CDK inhibitor solid pharmaceutical composition and preparation method thereof

Abstract

The invention relates to an abesilib solid pharmaceutical composition and a preparation method thereof, and provides an abesilib solid pharmaceutical composition, which comprises abesilib, a filler, a disintegrating agent, a solubilizer, a flow aid and a lubricant. The solid pharmaceutical composition of abelsilil provided by the invention has the advantages of simple process steps, high dissolution rate, good dissolution effect and high bioavailability, and can achieve an equivalent treatment effect at a low dosage.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to a CDK inhibitor solid pharmaceutical composition and a preparation method thereof. Background Art

[0002] Abemaciclib is an orally effective inhibitor of cyclin-dependent kinases 4 and 6 (CDK4, CDK6), which can restore cell cycle regulation and prevent tumor cell proliferation, and has good anti-tumor activity. Abemaciclib tablets were approved by the US FDA for the treatment of breast cancer in 2017, and were launched in the EU and Japan in 2018. In 2020, they were approved for import and listing in China. Currently, there are three tablet specifications available in China, namely 50mg, 100mg and 150mg.

[0003] The chemical name of Abemaciclib is N-[5-[(4-ethyl-1-piperazinyl)methyl]-2-pyridinyl]-5-fluoro-4-[4-fluoro-2-methyl-1-isopropyl-1H-benzimidazol-6-yl]-2-pyrimidinamine, and the structural formula is as follows:

[0004]

[0005] The original formulation of Abemaciclib Tablets (trade name: ) The excipients used are: microcrystalline cellulose 101, microcrystalline cellulose 102, cross-linked sodium carboxymethyl cellulose, lactose, silicon dioxide, sodium stearyl fumarate, pigment, etc.

[0006] "Biopharmaceutics and Pharmacokinetics" (Liang Wenquan, People's Medical Publishing House, 2005) points out that the main site of intestinal absorption of oral drugs is the small intestine, and the corresponding pH value is around 6.8. Therefore, the solubility of abemaciclib tablets in phosphate buffer (pH 6.8) can reflect its absorption in vivo. However, the inventors found that in the in vitro dissolution test, the solubility of the original preparation of abemaciclib tablets in 900mL pH 6.8 phosphate buffer at 60min was less than 35%. In addition, when the original preparation was completely dissolved in 0.01mol / L hydrochloric acid solution and the pH of the medium was adjusted to 6.8, its solubility also decreased significantly. These in vitro dissolution results are consistent with the slow absorption and T mentioned in the instructions for the original preparation. max The information is consistent for 8 hours.

[0007] The prior art CN116251066A discloses an abemaciclib tablet, but it only focuses on the solubility of the original preparation in a 0.01 mol / L hydrochloric acid solution, and does not find the defect of its poor solubility in phosphate buffer (pH 6.8), nor does it provide corresponding technical means to solve this problem.

[0008] Therefore, in order to better meet clinical and market needs, it is urgent to develop an abemaciclib tablet with better dissolution effect. Summary of the invention

[0009] Based on the above technical problems, the present invention provides a solid pharmaceutical composition of abemaciclib, which replaces the commercially available preparation (trade name: ) The disintegrant and lubricant in the prescription are added with a solubilizer, which effectively reduces the effect of the disintegrant and lubricant in the commercially available preparation on drug release under pH 6.8 conditions, improves the dissolution rate and bioavailability, and can achieve an equivalent therapeutic effect by reducing the drug dosage.

[0010] In a first aspect of the present invention, there is provided a solid pharmaceutical composition of abemaciclib, the pharmaceutical composition comprising abemaciclib, a filler, a disintegrant, a solubilizer, a glidant and a lubricant;

[0011] Wherein, the solubilizer is selected from the following group: sodium lauryl sulfate, vitamin E polyethylene glycol succinate, glycocholic acid, or a combination thereof.

[0012] In a preferred example, the filler is selected from the following group: microcrystalline cellulose, lactose, or a combination thereof.

[0013] In a preferred example, the disintegrant is selected from the following group: cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, or a combination thereof.

[0014] In a preferred embodiment, the flow aid is silicon dioxide.

[0015] In a preferred example, the lubricant is selected from the following group: magnesium stearate, talc, or a combination thereof.

[0016] In a preferred example, the solid pharmaceutical composition contains 30-40 parts by weight of abemaciclib, 35-65 parts by weight of a filler, 1-10 parts by weight of a disintegrant, 2-11 parts by weight of a solubilizer, 1-5 parts by weight of a glidant and 1-5 parts by weight of a lubricant.

[0017] In another preferred example, the solid pharmaceutical composition contains 32 to 38 parts by weight of abemaciclib, preferably 35 to 36 parts by weight.

[0018] In another preferred embodiment, the solid pharmaceutical composition contains 40 to 60 parts by weight of the filler, preferably 45 to 55 parts by weight, and more preferably 47 to 54 parts by weight.

[0019] In another preferred embodiment, the solid pharmaceutical composition contains 2 to 10 parts by weight, or 3 to 8 parts by weight of a disintegrant.

[0020] In another preferred embodiment, the solid pharmaceutical composition contains 2 to 10 parts by weight, preferably 2 to 8 parts by weight, and more preferably 3 to 7 parts by weight of the solubilizer.

[0021] In another preferred embodiment, the solid pharmaceutical composition contains 1 to 3 parts by weight, preferably 1 to 2 parts by weight, of a glidant.

[0022] In another preferred embodiment, the solid pharmaceutical composition contains 1 to 4 parts by weight of a lubricant.

[0023] In a preferred embodiment, the abemaciclib accounts for 30-40wt% of the total weight of the pharmaceutical composition;

[0024] The filler accounts for 35 to 66 wt% of the total weight of the pharmaceutical composition;

[0025] The disintegrant accounts for 1 to 10 wt% of the total weight of the pharmaceutical composition;

[0026] The solubilizer accounts for 2 to 11 wt% of the total weight of the pharmaceutical composition;

[0027] The glidant accounts for 1 to 5 wt% of the total weight of the pharmaceutical composition; and

[0028] The lubricant accounts for 1 to 5 wt % of the total weight of the pharmaceutical composition.

[0029] In another preferred embodiment, the abemaciclib accounts for 32-38 wt %, preferably 35-36 wt %, of the total weight of the pharmaceutical composition.

[0030] In another preferred embodiment, the filler accounts for 40-60wt% of the total weight of the pharmaceutical composition, preferably 45-55wt%, and more preferably 47-54wt%.

[0031] In another preferred embodiment, the disintegrant accounts for 2-10 wt %, preferably 3-8 wt %, of the total weight of the pharmaceutical composition.

[0032] In another preferred embodiment, the solubilizer accounts for 2 to 10 wt %, preferably 2 to 8 wt %, more preferably 3 to 7 wt %, and most preferably 4 to 5 wt % of the total weight of the pharmaceutical composition.

[0033] In another preferred embodiment, the glidant accounts for 1 to 3 wt %, preferably 1 to 2 wt %, of the total weight of the pharmaceutical composition.

[0034] In another preferred embodiment, the lubricant accounts for 1 to 4 wt % of the total weight of the pharmaceutical composition.

[0035] In a preferred embodiment, the D of the abemaciclib raw material is 90 50~150μm.

[0036] The second aspect of the present invention provides a method for preparing the pharmaceutical composition as described in the first aspect of the present invention, comprising the following steps: mixing abemaciclib, a filler, a disintegrant, a solubilizer, a glidant and a lubricant to obtain abemaciclib solid pharmaceutical composition.

[0037] In another preferred embodiment, the preparation method comprises the following steps:

[0038] S1. Mix abemaciclib, filler, disintegrant, solubilizer and glidant uniformly;

[0039] S2. Add lubricant and mix well;

[0040] S3. tableting to obtain tablet cores;

[0041] S4. Film coating is performed to obtain the abemaciclib solid pharmaceutical composition.

[0042] In another preferred embodiment, the preparation method comprises the following steps:

[0043] S1. Pass abemaciclib, filler, disintegrant, solubilizer and glidant through a 2-40 mesh sieve and mix well;

[0044] S2. Add lubricant and mix well;

[0045] S3. Tablets were obtained by pressing with an elliptical punch (11*6mm);

[0046] S4. Film coating is performed to obtain the abemaciclib solid pharmaceutical composition.

[0047] The third aspect of the present invention provides a use of the abemaciclib solid pharmaceutical composition as described in the first aspect of the present invention or the abemaciclib solid pharmaceutical composition prepared by the preparation method as described in the second aspect of the present invention in the preparation of a medicament for treating diseases associated with CDK4 and / or CDK6.

[0048] In another preferred embodiment, the disease associated with CDK4 and / or CDK6 is selected from the group consisting of breast cancer, colorectal cancer, lung cancer, prostate cancer, glioblastoma, mantle cell lymphoma, chronic myeloid leukemia and acute myeloid leukemia.

[0049] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0050] After long-term and in-depth research and extensive screening, the inventors have developed for the first time a solid pharmaceutical composition of Abemaciclib, comprising Abemaciclib, a filler, a disintegrant, a solubilizer, a glidant and a lubricant, wherein the solubilizer is glycocholic acid. The solid pharmaceutical composition of Abemaciclib of the present invention has simple process steps, high dissolution rate, good dissolution effect, high bioavailability, and can achieve an equivalent therapeutic effect at a low dose. Based on this, the inventors have completed the present invention.

[0051] Beneficial effects:

[0052] 1. Compared with the original preparation, the solid composition of abemaciclib provided by the present invention has improved dissolution rate and bioavailability, can achieve equivalent therapeutic effects with a lower drug dose, and has clinical value.

[0053] 2. The preparation process is simple and easy, suitable for industrial production.

[0054] In order to enable those skilled in the art to better understand the technical solution of the present invention, some non-limiting embodiments are further disclosed below to further illustrate the present invention in detail.

[0055] Sources of reagents used in the present invention: microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose were purchased from Danisco Biotechnology (Shanghai) Co., Ltd.; lactose was purchased from Kerry Ingredients Trading (Shanghai) Co., Ltd.; sodium carboxymethyl starch and sodium stearyl fumarate were purchased from Redenmeier (Shanghai) Fiber Trading Co., Ltd.; cross-linked polyvinylpyrrolidone was purchased from Ashland (China) Investment Co., Ltd.; poloxamer was purchased from BASF (China) Co., Ltd.; silicon dioxide was purchased from Grace Trading (Shanghai) Co., Ltd.; low-substituted hydroxypropyl cellulose, sodium lauryl sulfate and magnesium stearate were purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd., and talc was purchased from Guangxi Longsheng Huamei Talc Development Co., Ltd.; vitamin E succinate polyethylene glycol ester (TPGS) was purchased from Shanghai Changwei Pharmaceutical Excipients Technology Co., Ltd.; glycocholic acid was purchased from Sichuan Haisike Pharmaceutical Co., Ltd.; abemaciclib raw material was purchased from Jiangsu Xidi Pharmaceutical Co., Ltd., with a particle size of D 90 50~150μm.

[0056] UV-visible spectrophotometer, model: UV-1900i, manufacturer: Shimadzu

[0057] Dissolution instrument, model: DS0806, manufacturer: Shenzhen Huarong Analytical Instrument Co., Ltd.

[0058] Comparative Example 1 Dissolution test of commercially available abemaciclib tablets

[0059] Abemaciclib tablets are available on the market under the following trade names: Place of purchase: China, specification 150 mg, product batch number D635887.

[0060] Take 12 commercially available abemaciclib tablets, and measure the dissolution according to the dissolution and release method (Chinese Pharmacopoeia 2020 Edition Part 4 General Rules 0931 Method 2).

[0061] Instruments: UV-visible spectrophotometer and dissolution apparatus,

[0062] Dissolution medium: 0.01 mol / L hydrochloric acid solution, acetate buffer (pH 4.5), phosphate buffer (pH 6.8),

[0063] Dissolution medium volume: 900 ml, paddle method, rotation speed: 75 rpm.

[0064] 5 ml of the dissolution solution was aspirated at 5 min, 10 min, 15 min, 20 min, 30 min, 45 min and 60 min respectively, filtered, and UV-measured to calculate the average dissolution rate of each sample. The results are shown in Table 1.

[0065] Table 1. Results of dissolution test of commercially available abemaciclib tablets

[0066]

[0067] As can be seen from Table 1, in a 0.01 mol / L hydrochloric acid solution, the commercially available abemaciclib tablets can be completely dissolved within 5 minutes, but in an acetate buffer (pH 4.5), its solubility within 60 minutes is less than 85%, and in a phosphate buffer (pH 6.8), its solubility within 60 minutes is less than 35%, indicating that the commercially available abemaciclib tablets have poor dissolution in the small intestine and are difficult to be absorbed in the small intestine, which is consistent with the slow absorption mentioned in the instructions for the original preparation. Therefore, it is necessary to improve its solubility in the small intestine (i.e., pH 6.8 phosphate buffer).

[0068] Example 1 Two-stage dissolution test of API + different disintegrants

[0069] Test method: Accurately weigh 150 mg of abemaciclib API and mix it with 21 mg of different disintegrants as the test sample. Refer to the dissolution and release determination method (Method 0931, Part 4, General Rules, 2020 Edition of the Chinese Pharmacopoeia) to conduct a two-stage dissolution test, paddle method, rotation speed: 75 rpm.

[0070] The test steps are as follows:

[0071] (1) Measure 750 ml of 0.1 mol / L hydrochloric acid solution and place it in a dissolution cup. Place the test samples into the dissolution cups and start the instrument. After 30 minutes, draw out 5 ml of the solution, filter it, and measure and calculate the solubility of each sample in acid.

[0072] Add 250 ml of pH 7.0 phosphate buffer to the above acid solution to adjust the pH value to 6.8, draw 5 ml of the dissolution solution at 30 min and 60 min, filter, measure and calculate the solubility of each sample in pH 6.8 buffer.

[0073] (2) Measure 750 ml of pH 4.5 acetate buffer and place it in a dissolution cup. Place the test samples into the dissolution cups and start the instrument. After 30 minutes, aspirate 5 ml of the dissolution solution, filter it, and measure and calculate the solubility of each sample in acid.

[0074] Add 250 ml of pH 6.9 phosphate buffer to the above acid solution to adjust the pH value to 6.8, draw 5 ml of the dissolution solution at 30 min and 60 min, filter, measure and calculate the solubility of each sample in pH 6.8 buffer.

[0075] The results are shown in Table 2.

[0076] Table 2. Results of two-stage dissolution test of API + different disintegrants

[0077]

[0078] *: Croscarmellose sodium is the disintegrant used in the original formulation.

[0079] The results showed that when the disintegrant was cross-linked sodium carboxymethyl cellulose or sodium carboxymethyl starch, the dissolution rate of the API in the acetate buffer (pH 4.5) medium was less than 85%, and the dissolution rate also dropped significantly after adjusting the pH of the medium to 6.8, to less than 85%.

[0080] In contrast, when the disintegrant is cross-linked polyvinylpyrrolidone or low-substituted hydroxypropyl cellulose, the API can be completely dissolved in the acetate buffer (pH 4.5) medium, and the solubility is still higher than 85% after adjusting the medium pH to 6.8, indicating that cross-linked polyvinylpyrrolidone or low-substituted hydroxypropyl cellulose contributes to the dissolution of abemaciclib in the stomach and small intestine, and these two disintegrants have little effect on the drug release process in the stomach and small intestine.

[0081] Therefore, the disintegrant of the preparation of the present invention is preferably crospovidone and / or low-substituted hydroxypropylcellulose.

[0082] Example 2 Two-stage dissolution test of API + different lubricants

[0083] Test method: Accurately weigh 150 mg of abemaciclib API and mix it with 12 mg of different lubricants as the test sample. Refer to the dissolution and release determination method (Method 2 of Part 4 of the Chinese Pharmacopoeia 2020 Edition 0931), and conduct a two-stage dissolution test using the paddle method at a rotation speed of 75 rpm.

[0084] The test procedure is the same as in Example 1.

[0085] The results are shown in Table 3.

[0086] Table 3. Results of two-stage dissolution test of API + different lubricants

[0087]

[0088] *: Sodium stearyl fumarate is the lubricant used in the original formulation.

[0089] The results showed that when the lubricant was sodium stearyl fumarate, the dissolution rate of the API in the acetate buffer (pH 4.5) medium would decrease, and the dissolution rate would decrease significantly after adjusting the pH of the medium to 6.8, which was less than 85%.

[0090] In contrast, when the lubricant is magnesium stearate or talc, the API can be completely dissolved in the acetate buffer (pH 4.5) medium, and after adjusting the pH of the medium to 6.8, the dissolution rate of the API is still higher than 85% at 30 minutes, indicating that magnesium stearate or talc contributes to the dissolution of abemaciclib in the stomach and small intestine, and these two lubricants have little effect on the release process of the drug in the stomach and small intestine.

[0091] Therefore, the lubricant of the formulation of the present invention is preferably magnesium stearate and / or talc.

[0092] Example 3 Two-stage dissolution test of API + different solubilizers

[0093] Test method: Accurately weigh 150 mg of abemaciclib API and mix it with 21 mg of different solubilizers as the test sample. Refer to the dissolution and release determination method (Method 0931, Part 4, General Rules, 2020 Edition of the Chinese Pharmacopoeia) to conduct a two-stage dissolution test, paddle method, rotation speed: 75 rpm.

[0094] The test procedure is the same as in Example 1.

[0095] The results are shown in Table 4.

[0096] Table 4. Results of two-stage dissolution test of API + different solubilizers

[0097]

[0098]

[0099] The results showed that when the solubilizer was sodium dodecyl sulfate, poloxamer or vitamin E polyethylene glycol succinate, the API could be completely dissolved in the medium of 0.01 mol / L hydrochloric acid and acetate buffer (pH 4.5), but the solubility of the API decreased by about 10% after adjusting the pH of the medium to 6.8. In contrast, no decrease in solubility was observed when the solubilizer was glycocholic acid, indicating that glycocholic acid helps the dissolution of abemaciclib in the stomach and small intestine, and this solubilizer has little effect on the drug release process in the stomach and small intestine.

[0100] Therefore, the solubilizer of the preparation of the present invention is preferably glycocholic acid.

[0101] Example 4 Effect of different amounts of glycocholic acid on dissolution

[0102] The in vitro dissolution tests were performed on the formulations with different glycocholic acid dosages to investigate the effects of different glycocholic acid dosages on the dissolution. According to the dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0931 Second Method), the dissolution medium was 900 ml phosphate buffer (pH 6.8), paddle method, speed: 75 rpm, 5 ml of the dissolution solution was drawn in 30 minutes, filtered, UV measured and the average dissolution of each sample was calculated. The results are shown in Table 5.

[0103] Table 5. Effect of different glycocholic acid dosages on dissolution

[0104]

[0105]

[0106] / : indicates unknown dosage NA: indicates not applicable The data showed that the dissolution rate of prescription 1 within 30 min was low without using glycocholic acid, and the dissolution rate increased with the increase of the dosage of solubilizing agent glycocholic acid (prescriptions 2 to 4);

[0107] Among them, both Prescription 3 and Prescription 4 can be quickly dissolved within 30 minutes, and there is no significant difference in solubility. However, the increase in the amount of solubilizer in Prescription 4 will affect the compressibility of the total mixed particles. Therefore, the dosage of Prescription 3 is preferred for the preparation of the present invention.

[0108] Example 5

[0109] Prescription: Abemaciclib 75g, microcrystalline cellulose 102 69.5g, microcrystalline cellulose 101 21g, lactose 21g, cross-linked polyvinylpyrrolidone 7g, glycocholic acid 10.5g, silicon dioxide 3g, magnesium stearate 3g, a total of 1000 tablets.

[0110] Preparation process:

[0111] 1) Weigh abemaciclib, fillers (microcrystalline cellulose 102, microcrystalline cellulose 101 and lactose), disintegrant (crospovidone), solubilizer (glycocholic acid) and glidant (silicon dioxide) according to the prescription amount, pass through a 30-mesh sieve and mix them evenly;

[0112] 2) Add lubricant (magnesium stearate) and mix well;

[0113] 3) The tablets were compressed using an elliptical punch (11*6 mm) and weighed 210 mg.

[0114] 4) Film coating is performed.

[0115] Example 6

[0116] Prescription: Abemaciclib 75g, microcrystalline cellulose 102 66.5g, microcrystalline cellulose 101 21g, lactose 21g, cross-linked polyvinylpyrrolidone 9g, glycocholic acid 10.5g, silicon dioxide 3g, magnesium stearate 4g, a total of 1000 tablets.

[0117] The preparation process is the same as that of Example 5.

[0118] Example 7

[0119] Prescription: Abemaciclib 75g, microcrystalline cellulose 102 63.5g, microcrystalline cellulose 101 21g, lactose 21g, cross-linked polyvinylpyrrolidone 11g, glycocholic acid 10.5g, silicon dioxide 3g, magnesium stearate 5g, a total of 1000 tablets.

[0120] The preparation process is the same as that of Example 5.

[0121] Example 8

[0122] Prescription: Abemaciclib 75g, microcrystalline cellulose 102 60.5g, microcrystalline cellulose 101 21g, lactose 21g, cross-linked polyvinylpyrrolidone 13g, glycocholic acid 10.5g, silicon dioxide 3g, magnesium stearate 6g, a total of 1000 tablets.

[0123] The preparation process is the same as that of Example 5.

[0124] Example 9

[0125] Prescription: Abemaciclib 75g, microcrystalline cellulose 102 57.5g, microcrystalline cellulose 101 21g, lactose 21g, cross-linked polyvinylpyrrolidone 15g, glycocholic acid 10.5g, silicon dioxide 3g, magnesium stearate 7g, a total of 1000 tablets.

[0126] The preparation process is the same as that of Example 5.

[0127] Example 10

[0128] Prescription: Abemaciclib 75g, microcrystalline cellulose 102 69.5g, microcrystalline cellulose 101 21g, lactose 21g, low-substituted hydroxypropyl cellulose 7g, glycocholic acid 10.5g, silicon dioxide 3g, talc 3g, a total of 1000 tablets.

[0129] The preparation process is the same as that of Example 5.

[0130] Embodiment 11

[0131] Prescription: Abemaciclib 75g, microcrystalline cellulose 102 66.5g, microcrystalline cellulose 101 21g, lactose 21g, low-substituted hydroxypropyl cellulose 9g, glycocholic acid 10.5g, silicon dioxide 3g, talc 4g, a total of 1000 tablets.

[0132] The preparation process is the same as that of Example 5.

[0133] Example 12

[0134] Prescription: Abemaciclib 75g, microcrystalline cellulose 102 63.5g, microcrystalline cellulose 101 21g, lactose 21g, low-substituted hydroxypropyl cellulose 11g, glycocholic acid 10.5g, silicon dioxide 3g, talc 5g, a total of 1000 tablets.

[0135] The preparation process is the same as that of Example 5.

[0136] Example 13

[0137] Prescription: Abemaciclib 75g, microcrystalline cellulose 102 60.5g, microcrystalline cellulose 101 21g, lactose 21g, low-substituted hydroxypropyl cellulose 13g, glycocholic acid 10.5g, silicon dioxide 3g, talc 6g, a total of 1000 tablets.

[0138] The preparation process is the same as that of Example 5.

[0139] Embodiment 14

[0140] Prescription: Abemaciclib 75g, microcrystalline cellulose 102 57.5g, microcrystalline cellulose 101 21g, lactose 21g, low-substituted hydroxypropyl cellulose 15g, glycocholic acid 10.5g, silicon dioxide 3g, talc 7g, a total of 1000 tablets.

[0141] The preparation process is the same as that of Example 5.

[0142] Embodiment 15

[0143] Prescription: Abemaciclib 75g, microcrystalline cellulose 102 57.5g, microcrystalline cellulose 101 21g, lactose 21g, low-substituted hydroxypropyl cellulose 15g, poloxamer 10.5g, silicon dioxide 3g, talc 7g, a total of 1000 tablets.

[0144] The preparation process is the same as that of Example 5.

[0145] Test Example 1 Dissolution Test

[0146] Take the samples of Examples 5 to 15, and according to the dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0931, Method 2), the dissolution medium is 900 ml of phosphate buffer (pH 6.8), paddle method, rotation speed: 75 rpm, and 5 ml of the dissolution solution is absorbed at 5 min, 10 min, 15 min, 20 min, and 30 min, respectively. Filter, ultraviolet determination and calculate the average solubility of each sample. The results are shown in Table 6.

[0147] Table 6. In vitro dissolution of the original formulation and Examples 5 to 15

[0148] Dissolution % 5min 10min 15min 20min 30min Original preparation 8 12 17 20 26 Example 5 30 53 72 84 95 Example 6 34 53 68 78 94 Example 7 28 52 74 86 97 Example 8 31 56 72 80 90 Example 9 31 54 74 84 94 Example 10 30 56 74 83 95 Embodiment 11 28 56 75 85 94 Example 12 30 53 72 83 94 Example 13 31 55 74 84 96 Embodiment 14 32 58 71 81 96 Embodiment 15 11 32 45 52 61

[0149] The data in Table 6 show that the dissolution rates of Examples 5 to 15 of the present invention are significantly higher than that of the original preparation, indicating that the dissolution effect of the preparation of the present invention is significantly better than that of the original preparation.

[0150] Among them, there is no significant difference in the dissolution of Examples 5 to 14, and the dissolution after 30 minutes is greater than 85%, indicating that the preparation of the present invention can be released quickly and meets the "Guidelines for Exemption of Human Bioequivalence Studies".

[0151] The dissolution effect of Example 15 is worse than that of Examples 5 to 14, and different from Examples 5 to 14, the solubilizer of Example 15 is poloxamer instead of glycocholic acid used in Examples 5 to 14, so the preferred solubilizer of the present invention is glycocholic acid.

[0152] Test Example 2 Beagle dog pharmacokinetic test

[0153] The concentration levels of abemaciclib in plasma and its basic pharmacokinetic characteristics were investigated after a single oral administration of the sample of Example 14 (75 mg), the sample of Example 15 (75 mg) and the original preparation (150 mg) to beagle dogs.

[0154] Test drugs: Example 14 sample, Example 15 sample, original preparation

[0155] Experimental animals: 3 beagle dogs, male, weighing 10±2kg, aged 10-12 months;

[0156] Experimental design: 3-cycle trial, 1 drug is given in each cycle, and all animals need to wash out for 7 days between cycles;

[0157] Blood collection point design: 0.5 ml of blood was collected from the forelimb or hindlimb vein at 0, 15 min, 30 min, 45 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12 h, and 24 h, placed in EDTA-K2 tubes, centrifuged at 3000 r / min at 4 °C for 10 min, the plasma was separated, and stored in a -70 °C refrigerator.

[0158] Table 7 Pharmacokinetic parameters of abemaciclib in plasma

[0159] Embodiment 14 Embodiment 15 Original preparation <![CDATA[T max (h)]]> 5.61±2.64 5.47±2.32 6.38±2.76 <![CDATA[C max (of mL) -1 )]]> 168±51.8 129±21.0 144±19.0 <![CDATA[AUC last (h·ng·mL) -1 )]]> 3024±566 2133±413 2769±334

[0160] It can be seen from the test results in Table 7 that the sample in Example 14 can achieve the same in vivo exposure as the reference preparation, while Example 15 cannot achieve the same in vivo exposure as the reference preparation, and the difference between the prescriptions of Example 14 and Example 15 is that the solubilizers are different. The solubilizer in Example 14 is glycocholic acid, and the solubilizer in Example 15 is poloxamer, which further suggests that the preferred solubilizer of the present invention is glycocholic acid.

[0161] In addition, although the in vivo exposure amounts of Example 14 of the present invention and the reference preparation are the same, the content of abemaciclib in Example 14 of the present invention is only half of that of the reference preparation, indicating that the bioavailability of the abemaciclib solid pharmaceutical composition provided by the present invention is improved, and the therapeutic effect equivalent to that of the original drug can be achieved with half the drug dose of the original drug.

[0162] In summary, the abemaciclib solid pharmaceutical composition of the present invention can reduce the patient's drug intake, reduce the risk of potential side effects, improve the patient's compliance, and reduce treatment costs.

[0163] In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A solid pharmaceutical composition of abemaciclib, characterized in that: The pharmaceutical composition contains abemaciclib, a filler, a disintegrant, a solubilizer, a glidant and a lubricant; Wherein, the solubilizer is selected from the following group: sodium lauryl sulfate, vitamin E polyethylene glycol succinate, glycocholic acid, or a combination thereof.

2. The pharmaceutical composition according to claim 1, characterized in that The filler is selected from the group consisting of microcrystalline cellulose, lactose, or a combination thereof.

3. The pharmaceutical composition according to claim 1, characterized in that The disintegrant is selected from the group consisting of cross-linked polyvinylpyrrolidone, low-substituted hydroxypropylcellulose, or a combination thereof.

4. The pharmaceutical composition according to claim 1, characterized in that The glidant is silicon dioxide.

5. The pharmaceutical composition according to claim 1, characterized in that The lubricant is selected from the group consisting of magnesium stearate, talc, or a combination thereof.

6. The pharmaceutical composition according to claim 1, characterized in that The solid pharmaceutical composition contains 30 to 40 parts by weight of abemaciclib, 35 to 65 parts by weight of a filler, 1 to 10 parts by weight of a disintegrant, 2 to 11 parts by weight of a solubilizer, 1 to 5 parts by weight of a glidant and 1 to 5 parts by weight of a lubricant.

7. The pharmaceutical composition according to claim 1, characterized in that The abemaciclib accounts for 30-40wt% of the total weight of the pharmaceutical composition; The filler accounts for 35 to 66 wt% of the total weight of the pharmaceutical composition; The disintegrant accounts for 1 to 10 wt% of the total weight of the pharmaceutical composition; The solubilizer accounts for 2 to 11 wt% of the total weight of the pharmaceutical composition; The glidant accounts for 1 to 5 wt% of the total weight of the pharmaceutical composition; and The lubricant accounts for 1 to 5 wt % of the total weight of the pharmaceutical composition.

8. The pharmaceutical composition according to claim 1, characterized in that The D of the abemaciclib raw material 90 50~150μm.

9. A method for preparing the pharmaceutical composition according to any one of claims 1 to 8, characterized in that: The method comprises the following steps: mixing abemaciclib, a filler, a disintegrant, a solubilizer, a glidant and a lubricant to obtain abemaciclib solid pharmaceutical composition.

10. Use of the abemaciclib solid pharmaceutical composition according to any one of claims 1 to 8 or the abemaciclib solid pharmaceutical composition prepared by the preparation method according to claim 9 in the preparation of a medicament for treating diseases associated with CDK4 and / or CDK6.

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