrups, and the like. The dosage form of this solid preparation is more preferably a tablet. Examples of tablets include monolayer tablets; laminated tablets such as multilayer tablets; and dry-coated tablets.

The shape of the present solid preparation is not particularly limited, and any shape can be adopted. When the formulation of the present invention is a tablet, it may be, for example, circular, oval, spherical, rod-shaped, donut-shaped, or the like.

When the present solid preparation is a tablet, its hardness is preferably 30 to 300N. In the case of a circular tablet, the thickness (tablet thickness) is, for example, 1 to 10 mm, preferably 4 to 8 mm, and the diameter is not particularly limited, but from the viewpoint of handling, for example, 4 to 8 mm. -20 mm, preferably 5-16 mm. In the case of an oval tablet, the thickness (tablet thickness) is, for example, 1 to 10 mm, preferably 2 to 8 mm, and the major axis is not particularly limited, but from the viewpoint of handling, for example, 20 mm, preferably 6 to 16 mm, and the short axis is not particularly limited, but from the viewpoint of handling, it is, for example, 3 to 12 mm, preferably 4 to 10 mm.

When the solid preparation is a tablet, it contains, for example, 25 to 125 mg of palbociclib or a pharmaceutically acceptable salt thereof.

This solid preparation may be further coated as necessary. The coating agent used for coating is not particularly limited, but examples include hydroxypropylcellulose, hydroxypropylmethylcellulose (also referred to as "hypromellose"), polyvinyl alcohol, polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, etc. . Further, coating may be performed by adding a light shielding agent or a plasticizer as appropriate. Examples of the light shielding agent include yellow iron sesquioxide, iron sesquioxide, titanium oxide, and blue No. 2 aluminum lake. Examples of the plasticizer include triacetin, macrogol, hydroxypropylcellulose, propylene glycol, triethyl citrate, and the like.

The amount of coating agent used for coating may be adjusted as appropriate; for example, when the present solid preparation is a tablet, it is coated in an amount ranging from 1 to 10% by weight based on the weight of the tablet.

Further, the present solid preparation may be packaged using PTP packaging, bottle filling, aluminum packaging, etc., as necessary.

Examples of materials for PTP packaging include resins such as polyvinyl chloride, polypropylene, polyvinylidene chloride, polychlorotrifluoroethylene, polyethylene, polystyrene, or polycarbonate, and metals such as aluminum. These materials may be used alone or in combination. Examples of combinations include, for example, laminating polyvinyl chloride and polyvinylidene chloride, or laminating polyvinyl chloride and polychlorotrifluoroethylene. The solid preparation can be packaged by placing the solid preparation in a molded pocket of a resin sheet molded from the above-mentioned resin by a known method and covering it with aluminum foil.

The PTP package containing the present solid preparation may be further wrapped with an aluminum pillow. This aluminum pillow may further contain a desiccant. Examples of the desiccant include calcium chloride, calcium oxide, magnesium oxide, silica gel, and zeolite.

[2. Manufacturing method of solid preparation]
A method for producing a solid dosage form according to one aspect of the present invention (hereinafter sometimes referred to as "the present manufacturing method") includes incorporating palbociclib or a pharmaceutically acceptable salt thereof and a water-soluble acid into a solid dosage form. Including manufacturing process. In this manufacturing method, the description of each component (for example, "palbociclib or a pharmaceutically acceptable salt thereof" and "water-soluble acid") is as follows [1. Solid preparations] are incorporated herein by reference.

(Manufacturing process)
In the above manufacturing process, for example, by adding a water-soluble acid to palbociclib or a pharmaceutically acceptable salt thereof, palbociclib or a pharmaceutically acceptable salt thereof and a water-soluble acid are included in the solid preparation. I can do it. The water-soluble acid may be added, for example, in a manner in which it is added and mixed simultaneously with the other components mentioned above, or in a manner in which components other than the water-soluble acid are prepared in advance and the water-soluble acid is added to the preparation. You may go.

Further, the manufacturing process may be, for example, one or more steps selected from the group consisting of the following steps (A), (B), and (C).

(A) a step of mixing palbociclib or a pharmaceutically acceptable salt thereof and a water-soluble acid and tableting;
(B) a step of laminating a layer containing palbociclib or a pharmaceutically acceptable salt thereof and a layer containing a water-soluble acid and tableting;
(C) A step of disposing palbociclib or a pharmaceutically acceptable salt thereof as an outer layer on an inner core containing a water-soluble acid and then tableting.

(Process (A))
In step (A), palbociclib or a pharmaceutically acceptable salt thereof and a water-soluble acid are mixed. In the mixing, a mixture of palbociclib or a pharmaceutically acceptable salt thereof and an additive, and a mixture of a water-soluble acid and an additive may be mixed. The mixture may be subjected to granulation such as dry granulation or granulation.

A solid preparation can be obtained by tabletting a mixture of palbociclib or a pharmaceutically acceptable salt thereof and a water-soluble acid.

(Process (B))
In step (B), a layer containing palbociclib or a pharmaceutically acceptable salt thereof and a layer containing a water-soluble acid are laminated. Through step (B), a solid preparation having a multilayer structure of two or more layers (for example, a laminated tablet such as a multilayer tablet) is obtained. Each of the layer containing palbociclib or a pharmaceutically acceptable salt thereof and the layer containing a water-soluble acid may contain an additive. Alternatively, palbociclib or a pharmaceutically acceptable salt thereof or a water-soluble acid may be laminated with an additive and a processed product such as granulation or sizing.

After lamination, a solid preparation can be obtained by tabletting.

(Steps (C) and (D))
In step (C), an outer layer containing palbociclib or a pharmaceutically acceptable salt thereof is placed on the inner core containing a water-soluble acid. In step (D), an outer layer containing a water-soluble acid is placed on the inner core containing palbociclib or a pharmaceutically acceptable salt thereof. By step (C) or (D), a solid preparation (for example, a dry-coated tablet) is obtained which is formed from two parts: an inner core (inner core part) and an outer shell (outer shell part, outer layer).

In steps (C) and (D), the inner core and outer layer may each contain additives. In addition, in steps (C) and (D), palbociclib or its pharmaceutically acceptable salt or water-soluble acid is treated with additives and granulated or sized as an inner core or outer layer. good.

In steps (C) and (D), a solid preparation may be obtained by compression molding the components constituting the inner core, disposing an outer layer, and then tableting.

The tableting pressure in this production method can be appropriately adjusted depending on the formulation, type, shape, etc. of the solid preparation, but is preferably in the range of 4 to 20 kN, for example.

In this manufacturing method, in addition to the above-mentioned steps, any steps that are carried out in the manufacturing of solid preparations may be performed. Examples of the optional steps include a step of laminating and coating a solid preparation with a film or the like containing a water-soluble polymer.

The moisture value in the tablet is not particularly limited, but is usually in the range of 0.1 to 12% by mass, preferably in the range of 0.5 to 10% by mass, and preferably in the range of 1 to 8% by mass. is more preferable, more preferably in the range of 1.5 to 6% by mass, and even more preferably in the range of 2 to 5% by mass. Note that the moisture value in this specification is a value measured based on the Karl Fischer method, but a drying loss test method or the like may be adopted as appropriate.

[3. Method for stabilizing solid preparations]
The method for stabilizing a solid dosage form according to one aspect of the present invention (hereinafter sometimes referred to as "the present stabilization method") is a method for stabilizing palbociclib or a pharmaceutically acceptable salt thereof in the present solid dosage form. be. This stabilization method includes the step of incorporating a water-soluble acid into a solid preparation containing palbociclib or a pharmaceutically acceptable salt thereof. In this stabilization method, the description of each component (for example, "palbociclib or a pharmaceutically acceptable salt thereof" and "water-soluble acid") is as follows [1. Solid preparations] are incorporated herein by reference.

As described above, the present stabilization method reduces the production of impurities by incorporating a water-soluble acid into a solid formulation containing palbociclib or a pharmaceutically acceptable salt thereof. By reducing the production of impurities, the stability of solid formulations containing palbociclib or a pharmaceutically acceptable salt thereof can be improved. Therefore, the present stabilization method is extremely useful in designing a solid formulation containing palbociclib or a pharmaceutically acceptable salt thereof with improved stability.

The amount of impurities in the present solid preparation can be determined, for example, by HPLC (high performance liquid chromatography).

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

An embodiment of the present invention will be described below. In the following examples, unless otherwise specified, % represents mass %.

[Example 1] Preparation of test composition 6 mg of palbociclib (active drug substance) and 6 mg of fumaric acid were mixed to prepare a test composition.

[Example 2] Preparation of test composition A test composition was prepared in the same manner as in Example 1 except that fumaric acid was changed to benzoic acid.

[Example 3] Preparation of test composition A test composition was prepared in the same manner as in Example 1 except that fumaric acid was changed to aspartic acid.

[Comparative Example] Preparation of Test Composition A test composition was prepared in the same manner as in Example 1 except that fumaric acid was changed to succinic acid.

[Evaluation Example 1] Evaluation of storage stability of palbociclib The test compositions of Examples 1 to 3 and Comparative Example were each left open at 50° C. and 75% RH for 14 days. The total amount of palbociclib related substances in each test composition before and after standing for 14 days was measured by the measurement method shown below. Further, as a reference example, only 6 mg of palbociclib (drug substance) was similarly evaluated.

<Method for measuring the amount of total related substances>
(Preparation of sample solution for HPLC)
Each test composition was placed in a brown volumetric flask, and a 100 mL volumetric flask was used.

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

After ultrasonication, it was diluted with acetonitrile. The solution after dilution was centrifuged at 3000 rpm for 5 minutes at 10°C, and the supernatant was collected. 5 mL of the collected supernatant was collected and poured into a 20 mL brown volumetric flask. Then, the sample solution was diluted with a diluent to prepare a sample solution having a palbociclib concentration of about 0.3 mg/mL. As the diluent, a mixture of phosphoric acid diluted 100 times with water and acetonitrile at a ratio of 1:1 was used.

(Measurement of total related substances by HPLC)
Total related substances were measured by HPLC under the conditions shown below.
・HPLC: LC-20A manufactured by Shimadzu Corporation
・Detector: Ultraviolet absorption photometer ・Measurement wavelength: 364nm
・Column: YMC-Triart PEP, 4.6mm x 150mm, 3μm
・Column temperature: Constant temperature around 40°C ・Mobile phase A: A solution of 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 : Approximately 1.0mL/min
・Injection volume (sample solution): 10 μL
・Sample cooler temperature: 10℃
Table 1 shows the gradients of mobile phases A and B in the above HPLC measurement. The numerical values of mobile phases A and B in Table 1 indicate the proportions (%) of mobile phases A and B contained in the mobile phase (eluent).

Table 2 shows the measurement results for all related substances of palbociclib. In Table 2, "initial" is the test result of the test composition before being left under the above-mentioned open conditions. "50° C. 75% RH" is the test result of the test composition after being left under the above open conditions. The amount (%) of total related substances in "initial" and "50°C 75%RH" is the ratio when the amount of drug substance is taken as 100%. “Increase amount (%)” is the value obtained by subtracting the initial total related substances (%) from the total related substances (%) at 50°C and 75% RH.

As shown in Table 2, the amount of increase in total related substances in the test composition of Example 1 was the same as that of the reference example (drug substance only). Although the amount of total related substances in the test composition of Example 2 or Example 3 was increased compared to the results of the reference example, the amount of total related substances in the test composition with succinic acid used in palbociclib tablets (comparative example) It was found that the amount of total related substances was within an acceptable range. These results showed that even when fumaric acid, benzoic acid, or aspartic acid was brought into contact with palbociclib, the production of all related substances was suppressed. That is, it was found that the storage stability of palbociclib was improved by using fumaric acid, benzoic acid, or aspartic acid.

[Formulation Example 1] Preparation of tablets Palbociclib, crystalline cellulose (Asahi Kasei Corporation, Ceolus PH-101), light silicic anhydride (Freund Sangyo Co., Ltd., Adsolider (registered trademark)-101), and crospovidone (BASF Japan) (manufactured by Kollidon CL-F) was roughly mixed in the amounts shown in Table 3, and after sieving, the mixture was mixed to obtain a powder.

Next, the powder powder and magnesium stearate were mixed in the amounts shown in Table 3 to obtain a lubricant mixed powder. The obtained lubricant mixed powder was dry granulated and sized to obtain a sized powder. Uncoated tablets were obtained by mixing the obtained sized powder with the final powder shown in Table 3 containing fumaric acid and compressing the mixture.

A coating solution was prepared by dissolving or dispersing hypromellose (manufactured by Shin-Etsu Chemical Co., Ltd., TC-5R), titanium oxide, triacetin, blue No. 2 aluminum lake, and iron sesquioxide in purified water. The uncoated tablet was placed in a coating pan machine, sprayed with the coating liquid, and then dried to obtain a film-coated tablet.

[Formulation Example 2] Preparation of Tablets Tablets were prepared in the same manner as in Formulation Example 1, except that the amounts of each component were changed to those shown in Table 3.

[Formulation Example 3] Preparation of Tablets Tablets were prepared in the same manner as in Formulation Example 1, except that the amounts of each component were changed to those shown in Table 3.

[Formulation Example 4] Preparation of tablets Palbociclib, crystalline cellulose (Asahi Kasei Corporation, Ceolus PH-101), light silicic anhydride (Freund Sangyo Co., Ltd., Adsolider (registered trademark)-101), and crospovidone (BASF Japan) Kollidon CL-F) (manufactured by Kollidon CL-F) was placed in a wet high shear granulator in the amounts shown in Table 4 and mixed.

Hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd., HPC-L) was dissolved in purified water to prepare a granulation solution. Then, a granulation liquid was sprayed onto the mixture to granulate it.

After drying the granulated product, it was sized to obtain a sized powder. Uncoated tablets were obtained by mixing the resulting sized powder with the final powder shown in Table 4 containing fumaric acid and compressing the mixture.

A coating solution was prepared by dissolving or dispersing hypromellose (manufactured by Shin-Etsu Chemical Co., Ltd., TC-5R), titanium oxide, triacetin, blue No. 2 aluminum lake, and iron sesquioxide in purified water. The uncoated tablet was placed in a coating pan machine, sprayed with the coating liquid, and then dried to obtain a film-coated tablet.

[Formulation Example 5] Preparation of Tablets Tablets were prepared in the same manner as in Formulation Example 4, except that the amounts of each component were changed to those shown in Table 4.

[Formulation Example 6] Preparation of Tablets Bilayer tablets were prepared according to steps 1 to 3 below.

(Procedure 1) Preparation of palbociclib mixed powder (first layer) Palbociclib (active drug substance), crystalline cellulose (manufactured by Asahi Kasei Corporation, Ceolus KG-1000), light silicic anhydride (manufactured by Nippon Aerosil Co., Ltd., AEROSIL (registered trademark)) 200) and crospovidone (manufactured by BASF Japan Co., Ltd., Kollidon CL-F) were roughly mixed in the amounts shown in Table 5, passed through a sieve, and mixed to obtain a triturated powder.

Next, the powder powder and magnesium stearate (general grade) were mixed in the amounts shown in Table 5 to obtain a lubricant mixed powder. The obtained lubricant mixed powder was dry granulated and sized to obtain a sized powder. The obtained sized powder, crystalline cellulose (CEOLUS KG-1000), crospovidone (manufactured by BASF Japan Co., Ltd., Kollidon CL), and magnesium stearate (general grade) were mixed in the amounts shown in Table 5, and the mixed powder (1 layer) was obtained.

(Procedure 2) Preparation of aspartic acid mixed powder (second layer) Aspartic acid, crystalline cellulose (CEOLUS KG-1000), crospovidone (Kollidon CL), and magnesium stearate (general grade) were mixed in the amounts shown in Table 5. , a mixed powder (second layer) was obtained.

(Procedure 3) Tablet Compression A two-layer tablet was obtained by laminating the mixed powder (first layer) and the mixed powder (second layer) (tableting pressure: 4 kN).

[Formulation Example 7] Preparation of Tablets Tablets were prepared in the same manner as in Formulation Example 6, except that the amounts of each component were changed to those shown in Table 5.

[Evaluation Example 2] Evaluation of storage stability of palbociclib in tablets The tablets of Formulation Example 6 were evaluated for storage stability of palbociclib when stored under conditions 1 to 4 below.
・Condition 1: Stored at 70℃ for 9 days in double-sided AL packaging conditions. ・Condition 2: Stored at 40℃ 75% RH for 1 month in double-sided AL packaging conditions. ・Condition 3: Stored at 40℃ 75%RH for 2 months. Stored in double-sided AL packaging conditions ・Condition 4: Stored in open conditions at 40°C and 75%RH for 1 month

The total amount of palbociclib related substances in each tablet stored under conditions 1 to 4 above was measured by HPLC under the same conditions as Evaluation Example 1.

Table 6 shows the measurement results for all related substances of palbociclib. In Table 6, "initial" is the test result of the tablet before starting the stability evaluation.

As shown in Table 6, no significant increase in related substances was observed by using aspartic acid.

INDUSTRIAL APPLICABILITY The present invention can improve the stability of solid preparations containing palbociclib or a pharmaceutically acceptable salt thereof, and can be suitably used in the treatment of malignant tumors.

Claims (4)

comprising palbociclib or a pharmaceutically acceptable salt thereof, and a water-soluble acid;
A solid preparation, wherein the water-soluble acid is at least one water-soluble acid selected from the group consisting of fumaric acid, aspartic acid, and benzoic acid. A manufacturing process of containing palbociclib or a pharmaceutically acceptable salt thereof and a water-soluble acid in a solid preparation,
A method for producing a solid preparation, wherein the water-soluble acid is at least one water-soluble acid selected from the group consisting of fumaric acid, aspartic acid, and benzoic acid. The method for manufacturing a solid preparation according to claim 2, wherein the manufacturing step is any one or more steps selected from the group consisting of the following steps (A) to (D):
(A) mixing the palbociclib or a pharmaceutically acceptable salt thereof and the water-soluble acid and tableting;
(B) a step of laminating the layer containing the palbociclib or a pharmaceutically acceptable salt thereof and the layer containing the water-soluble acid and compressing into a tablet;
(C) disposing an outer layer containing the palbociclib or a pharmaceutically acceptable salt thereof on the inner core containing the water-soluble acid and tableting;
(D) A step of disposing an outer layer containing the water-soluble acid on the inner core containing the palbociclib or a pharmaceutically acceptable salt thereof, and then tableting. In a solid preparation containing palbociclib or a pharmaceutically acceptable salt thereof,
A method for stabilizing palbociclib or a pharmaceutically acceptable salt thereof in a solid preparation, the method comprising the step of containing at least one water-soluble acid selected from the group consisting of fumaric acid, aspartic acid and benzoic acid.