CN114177180A - Pharmaceutical composition of ibrutinib - Google Patents

Pharmaceutical composition of ibrutinib Download PDF

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CN114177180A
CN114177180A CN202111389040.6A CN202111389040A CN114177180A CN 114177180 A CN114177180 A CN 114177180A CN 202111389040 A CN202111389040 A CN 202111389040A CN 114177180 A CN114177180 A CN 114177180A
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ibrutinib
pharmaceutically acceptable
acceptable salts
toxic pharmaceutically
pharmaceutical composition
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王建明
杨家俊
王进京
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Beijing Meibeita Drug Res Co ltd
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Beijing Meibeita Drug Res Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol

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Abstract

The invention relates to a pharmaceutical composition of an antitumor drug ibrutinib and a CYP3A enzyme inhibitor; wherein the CYP3A enzyme inhibitor is ritonavir, ketoconazole or costatase; the weight ratio of ibrutinib to ritonavir is 1:0.5 to 1:20, the weight ratio of ibrutinib to ketoconazole is 1:2 to 1:40, and the weight ratio of ibrutinib to collidine is 1:1 to 1: 30. The invention provides application of a pharmaceutical composition containing effective treatment amount of ibrutinib and non-toxic pharmaceutically acceptable salts thereof, a cytochrome CYP3A inhibitor and non-toxic pharmaceutically acceptable salts thereof in preparing an anti-tumor medicament as a Bruton tyrosine kinase inhibitor, wherein the daily dosage of ibrutinib is 0.2-2.0mg/kg per person.

Description

Pharmaceutical composition of ibrutinib
Information of related applications
The application is a divisional application of Chinese patent application with the application number of 201510530674.7 and the title of ibrutinib pharmaceutical composition filed by 8, 27 and 2015 to the Chinese intellectual Property office.
Technical Field
The invention relates to a pharmaceutical composition of an antitumor drug ibrutinib and a CYP3A enzyme inhibitor; wherein the CYP3A enzyme inhibitor is ritonavir, ketoconazole or costatase; the weight ratio of ibrutinib to ritonavir is 1:0.5 to 1:20, the weight ratio of ibrutinib to ketoconazole is 1:2 to 1:40, and the weight ratio of ibrutinib to cobicistat is 1:1 to 1: 30.
Background
Ibrutinib (Ibrutinib) effectively prevents tumor from migrating from B cell to lymphoid tissue adapted to tumor growth environment by selectively inhibiting Bruton Tyrosine Kinase (BTK), and plays a role in targeting anti-tumor; has good therapeutic effect on Mantle Cell Lymphoma (Mantle Cell Lymphoma), Chronic Lymphocytic Leukemia (CLL) and B-Cell non-Hodgkin Lymphoma (B-NHL).
Ibrutinib is metabolized primarily by cytochrome P450 CYP3a4 enzymes. Due to strong drug interactions, unknown toxicity or side effects result. Therefore, ibrutinib should avoid use with CYP3A4 enzyme inhibitors such as ritonavir (ritonavir), indinavir (indinavir), nelfinavir (nelfinavir), saquinavir (saquinavir), boceprevir (boceprevir), and ketoconazole (ketoconazole) (http:// www.accessdata.fda.gov/drug of ddada _ docs/label/2013/205552lbl. pdf).
Disclosure of Invention
The invention unexpectedly discovers that the combination of ibrutinib and a CYP3A enzyme inhibitor in a certain proportion not only can obviously enhance the anti-tumor effect of ibrutinib, but also can obviously reduce the side effect of ibrutinib. Such CYP3A enzyme inhibitors include, but are not limited to, ritonavir (ritonavir), ketoconazole (ketoconazole) or cobicistat.
Accordingly, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of ibrutinib and its non-toxic pharmaceutically acceptable salts and ritonavir and its non-toxic pharmaceutically acceptable salts, characterized by a weight ratio of ibrutinib and ritonavir of from 1:0.5 to 1: 20.
Preferably, the present invention provides pharmaceutical compositions comprising therapeutically effective amounts of ibrutinib and its non-toxic pharmaceutically acceptable salts and ritonavir and its non-toxic pharmaceutically acceptable salts characterized by a weight ratio of ibrutinib and ritonavir of from 1:1 to 1: 20.
More preferably, the present invention provides pharmaceutical compositions containing therapeutically effective amounts of ibrutinib and its non-toxic pharmaceutically acceptable salts and ritonavir and its non-toxic pharmaceutically acceptable salts, characterized by a weight ratio of ibrutinib and ritonavir of from 1:1 to 1: 10.
The invention also provides a pharmaceutical composition containing an effective therapeutic amount of ibrutinib and non-toxic pharmaceutically acceptable salts thereof and ketoconazole and non-toxic pharmaceutically acceptable salts thereof, wherein the weight ratio of ibrutinib to ketoconazole is 1:2 to 1: 40.
Preferably, the invention also provides a pharmaceutical composition containing therapeutically effective amount of ibrutinib and its non-toxic pharmaceutically acceptable salt and ketoconazole and its non-toxic pharmaceutically acceptable salt, wherein the weight ratio of ibrutinib and ketoconazole is 1:4 to 1: 40.
More preferably, the invention also provides a pharmaceutical composition containing therapeutically effective amount of ibrutinib and its non-toxic pharmaceutically acceptable salt and ketoconazole and its non-toxic pharmaceutically acceptable salt, wherein the weight ratio of ibrutinib and ketoconazole is 1:4 to 1: 20.
The invention finally provides a pharmaceutical composition comprising a therapeutically effective amount of ibrutinib and non-toxic pharmaceutically acceptable salts thereof and of cosmostat and non-toxic pharmaceutically acceptable salts thereof, wherein the weight ratio of ibrutinib to cosmostat is from 1:1 to 1: 30.
Preferably, the invention finally provides a pharmaceutical composition comprising a therapeutically effective amount of ibrutinib and its non-toxic pharmaceutically acceptable salts and of cosmostat and its non-toxic pharmaceutically acceptable salts, wherein the weight ratio of ibrutinib and cosmostat is from 1:1 to 1: 15.
More preferably, the invention finally provides a pharmaceutical composition comprising a therapeutically effective amount of ibrutinib and its non-toxic pharmaceutically acceptable salts and of cosmostat and its non-toxic pharmaceutically acceptable salts, wherein the weight ratio of ibrutinib and cosmostat is from 1:1 to 1: 7.5.
The invention also provides application of a pharmaceutical composition containing effective therapeutic amount of ibrutinib and non-toxic pharmaceutically acceptable salts thereof and cytochrome CYP3A inhibitor and non-toxic pharmaceutically acceptable salts thereof as a Bruton tyrosine kinase inhibitor in preparing antitumor drugs.
The invention also provides application of a pharmaceutical composition containing effective therapeutic amount of ibrutinib and non-toxic pharmaceutically acceptable salts thereof, a cytochrome CYP3A inhibitor and non-toxic pharmaceutically acceptable salts thereof as a Bruton tyrosine kinase inhibitor in preparing antitumor drugs, wherein the daily dosage of ibrutinib is 0.2-2.0mg/kg per person.
Preferably, the invention also provides application of a pharmaceutical composition containing therapeutically effective amount of ibrutinib and non-toxic pharmaceutically acceptable salts thereof and cytochrome CYP3A inhibitor and non-toxic pharmaceutically acceptable salts thereof as a Bruton tyrosine kinase inhibitor in preparing antitumor drugs, wherein the daily dosage of ibrutinib is 0.4-2.0mg/kg per person.
Detailed Description
The following examples may further illustrate the invention; however, these examples should not be construed as limiting the scope of the present invention.
Example 1 inhibition of target and non-target cells by a combination of Ibrutinib and ritonavir
The inhibition of Pfeiffer cells, obtained from shanghai gazei biotechnology limited), as well as non-target cells HepG2 and HEK293 cells (obtained from shanghai gazei biotechnology limited) by different ratios of the combination of ibrutinib and ritonavir was tested by the MTT method.
Culturing the cell to be detected to obtain the cell with the concentration of about 2.5 × 104Cell suspension/mL, inoculated into 96-well culture plate, 100.0 uL/well, placed at 37 deg.C, 5% CO2Incubating for 24 hours in an incubator; adding the test substances with different concentrations into a 96-well plate of the cultured tumor cells, and continuously culturing for 72 hours; discarding the culture solution, adding 100.0 μ L of 0.05% MTT application solution into each well, and culturing for 4 hr; the culture medium was discarded, 100. mu.L of DMSO was added to each well, the mixture was dissolved by shaking for 5 minutes, and the absorbance at 490nm was measured.
Figure BDA0003368142920000031
Comparison: absorbance of wells with cells, MTT solution and no drug
Blank: absorbance of wells with media and MTT solution without cells
Adding medicine: absorbance of wells with cells, MTT solution and composition drug solution
Finally, the half Inhibitory Concentration (IC) of each composition on the growth of tumor cells was calculated by the corresponding processing software50In terms of the molar concentration of ibrutinib). The results are shown in Table 1:
TABLE 1 evaluation results of antitumor Activity of composition of Ibrutinib and ritonavir
Figure BDA0003368142920000041
As can be seen from Table 1, the addition of ritonavir in different proportions does not affect the inhibitory effect of ibrutinib on target cell lymphoma B lymphocytes; however, the addition of a high proportion of ritonavir increased the inhibitory effect on non-target cells HepG2 cells (hepatogenic) and HEK293 cells (nephrogenic), suggesting that compositions containing a high proportion of ritonavir may have some liver and kidney toxicity.
Example 2 inhibition of target and non-target cells by a combination of Ibrutinib and ketoconazole
With reference to the method of example 1, the inhibitory effect of different ratios of compositions of ibrutinib and ketoconazole on Pfeiffer cells, HepG2 cells and HEK293 cells was tested. The results are shown in Table 2.
TABLE 2 evaluation results of antitumor Activity of composition of Ibrutinib and ketoconazole
Figure BDA0003368142920000051
As can be seen from Table 2, the addition of ketoconazole in different proportions does not affect the inhibitory effect of ibrutinib on B lymphocytes of target cell lymphoma; however, the addition of a high proportion of ketoconazole increases the inhibitory effect on non-target cells, namely HepG2 cells (liver-derived) and HEK293 cells (kidney-derived), and particularly has significant toxicity on HepG2 cells, suggesting that the composition containing a high proportion of ketoconazole may have strong liver toxicity.
Example 3 inhibition of target and non-target cells by compositions of ibrutinib and costerol
With reference to the method of example 1, different ratios of ibrutinib and comparastat compositions were tested for inhibition of Pfeiffer cells, HepG2 cells and HEK293 cells. The results are shown in Table 3.
TABLE 3 evaluation results of antitumor Activity of Ibrutinib and Cobicistat composition
Figure BDA0003368142920000052
As can be seen from Table 3, the addition of comparastat in different proportions does not affect the inhibitory effect of ibrutinib on target cell lymphoma B lymphocytes; however, the addition of a high proportion of bisastat increased the inhibitory effect on non-target cells HepG2 cells (hepatogenic) and HEK293 cells (nephrogenic), suggesting that compositions containing a high proportion of bisastat may have some liver and kidney toxicity.
EXAMPLE 4 evaluation of hERG Potassium channel blocking Effect of the compositions
Ibrutinib shows clinically some cardiac side effects (incidence of atrial fibrillation 6-9%, http:// www.accessdata.fda.gov/drug atfdda _ docs/label/2013/205552lbl. pdf). Thus, the potential cardiac side effects of the compositions were evaluated by determining their blocking effect on the hERG potassium channel.
The fully automatic patch clamp Qpatch 16X was used to act on the stable hERG channel-expressing CHO hERG DUO cells in descending order of concentration and to record the effect on the hERG potassium channel current. Through the fitting of dose-effect curve, the IC is obtained50(in terms of the molar concentration of ibrutinib). The results are shown in Table 4.
TABLE 4 evaluation results of Ibrutinib compositions on hERG potassium channel blockade
Figure BDA0003368142920000061
As can be seen from Table 4, the addition of a high proportion of CYP3A enzyme inhibitor has a certain blocking effect on the hERG potassium channel, especially the composition containing coustat has a stronger blocking effect on the hERG potassium channel, which suggests that the composition containing a high proportion of the enzyme has higher cardiac side effects than the composition containing coustat.
Example 5 in vivo antitumor Effect
Female CB17/SCID mice (purchased from Shanghai Fuzhong Biotech development Co., Ltd.) were inoculated subcutaneously with 5X 106Individual blast cell lymphoma cells DoHH2 cells (purchased from shanghai bayer biotechnology limited). Two weeks later (mean tumor volume 150 mm)3) Animals were randomly grouped, 6 animals/group. The samples to be tested were ground and suspended in a 0.5% solution of sodium carboxymethylcellulose, and a sodium carboxymethylcellulose suspension containing a dose of the composition was gavaged, and a blank sodium carboxymethylcellulose suspension was given as a control. After 14 days, animal body weight and tumor size were determined. The tumor inhibition rate was calculated as follows:
Figure BDA0003368142920000071
the results are shown in Table 5:
TABLE 5 results of evaluating antitumor Activity of Ibrutinib compositions
Figure BDA0003368142920000072
As can be seen from Table 5, the antitumor effect of the oral administration of ibrutinib 100mg/kg is inferior to that of the intravenous administration of ibrutinib 10 mg/kg; the compositions of Ibrutinib (10mg/kg) + ritonavir (30mg/kg), Ibrutinib (30mg/kg) + ritonavir (30mg/kg) and Ibrutinib (30mg/kg) + ritonavir (90mg/kg) all have remarkable tumor inhibiting effect; the anti-tumor effects of ibrutinib (30mg/kg) + ritonavir (30mg/kg) and ibrutinib (30mg/kg) + ritonavir (90mg/kg) are equivalent, which are obviously higher than that of 100mg/kg oral administration of ibrutinib and equivalent to that of 10mg/kg intravenous administration of ibrutinib.
The compositions of ibrutinib (10mg/kg) + ketoconazole (120mg/kg), ibrutinib (30mg/kg) + ketoconazole (120mg/kg) and ibrutinib (30mg/kg) + ketoconazole (360mg/kg)3 all have obvious tumor inhibiting effect; the anti-tumor effect of the ibrutinib (30mg/kg) + ketoconazole (120mg/kg) is equivalent to that of the ibrutinib (30mg/kg) + ketoconazole (360mg/kg), which is obviously higher than that of the ibrutinib 100mg/kg oral administration and equivalent to that of the ibrutinib 10mg/kg intravenous administration.
Similarly, the compositions of ibrutinib (10mg/kg) + cobicistat (40mg/kg), ibrutinib (30mg/kg) + cobicistat (40mg/kg) and ibrutinib (30mg/kg) + cobicistat (120mg/kg)3 all have remarkable tumor inhibiting effect; the anti-tumor effects of the ibrutinib (30mg/kg) + cobicistat (40mg/kg) and the ibrutinib (30mg/kg) + cobicistat (120mg/kg) are equivalent, which are obviously higher than that of the ibrutinib orally taken at 100mg/kg and equivalent to that of the ibrutinib intravenously taken at 10 mg/kg.
EXAMPLE 6 evaluation of subacute toxicity of compositions on rats
Male wistar rats were randomly grouped into 10 groups and weighed. Grinding a sample to be tested with a certain concentration, suspending the sample in 0.5% sodium carboxymethyl cellulose solution, gavage administration of sodium carboxymethyl cellulose suspension containing a certain dosage of the composition, administration of blank sodium carboxymethyl cellulose suspension as a control, 1 time per day for 14 consecutive days. After the last administration, fasting for 12 hours without water prohibition, anaesthetizing, taking blood from abdominal aorta, preparing serum according to the standard operation procedure for preparing serum of the national Beijing pharmaceutical safety evaluation research center SOPB093, and determining the biochemical index and immunological index of blood supply liquid; EDTA anticoagulation is prepared according to SOPB032 preparation of vacuum tube EDTA anticoagulation for general blood routine determination. Animal survival and weight data are shown in Table 6, hematology index evaluation results are shown in Table 7, and blood biochemical index evaluation results are shown in Table 8.
TABLE 6 survival and weight results for sub-acute toxicity animals for ibrutinib compositions
Figure BDA0003368142920000091
As can be seen from Table 6, when rats orally take 100mg/kg of ibrutinib, the weight increase of animals is obviously lower than that of normal groups, and 1 animal death occurs, which shows that the dose of ibrutinib has obvious toxic and side effects; the animals in the groups of ibrutinib (30mg/kg) + ritonavir (30mg/kg), ibrutinib (30mg/kg) + ritonavir (90mg/kg), ibrutinib (30mg/kg) + ketoconazole (120mg/kg) and ibrutinib (10mg/kg) + cobicistat (40mg/kg) have good growth conditions, and the body weight of the animals is equivalent to that of a normal control group; the weight increase of the animals in the group consisting of ibrutinib (30mg/kg) + ketoconazole (360mg/kg) is obviously lower than that of the normal group, and 3 animals die, which indicates that the composition has obvious toxic and side effects; ibrutinib (30mg/kg) + can gain body weight comparable to the normal group in animals of the staphylol (120mg/kg) group, but 4 sudden death of the animals occurred, possibly as a cardiac side effect.
TABLE 7 evaluation results of sub-acute toxicity hematological indexes of ibrutinib composition
Figure BDA0003368142920000101
As can be seen from Table 7, when rats orally take 100mg/kg of ibrutinib, the hematology index of animals is obviously lower than that of a normal group, which indicates that the dose of ibrutinib has obvious blood toxicity; the hematology indexes of animals with the compositions of ibrutinib (30mg/kg) + ritonavir (30mg/kg), ibrutinib (30mg/kg) + ritonavir (90mg/kg), ibrutinib (30mg/kg) + ketoconazole (120mg/kg) and ibrutinib (30mg/kg) + cobicistat (40mg/kg)4 are all obviously higher than that of the animals orally taken with 100mg/kg of ibrutinib and are equivalent to that of a normal control group; the hematology indexes of the animals in the groups of ibrutinib (30mg/kg) + ketoconazole (360mg/kg) and ibrutinib (30mg/kg) + ketoconazole (120mg/kg) are lower than those of the normal group, but are higher than those of the rats orally taking 100mg/kg of ibrutinib.
TABLE 8 evaluation results of sub-acute toxicity blood biochemical indexes of ibrutinib composition
Figure BDA0003368142920000111
As can be seen from Table 8, when rats orally take 100mg/kg of ibrutinib, the urea nitrogen level and the creatinine level of animals are obviously higher than those of normal groups, which indicates that the rats have certain renal toxicity; the transaminase level of the animals with ibrutinib (30mg/kg) + ketoconazole (120mg/kg) and ibrutinib (10mg/kg) + ketoconazole (360mg/kg) is significantly higher than that of the normal group, indicating that the animals have significant hepatotoxicity; the urea nitrogen level and the creatinine level of animals in the group of ibrutinib (30mg/kg) + cobicistat (40mg/kg) and the group of ibrutinib (30mg/kg) + cobicistat (120mg/kg) are obviously higher than those of the normal group, which indicates that the animals have certain renal toxicity; the blood biochemical indexes of the ibrutinib (30mg/kg) + ritonavir (30mg/kg) group and the ibrutinib (30mg/kg) + ritonavir (90mg/kg) group are equivalent to those of the normal group.

Claims (16)

1. A pharmaceutical composition comprising a therapeutically effective amount of Ibrutinib (Ibrutinib) and non-toxic pharmaceutically acceptable salts thereof and a cytochrome CYP3A enzyme inhibitor, together with pharmaceutically acceptable excipients.
2. The pharmaceutical composition of claim 1, comprising a therapeutically effective amount of ibrutinib and non-toxic pharmaceutically acceptable salts thereof and Ritonavir (Ritonavir) and non-toxic pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients.
3. The pharmaceutical composition of claim 2, comprising a therapeutically effective amount of ibrutinib and non-toxic pharmaceutically acceptable salts thereof and ritonavir and non-toxic pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients; wherein the weight ratio of ibrutinib to ritonavir is 1:0.5 to 1: 20.
4. The pharmaceutical composition of claim 2, comprising a therapeutically effective amount of ibrutinib and non-toxic pharmaceutically acceptable salts thereof and ritonavir and non-toxic pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients; wherein the weight ratio of ibrutinib to ritonavir is 1:1 to 1: 20.
5. The pharmaceutical composition of claim 2, comprising a therapeutically effective amount of ibrutinib and non-toxic pharmaceutically acceptable salts thereof and ritonavir and non-toxic pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients; wherein the weight ratio of ibrutinib to ritonavir is 1:1 to 1: 10.
6. The pharmaceutical composition of claim 1, comprising a therapeutically effective amount of ibrutinib and non-toxic pharmaceutically acceptable salts thereof and ketoconazole (ketoconazole) and non-toxic pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient.
7. The pharmaceutical composition of claim 6, comprising a therapeutically effective amount of ibrutinib and non-toxic pharmaceutically acceptable salts thereof and ketoconazole and non-toxic pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients; wherein the weight ratio of the ibrutinib to the ketoconazole is 1:2 to 1: 40.
8. The pharmaceutical composition of claim 6, comprising a therapeutically effective amount of ibrutinib and non-toxic pharmaceutically acceptable salts thereof and ketoconazole and non-toxic pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients; wherein the weight ratio of the ibrutinib to the ketoconazole is 1:4 to 1: 40.
9. The pharmaceutical composition of claim 6, comprising a therapeutically effective amount of ibrutinib and non-toxic pharmaceutically acceptable salts thereof and ketoconazole and non-toxic pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients; wherein the weight ratio of the ibrutinib to the ketoconazole is 1:4 to 1: 20.
10. The pharmaceutical composition of claim 1, comprising therapeutically effective amounts of ibrutinib and non-toxic pharmaceutically acceptable salts thereof and cobicistat and non-toxic pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients.
11. The pharmaceutical composition of claim 10, comprising therapeutically effective amounts of ibrutinib and non-toxic pharmaceutically acceptable salts thereof and of cosmostat and non-toxic pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients; wherein the weight ratio of ibrutinib to cobicistat is 1:1 to 1: 30.
12. The pharmaceutical composition of claim 10, comprising therapeutically effective amounts of ibrutinib and non-toxic pharmaceutically acceptable salts thereof and of cosmostat and non-toxic pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients; wherein the weight ratio of ibrutinib to cobicistat is 1:1 to 1: 15.
13. The pharmaceutical composition of claim 10, comprising therapeutically effective amounts of ibrutinib and non-toxic pharmaceutically acceptable salts thereof and of cosmostat and non-toxic pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients; wherein the weight ratio of ibrutinib to cobicistat is 1:1 to 1: 7.5.
14. Use of a pharmaceutical composition according to claims 1 to 13 as bruton's tyrosine kinase inhibitor for the preparation of an anti-tumor medicament.
15. Use of a pharmaceutical composition according to claims 1 to 13 as bruton's tyrosine kinase inhibitor for the preparation of an anti-tumor medicament, wherein the daily dose of ibrutinib is 0.2-2.0mg/kg per human.
16. Use of a pharmaceutical composition according to claims 1 to 13 as bruton's tyrosine kinase inhibitor for the preparation of an anti-tumor medicament, wherein the daily dose of ibrutinib is 0.4-2.0mg/kg per human.
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