Pharmaceutical preparation of protein kinase inhibitor citrate as well as preparation method and application of pharmaceutical preparation

Abstract

The invention discloses a pharmaceutical preparation of a protein kinase inhibitor citrate as well as a preparation method and application of the pharmaceutical preparation. The pharmaceutical preparation comprises citrate of a protein kinase CDK4 / 6 inhibitor and auxiliary materials including a filler, a disintegrating agent, an adhesive, a wetting agent, a glidant and a lubricant. The protein kinase inhibitor citrate pharmaceutical preparation has the advantages of being good in quality, high in stability, high in dissolution rate, simple in preparation method, controllable in quality and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a pharmaceutical preparation of a protein kinase inhibitor citrate, and a preparation method and application thereof. Background Art

[0002] Cyclin-dependent kinase CDK4 / 6 inhibitors can selectively inhibit CDK4 / 6 kinase activity, downregulate CDK / Rb signaling pathway, and block the cell cycle in the G1 phase; its activity is stronger than that of similar drugs such as ribociclib. At the cellular level, this protein kinase inhibitor has strong proliferation inhibition activity on Rb-positive tumor cell lines and has significant in vivo anti-tumor effects. It has shown a strong anti-tumor effect when administered alone in four in vivo models of Rb-positive breast cancer, colon cancer, and glioma; in an in vivo breast cancer model, the compound has a synergistic effect on fulvestrant when combined with fulvestrant. Clinical studies have shown that the combination with fulvestrant is suitable for hormone receptor (HR)-positive, human epidermal growth factor 2 (HER2)-negative locally advanced or metastatic breast cancer that has progressed after previous endocrine therapy.

[0003] The paragraphs

[0081] to

[0083] of CN116836177A disclose a protein kinase CDK4 / 6 inhibitor citrate; it has high stability and solubility, and can be further prepared into tablets, capsules, granules and other preparations. However, in the process of preparing tablets by wet granulation, the raw materials become sticky and easy to be sieved when exposed to water, and the dry granules after wet granulation are too hard, and some granules cannot be sieved, resulting in a low yield. At the same time, the solubility of the obtained tablets is low and they are unstable under light.

[0004] In view of this, the present invention is proposed. Summary of the invention

[0005] The purpose of the present invention is to provide a pharmaceutical preparation of protein kinase CDK4 / 6 inhibitor citrate, which has the advantages of good quality, high stability and high solubility, and the preparation method is simple and the quality is controllable.

[0006] In order to achieve the above object, the technical solution adopted by the present invention is as follows:

[0007] In a first aspect, the present invention provides a pharmaceutical preparation comprising the following components: 100 parts by weight of a protein kinase CDK4 / 6 inhibitor citrate, 15.0 to 150.0 parts by weight of a diluent / filler, 5.0 to 20.0 parts by weight of a disintegrant, 0 to 26.0 parts by weight of a binder, 0 to 7.0 parts by weight of a glidant, and 0.5 to 5.0 parts by weight of a lubricant.

[0008] The structure of the protein kinase CDK4 / 6 inhibitor citrate is shown in Formula I:

[0009]

[0010] The present invention optimizes auxiliary materials and dosages, and significantly improves the dissolution of protein kinase CDK4 / 6 inhibitor citrate while ensuring pharmacological activity and stability.

[0011] In the present invention, the diluent / filler in the pharmaceutical preparation is selected from one or more of microcrystalline cellulose, starch, lactose and mannitol, preferably lactose and mannitol.

[0012] In the present invention, the disintegrant in the pharmaceutical preparation is selected from one or more of cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch and low-substituted hydroxypropyl methylcellulose, preferably sodium carboxymethyl starch.

[0013] In the present invention, the binder in the pharmaceutical preparation is selected from one or more of methylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, povidone K30 and starch, preferably povidone K30.

[0014] In the present invention, the glidant in the pharmaceutical preparation is selected from silicon dioxide and / or talc, preferably silicon dioxide.

[0015] In the present invention, the wetting agent in the pharmaceutical preparation is selected from water and / or ethanol; preferably water.

[0016] In the present invention, the lubricant in the pharmaceutical preparation is selected from one or more of sodium stearyl fumarate, magnesium stearate and stearic acid, preferably sodium stearyl fumarate.

[0017] In the present invention, the dosage form of the pharmaceutical preparation is tablets, capsules, granules, and powders. Preferably, tablets and capsules are used. Depending on the dosage form, the pharmaceutical preparation includes one of the following situations:

[0018] The pharmaceutical preparation is a tablet, which comprises the following components: 100 parts by weight of protein kinase CDK4 / 6 inhibitor citrate, 15.0-150.0 parts by weight of diluent / filler, 5.0-20.0 parts by weight of disintegrant, 0-7.0 parts by weight of glidant, and 0.5-5.0 parts by weight of lubricant.

[0019] Preferably, the tablet is composed of the following components: 100 parts by weight of protein kinase CDK4 / 6 inhibitor citrate; 57.7 to 84.7 parts by weight of diluent / filler; 5.0 to 13.0 parts by weight of disintegrant; 1.0 to 5.0 parts by weight of glidant; and 0.5 to 5.0 parts by weight of lubricant.

[0020] The pharmaceutical preparation is a capsule, which comprises the following components: 100 parts by weight of protein kinase CDK4 / 6 inhibitor citrate, 15.0 to 150.0 parts by weight of diluent / filler, 0 to 7.0 parts by weight of glidant, and 0.5 to 5.0 parts by weight of lubricant;

[0021] Preferably, the capsule is composed of the following components: 100 parts by weight of protein kinase CDK4 / 6 inhibitor citrate; 57.7 to 84.7 parts by weight of diluent / filler; 1.0 to 5.0 parts by weight of glidant; and 0.5 to 5.0 parts by weight of lubricant.

[0022] The pharmaceutical preparation is a granule, which includes the following components: 100 parts by weight of protein kinase CDK4 / 6 inhibitor citrate, 15.0-150.0 parts by weight of diluent / filler, 5.0-20.0 parts by weight of disintegrant, 0-26.0 parts by weight of binder, 0-7.0 parts by weight of glidant, and 0.5-5.0 parts by weight of lubricant.

[0023] Preferably, the granules are composed of the following components: 100 parts by weight of protein kinase CDK4 / 6 inhibitor citrate; 57.7 to 84.7 parts by weight of diluent / filler; 5.0 to 13.0 parts by weight of disintegrant; 0 to 26.0 parts by weight of binder, 1.0 to 5.0 parts by weight of glidant; and 0.5 to 5.0 parts by weight of lubricant.

[0024] The pharmaceutical preparation is a powder, which comprises the following components: 100 parts by weight of protein kinase CDK4 / 6 inhibitor citrate, 15.0 to 150.0 parts by weight of diluent / filler, 0 to 7.0 parts by weight of glidant, and 0.5 to 5.0 parts by weight of lubricant.

[0025] Preferably, the powder is composed of the following components: 100 parts by weight of protein kinase CDK4 / 6 inhibitor citrate; 57.7 to 84.7 parts by weight of diluent / filler; 1.0 to 5.0 parts by weight of glidant; and 0.5 to 5.0 parts by weight of lubricant.

[0026] In a second aspect, the present invention also provides a method for preparing the above-mentioned pharmaceutical preparation, comprising the following steps: mixing the raw materials to prepare a dosage form.

[0027] According to different dosage forms, the pharmaceutical preparation is prepared as follows:

[0028] (1) The pharmaceutical preparation is a tablet, which is prepared according to the following steps: grinding and sieving the protein kinase CDK4 / 6 inhibitor citrate, mixing with auxiliary materials, tabletting, and coating;

[0029] (2) The pharmaceutical preparation is a granule, which is prepared according to the following operation: the protein kinase CDK4 / 6 inhibitor citrate is crushed and sieved, and added to water to prepare a solution with a protein kinase CDK4 / 6 inhibitor citrate concentration of 35.0% to 65.0%, and then the filler and disintegrant are premixed and added to a fluidized bed, and the solution is used for fluidized spray granulation, and the obtained granules are granulated and mixed with a glidant and a lubricant, and packaged;

[0030] (3) The pharmaceutical preparation is a capsule, which is prepared according to the following operation: the protein kinase CDK4 / 6 inhibitor citrate is crushed and sieved, mixed with a filler, and then a glidant and a lubricant are added and mixed, and then filled into a capsule;

[0031] (4) The pharmaceutical preparation is a powder, which is prepared according to the following operation: the protein kinase CDK4 / 6 inhibitor citrate is crushed and sieved, mixed with a filler, and then a glidant and a lubricant are added and mixed, and then packaged.

[0032] In a third aspect, the present invention provides use of the above-mentioned pharmaceutical preparation in the preparation of a drug for treating, improving or preventing abnormal cell proliferation.

[0033] Compared with the prior art, the present invention has the following beneficial effects:

[0034] The protein kinase CDK4 / 6 inhibitor citrate pharmaceutical preparation provided by the present invention has the advantages of good quality, high stability, high solubility, etc., and the preparation method is simple and controllable. In particular, the preparation of tablets can adopt a simple traditional powder direct compression process, with good compressibility, and obtain a bright tablet surface, no cracks, no sticking, high yield, and good dissolution and stability of the tablets prepared by film coating, which solves the problems of hard particles, low yield, and low solubility of the prepared tablets using the existing wet granulation method. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 This is the dissolution curve of the tablets prepared by wet granulation in Comparative Example 1.

[0036] Figure 2 This is the dissolution curve of the tablets prepared by one-step granulation in Comparative Example 2.

[0037] Figure 3 This is the dissolution curve of the tablets obtained by direct compression of the powder in Example 1.

[0038] Figure 4 The dissolution curves of Comparative Example 1, Comparative Example 2 and Example 1 in a pH 1.2 medium are compared.

[0039] Figure 5 The dissolution curves of Comparative Example 1, Comparative Example 2 and Example 1 in a pH 4.5 medium are compared.

[0040] Figure 6 The dissolution curves of Comparative Example 1, Comparative Example 2 and Example 1 in a pH 6.8 medium are compared.

[0041] Figure 7 The dissolution curves of Comparative Example 1, Comparative Example 2 and Example 1 in aqueous medium are compared.

[0042] Figure 8 The dissolution curve of the powder prepared in Example 2.

[0043] Fig. 9 The dissolution curve of the capsule prepared in Example 3.

[0044] Fig.10 The dissolution curve of the granules prepared in Example 4. DETAILED DESCRIPTION

[0045] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0046] Unless otherwise specified, the reagents, materials, instruments, etc. used in the following examples can be obtained from commercial sources.

[0047] The auxiliary materials used in the embodiments of the present invention are all domestic commercial products, and those skilled in the art can purchase them from domestic commercial channels.

[0048] The raw material protein kinase CDK4 / 6 inhibitor citrate used in the embodiments of the present invention has a structure as shown in Formula I, and its chemical name is 7-cyclopentyl-N,N-dimethyl-2-((5-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide dicitrate, CAS No.: 2854300-81-3, molecular formula C 29 H 40 N8OS·2C6H8O7, molecular weight 933.006, no chiral carbon atom in the stereostructure, no chiral isomerism. The protein kinase CDK4 / 6 inhibitor citrate can be obtained according to the preparation method disclosed in paragraphs

[0160] to

[0210] of Chinese patent application CN116836177A.

[0049] The structural formula of protein kinase CDK4 / 6 inhibitor citrate is as follows:

[0050]

[0051] Example 1: Preparation of tablets by direct powder compression

[0052] prescription:

[0053] Table 1 Recipe

[0054] Raw materials Prescription ratio (w / w) API Protein kinase CDK4 / 6 inhibitor citrate 567％ Thinner / filler lactose 37.3％ Disintegrants Sodium carboxymethyl starch 4.0％ Glidants Silicon dioxide 1.0％ Lubricants Sodium stearyl fumarate 1.0％ Coating materials Coating powder 3％

[0055] Preparation method: Crush and sieve the raw material, mix it with the prescribed amount of lactose and sodium carboxymethyl starch, add silicon dioxide and sodium stearyl fumarate, mix evenly, press into tablets, and coat.

[0056] Embodiment 2, powder

[0057] prescription:

[0058] Table 2 Formulation

[0059] Raw materials Prescription ratio (w / w) API Protein kinase CDK4 / 6 inhibitor citrate 56.7％ Thinner / filler lactose 40.3％ Glidants Silicon dioxide 2％ Lubricants Sodium stearyl fumarate 1％

[0060] Preparation method: Crush the raw material drug through a 60-mesh sieve, mix it with the prescribed amount of lactose, add silicon dioxide and sodium stearyl fumarate, mix evenly, and pack it in bags to prepare powders.

[0061] Embodiment 3, capsule

[0062] prescription:

[0063] Table 3 Recipe

[0064] Raw materials Prescription ratio (w / w) API Protein kinase CDK4 / 6 inhibitor citrate 56.7％ Thinner / filler lactose 40.3％ Glidants Silicon dioxide 2％ Lubricants Sodium stearyl fumarate 1％

[0065] Preparation method: Crush and sieve the raw material, mix it with the prescribed amount of lactose, add silicon dioxide and sodium stearyl fumarate, mix evenly, and fill the capsules.

[0066] Example 4, granules

[0067] prescription:

[0068] Table 4 Recipe

[0069] Raw materials Prescription ratio (w / w) API Protein kinase CDK4 / 6 inhibitor citrate 56.7％ Thinner / filler Mannitol 37.4％ Disintegrants Sodium carboxymethyl starch 4.0％ Glidants Silicon dioxide 10％ Lubricants Sodium stearyl fumarate 1 0％ Wetting Agents water Moderate

[0070] Preparation method: The raw material drug is crushed and sieved and added to purified water to prepare a solution with a raw material drug concentration of 35.0% to 65.0%, which is set aside. The prescribed amount of mannitol and sodium carboxymethyl starch is added to the fluidized bed, and the prepared solution is used for fluidized spray granulation. The obtained granules are granulated and mixed with silicon dioxide and sodium stearyl fumarate, and then packaged in bags to prepare granules.

[0071] Comparative Example 1: Preparation of tablets by wet granulation

[0072] prescription:

[0073] Table 5 Formulation

[0074]

[0075] Preparation method: The raw material is crushed and sieved, and evenly mixed with the prescribed amount of lactose, microcrystalline cellulose, sodium carboxymethyl starch, and silicon dioxide, and an appropriate amount of purified water is added to prepare wet granules. The wet granules are granulated and then dried. After the dried dry granules are granulated again, sodium stearyl fumarate is added to the total mixture, and then tablets are pressed and coated.

[0076] Comparative Example 2: Preparation of tablets using a one-step method

[0077] prescription:

[0078] Table 6 Recipe

[0079]

[0080] Preparation method: grind and sieve the raw material drug and add purified water to prepare a solution with a raw material drug concentration of 35.0% to 65.0% for standby use. Premix the prescribed amount of lactose, microcrystalline cellulose, and sodium carboxymethyl starch and add them to the fluidized bed. Use the prepared solution for fluidized spray granulation. After the obtained granules are granulated, mix them with silicon dioxide sodium stearyl fumarate, press them into tablets, and coat them.

[0081] Comparative Example 3: Preparation of tablets using microcrystalline cellulose P102

[0082] prescription:

[0083] Table 7 Recipe

[0084] Raw materials Prescription ratio (w / w) API Protein kinase CDK4 / 6 inhibitor citrate 56.7％ Thinner / filler Microcrystalline Cellulose P102 37.3％ Disintegrants Sodium carboxymethyl starch 4.0％ Glidants Silicon dioxide 10％ Lubricants Sodium stearyl fumarate 1.0％ Coating materials Coating powder 3％

[0085] Preparation method: Grind and sieve the raw material, mix it with the prescribed amount of microcrystalline cellulose P102 and sodium carboxymethyl starch, add silicon dioxide and sodium stearyl fumarate, mix evenly, press into tablets, and coat.

[0086] Test Case

[0087] 1. The granulation process, powder properties of the granules and the properties of the plain tablets were investigated. The results are shown in Table 8.

[0088] Table 8 Investigation results during preparation

[0089]

[0090] Conclusion: It can be seen from the above table that there are various granulation problems in the granulation process of Comparative Example 1, such as the sieving phenomenon, and the obtained dry granules are hard and cannot be sieved, resulting in a low yield; the total mixed material obtained in Comparative Example 3 has poor fluidity, resulting in unstable tablet weight during tableting and an unsmooth preparation process; the intermediate granules obtained in Comparative Example 2 and Example 1 have good fluidity and compressibility, and the preparation process is smooth, but compared with Comparative Example 2, Example 1 consumes less energy while ensuring a high yield, has lower cost, and has a simpler and easier process.

[0091] 2. Dissolution

[0092] Dissolution rate refers to the speed and degree of dissolution of active pharmaceutical ingredients from tablets, capsules or granules under specified conditions. The dissolution curve is a dissolution time curve drawn based on the dissolution rate obtained at different time points of the preparation. The dissolution curve reflects the dissolution and dissolution process of the preparation.

[0093] The specific test is as follows: at 37°C, pH 1.2 hydrochloric acid solution, pH 4.5 acetate buffer, pH 6.8 phosphate buffer and water were used as dissolution media, with a preparation volume of 900 mL, and the paddle method was used for testing at a rotation speed of 50 rpm.

[0094] Table 9 Dissolution curve

[0095]

[0096] Conclusion: From the above table and Figure 1 to Figure 3 It can be seen that the tablets obtained in Comparative Examples 1 and 2 require 45 minutes when the cumulative dissolution is greater than 85% in pH 1.2, pH 4.5, pH 6.8, and aqueous media, while the tablets obtained in Example 1 can achieve faster dissolution in pH 1.2, pH 4.5, pH 6.8, and aqueous media, with a cumulative dissolution greater than 85% in 15 minutes, indicating that the dissolution rate of the tablets obtained in Example 1 is significantly improved, and Example 1 adopts the best direct tableting preparation process. Because the tablet weight of Comparative Example 3 was unstable during the tableting process and the process feasibility was poor, the dissolution test was not performed on it.

[0097] Table 10 Dissolution curve

[0098]

[0099] Conclusion: From the above table and Figures 4 to 6 It can be seen that the powders, capsules and granules obtained in Example 2, Example 3 and Example 4 can achieve rapid dissolution in pH 1.2, pH 4.5, pH 6.8 and aqueous media, and the cumulative dissolution rate in 15 minutes is greater than 85%.

[0100] 3. Stability

[0101] Table 11 Stability results

[0102]

[0103] Conclusion: It can be seen from the above table that Example 1 and Example 3 have good stability under high temperature and high humidity conditions; and the plain tablets obtained in Example 1, Comparative Example 1 and Comparative Example 2 have obvious growth of related substances under light conditions, while the related substances slightly increase when placed under light conditions after being prepared into coated tablets by film coating, and the growth trend is significantly reduced; the related substances slightly increase when placed under light conditions in Example 3. The results show that the use of film coating technology or preparation into capsules can improve the photostability of the product.

[0104] Although the present invention has been described in detail above with general descriptions and specific embodiments, it is obvious to those skilled in the art that some modifications or improvements may be made thereto based on the present invention. Therefore, these modifications or improvements made without departing from the spirit of the present invention all fall within the scope of protection claimed by the present invention.

Claims

1. A pharmaceutical preparation comprising the following components: 100 parts by weight of a citrate of a protein kinase CDK4 / 6 inhibitor, 15.0 to 150.0 parts by weight of a diluent / filler, 5.0 to 20.0 parts by weight of a disintegrant, 0 to 26.0 parts by weight of a binder, 0 to 7.0 parts by weight of a glidant, and 0.5 to 5.0 parts by weight of a lubricant.

2. The pharmaceutical preparation according to claim 1, characterized in that The diluent / filler is selected from one or more of microcrystalline cellulose, starch, lactose and mannitol; The disintegrant is selected from one or more of cross-linked carboxymethyl cellulose sodium, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch and low-substituted hydroxypropyl methylcellulose; The binder is selected from one or more of methyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, povidone K30 and starch; The glidant is selected from silicon dioxide and / or talc; The wetting agent is selected from water and / or ethanol; The lubricant is selected from one or more of sodium stearyl fumarate, magnesium stearate and stearic acid.

3. The pharmaceutical preparation according to claim 1 or 2, characterized in that The dosage forms of the pharmaceutical preparation are tablets, capsules, granules and powders.

4. The pharmaceutical preparation according to claim 3, characterized in that The pharmaceutical preparation is a tablet, which comprises the following components: 100 parts by weight of protein kinase CDK4 / 6 inhibitor citrate, 15.0-150.0 parts by weight of diluent / filler, 5.0-20.0 parts by weight of disintegrant, 0-7.0 parts by weight of glidant, and 0.5-5.0 parts by weight of lubricant.

5. The pharmaceutical preparation according to any one of claims 1 to 3, characterized in that The pharmaceutical preparation is a capsule, which comprises the following components: 100 parts by weight of protein kinase CDK4 / 6 inhibitor citrate, 15.0 to 150.0 parts by weight of diluent / filler, 0 to 7.0 parts by weight of glidant, and 0.5 to 5.0 parts by weight of lubricant.

6. The pharmaceutical preparation according to any one of claims 1 to 3, characterized in that The pharmaceutical preparation is a granule, which includes the following components: 100 parts by weight of protein kinase CDK4 / 6 inhibitor citrate, 15.0-150.0 parts by weight of diluent / filler, 5.0-20.0 parts by weight of disintegrant, 0-26.0 parts by weight of binder, 0-7.0 parts by weight of glidant, and 0.5-5.0 parts by weight of lubricant.

7. The pharmaceutical preparation according to any one of claims 1 to 3, characterized in that The pharmaceutical preparation is a powder, which comprises the following components: 100 parts by weight of protein kinase CDK4 / 6 inhibitor citrate, 15.0 to 150.0 parts by weight of diluent / filler, 0 to 7.0 parts by weight of glidant, and 0.5 to 5.0 parts by weight of lubricant.

8. The method for preparing the pharmaceutical preparation according to any one of claims 1 to 7, comprising the steps of: mixing the raw materials to prepare a dosage form.

9. The preparation method according to claim 8, characterized in that: According to different dosage forms, the pharmaceutical preparation is prepared as follows: (1) The pharmaceutical preparation is a tablet, which is prepared according to the following steps: grinding and sieving the protein kinase CDK4 / 6 inhibitor citrate, mixing with auxiliary materials, tabletting, and coating; (2) The pharmaceutical preparation is a granule, which is prepared according to the following operation: the protein kinase CDK4 / 6 inhibitor citrate is crushed and sieved, and added to water to prepare a solution, and then the filler and disintegrant are premixed and added to a fluidized bed, and the above solution is used for fluidized spray granulation, and the obtained granules are granulated and then mixed with a glidant and a lubricant, and packaged; (3) The pharmaceutical preparation is a capsule, which is prepared according to the following operation: the protein kinase CDK4 / 6 inhibitor citrate is crushed and sieved, mixed with a filler, and then a glidant and a lubricant are added and mixed, and then filled into a capsule; (4) The pharmaceutical preparation is a powder, which is prepared according to the following operation: the protein kinase CDK4 / 6 inhibitor citrate is crushed and sieved, mixed with a filler, and then a glidant and a lubricant are added and mixed, and then packaged.

10. Use of the pharmaceutical preparation according to any one of claims 1 to 7 in the preparation of a drug for treating, improving or preventing abnormal cell proliferation.

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