A pharmaceutical composition containing ibrutinib and a preparation method thereof

Abstract

This application relates to the technical field of pharmaceutical preparations, and specifically discloses a pharmaceutical composition containing ibrutinib and its preparation method. The composition includes the active ingredient ibrutinib, colloidal silicon dioxide, solubilizers, and other excipients such as excipients; its preparation method is: the active ingredient ibrutinib is preferentially mixed with colloidal silicon dioxide and solubilizers, followed by dry granulation, mixing, and capsule filling. The composition of this application can be used for the treatment of diseases such as mantle cell lymphoma (MCL) / chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma, etc. It can effectively break the insoluble complex salt formed by ibrutinib and solubilizers, and has the advantages of fast dissolution rate and significantly improved bioavailability; in addition, the preparation method of this application has the advantages of good process reproducibility, simple process steps, low production cost, and being suitable for large-scale industrial production.

Description

Technical Field

[0001] This application relates to the technical field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition containing ibrutinib and a preparation method thereof. Background Art

[0002] BTK inhibitor (Bruton's tyrosine kinase) is a key kinase in the B-cell receptor (BCR) signal transduction pathway, which is widely expressed in different types of malignant hematological diseases and participates in the processes of B-cell proliferation, differentiation and apoptosis. Due to the very good specificity of BTK small molecule inhibitors, they show very good advantages in the treatment of B-cell malignancies and some B-cell immune diseases. Therefore, BTK inhibitors have become the drugs with the best market prospects in the hematological tumor market. Targeted drugs developed based on tumor biological characteristics have provided more treatment options for tumor patients and have become popular targets for the treatment of hematological malignancies and autoimmune disorders.

[0003] Ibrutinib is the world's first marketed BTK inhibitor, which was approved by the US FDA for marketing in 2013, by the European EMA in 2014, by Japan in 2016, and by China in 2017. The initially approved indication by the FDA was mantle cell lymphoma (MCL) that had received at least 1 previous treatment. Subsequently, multiple indications were approved, including chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma, Waldenström macroglobulinemia patients who had received at least one previous treatment, or first-line treatment of Waldenström macroglobulinemia patients who were not suitable for chemoimmunotherapy, in combination with rituximab, which is suitable for the treatment of Waldenström macroglobulinemia patients.

[0004] Ibrutinib, chemical name: 1-{ (3R)-3-[4-amino-3-(4-phenoxyphenol)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl}prop-2-en-1-one, molecular formula: C 25 H 24 N6O2, and the structural formula is as follows: Ibrutinib is a poorly soluble drug, which is easily soluble in dimethyl sulfoxide, slightly soluble in methanol, slightly soluble in acetonitrile, and almost insoluble in water. Developing it into an oral preparation has great difficulties. Many companies and research institutions have made various attempts and disclosed various solutions. When the original research company developed the preparation, it used micronization treatment of the raw material to reduce the particle size of the raw material, increase its specific surface area, and accelerate the wetting and dissolution of the raw material in water. In addition, a surfactant sodium dodecyl sulfate was added to the formula, intending to increase the apparent solubility of the drug by the solubilization of the surfactant and reducing the surface tension during the dissolution of the raw material, so as to improve the feasibility of developing it into an oral dosage form.

[0005] Surfactants can form micelles in aqueous solutions, significantly altering the surface tension of the solution and reducing the contact angle of the substance in water, thereby producing a series of effects such as solubilization, foaming, and increased wetting. Surfactants are categorized as ionic or nonionic. Whether a surfactant dissociates, as well as differences in their properties, can have varying effects on drugs. For example, ionic surfactants can dissociate into both anionic and cationic forms, and their ions may react with drugs in a variety of ways.

[0006] Sodium lauryl sulfate, as an anionic surfactant, reacts with compounds containing amino groups, especially primary and secondary amino groups, under acidic conditions to form insoluble double salts. These double salts are sticky flocculent substances. Once formed, they cannot effectively release the active substance (ibrutinib), resulting in low bioavailability in the body.

[0007] Due to the presence of insoluble double salts, ibrutinib capsules, an oral drug, have a clinical trial showing an absolute oral bioavailability of only 2.9% under fasting conditions; if taken with a meal, the bioavailability only doubles. Furthermore, this low bioavailability results in significant intra- and inter-individual variability, impacting the safety and efficacy of clinical use.

[0008] In order to solve the above problems, many patents have disclosed different optimization solutions.

[0009] CN107427498A discloses a solution for a large-load ibrutinib tablet. The drug specifications far exceed the clinical use specifications, the clinical application value is limited, and its preparation solution does not effectively solve the problems of insoluble double salt formation and low bioavailability.

[0010] CN106573002A discloses a formulation composition comprising a solid dispersion of ibrutinib, which is used to increase the solubility of the drug, improve its dissolution rate and dissolution amount through the solid dispersion method. However, the complexity of the solid dispersion technology significantly increases the production cost and also limits the large-scale industrial production of the product.

[0011] CN115192522A discloses a liquid formulation composition comprising ibrutinib and various solubilizers. This method can increase the solubility of the drug, accelerate drug release, and improve the bioequivalence of the drug in the body. However, the solution state is prone to problems such as instability, difficulty in processing, poor convenience of medication, and troublesome product transportation.

[0012] CN115054603A discloses a pharmaceutical composition containing an ibrutinib solid dispersion, which is produced by hot-melt extrusion to increase the solubility of the drug. However, the hot-melt extrusion technology is complex and has a low yield, increasing the production cost. In addition, ibrutinib is prone to degradation under high-temperature conditions, and the high temperature in the hot-melt extrusion process is likely to trigger the degradation of ibrutinib, resulting in an increase in the impurity content in the drug and an increase in the safety risk of medication.

[0013] CN112206233A discloses a pharmaceutical composition containing a solid dispersion of ibrutinib and copovidone, which is also produced by hot-melt extrusion to increase the solubility of the drug. This method has the same problems as CN115054603A.

[0014] CN106573002A discloses a solubilizing preparation of a solid dispersion containing ibrutinib, which is prepared by spray drying and can produce a good solubilizing effect. However, organic solvents are used in the spray drying process, there is a risk of solvent residue, and there is a need for subsequent solvent recovery and treatment, resulting in an increase in production cost and a burden on the environment.

[0015] CN111617028A discloses a pharmaceutical composition containing ibrutinib and a water-soluble carrier, which is prepared into a solid dispersion by spray drying and extrusion granulation methods to produce a better solubilizing effect. Due to the use of the spray drying method, it has the same problems as CN106573002A.

[0016] CN106619643A discloses a pharmaceutical composition of ibrutinib, which combines an oil-phase solvent and a solubilizer to improve the solubility of ibrutinib. However, the long-term use of aldehyde oil-phase reagents will bring safety risks.

[0017] Generally speaking, at present, the original research companies and generic drug companies have not found good solutions. Some of the disclosed research content on improving bioavailability has also greatly increased the complexity of the process, which is not conducive to large-scale industrial production and cannot effectively meet the large amount of clinical medication needs. Summary of the Invention

[0018] In order to improve the bioavailability of ibrutinib and control the production cost for large-scale industrial production, the present application provides a pharmaceutical composition containing ibrutinib and its preparation method.

[0019] The pharmaceutical composition containing ibrutinib and its preparation method provided by the present application adopt the following technical solutions:

[0020] In the first aspect, the present application provides a pharmaceutical composition containing ibrutinib, adopting the following technical solutions:

[0021] A pharmaceutical composition containing ibrutinib, calculated by weight percentage: including ibrutinib 35 - 45%, colloidal silica 2 - 6%, solubilizer 1 - 6%, and other excipients 43 - 62%. The other excipients include excipients, disintegrants, lubricants, and glidants.

[0022] Preferably, calculated by weight percentage, it includes the excipient 40 - 50%, the disintegrant 5 - 10%, the lubricant 0.3 - 1%, and the glidant 0.5 - 1%.

[0023] Preferably, calculated by weight percentage, it includes the colloidal silica 3.5 - 5.5%.

[0024] Preferably, the solubilizer is sodium dodecyl sulfate.

[0025] Preferably, the excipient is one or a combination of lactose, microcrystalline cellulose, mannitol, and calcium hydrogen phosphate.

[0026] Preferably, the disintegrant is one or a combination of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose.

[0027] Preferably, the lubricant is one of magnesium stearate and sodium stearyl fumarate; the glidant is one of talc powder and microcrystalline silica gel.

[0028] In the second aspect, the present application provides a preparation method of a pharmaceutical composition containing ibrutinib, adopting the following technical solution:

[0029] A preparation method of a pharmaceutical composition containing ibrutinib, including the following steps:

[0030] 1) Add the ibrutinib raw material, colloidal silica, and solubilizer into a hopper mixer and mix evenly to obtain a first physical mixture;

[0031] 2) Add the first physical mixture, excipient, disintegrant, and lubricant into a hopper mixer and mix evenly to obtain a second physical mixture;

[0032] 3) Transfer the second physical mixture to a dry granulator for granulation to obtain dry granules;

[0033] 4) Add the dry granules, disintegrant, glidant, and lubricant into a hopper mixer and mix evenly to obtain a total mixed material;

[0034] 5) Transfer the total mixed material to a capsule filling machine for capsule filling to obtain capsules.

[0035] Preferably, in step 2), the first physical mixture, excipient, and disintegrant are added to a hopper mixer and mixed evenly to obtain a primary premixed material; the primary premixed material and lubricant are added to a hopper mixer and mixed evenly to obtain a second physical mixture.

[0036] Preferably, in step 4), the dry granules, disintegrant, and glidant are added to a hopper mixer and mixed evenly to obtain a secondary premixed material; the secondary premixed material and lubricant are added to a hopper mixer and mixed evenly to obtain a total mixed material.

[0037] In summary, the present application includes at least one of the following beneficial technical effects:

[0038] The present application uses colloidal silica as a co-dispersant, which can effectively break the phenomenon of insoluble complex salts formed by ibrutinib and sodium dodecyl sulfate under acidic conditions; and silica has a unique silanol group structure, so it has good hydrophilicity, which can increase the rate of solution penetration, enabling ibrutinib molecules to quickly and fully contact the solution, increasing its dissolution rate and solubility, thereby significantly increasing the systemic exposure and blood drug concentration of the drug, achieving the purpose of improving the bioavailability of the drug;

[0039] The present application creatively develops a unique dry granulation and mixing combined process, enabling colloidal silica to preferentially and fully contact with sodium dodecyl sulfate and ibrutinib raw materials. While ensuring that the surfactant has a local solubilization effect, it also plays the hydrophilic role of the silanol group of silica. Most importantly, it can effectively break the insoluble complex salts formed by the reaction of ibrutinib and sodium dodecyl sulfate, improve solubility and dissolution rate, and increase bioavailability; while ensuring the effect, the overall solution significantly reduces the process complexity, making it more suitable for large-scale industrial production. Description of the Drawings

[0040] Figure 1 is a comparison graph of dissolution curves of Examples 1-2 and Comparative Examples 1-4.

[0041] Figure 2 is a graph of the average plasma concentration-time curve of ibrutinib in human subjects under fasting conditions for Examples 1-2, Comparative Example 1, and Comparative Example 4. Detailed Description of the Embodiments

[0042] The following further elaborates on the present application with reference to the drawings and embodiments, but the embodiments of the present invention are not limited to the scope shown in the embodiments. The embodiments are only used to illustrate the present invention and are not used to limit the scope of the present invention.

[0043] Ibrutinib: micronized ibrutinib raw material.

[0044] Excipients: one or more combinations of lactose, microcrystalline cellulose, mannitol, and calcium hydrogen phosphate; lactose is selected from α-lactose monohydrate or anhydrous lactose, which are white or almost white crystalline granules and powders, and the common range is 0 - 90%; microcrystalline cellulose is white or almost white crystalline granules and powders, and the common range is 0 - 85%; mannitol is selected as powders with smaller particle sizes, such as 25C, 50C, 120C, etc., and the common range is 0 - 80%; calcium hydrogen phosphate is white or almost white crystalline powder, and the common range is 0 - 30%.

[0045] Disintegrants: one or more combinations of crospovidone, croscarmellose sodium, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose; crospovidone, the common range is 0.5 - 15%; croscarmellose sodium, the common range is 0.5 - 20%; sodium carboxymethyl starch, the common range is 0.5 - 20%; low-substituted hydroxypropyl cellulose, the common range is 0.5 - 30%.

[0046] Solubilizers: sodium dodecyl sulfate, which has good compatibility with ibrutinib, and the common range is 1 - 10%.

[0047] Co-dispersants: colloidal silicon dioxide, which has good compatibility with ibrutinib, and the common range is 1 - 10%.

[0048] Lubricants: one of magnesium stearate and sodium stearyl fumarate, and the common range is 0.5 - 5%.

[0049] Glidants: one of talc and colloidal silica, both of which have extremely fine particle sizes and a large specific surface area, and can effectively fill the depressions on the surface of the particles, making the material morphology closer to spherical, and the common range is 0.5 - 3%.

[0050] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. In case of contradiction, the definitions provided herein shall prevail.

[0051] Unless otherwise indicated, the numerical ranges listed herein are intended to include the endpoints of the range, and all integers and fractions within the range.

[0052] The term "prescription dosage percentage" means that various substances are proportioned by a certain weight. For example, in this invention, the active ingredient (ibrutinib or its pharmaceutically acceptable salt), co-dispersant, solubilizer, and optionally present pharmaceutically acceptable pharmaceutical excipients are proportioned by a certain weight ratio.

[0053] The term "bioavailability" refers to the degree to which a drug can be utilized by the target tissue after administration, and can also be characterized by the exposure in the blood circulation system and the maximum plasma drug concentration.

[0054] The term "time to reach the peak plasma drug concentration (Tm)" refers to the time when the peak plasma drug concentration (Cmax) is reached after administration of the drug.

[0055] The term "peak plasma drug concentration (Cmax)" refers to the maximum plasma drug concentration reached after administration of the drug.

[0056] The term "AUC 0-∞" refers to the area under the curve of the plasma drug concentration-time curve from time 0 to infinity after administration of the drug.

[0057] The term "AUC 0-t" refers to the area under the curve of the plasma drug concentration-time curve from time 0 to time t after administration of the drug.

[0058] Examples 1 and 2

[0059] Examples 1 and 2 adopt the same preparation process, but the specific ingredient ratios are different. The specific ratios are shown in Table 1.

[0060] Table 1 Specific raw material ratio table for Examples 1 and 2

[0061]

[0062] Preparation process:

[0063] 1) Micronized ibrutinib raw material and colloidal silica are passed through an 80-mesh sieve, and sodium dodecyl sulfate is passed through a 60-mesh sieve. The three are mixed evenly in a hopper mixer at a mixing speed of 15 rpm for 10 min to form a first physical mixture.

[0064] 2) Excipients and disintegrants are added to the first physical mixture and mixed evenly in a hopper mixer at a mixing speed of 15 rpm for 15 min to obtain a primary premixed material.

[0065] 3) Lubricants are added to the primary premixed material and mixed evenly in a hopper mixer at a mixing speed of 15 rpm for 3 min to obtain a second physical mixture.

[0066] 4) The second physical mixture is transferred to a dry granulator for granulation. The rotation frequency of the pressing roller is 12 - 25 Hz, the pressure of the pressing roller is 0.2 - 0.5 MPa, the rotation frequency of the feeding screw is 8 - 15 Hz, the rotation frequency of the first-stage sizing roller is 10 - 30 Hz, the aperture of the first-stage sizing screen is 8 meshes, the rotation frequency of the second-stage sizing roller is 20 - 45 Hz, and the aperture of the second-stage sizing screen is 18 - 20 meshes to obtain dry granules.

[0067] 5) The dry granules are transferred to a hopper mixer, and disintegrants and glidants are added. The mixture is mixed evenly at a mixing speed of 15 rpm for 10 min to obtain a secondary premixed material.

[0068] 6) Add lubricant to the secondary premixed materials, mix evenly at a mixing speed of 15 rpm for 5 minutes to obtain the total mixed materials;

[0069] 7) Transfer the total mixed materials to a capsule filling machine for capsule filling to obtain capsules.

[0070] Comparative Example 1

[0071] Comparative Example 1 uses the same preparation process as Example 1, but with different specific component ratios, as shown in Table 2. Table 2 Specific raw material ratio table of Comparative Example 1

[0072]

[0073] Comparative Example 2

[0074] Comparative Example 2 uses the same specific component ratio as Example 1, but with a different preparation process. The specific preparation process is as follows:

[0075] 1) Pass the micronized ibrutinib raw material through an 80-mesh sieve, and mix it with the excipient and disintegrant in a hopper mixer at a mixing speed of 15 rpm for 15 minutes to form the first physical mixture;

[0076] 2) Pass the colloidal silica through an 80-mesh sieve and the sodium lauryl sulfate through a 60-mesh screen, add them to the first physical mixture, and mix in a hopper mixer at a mixing speed of 15 rpm for 10 minutes to obtain the primary premixed materials;

[0077] 3) Add lubricant to the primary premixed materials, and mix in a hopper mixer at a mixing speed of 15 rpm for 3 minutes to obtain the second physical mixture;

[0078] 4) Transfer the second physical mixture to a dry granulator for granulation. The rotation frequency of the pressing roller is 12 - 25 Hz, the pressure of the pressing roller is 0.2 - 0.5 MPa, the rotation frequency of the feeding screw is 8 - 15 Hz, the rotation frequency of the first-stage sizing roller is 10 - 30 Hz, the aperture of the first-stage sizing screen is 8 meshes, the rotation frequency of the second-stage sizing roller is 20 - 45 Hz, and the aperture of the second-stage sizing screen is 18 - 20 meshes to obtain dry granules;

[0079] 5) Transfer the dry granules to a hopper mixer, add the disintegrant and glidant, and mix at a mixing speed of 15 rpm for 10 minutes to mix evenly and obtain the secondary premixed materials;

[0080] 6) Add lubricant to the secondary premixed materials, mix evenly at a mixing speed of 15 rpm for 5 minutes to obtain the total mixed materials;

[0081] 7) The blended material is transferred to a capsule filling machine for capsule filling to obtain capsules.

[0082] Comparative Example 3

[0083] Comparative Example 3 has the same specific ingredient ratio as Example 1, but the preparation process is different. The specific preparation process is as follows:

[0084] 1) The micronized ibrutinib API is sieved through a 80-mesh sieve, colloidal silicon dioxide is sieved through a 80-mesh sieve, sodium lauryl sulfate is sieved through a 60-mesh screen, and together with the excipient and disintegrant, they are mixed evenly by a hopper mixer at a mixing speed of 15 rpm for 20 min to form the first physical mixture.

[0085] 2) Lubricant is added to the first physical mixture and mixed evenly by a hopper mixer at a mixing speed of 15 rpm for 3 min to obtain the second physical mixture.

[0086] 3) The second physical mixture is transferred to a dry granulator for granulation. The rotation frequency of the pressing roller is 12 - 25 Hz, the pressure of the pressing roller is 0.2 - 0.5 MPa, the rotation frequency of the feeding screw is 8 - 15 Hz, the rotation frequency of the first-stage sizing roller is 10 - 30 Hz, the aperture of the first-stage sizing screen is 8 meshes, the rotation frequency of the second-stage sizing roller is 20 - 45 Hz, and the aperture of the second-stage sizing screen is 18 - 20 meshes to obtain dry granules.

[0087] 4) The dry granules are transferred to a hopper mixer, and disintegrant and glidant are added. They are mixed evenly at a mixing speed of 15 rpm for 10 min to obtain the second-stage material to be mixed.

[0088] 5) Lubricant is added to the material to be mixed and mixed evenly at a mixing speed of 15 rpm for 5 min to obtain the blended material.

[0089] 6) The blended material is transferred to a capsule filling machine for capsule filling to obtain capsules.

[0090] Comparative Example 4

[0091] Comparative Example 4 uses the commercially available original research product of ibrutinib (trade name: IMBRUVICA®), specification: 140 mg, the holder of the drug marketing authorization: Pharmacyclics LLC, and the manufacturer: Catalent CTS LLC.

[0092] To further study the effects of each component and preparation parameters, the present application further conducts the following examples for verification.

[0093] The specific comparative design intentions and corresponding verification methods of the examples and comparative examples are shown in Table 3. Table 3 Comparative design table of Examples 1 - 2 and Comparative Examples 1 - 4

[0094] Dissolution test research:

[0095] The dissolution test research design tables of Examples 1-2 and Comparative Examples 1-4 are shown in Table 4.

[0096] Table 4 Dissolution test design tables of Examples 1-2 and Comparative Examples 1-4

[0097] The dissolution data of Examples 1-2 and Comparative Examples 1-4 are shown in Table 5, and the comparison graph of their dissolution curves is as Figure 1 shown.

[0098] Table 5 Comparative table of dissolution curve research of Examples 1-2 and Comparative Examples 1-4

[0099] The research results show that:

[0100] 1) By comparing the data of Example 1 with those of Comparative Example 1 and Comparative Example 4, it can be seen that colloidal silica has a great influence on the dissolution curve of the product and can greatly promote the dissolution and release of the product.

[0101] 2) By comparing the data of Example 1 and Example 2, it can be seen that when the dosage of colloidal silica is within the range of 3.5% - 5.5%, there is no obvious influence on the dissolution and release of the product, and both can well promote the release of the product.

[0102] 3) By comparing the data of Example 1 with those of Comparative Example 2 and Comparative Example 3, it can be seen that the addition order during material mixing has a great influence on dissolution. When sodium dodecyl sulfate and colloidal silica are preferentially mixed with the active ingredient, the contact degree can be made closer, and the promoting effect on dissolution is stronger.

[0103] This experiment aims to study the pharmacokinetic characteristics of orally administered ibrutinib capsules under fasting conditions; taking Cmax, AUC0-t, and AUC0-∞ as the main research indicators, the pharmacokinetic differences between different examples and comparative example samples are compared and studied.

[0104] Inclusion criteria:

[0105] 1) Age 18 - 50 years old, both male and female are acceptable;

[0106] 2) The weight of male subjects ≥ 50 kg, the weight of female subjects ≥ 45 kg, and the body mass index (BMI) is between 19 - 26 kg / m2 (including the boundary values);

[0107] 3) The subjects voluntarily sign a written informed consent form.

[0108] Exclusion criteria:

[0109] 1) (Medical interview) Subjects with any clinically severe diseases in the circulatory system, endocrine system, nervous system, digestive system, respiratory system, hematology, immunology, psychiatry, metabolic disorders, or any other diseases that can interfere with the test results, either in the past or currently;

[0110] 2) (Medical interview) Subjects with a history of chronic or active digestive tract diseases such as intestinal perforation, gastrointestinal, esophageal diseases, gastritis, gastrointestinal ulcers, enteritis, gastroesophageal reflux, omphalitis, active gastrointestinal bleeding, or who have undergone digestive tract surgery, and the investigator believes that there is still clinical significance currently; or subjects with digestive tract symptoms (diarrhea, constipation, nausea, vomiting, irregular bowel movements, or alternating diarrhea and constipation) within 7 days before the first administration of the study drug, and the investigator believes that they are not suitable to participate in the trial;

[0111] 3) (Medical interview) Subjects with a history of allergy to drugs, foods, or other substances, or who are allergic to ibrutinib capsules or any excipients (such as immediate hypersensitivity and anaphylactoid reactions);

[0112] 4) (Medical interview) Subjects who have undergone surgery within 28 days before the first administration of the study drug, or who plan to have surgery during the trial;

[0113] 5) (Medical interview) Subjects who have used any drugs (including vaccines) or health products (including traditional Chinese herbs) within 14 days before the first administration of the study drug;

[0114] 6) (Medical interview) Subjects who have used any drugs that inhibit or induce liver drug metabolism within 30 days before the first administration of the study drug;

[0115] 7) (Medical interview) Subjects who have used any clinical trial drugs or participated in any drug clinical trials within 1 month before the first administration of the study drug;

[0116] 8) (Medical interview) Subjects who have donated blood within 3 months before the first administration of the study drug, or who have lost more than 400 mL of blood within 3 months before the first administration of the study drug;

[0117] 9) (Medical interview) Subjects who cannot tolerate intravenous puncture and / or have a history of blood faint or needle faint;

[0118] 10) (Medical interview) Subjects who have used oral contraceptives within 30 days before the first administration of the study drug, or who have used long-acting estrogen or progesterone injections or implants within 6 months before the first administration of the study drug;

[0119] 11) (Medical interview) Female subjects who have had unprotected sexual intercourse within 14 days before the first administration of the study drug, or pregnant or lactating women;

[0120] 12) (Inquiry) Subjects and their partners are not allowed to take one or more non-drug contraceptive measures during the entire trial period, or those who have a fertility plan and a sperm donation or egg donation plan within 3 months after the end of the study;

[0121] 13) (Inquiry) Those with special dietary requirements, unable to follow a unified diet or having difficulty swallowing;

[0122] 14) (Inquiry) Smokers or those who smoke more than 5 cigarettes per day within 3 months before the first administration of the study drug;

[0123] 15) (Inquiry) Alcoholics or those who often drink alcohol within 6 months before the first administration of the study drug, that is, those who drink more than 14 units of alcohol per week.

[0124] Biological sample detection: The concentration of ibrutinib in plasma was determined by UPLC-MS / MS method.

[0125] Pharmacokinetic parameter calculation: According to the individual plasma drug concentration - actual blood sampling end point data of the subjects, the non-compartmental model method (CNCA module) of Phoenix WinNonlin pharmacokinetic parameter calculation software (Certara, USA) was used to calculate the pharmacokinetic parameters of ibrutinib (Cmax, AUC0-t, and AUC0-∞, etc.).

[0126] Safety evaluation:

[0127] 1) Any spontaneously reported and all directly observed adverse events, serious adverse events;

[0128] 2) Any clinically significant changes in vital signs (reference value range: 90 mmHg ≤ systolic blood pressure < 140 mmHg, 60 mmHg ≤ diastolic blood pressure < 90 mmHg, 60 beats / min ≤ pulse (resting) ≤ 100 beats / min; subject to the judgment of the research doctor);

[0129] 3) Abnormalities in physical examination, laboratory examination, and electrocardiogram examination during the experiment that are clinically significant (subject to the judgment of the research doctor).

[0130] Trial design: This trial adopts a randomized, open-label, single-dose, four-formulation, two-period, two-sequence crossover design, which is a fasting human pharmacokinetic comparative study. All enrolled subjects are randomly divided into 4 groups with an equal number of people in each group. Each subject takes one of the four study formulations in each period, and is administered only once per period. The dosing sequence is shown in Table 6 "Crossover Dosing Scheme Table", and the washout period is 7 days.

[0131] Table 6 Crossover Dosing Scheme Table for Examples 1-2, Comparative Example 1, and Comparative Example 4

[0132] The blood sampling points were designed to collect approximately 3 mL of venous blood at 0 h (before drug administration) and 0.25, 0.5, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 36 h after drug administration.

[0133] The results of the pharmacokinetic studies of Example 1, Example 2, Comparative Example 1, and Comparative Example 4 under fasting conditions are shown in Table 7, and the mean plasma concentration-time curves of ibrutinib in human subjects under fasting conditions are as Figure 2 shown:

[0134] Table 7 Pharmacokinetic study table of Example 1-2, Comparative Example 1, and Comparative Example 4 under fasting conditions

[0135] From the pharmacokinetic results, the following conclusions can be drawn:

[0136] 1) By comparing the data of Example 1 with those of Comparative Example 1 and Comparative Example 4, it can be seen that colloidal silica has a great promoting effect on the release of the drug in vivo, can effectively increase Cmax and AUC, significantly increase the exposure of the drug in vivo, increase the bioavailability of the drug in vivo by nearly 7-8 times, and increase the effectiveness of the drug in vivo.

[0137] 2) By comparing the data of Example 1 and Example 2, it can be seen that when the amount of colloidal silica is within the range of 3.5%-5.5%, it has an effect on increasing the exposure and bioavailability of the product in vivo. Within this dosage range, the exposure and bioavailability of the drug can be significantly improved.

[0138] The above are all preferred embodiments of this application. The protection scope of this application is not limited by this. Therefore, all equivalent changes made according to the structure, shape, and principle of this application should be covered within the protection scope of this application.

Claims

1. A pharmaceutical composition containing ibrutinib, characterized in that: According to weight percentage, it includes: 35-45% ibrutinib, 2-6% colloidal silicon dioxide, 1-6% solubilizer, and 43-62% other excipients, wherein the other excipients include excipients, disintegrants, lubricants and glidants; the solubilizer is sodium lauryl sulfate; The method for preparing the pharmaceutical composition containing ibrutinib comprises the following steps: 1) adding the ibrutinib API, colloidal silica, and a solubilizing agent into a hopper mixer and mixing to obtain a first physical mixture; 2) adding the first physical mixture, excipient, disintegrant, and lubricant into a hopper mixer and mixing to obtain a second physical mixture; 3) transferring the second physical mixture to a dry granulator for granulation to obtain dry granules; 4) Add the dry granules, disintegrant, glidant, and lubricant into a hopper mixer and mix to obtain a total mixed material; 5) The mixed material is transferred to a capsule filling machine for capsule filling to obtain capsules.

2. A pharmaceutical composition containing ibrutinib according to claim 1, characterized in that Calculated by weight, the composition comprises 40-50% of the excipient, 5-10% of the disintegrant, 0.3-1% of the lubricant, and 0.5-1% of the glidant.

3. A pharmaceutical composition containing ibrutinib according to claim 1, characterized in that Calculated by weight, the colloidal silicon dioxide comprises 3.5-5.5%.

4. A pharmaceutical composition containing ibrutinib according to claim 2, characterized in that The excipient is one or more combinations of lactose, microcrystalline cellulose, mannitol, and calcium hydrogen phosphate.

5. A pharmaceutical composition containing ibrutinib according to claim 2, characterized in that: The disintegrant is one or more combinations of cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose.

6. A pharmaceutical composition containing ibrutinib according to claim 2, characterized in that: The lubricant is one of magnesium stearate and sodium stearyl fumarate; the glidant is one of talc and micro-powder silica gel.

7. The pharmaceutical composition containing ibrutinib according to claim 1, characterized in that: In step 2), the first physical mixture, excipients, and disintegrant are added to a hopper mixer and mixed to obtain a primary material to be mixed; the primary material to be mixed and a lubricant are added to the hopper mixer and mixed to obtain a second physical mixture.

8. The method for preparing a pharmaceutical composition containing ibrutinib according to claim 1, wherein: In step 4), the dry granules, disintegrant, and glidant are added to a hopper mixer and mixed to obtain a secondary mixed material; the secondary mixed material and lubricant are added to the hopper mixer and mixed to obtain a total mixed material.

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