Pharmaceutical composition containing ibrutinib and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, and particularly discloses a pharmaceutical composition containing ibrutinib and a preparation method of the pharmaceutical composition. The composition comprises an active component ibrutinib, colloidal silicon dioxide, a solubilizer, an excipient and other auxiliary materials. The preparation method comprises the following steps: preferentially mixing the active component ibrutinib with the colloidal silicon dioxide and the solubilizer, and carrying out dry granulation, mixing and capsule filling. The composition can be used for treating diseases such as mantle cell lymphoma (MCL) / chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma, can effectively break insoluble double salt formed by ibrutinib and a solubilizer, and has the advantages of being high in dissolution rate and remarkably improving bioavailability; in addition, the preparation method has the advantages of being good in process reproducibility, simple in process step, low in production cost and suitable for large-scale industrial production.

Description

Technical Field

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

[0002] BTK inhibitors (Bruton's tyrosine kinase) are key kinases in the B cell receptor (BCR) signal transduction pathway. They are widely expressed in different types of hematological malignancies and are involved in the proliferation, differentiation and apoptosis of B cells. Since BTK small molecule inhibitors have very good specificity, they have shown great advantages in the treatment of B cell malignancies and some B cell immune diseases. Therefore, BTK inhibitors have become the most promising drugs in the hematological tumor market. Targeted drugs developed based on the biological characteristics of tumors have provided more treatment options for cancer patients and have become a popular target for the treatment of hematological malignancies and autoimmune disorders.

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

[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, the structural formula is as follows:

[0005] Ibrutinib is a poorly soluble drug, easily soluble in dimethyl sulfoxide, slightly soluble in methanol, slightly soluble in acetonitrile, and almost insoluble in water. It is very difficult to develop it into an oral preparation. Many companies and research and development institutions have made various attempts and disclosed various solutions. When developing the preparation, the original research company used micronization of the raw materials to reduce the particle size of the raw materials, increase its specific surface area, and accelerate the wetting and dissolution of the raw materials in water. In addition, the surfactant sodium dodecyl sulfate was added to the formula, intending to increase the apparent solubility of the drug by solubilizing the surfactant and reducing the surface tension of the raw materials when they are dissolved, so as to improve its feasibility of developing it into an oral preparation.

[0006] Surfactants can form micelles in aqueous solutions, significantly changing 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 divided into ionic and non-ionic types. Whether the surfactant dissociates and the differences in its characteristics will have different effects on drugs. For example, ionic surfactants can dissociate into anionic and cationic properties, and their ions may react with drugs in a series of ways.

[0007] As an anionic surfactant, sodium dodecyl sulfate reacts with compounds containing amino groups, especially primary and secondary amino groups, under acidic conditions to form insoluble double salts. The double salts are viscous flocculent substances. Once formed, they cannot effectively release the active substance (ibrutinib), resulting in low bioavailability in the body.

[0008] Due to the presence of insoluble double salts, ibrutinib capsules are an oral drug, and its clinical trial studies have shown that its absolute oral bioavailability under fasting conditions is only 2.9%; if taken after meals, its bioavailability is only increased by 1 times. In addition, too low bioavailability also causes large differences within and between individuals, affecting the safety and effectiveness of clinical medication.

[0009] In order to solve the above problems, many patents disclose different optimization solutions.

[0010] CN107427498A discloses a solution for a large-load ibrutinib tablet, the drug specifications of which far exceed the clinical use specifications, and the clinical application value is limited, and the preparation scheme thereof does not effectively solve the problems of the formation of insoluble double salts and low bioavailability.

[0011] 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 by means of a solid dispersion. However, the complexity of the solid dispersion technology significantly increases the production cost and also limits the mass industrial production of the product.

[0012] CN115192522A discloses a liquid preparation composition comprising ibrutinib and various solubilizers. The method can increase the solubility of the drug, accelerate the release of the drug, 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.

[0013] CN115054603A discloses a preparation composition containing a solid dispersion of ibrutinib, which is produced by hot melt extrusion to increase the solubility of the drug, but the hot melt extrusion technology is complex and the output is low, which increases the production cost. In addition, ibrutinib is prone to degradation under high temperature conditions. The high temperature during the hot melt extrusion process is prone to cause the degradation of ibrutinib, which increases the impurity content in the drug and increases the safety risk of medication.

[0014] CN112206233A discloses a preparation 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.

[0015] CN106573002A discloses a solid dispersion solubilized preparation containing ibrutinib, which is prepared by a spray drying method and can produce a good solubilization effect. However, an organic solvent is used in the spray drying process, which has the risk of solvent residue and the need for subsequent solvent recovery treatment, resulting in increased production costs and a burden on the environment.

[0016] CN111617028A discloses a preparation composition containing ibrutinib and a water-soluble carrier, which is prepared as a solid dispersion by a spray drying method and an extrusion granulation method to produce a better solubilization effect. Due to the use of the spray drying method, the same problem as CN106573002A exists.

[0017] CN106619643A discloses a preparation composition of ibrutinib, which uses a combination of an oil phase solvent and a solubilizer to improve the solubility of ibrutinib. However, long-term use of aldehyde oil phase reagents will bring safety risks.

[0018] In summary, original research companies and generic drug companies have not found a good solution yet. Some of the research content on improving bioavailability that has been made public has also greatly increased the complexity of the process, which is not conducive to large-scale industrial production and cannot effectively meet the large number of clinical drug needs. Summary of the invention

[0019] In order to improve the bioavailability of ibrutinib and control the production cost at the same time to facilitate large-scale industrial production, the present application provides a pharmaceutical composition containing ibrutinib and a preparation method thereof.

[0020] The present application provides a pharmaceutical composition containing ibrutinib and a preparation method thereof using the following technical scheme: In a first aspect, the present application provides a pharmaceutical composition containing ibrutinib, which adopts the following technical solution: A pharmaceutical composition containing ibrutinib, comprising, by weight percentage: 35-45% of ibrutinib, 2-6% of colloidal silicon dioxide, 1-6% of a solubilizer, and 43-62% of other auxiliary materials, wherein the other auxiliary materials include an excipient, a disintegrant, a lubricant, and a glidant.

[0021] Preferably, the excipient comprises 40-50%, the disintegrant 5-10%, the lubricant 0.3-1%, and the glidant 0.5-1%, by weight percentage.

[0022] Preferably, the colloidal silicon dioxide comprises 3.5-5.5% by weight.

[0023] Preferably, the solubilizing agent is sodium dodecyl sulfate.

[0024] Preferably, the excipient is one or more combinations of lactose, microcrystalline cellulose, mannitol and calcium hydrogen phosphate.

[0025] Preferably, 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.

[0026] Preferably, the lubricant is one of magnesium stearate and sodium stearyl fumarate; the glidant is one of talc and micro-powdered silica gel.

[0027] In a second aspect, the present application provides a method for preparing a pharmaceutical composition containing ibrutinib, using the following technical solution: A method for preparing a 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, excipients, disintegrants, and lubricants into a hopper mixer and mixing them to obtain a second physical mixture; 3) transferring the second physical mixture to a dry granulator for granulation to obtain dry granules; 4) adding the dry granules, disintegrant, glidant and lubricant into a hopper mixer and mixing to obtain a total mixed material; 5) The total mixed material is transferred to a capsule filling machine for capsule filling to obtain capsules.

[0028] Preferably, 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 a hopper mixer and mixed to obtain a second physical mixture.

[0029] Preferably, 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.

[0030] In summary, the present application includes at least one of the following beneficial technical effects: The present application uses colloidal silica as a dispersant, which can effectively eliminate the insoluble complex salt phenomenon formed by ibrutinib and sodium dodecyl sulfate under acidic conditions; and silica has a unique silanol structure, and thus has good hydrophilicity, which can increase the rate of solution penetration, so that ibrutinib molecules can quickly and fully contact with the solution, increase its dissolution rate and solubility, thereby significantly increasing the systemic exposure of the drug and the blood drug concentration, and achieving the purpose of improving the bioavailability of the drug; The present application creatively develops a unique dry granulation and mixing combination process, so that colloidal silica can be in full contact with sodium dodecyl sulfate and ibrutinib raw materials in a preferential manner, while ensuring that the surfactant has a local solubilization effect, the hydrophilic effect of the silanol group of silica is also brought into play. Most importantly, the insoluble complex salt formed by the reaction of ibrutinib and sodium dodecyl sulfate can be effectively broken down, solubility and dissolution rate can be improved, and bioavailability can be increased. The overall solution significantly reduces the process complexity while ensuring the effect, making it more suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 It is a comparison chart of the dissolution curves of Examples 1-2 and Comparative Examples 1-4.

[0032] Figure 2 It is a graph of the average blood concentration-time curve of ibrutinib of human subjects in Examples 1-2, Comparative Example 1, and Comparative Example 4 under fasting conditions. DETAILED DESCRIPTION

[0033] The present application is further described in detail below in conjunction with the accompanying drawings and examples, but the embodiments of the present invention are not limited to the scope of the examples. The examples are only used to illustrate the present invention, not to limit the scope of the present invention.

[0034] Ibrutinib: Micronized Ibrutinib API.

[0035] 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 is white or off-white crystalline granules and powder, and the common range is 0-90%; microcrystalline cellulose is white or off-white crystalline granules and powder, and the common range is 0-85%; mannitol is selected from powders with smaller particle sizes, such as 25C, 50C, 120C, etc., and the common range is 0-80%; calcium hydrogen phosphate is white or off-white crystalline powder, and the common range is 0-30%.

[0036] Disintegrants: one or more combinations of cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium starch glycolate, and low-substituted hydroxypropyl cellulose; cross-linked polyvinyl pyrrolidone, commonly used range is 0.5-15%; cross-linked sodium carboxymethyl cellulose, commonly used range is 0.5-20%; sodium starch glycolate, commonly used range is 0.5-20%; low-substituted hydroxypropyl cellulose, commonly used range is 0.5-30%.

[0037] Solubilizer: Sodium dodecyl sulfate, which has good compatibility with ibrutinib, and the commonly used range is 1-10%.

[0038] Dispersant: Colloidal silica, which has good compatibility with ibrutinib and is commonly used in the range of 1-10%.

[0039] Lubricant: Magnesium stearate, one of sodium stearyl fumarate, commonly used range is 0.5-5%.

[0040] Glidant: One of talcum powder and micro-powdered silica gel. Both have extremely fine particle size and large specific surface area. They can effectively fill the depressions on the surface of particles, making the material shape closer to a spherical shape. The common range is 0.5-3%.

[0041] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the event of a conflict, the definitions provided herein shall prevail.

[0042] Unless otherwise indicated, numerical ranges listed herein are intended to include the endpoints of the range, and all integers and fractions within that range.

[0043] The term "prescription dosage percentage" refers to the proportion of various substances according to a certain weight. For example, in the present invention, the active ingredient (ibrutinib or a pharmaceutically acceptable salt thereof), the dispersant and the solubilizer and the optional pharmaceutically acceptable pharmaceutical excipients are proportioned according to a certain weight ratio.

[0044] The term "bioavailability" refers to the extent to which a drug is available to target tissues after administration and can also be characterized by exposure to the blood circulation system and maximum blood drug concentration.

[0045] The term "time to peak plasma drug concentration (Tm)" refers to the time it takes to reach the peak plasma drug concentration (Cmax) after drug administration.

[0046] The term "peak plasma drug concentration (Cmax)" refers to the maximum plasma drug concentration achieved after administration of a drug.

[0047] The term "AUC 0-∞" refers to the area under the curve of the plasma drug concentration versus time curve from time 0 to infinity after drug administration.

[0048] The term "AUC 0-t" refers to the area under the curve of the plasma drug concentration versus time curve from time 0 to time t after drug administration.

[0049] Embodiment 1, 2 Examples 1 and 2 use the same preparation process, but have different specific component ratios, as shown in Table 1.

[0050] Preparation process: 1) passing the micronized ibrutinib API and colloidal silicon dioxide through an 80-mesh sieve, passing the sodium dodecyl sulfate through a 60-mesh sieve, and mixing the three in a hopper mixer at a mixing speed of 15 rpm for 10 min to prepare a first physical mixture; 2) adding excipients and disintegrants to the first physical mixture, and mixing with a hopper mixer at a mixing speed of 15 rpm for 15 min to obtain a primary mixed material; 3) adding a lubricant to the primary material to be mixed, and mixing with a hopper mixer at a mixing speed of 15 rpm for a mixing time of 3 min to obtain a second physical mixture; 4) transferring the second physical mixture to a dry granulator for granulation, wherein the roller rotation frequency is 12-25 Hz, the roller pressure is 0.2-0.5 MPa, the feed screw rotation frequency is 8-15 Hz, the primary granulation roller rotation frequency is 10-30 Hz, the primary granulation screen aperture is 8 mesh, the secondary granulation roller rotation frequency is 20-45 Hz, the secondary granulation screen aperture is 18-20 mesh, to obtain dry granules; 5) The dry granules are transferred to a hopper mixer, and disintegrants and flow aids are added. The mixing speed is 15 rpm, the mixing time is 10 min, and the mixture is mixed evenly to obtain a secondary mixed material; 6) Add lubricant to the secondary mixed material, mix evenly, mix at a speed of 15 rpm, and mix for 5 min to obtain a total mixed material; 7) The total mixed material is transferred to a capsule filling machine for capsule filling to obtain capsules.

[0051] Comparative Example 1 Comparative Example 1 and Example 1 use the same preparation process, but the specific composition ratio is different, and the specific composition ratio is shown in Table 2.

[0052] Comparative Example 2 Comparative Example 2 and Example 1 use the same specific component ratio, but the preparation process is different. The specific preparation process is as follows: 1) passing the micronized ibrutinib API through an 80-mesh sieve, and mixing it with the excipient and disintegrant using a hopper mixer at a mixing speed of 15 rpm for 15 min to prepare a first physical mixture; 2) Passing colloidal silicon dioxide through an 80-mesh sieve and sodium lauryl sulfate through a 60-mesh sieve, adding the mixture to the first physical mixture, and mixing the mixture with a hopper mixer at a mixing speed of 15 rpm for 10 min to obtain a primary mixed material; 3) adding a lubricant to the primary material to be mixed, and mixing with a hopper mixer at a mixing speed of 15 rpm for a mixing time of 3 min to obtain a second physical mixture; 4) transferring the second physical mixture to a dry granulator for granulation, wherein the roller rotation frequency is 12-25 Hz, the roller pressure is 0.2-0.5 MPa, the feed screw rotation frequency is 8-15 Hz, the primary granulation roller rotation frequency is 10-30 Hz, the primary granulation screen aperture is 8 mesh, the secondary granulation roller rotation frequency is 20-45 Hz, the secondary granulation screen aperture is 18-20 mesh, to obtain dry granules; 5) The dry granules are transferred to a hopper mixer, and disintegrants and flow aids are added. The mixing speed is 15 rpm, the mixing time is 10 min, and the mixture is mixed evenly to obtain a secondary mixed material; 6) Add lubricant to the secondary mixed material, mix evenly, mix at a speed of 15 rpm, and mix for 5 min to obtain a total mixed material; 7) The total mixed material is transferred to a capsule filling machine for capsule filling to obtain capsules.

[0053] Comparative Example 3 Comparative Example 3 and Example 1 use the same specific component ratio, but the preparation process is different. The specific preparation process is as follows: 1) passing the micronized ibrutinib API through an 80-mesh sieve, passing the colloidal silicon dioxide through an 80-mesh sieve, passing the sodium dodecyl sulfate through a 60-mesh sieve, and mixing them with the excipients and disintegrant using a hopper mixer at a mixing speed of 15 rpm for 20 min to prepare a first physical mixture; 2) adding a lubricant to the first physical mixture and mixing it with a hopper mixer at a mixing speed of 15 rpm for 3 min to obtain a second physical mixture; 3) transferring the second physical mixture to a dry granulator for granulation, wherein the roller rotation frequency is 12-25 Hz, the roller pressure is 0.2-0.5 MPa, the feed screw rotation frequency is 8-15 Hz, the primary granulation roller rotation frequency is 10-30 Hz, the primary granulation screen aperture is 8 mesh, the secondary granulation roller rotation frequency is 20-45 Hz, the secondary granulation screen aperture is 18-20 mesh, to obtain dry granules; 5) The dry granules are transferred to a hopper mixer, and disintegrants and flow aids are added. The mixing speed is 15 rpm, the mixing time is 10 min, and the mixture is mixed evenly to obtain a secondary mixed material; 6) Add lubricant to the material to be mixed, mix evenly, mix at a speed of 15 rpm, and mix for 5 min to obtain a total mixed material; 7) The total mixed material is transferred to a capsule filling machine for capsule filling to obtain capsules.

[0054] Comparative Example 4 Comparative Example 4 uses the commercially available original product of ibrutinib (trade name: IMBRUVICA®), specification: 140 mg, drug marketing license holder: Pharmacyclics LLC, manufacturer: Catalent CTS LLC.

[0055] In order to further study the effects of various components and preparation parameters, the present application further carried out the following examples for verification.

[0056] The specific comparison design intentions and corresponding verification methods of the embodiments and comparative examples are shown in Table 3.

[0057] The dissolution test study design table of Examples 1-2 and Comparative Examples 1-4 is shown in Table 4.

[0058] The dissolution data of Examples 1-2 and Comparative Examples 1-4 are shown in Table 5, and the dissolution curve comparison diagram is shown in Figure 1 shown.

[0059] The results of the study showed that: 1) By comparing the data of Example 1 with Comparative Examples 1 and 4, it can be seen that colloidal silicon dioxide has a great influence on the dissolution curve of the product and can greatly promote the dissolution and release of the product.

[0060] 2) Comparison of the data of Example 1 and Example 2 shows that the amount of colloidal silicon dioxide in the range of 3.5%-5.5% has no significant effect on the dissolution and release of the product, and both can well promote the release of the product.

[0061] 3) Comparison of the data of Example 1 and Comparative Examples 2 and 3 shows that the order of adding materials during mixing has a great influence on dissolution. Sodium dodecyl sulfate and colloidal silicon dioxide are preferentially mixed with the active ingredient, which can make the contact degree closer and the promoting effect on dissolution stronger.

[0062] The purpose of this study is to study the pharmacokinetic characteristics of oral ibrutinib capsules under fasting conditions; using Cmax, AUC0-t, and AUC0-∞ as the main research indicators, the pharmacokinetic differences between different examples and comparative examples were compared.

[0063] Inclusion criteria: 1) Ages 18 to 50, both male and female; 2) Male subjects weigh ≥50kg, female subjects weigh ≥45kg, and body mass index (BMI) is between 19-26 kg / m2 (including the boundary value); 3) The subjects voluntarily signed a written informed consent.

[0064] Exclusion criteria: 1) (Interview) Those who have had or are currently suffering from any clinically serious diseases such as circulatory system, endocrine system, nervous system, digestive system, respiratory system, hematology, immunology, psychiatry and metabolic disorders, or any other diseases that may interfere with the test results; 2) (Interview) Patients with past or current chronic or active gastrointestinal diseases such as intestinal perforation, gastrointestinal tract, esophageal disease, gastritis, gastrointestinal ulcer, enteritis, gastroesophageal reflux, omphalitis, active gastrointestinal bleeding, or gastrointestinal surgery, and the investigator believes that the disease is still clinically significant; or patients with gastrointestinal symptoms (diarrhea, constipation, nausea, vomiting, irregular bowel movements, or alternating diarrhea and constipation) within 7 days before the first dose of the study drug, and the investigator believes that they are not suitable for participating in the trial; 3) (Inquiry) Those with a history of allergy to drugs, food or other substances, or allergy to ibrutinib capsules or any excipients (such as anaphylaxis and anaphylactic-like reactions); 4) (Questionnaire) Those who have undergone surgery within 28 days before the first use of the study drug, or plan to undergo surgery during the trial; 5) (Inquiry) Those who have used any drugs (including vaccines) or health products (including Chinese herbal medicines) within 14 days before the first use of study drugs; 6) (Inquiry) Any drug that inhibits or induces liver metabolism of drugs has been used within 30 days before the first use of study drugs; 7) (Questionnaire) Patients who used any clinical trial drugs or were enrolled in any drug clinical trial within one month before taking the study drug for the first time; 8) (Interview) Those who donated blood within 3 months before taking the study drug for the first time, or those who lost more than 400mL of blood within 3 months before taking the study drug for the first time; 9) Interview) Those who cannot tolerate venipuncture and / or have a history of blood phobia or needle phobia; 10) (Questionnaire) Patients who have used oral contraceptives within 30 days before taking the study drug for the first time, or patients who have used long-acting estrogen or progesterone injections or implants within 6 months before taking the study drug for the first time; 11) (Questionnaire) Those who have had unprotected sex within 14 days before taking the study drug for the first time (female) or women who are pregnant or breastfeeding; 12) (Inquiry) The subject and his / her partner cannot take one or more non-drug contraceptive measures during the entire trial, or have plans to have children and donate sperm or eggs within 3 months after the end of the study; 13) (Inquiry) Those who have special dietary requirements, cannot follow a unified diet, or have difficulty swallowing; 14) (Questionnaire) Smokers or those who smoked more than 5 cigarettes a day within 3 months before taking the study drug for the first time; 15) (Questionnaire) Alcoholics or regular drinkers within 6 months before first taking the study drug, that is, drinking more than 14 units of alcohol per week.

[0065] Biological sample detection: The concentration of ibrutinib in plasma was determined by UPLC-MS / MS.

[0066] Calculation of pharmacokinetic parameters: Based on the individual blood drug concentration of the subjects - the actual end point data of blood sampling, the pharmacokinetic parameters of ibrutinib (Crnax, AUC0-t., and AUC0-∞, etc.) were calculated using the non-compartmental model method (CNCA module) of Phoenix WinNonlin pharmacokinetic parameter calculation 8.2 (Celtara. USA) statistical software.

[0067] Safety evaluation: 1) Any spontaneously reported and all directly observed adverse events and serious adverse events; 2) Any abnormalities of vital signs with clinically significant changes (reference 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 physician); 3) Abnormalities in physical examination, laboratory tests, and electrocardiogram during the experiment are clinically significant (subject to the judgment of the research physician).

[0068] Experimental design: This experiment adopts a randomized, open, single-dose, four-preparation, two-cycle, two-sequence crossover design for a comparative study of human pharmacokinetics of fasting administration. All enrolled subjects were randomly divided into four groups, with equal numbers in each group. Each subject took one of the four research preparations per cycle, and only took the drug once per cycle. The order of taking the drugs is shown in Table 6 "Crossover Dosing Scheme Table", and the washout period is 7 days.

[0069] The blood collection points were designed to collect about 3 mL of venous blood before medication (0 h) and 0.25, 0.5, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 45, 6, 8, 10, 12, 24, and 36 h after medication.

[0070] The pharmacokinetic study results of Example 1, Example 2, Comparative Example 1 and Comparative Example 4 under fasting conditions are shown in Table 7. The average blood concentration-time curve of ibrutinib in human subjects under fasting conditions is shown in Table 7. Figure 2 As shown:

[0071] The pharmacokinetic results lead to the following conclusions: 1) By comparing the data of Example 1 with Comparative Examples 1 and 4, it can be seen that colloidal silicon dioxide has a significant 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.

[0072] 2) Comparison of the data of Example 1 and Example 2 shows that the amount of colloidal silicon dioxide in the range of 3.5%-5.5% has an effect on increasing the exposure and bioavailability of the product in the body. Within this dosage range, the exposure and bioavailability of the drug can be significantly improved.

[0073] The above are all preferred embodiments of the present application, and the protection scope of the present application is not limited thereto. Therefore, any equivalent changes made according to the structure, shape, and principle of the present application should be included in the protection scope of the present application.

Claims

1. A pharmaceutical composition containing ibrutinib, characterized in that: Calculated by weight percentage: comprising 35-45% of ibrutinib, 2-6% of colloidal silicon dioxide, 1-6% of solubilizer, and 43-62% of other auxiliary materials, wherein the other auxiliary materials include excipients, disintegrants, lubricants and glidants.

2. A pharmaceutical composition containing ibrutinib according to claim 1, characterized in that: According to weight percentage, it includes 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: According to weight percentage, the colloidal silicon dioxide is included in an amount of 3.5-5.5%.

4. A pharmaceutical composition containing ibrutinib according to claim 2, characterized in that: The solubilizing agent is sodium lauryl sulfate.

5. 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.

6. 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.

7. 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 talcum powder and micro-powder silica gel.

8. A method for preparing a pharmaceutical composition containing ibrutinib, characterized in that: The following steps are involved: 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, excipients, disintegrants, and lubricants into a hopper mixer and mixing them to obtain a second physical mixture; 3) transferring the second physical mixture to a dry granulator for granulation to obtain dry granules; 4) adding the dry granules, disintegrant, glidant and lubricant into a hopper mixer and mixing to obtain a total mixed material; 5) The total mixed material is transferred to a capsule filling machine for capsule filling to obtain capsules.

9. The method for preparing a pharmaceutical composition containing ibrutinib according to claim 8, 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.

10. The method for preparing a pharmaceutical composition containing ibrutinib according to claim 8, characterized in that: 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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