BTK inhibitor solid tablet and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a BTK inhibitor solid tablet and a preparation method thereof.The BTK inhibitor solid tablet is prepared from, by weight, 4.5-5.5% of a compound shown in the formula I, 80-90% of filler, 1-5% of adhesive, 3-10% of disintegrating agent and 0.1-5% of lubricant, and the particle size of the compound shown in the formula I is D90lt; the dissolution rate of the solid tablet of the compound shown in the formula I in a medium with the pH value of 1.0 for 15 min is larger than 85%, the dissolution rate after acceleration is not remarkably changed, and the preparation is simple in process, capable of guaranteeing the stability, convenient to transport and store and suitable for large-scale production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, in particular to a BTK inhibitor solid tablet and a preparation method thereof. BACKGROUND

[0002] The B cell receptor (BCR) signaling pathway plays a crucial role in the proliferation and differentiation of B cells, and abnormalities in this pathway can lead to the occurrence of malignant B-cell lymphoma. Bruton's tyrosine kinase (BTK) is a key enzyme in the BCR pathway, which can be activated by upstream molecules such as spleen tyrosine kinase, and activate downstream phospholipase Cγ2, ultimately promote the nuclear translocation of nuclear factor kappa B and thus lead to B cell proliferation. BTK inhibitors can down-regulate the BCR pathway and inhibit the proliferation of malignant B cells, and have been used as targeted drugs for malignant B-cell lymphoma in clinical practice.

[0003] BTK inhibitors can be divided into two categories according to their mechanism of action and binding mode: one category is irreversible inhibitors, which are characterized by a Michael acceptor moiety that can form a covalent bond with the conserved Cys481 residue in the ATP binding site; the other category is reversible inhibitors, which bind to a specific pocket in the SH3 domain through weak reversible interactions such as hydrogen bonds or hydrophobic interactions.

[0004] Patent CN114728974B discloses a reversible BTK inhibitor as shown in formula I. The compound of formula I is almost insoluble in water or 0.1 mol / L hydrochloric acid, so if it is to be truly used for treating patients' diseases, a mature pharmaceutical preparation needs to be developed to improve the dissolution rate of the drug and thus improve the bioavailability of the drug.

[0005] SUMMARY

[0006] In view of the defects of the prior art, the present application aims to provide a solid tablet of a compound of formula I with a certain particle size and a preparation method thereof, which can improve the dissolution rate of the compound of formula I.

[0007] In one aspect, the present application provides a BTK inhibitor solid tablet, which comprises the following components in a weight ratio: 4.5-5.5% of a compound of formula I, 80-90% of a filler, 1-5% of a binder, 3-10% of a disintegrant, and 0.1-5% of a lubricant; and the particle size D90 of the compound of formula I is less than 20 um, and the structure of the compound of formula I is as follows:

[0008]

[0009] In some embodiments, the filler is selected from one or more of lactose, sucrose, starch, pregelatinized starch, dextrin, mannitol, sorbitol, microcrystalline cellulose, preferably lactose, further preferably lactose monohydrate.

[0010] In some embodiments, the binder is selected from one or more of hypromellose, carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, povidone, hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylcellulose, ethylcellulose, preferably hypromellose, sodium carboxymethylcellulose, povidone, methylcellulose, further preferably hypromellose.

[0011] In some embodiments, the disintegrant is selected from one or more of sodium starch glycolate, crospovidone, sodium croscarmellose, croscarmellose, preferably one or more of sodium croscarmellose, sodium starch glycolate, further preferably sodium starch glycolate.

[0012] In some embodiments, the lubricant is selected from one or more of talc, calcium stearate, zinc stearate, stearic acid, glycerol monostearate, glycerol palmitostearate, magnesium stearate, sodium stearyl fumarate, preferably magnesium stearate, sodium stearyl fumarate, talc, further preferably magnesium stearate.

[0013] In particular, the present application provides a solid tablet comprising the above-mentioned BTK inhibitor, which comprises the following components in weight ratio:

[0014]

[0015] The particle size D90 of the compound of formula I is < 20 um; the binder is selected from one or more of hypromellose, carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, povidone, hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylcellulose, ethylcellulose, preferably hypromellose, sodium carboxymethylcellulose, povidone, methylcellulose, further preferably hypromellose; the lubricant is selected from one or more of talc, calcium stearate, zinc stearate, stearic acid, glycerol monostearate, glycerol palmitostearate, magnesium stearate, sodium stearyl fumarate, preferably magnesium stearate, sodium stearyl fumarate, talc, further preferably magnesium stearate.

[0016] In particular, the present application provides a solid tablet comprising the above-mentioned BTK inhibitor, which comprises the following components in weight ratio:

[0017]

[0018] The particle size D90 of the compound of formula I is less than 20 um; the binder is selected from one or more of hydroxypropyl methylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, povidone, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, preferably hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, povidone, methyl cellulose, and further preferably hydroxypropyl methylcellulose; the lubricant is selected from one or more of talc, calcium stearate, zinc stearate, stearic acid, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium stearate fumarate, preferably magnesium stearate, sodium stearate fumarate, talc, and further preferably magnesium stearate.

[0019] In particular, the present application provides a BTK inhibitor solid tablet comprising the following components in weight ratio:

[0020]

[0021] The particle size D90 of the compound of formula I is less than 20 um.

[0022] The BTK inhibitor solid tablet of the present application further comprises a coating agent, which increases the weight of the solid tablet by 2-4%.

[0023] In some embodiments, the coating agent is selected from one or more of gastro-soluble film coating, preferably Opadry.

[0024] In some embodiments, the coating agent increases the weight of the solid tablet by 3-4%, and further preferably 4%.

[0025] Another object of the present application is to provide a preparation method of the above-mentioned BTK inhibitor solid tablet, comprising the following steps:

[0026] (1) micronizing the compound of formula I, with a particle size D90 less than 20 um;

[0027] (2) mixing the prescription amount of filler and 50% of the prescription amount of disintegrant as an internal additive component, and mixing the prescription amount of the compound of formula I obtained in step (1) and the internal additive component;

[0028] (3) wet granulating the mixture obtained in step (2) with an aqueous solution containing the prescription amount of binder, drying and sizing;

[0029] (4) mixing the prescription amount of lubricant and the remaining disintegrant as an external additive component, mixing the sized granules with the external additive component, and tabletting;

[0030] In some embodiments, the wet granulation is selected from high-shear wet granulation.

[0031] The preparation method of the BTK inhibitor solid tablet of the present application further comprises a coating step: the tablet obtained by tabletting is coated, and the coating agent increases the weight of the tablet by 2-4%, preferably 3-4%, and further preferably 4%.

[0032] The present application has the following advantages: (1) the problem of low dissolution of the compound of formula I in in-vitro medium is solved, and the in-vitro dissolution rate is greatly improved, the dissolution of the solid tablet of the compound of formula I in a medium with pH 1.0 is >85% in 15 min, and the accelerated dissolution has no significant change; (2) no surfactant is added in the prescription, and no sodium dodecyl sulfate is needed to increase the dissolution of the compound of formula I, and no toxic side effects caused by the surfactant; (3) the prescription process is simple and suitable for mass production.

[0033] Definitions and explanations

[0034] Unless otherwise indicated, the following terms and phrases used in the present application are intended to have the following meanings. A particular phrase or term should not be construed as being indefinite or unclear unless defined, but should be understood according to the ordinary meaning.

[0035] "D90 < 20 μm" means that 90% of the particle size is < 20 μm.

[0036] The term "filler", also known as diluent, is used to fill the volume or weight of the tablet or capsule, thereby diluting the main drug, facilitating tabletting and filling. Common fillers include starches, sugars and celluloses, including but not limited to one or a mixture of lactose, sucrose, starch, pregelatinized starch, dextrin, mannitol, sorbitol, microcrystalline cellulose; more specifically, including but not limited to one or a mixture of lactose monohydrate, pregelatinized starch, microcrystalline cellulose.

[0037] The term "binder" refers to a substance that causes the material to aggregate, agglomerate and form particles under the action of a wetting agent in the solid preparation of the compound of formula I, thereby improving the uniformity and flowability of the material to meet the production needs of the preparation, including but not limited to hydroxypropyl methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, povidone, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose.

[0038] The term "disintegrant" refers to a substance that causes the tablet to rapidly break into small particles in the solid preparation of the compound of formula I, thereby causing the functional ingredients to be rapidly dissolved and absorbed to exert their effects, including but not limited to sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose, cross-linked carboxymethyl cellulose.

[0039] The term "lubricant" is a substance that increases the flowability of the granules (or powder) and reduces the friction between the granules (or powder) and the die, including but not limited to talc, calcium stearate, zinc stearate, stearic acid, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium stearate fumarate. BRIEF DESCRIPTION OF DRAWINGS

[0040] Figure 1 Dissolution profile for Formulation 1, 2, 3 (0 days, dissolution medium pH 2.0).

[0041] Figure 2 Dissolution profile for Formulation 3, 4, 5 (0 days, dissolution medium pH 2.0).

[0042] Figure 3 Dissolution profile for Formulation 3 (accelerated 7 days, dissolution medium pH 2.0).

[0043] Figure 4 Dissolution profile for Formulation 4 (accelerated 7 days, dissolution medium pH 2.0).

[0044] Figure 5 Dissolution profile for Formulation 4, 6, 7, 8 (0 days, dissolution medium pH 2.0).

[0045] Figure 6 Dissolution profile for Formulation 7 (accelerated 7 days, dissolution medium pH 2.0).

[0046] Figure 7 Dissolution profile for Formulation 8 (accelerated 7 days, dissolution medium pH 2.0).

[0047] Figure 8 Dissolution profile for Formulation 7, 9, 10, 11 (0 days, dissolution medium pH 2.0).

[0048] Figure 9 Dissolution profile for Formulation 7, 12, 13 (0 days, dissolution medium pH 2.0).

[0049] Figure 10 Dissolution profile for Formulation 7, 14-19 (0 days, dissolution medium pH 2.0)

[0050] Figure 11 Dissolution profile for 5 mg strength plain tablet 1 and coated tablet 1 (0 days, dissolution medium pH 2.0).

[0051] Figure 12 Dissolution profile for 20 mg strength plain tablet 2 and coated tablet 2, 2-1 (0 days, dissolution medium pH 1.0).

[0052] Figure 13Dissolution profile of plain tablet and coated tablet of 20 mg strength (accelerated for 7 days, dissolution medium pH 1.0).

[0053] Figure 14 Dissolution profile of plain tablet 1 and coated tablet 1 of 5 mg strength (dissolution medium pH 1.0).

[0054] Figure 15 Blood concentration-time curve of beagle dogs after taking prescription 4, 7, 8 formulations.

[0055] Figure 16 Blood concentration-time curve of beagle dogs after injection of compound I.

[0056] Figure 17 HPLC spectrum of related substances of coated tablet 1 accelerated for 7 days at 60°C / 75% RH sealed with desiccant. DETAILED DESCRIPTION

[0057] In order to better understand the technical solutions of the present application, the technical solutions of the present application will be further described below in combination with specific examples, which are only used to help understand the present application and should not be regarded as specific limitations to the present application.

[0058] The sample acceleration and release conditions of the BTK inhibitor of the present application: the sample is placed in a high-density polyethylene bottle, and the changes in dissolution and related substances under the conditions of 60°C / 75% RH open and sealed with desiccant for 7 days are investigated.

[0059] Example 1

[0060] Effect of different fillers on dissolution performance of the preparation

[0061] Table 1 Formulations 1, 2, 3

[0062]

[0063]

[0064] Preparation process of prescription 1: take the prescription amount of lactose monohydrate, microcrystalline cellulose, sodium croscarmellose (added inside) and compound I (not micronized, D90≤100 μm), mix in a high-shear mixer for 10 min, then add 6.5% hydroxypropyl methylcellulose aqueous solution for granulation; after granulation, the wet granules are sieved with an 18-mesh sieve, then dried in a fluidized bed granulator at 60°C until the moisture content is ≤3.0%; the above dried granules are sized with an 18-mesh sieve and mixed with sodium croscarmellose (added outside) and magnesium stearate for 20 min; finally, the above mixture is tableted to obtain plain tablets, which are prescription 1.

[0065] Preparation process of prescription 2, 3: on the basis of prescription 1 preparation process, replace lactose monohydrate with pre-gelatinized starch, and the amount of other excipients does not change, to obtain prescription 2; on the basis of prescription 1, only change the ratio of lactose monohydrate and microcrystalline cellulose, and the amount of other excipients does not change, to obtain prescription 3.

[0066] Compare the dissolution performance of prescription 1, 2, 3. Dissolution conditions: keep 37±0.5℃, use 500mL pH2.0 hydrochloric acid solution as dissolution medium, use paddle method 50rpm, increase to 250rpm after 60min, investigate the dissolution curve of drug within 90min.

[0067] Table 2 dissolution data of prescription 1, 2, 3 (0 days)

[0068] Formulation Formulation 1 Formulation 2 Formulation 3 Time (min) Dissolution (%) Dissolution (%) Dissolution (%) 5 12 10 2 10 37 32 39 15 47 38 57 20 54 43 67 30 60 48 75 45 66 52 83 60 71 57 89 90 92 87 97

[0069] Draw the dissolution curve according to the dissolution data of prescription 1, 2, 3 (0 days) Figure 1 ), the results show that: the dissolution curves of prescription 1, 2, 3 in 500mL pH2.0 hydrochloric acid solution are obviously distinguishable, the dissolution rate of prescription 2 is the slowest, the dissolution rate of prescription 3 is slow at the beginning, but it is obviously better than the other two prescriptions after 15min, and the dissolution rate of prescription 3 is relatively better.

[0070] Example 2

[0071] Effect of different disintegrants on dissolution performance of preparation

[0072] Table 3 prescription 4, 5

[0073]

[0074] Preparation process of prescription 4, 5: on the basis of prescription 3 preparation process, replace disintegrant cross-linked sodium carboxymethyl cellulose with sodium carboxymethyl starch, and the same use half inside and half outside, and the amount of other excipients does not change, to obtain prescription 4; on the basis of prescription 3, only replace the outside part of the disintegrant with sodium carboxymethyl starch, and the amount of other excipients does not change, to obtain prescription 5.

[0075] Compare the dissolution performance of prescription 3, 4, 5. Dissolution conditions: keep 37±0.5℃, use 500mL pH2.0 hydrochloric acid solution as dissolution medium, use paddle method 50rpm, increase to 250rpm after 60min, investigate the dissolution curve of drug within 90min.

[0076] Table 4 dissolution data of prescription 3, 4, 5 (0 days)

[0077]

[0078]

[0079] The dissolution curves of the prescription 3, 4, 5 were plotted according to the dissolution data of 0 day ( Figure 2 ), the results showed that the dissolution rate of prescription 5 was the slowest, the dissolution rate of prescription 3 was slightly slower than that of prescription 4 at the beginning, but it was significantly better than the other two after 15 min.

[0080] The dissolution of prescription 3 and prescription 4 was investigated under the conditions of 60℃ / 75%RH open and closed with desiccant for 7 days of acceleration.

[0081] Table 5 dissolution data of prescription 3, 4 (7 days of acceleration)

[0082]

[0083] The dissolution curves of the prescription 3, 4 were plotted according to the dissolution data of 7 days of acceleration ( Figure 3 and Figure 4 ), the results showed that the dissolution of prescription 3 decreased significantly, and prescription 4 was more stable than prescription 3.

[0084] Example 3

[0085] On the basis of prescription 4, the compound of formula I was micronized to have a particle size D90<20μm, the rest of the prescription and process remained unchanged, to obtain prescription 6; on the basis of prescription 6, the filler microcrystalline cellulose was removed, and all the filler was replaced by lactose monohydrate, to obtain prescription 7; on the basis of prescription 6, the surfactant sodium dodecyl sulfate was added, and the amount of lactose monohydrate was adjusted slightly, the rest of the prescription and process remained unchanged, to obtain prescription 8.

[0086] Table 6 prescription 6, 7, 8

[0087]

[0088] The dissolution performance of prescription 4, 6, 7, 8 was compared. The dissolution conditions were as follows: keeping at 37±0.5℃, using 500mL of pH2.0 hydrochloric acid solution as the dissolution medium, using paddle method at 50rpm, increasing to 250rpm after 60min, and investigating the dissolution curve of the drug within 90min.

[0089] Table 7 dissolution data of prescription 6, 7, 8 (0 day)

[0090] Formulation Formulation 6 Formulation 7 Formulation 8 Time (min) Dissolution (%) Dissolution (%) Dissolution (%) 5 29 39 36 10 42 56 54 15 52 63 63 20 57 67 69 30 63 72 74 45 68 76 77 60 72 79 81 90 80 87 89

[0091] The dissolution curves of the prescription 4, 6, 7, 8 were plotted according to the dissolution data of 0 day ( Figure 5 ), the results showed that the dissolution rate of prescription 6, prescription 7 and prescription 8 was significantly improved compared with that of prescription 4 within the first 15min, prescription 6 was significantly slower than prescription 4 after 15min, while prescription 7 and 8 had no significant difference, and were significantly better than prescription 4.

[0092] The dissolution and related substance of prescription 7 and prescription 8 were accelerated for 7 days under open and closed conditions with desiccant at 60℃ / 75%RH.

[0093] Table 8 Dissolution data of prescription 7, 8 (accelerated for 7 days)

[0094]

[0095] Table 9 Results of related substance of prescription 7, 8

[0096]

[0097] Note: Total impurities is the sum of impurities ≥0.05.

[0098] The dissolution curves were drawn according to the dissolution data of prescription 7, 8 accelerated for 7 days (Figures Figure 6 and Figure 7 ), and the results showed that there was no significant difference in dissolution stability between prescription 8 and prescription 7.

[0099] The results of related substance showed that there was no significant difference in related substance stability between prescription 7 and prescription 8.

[0100] Example 4

[0101] On the basis of prescription 7, the binder hydroxypropyl methyl cellulose was replaced by sodium carboxymethyl cellulose, and the rest of the prescription and process remained unchanged to obtain prescription 9; on the basis of prescription 7, the binder hydroxypropyl methyl cellulose was replaced by povidone, and the rest of the prescription and process remained unchanged to obtain prescription 10; on the basis of prescription 7, the binder hydroxypropyl methyl cellulose was replaced by methyl cellulose, and the rest of the prescription and process remained unchanged to obtain prescription 11.

[0102] Table 10 Prescription 9, 10, 11

[0103]

[0104]

[0105] The dissolution performance of prescription 7, 9, 10, 11 was investigated, the dissolution method was to keep 37±0.5℃, 500mL of pH 2.0 hydrochloric acid solution as the dissolution medium, paddle method 50rpm, 60min increased to 250rpm, and the dissolution curve of the drug within 90min was investigated.

[0106] Table 11 Dissolution data of prescription 9, 10, 11 (0 days)

[0107] Formulation Formulation 7 Formulation 9 Formulation 10 Formulation 11 Time (min) Dissolution (%) Dissolution (%) Dissolution (%) Dissolution (%) 0 0 0 0 0 5 39 33 32 34 10 56 50 51 53 15 63 58 57 61 20 67 62 63 64 30 72 67 69 70 45 76 72 71 73 60 79 75 76 76 90 87 83 85 85

[0108] Dissolution curves were plotted based on the day 0 dissolution data for formulations 7, 9, 10, and 11. Figure 8 The results showed that there was no significant difference in dissolution among formulations 7, 9, 10 and 11, with formulation 7 exhibiting the best dissolution performance.

[0109] Example 5

[0110] Based on Formula 7, replace the lubricant magnesium stearate with sodium stearate fumarate, while keeping the rest of the formula and process unchanged, to obtain Formula 12; based on Formula 7, replace the lubricant magnesium stearate with talc, while keeping the rest of the formula and process unchanged, to obtain Formula 13.

[0111] Table 12 Prescriptions 12 and 13

[0112]

[0113]

[0114] The dissolution properties of formulations 7, 12, and 13 were investigated. The dissolution method was to maintain a temperature of 37±0.5℃, use 500mL of pH 2.0 hydrochloric acid solution as the dissolution medium, and use a paddle method at 50rpm for 60min, then increase the speed to 250rpm, and observe the dissolution curves of the drugs within 90min.

[0115] Table 13 Dissolution data for formulations 7, 12, and 13 (day 0)

[0116] Formulation Formulation 7 Formulation 12 Formulation 13 Time (min) Dissolution (%) Dissolution (%) Dissolution (%) 0 0 0 0 5 39 34 33 10 56 52 50 15 63 59 57 20 67 62 63 30 72 68 68 45 76 73 74 60 79 76 77 90 87 84 85

[0117] Dissolution curves were plotted based on the dissolution data of prescriptions 7, 12, and 13 on day 0. Figure 9 The results showed that there was no significant difference in dissolution among formulations 7, 12, and 13, with formulation 7 exhibiting the best dissolution performance.

[0118] Example 6

[0119] On the basis of prescription 7, the amount of filler monohydrate lactose was adjusted to 83%, the amount of disintegrant sodium carboxymethyl starch was adjusted to 10%, the rest of the prescription and process was unchanged, prescription 14 was obtained; on the basis of prescription 7, the amount of filler monohydrate lactose was adjusted to 90%, the amount of disintegrant sodium carboxymethyl starch was adjusted to 3%, the rest of the prescription and process was unchanged, prescription 15 was obtained; on the basis of prescription 7, the amount of filler monohydrate lactose was adjusted to 83%, the amount of lubricant magnesium stearate was adjusted to 4.5%, the rest of the prescription and process was unchanged, prescription 16 was obtained; on the basis of prescription 7, the amount of filler monohydrate lactose was adjusted to 85.5%, the amount of lubricant magnesium stearate was adjusted to 2%, the rest of the prescription and process was unchanged, prescription 17 was obtained. On the basis of prescription 7, the amount of filler monohydrate lactose was adjusted to 85.5%, the amount of binder hydroxypropyl methyl cellulose was adjusted to 3%, the rest of the prescription and process was unchanged, prescription 18 was obtained; on the basis of prescription 7, the amount of filler monohydrate lactose was adjusted to 84%, the amount of binder hydroxypropyl methyl cellulose was adjusted to 4.5%, the rest of the prescription and process was unchanged, prescription 19 was obtained.

[0120] Table 14 Prescriptions 14-19

[0121]

[0122] The dissolution performance of prescriptions 7, 14, 15, 16, 17, 18 and 19 was investigated, the dissolution method was to keep 37±0.5℃, 500mL of pH2.0 hydrochloric acid solution was used as the dissolution medium, the paddle method was used at 50rpm, after 60min it was increased to 250rpm, the dissolution curve of the drug within 90min was investigated.

[0123] Table 15 Dissolution data of prescriptions 7, 14-19 (0 days)

[0124]

[0125]

[0126] The dissolution curve was drawn according to the 0-day dissolution data of prescriptions 7, 14-19 (Fig. Figure 10 ), the results showed that the dissolution performance of prescription 7 was relatively the best.

[0127] Example 7

[0128] The dog PK experiment was performed for Formulation 4, 7 and 8: 8 beagles were randomly divided into four groups, 2 in each group. Before the experiment, all beagles were fasted for 12 hours in advance. The first group was orally administered with Formulation 4 (specification: 5 mg / tablet) tablets, the second group was orally administered with Formulation 7 (specification: 5 mg / tablet) tablets, the third group was orally administered with Formulation 8 (specification: 5 mg / tablet) tablets, and the fourth group was administered with a single intravenous injection of a solution of the compound of Formula I (1 mg / mL in 10% NMP / 60% PEG400 / 30% H20). The first group, the second group and the third group were administered with a dose of 2.5 mg / Kg per beagle, and the fourth group was administered with a dose of 1 mg / Kg per beagle. Plasma samples were collected before administration (0) and at 0.083 (only the fourth group), 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours after administration, and the plasma samples were determined for the blood drug concentration of the compound of Formula I by liquid chromatography-tandem mass spectrometry (LC-MS / MS) method. After administration, each beagle was observed and the adverse reactions after administration were recorded.

[0129] Table 16 PK parameters of the fourth group of API dogs after injection administration

[0130] PK parameters Mean [C0 (nM)] 2139 T 1 / 2 (hr) 4.19 V dss (L / kg) 1.53 Cl (mL / min / kg) 6.08 AUC 0-last (nM.h) 5352 AUC 0-inf (nM.h) 5410

[0131] Table 17 In vivo pharmacokinetic parameters of beagles after oral administration

[0132]

[0133]

[0134] Note: Oral bioavailability = AUC0-last of oral administration / AUC0-last of injection administration * dose of injection administration / dose of oral administration * 100%

[0135] The results of the dog PK experiment showed that the bioavailability of Formulation 4 at a dose of 2.5 mpk was 20.4%, the bioavailability of Formulation 8 was 24.7%, and one dog had a vomiting reaction within 30 minutes of administration; while the bioavailability of Formulation 7 was 27.3%, and the animals had no abnormal reactions.

[0136] Example 8

[0137] Effect of coating weight gain on dissolution performance of drug preparation

[0138] The prescription and process of prescription 7 were scaled up on the equipment, and the 20 mg specification was prepared with the same proportion of raw and auxiliary materials as the 5 mg specification. The tablet weight was adjusted to 400 mg. Since the compound of formula I itself has slight hygroscopicity, Opadry was used for coating (a 20% coating solution was prepared, and the plain tablets were coated, the pan speed was 8-10 rpm, and the coating weight gain was 2-4%). The related substances and dissolution stability of the plain tablets were compared, and the content and content uniformity of the final coated tablets were also investigated.

[0139] Table 18 5 mg and 20 mg specification plain tablets

[0140]

[0141] Table 19 5 mg and 20 mg specification coated tablets

[0142] Coated tablets Coated tablet 1 Coated tablet 2 Coated tablet 2-1 Plain tablets Plain tablet 1 Plain tablet 2 Plain tablet 2 Opadry weight gain (%) 4 4 3

[0143] Table 20 Content uniformity of different tablets

[0144]

[0145] According to the content uniformity results in Table 20, the content uniformity of coated tablets 1 of 5 mg specification and coated tablets 2 of 20 mg specification both meet the requirements.

[0146] Table 21 Related substance test results of different tablets

[0147]

[0148] Note: 1. Total impurities are the sum of impurities ≥0.05; 2. The difference in total related substances between plain tablets 1 and prescription 7 is due to different batches of BTK inhibitors.

[0149] According to the related substance results of plain tablets 1, coated tablets 1, plain tablets 2, and coated tablets 2 in Table 21, there is no significant difference in related substances between coated tablets and plain tablets at 0 days. Under accelerated conditions for 7 days, the related substance results of the coated tablets are relatively stable.

[0150] The dissolution performance of plain tablets 1 and coated tablets 1 of 5 mg specification was investigated. The dissolution conditions were as follows: maintaining 37 ± 0.5°C, using 500 mL of pH 2.0 hydrochloric acid solution as the dissolution medium, using the paddle method at 50 rpm, increasing to 250 rpm after 60 min, and investigating the dissolution curve of the drug within 90 min.

[0151] Table 22 Dissolution data of 5 mg specification plain tablets and coated tablets (0 days)

[0152] Tablet type Plain tablet 1 Coated tablet 1 Time (min) Dissolution Dissolution 5 43 53 10 63 73 15 71 82 20 76 88 30 82 93 45 86 96 60 89 97 90 95 98

[0153] Dissolution profiles were plotted based on the dissolution data of 5 mg plain and coated tablets at 0 day (Fig. 1). Figure 11

[0154] To meet the dissolution requirement of large size 20 mg tablets, pH 1.0 was selected as the dissolution medium which met the sink condition. The dissolution method was to maintain 37 ± 0.5 °C, using 900 mL of pH 1.0 hydrochloric acid solution as the dissolution medium, using the paddle method at 50 rpm, increasing to 250 rpm after 60 min, and investigating the dissolution profile of the drug within 90 min. The dissolution results of 20 mg tablets at 0 day and after 7 days of accelerated storage at 60 °C / 75% RH with a desiccant in the sealed container were also investigated.

[0155] Table 23 Dissolution data of 20 mg plain and coated tablets (0 day)

[0156] Tablet type Plain tablet 2 Coated tablet 2 (4% weight gain) Coated tablet 2-1 (3% weight gain) Time (min) Dissolution Dissolution Dissolution 5 58 62 63 10 85 93 90 15 97 99 95 20 102 100 97 30 103 101 97 45 103 102 97 60 103 101 98 90 103 102 97

[0157] Table 24 Dissolution data of 20 mg plain and coated tablets (accelerated for 7 days)

[0158]

[0159] The dissolution results of 20 mg tablets (Fig. 2, Figure 12 13 ) showed that coating with a weight gain of up to 4% had no significant effect on dissolution, and the dissolution stability of the coated tablets was consistent with that of the plain tablets.

[0160] The dissolution of the 20 mg samples in pH 1.0 medium can be completely dissolved within 30 min, which meets the dissolution requirement. This method was used to test the dissolution stability of 5 mg coated tablets, and the dissolution performance at 0 day and after 7 days of accelerated storage at 60 °C / 75% RH with a desiccant in the sealed container was investigated.

[0161] Table 25 Dissolution data of 5 mg plain and coated tablets (pH 1.0)

[0162]

[0163] Dissolution profiles were plotted based on the dissolution data of 5 mg plain and coated tablets in pH 1.0 medium (Fig. 3). Figure 14

[0164] ​​​In summary: Opadry increased the weight by 4%, and the coating had no significant effect on the related substances and dissolution rate. The results of the related substances and dissolution profiles of the placebo and coated tablets were essentially the same for the 5 mg and 20 mg strengths, and there were no significant differences between the accelerated and 0 day samples for the related substances and dissolution profiles.

Claims

1. A BTK inhibitor solid tablet characterized by, The BTK inhibitor solid tablet comprises the following components by weight ratio: 4.5-5.5% of the compound of formula I, 80-90% of a filler, 1-5% of a binder, 3-10% of a disintegrant, and 0.1-5% of a lubricant. The particle size D90 of the compound of formula I is less than 20 um, and the structure of the compound of formula I is shown as follows:

2. The solid tablet according to claim 1, characterized in that, The filler is selected from one or more of lactose, sucrose, starch, pregelatinized starch, dextrin, mannitol, sorbitol, and microcrystalline cellulose, preferably lactose, and further preferably lactose monohydrate.

3. The solid tablet according to claim 1, characterized in that, The binder is selected from one or more of hypromellose, carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, povidone, hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and methylcellulose, preferably hypromellose, sodium carboxymethylcellulose, povidone, and methylcellulose, and further preferably hypromellose.

4. The solid tablet according to claim 1, characterized in that, The disintegrant is selected from one or more of sodium starch glycolate, crospovidone, sodium croscarmellose, and croscarmellose, preferably one or more of sodium croscarmellose and sodium starch glycolate, and further preferably sodium starch glycolate.

5. The solid tablet according to claim 1, characterized in that, The lubricant is selected from one or more of talc, calcium stearate, zinc stearate, stearic acid, glycerol monostearate, glycerol palmitostearate, magnesium stearate, and sodium stearyl fumarate, preferably magnesium stearate, sodium stearyl fumarate, and talc, and further preferably magnesium stearate.

6. The solid tablet according to claim 1, characterized in that, The BTK inhibitor solid tablet comprises the following components by weight ratio: The particle size D90 of the compound of formula I is less than 20 um.

7. The solid tablet according to claim 1, characterized in that, The BTK inhibitor solid tablet comprises the following components by weight ratio: The particle size D90 of the compound of formula I is less than 20 um.

8. The solid tablet according to claim 1, characterized in that, The BTK inhibitor solid tablet comprises the following components by weight ratio: The particle size D90 of the compound of formula I is less than 20 um.

9. The solid tablet according to claim 1, characterized in that, The solid tablet further comprises a coating agent, which increases the weight of the solid tablet by 2-4%; the coating agent is selected from one or more of gastro-soluble film coatings, and preferably Opadry.

10. A process for the preparation of a solid tablet of a BTK inhibitor according to any one of claims 1 to 9, characterized in that, The preparation method comprises the following steps: (1) micronizing the compound of formula I, with a particle size D90 of less than 20 um; (2) mixing the prescription amount of filler and 50% of the prescription amount of disintegrant as an internal additive, and mixing the prescription amount of the compound of formula I obtained in step (1) with the internal additive; (3) wet granulating the mixture obtained in step (2) with an aqueous solution containing the prescription amount of binder, drying, and sizing; (4) mixing the prescription amount of lubricant and the remaining disintegrant as an external additive, mixing the sized granules with the external additive, and tabletting.

11. The method of claim 10, wherein, After tabletting, a coating step is further included: coating the tablet obtained by tabletting, and controlling the coating to increase the weight by 2-4%.

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