CN111053777A - Ibutinib pharmaceutical composition and application thereof - Google Patents
Ibutinib pharmaceutical composition and application thereof Download PDFInfo
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- CN111053777A CN111053777A CN201811200402.0A CN201811200402A CN111053777A CN 111053777 A CN111053777 A CN 111053777A CN 201811200402 A CN201811200402 A CN 201811200402A CN 111053777 A CN111053777 A CN 111053777A
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- pharmaceutical composition
- paclitaxel
- ibrutinib
- pharmaceutically acceptable
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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
- A61K31/495—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
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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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention discloses a pharmaceutical composition which is characterized by taking ibrutinib and paclitaxel or pharmaceutically acceptable derivatives thereof as effective components, wherein the mass ratio of the ibrutinib to the kaempferol or the pharmaceutically acceptable derivatives thereof is 1.5: 1-5: 1. The pharmaceutical composition has the advantages of improving the tumor inhibition effect and simultaneously showing a remarkable synergistic effect when the two are used in combination.
Description
Technical Field
The invention belongs to the field of medical application, and particularly relates to a pharmaceutical composition of ibrutinib and application thereof.
Background
Ibrutinib, also known as ibrutinib, known under the english name ibrutinib, tradename Imbruvica, chemically known as 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-D ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one, having the following structure:
ibutinib is a small-molecule BTK inhibitor, can be selectively and covalently combined with cysteine residue (Cys-481) on the active site of BTK, irreversibly inhibits the activity of BTK, further inhibits the activation of a BCR signal pathway, effectively prevents tumors from migrating from B cells to lymphoid tissues suitable for tumor growth, reduces the malignant proliferation of the B cells and induces the apoptosis of the cells, thereby playing a role in treating CLL and MCL. Non-clinical studies have shown that ibrutinib is able to inhibit the proliferation and survival of malignant B lymphocytes in vivo. Has good curative effect on mantle cell lymphoma, chronic lymphocytic leukemia and B-cell non-Hodgkin lymphoma.
Paclitaxel, alias taxol, violacein, tertin, chemical name 5 β, 20-epoxy-1, 2 α,4, 7 β, 10 β, 13 α -hexahydroxy-taxane-11-en-9-one-4, 10-diacetate-2-benzoate-13 [ (2'R, 3' S) -N-benzoyl-3-phenylisoserine ester]Molecular weight 853.92, formula C47H51NO14. It is a novel anti-microtubule drug, which inhibits depolymerization by promoting tubulin polymerization, maintains tubulin stability, and inhibits cell mitosis. In vitro experiments demonstrated that paclitaxel had significant radiosensitizing effects, probably stopping the cells in the G2 and M phases that were sensitive to radiotherapy. Through the clinical research of II-III, the taxol is mainly suitable for ovarian cancer and breast cancer, and has certain curative effect on lung cancer, colorectal cancer, melanoma, head and neck cancer, lymphoma and cerebroma. At present, no report about synergistic effect of the combined drugs of ibrutinib and paclitaxel when used in combination in the aspect of tumor resistance is found.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a pharmaceutical composition of ibrutinib and application thereof, wherein the pharmaceutical composition has a remarkable synergistic effect especially on the treatment of non-small cell lung cancer.
In order to achieve the purpose, the invention adopts the following technical scheme:
a pharmaceutical composition takes ibrutinib and paclitaxel or pharmaceutically acceptable derivatives thereof as effective components, wherein the mass ratio of the ibrutinib to the paclitaxel or pharmaceutically acceptable derivatives thereof is 1.5: 1-5: 1.
Preferably, the mass ratio of ibrutinib to paclitaxel or pharmaceutically acceptable derivatives thereof is 2: 1-5: 1.
Further preferably, the mass ratio of ibrutinib to paclitaxel or pharmaceutically acceptable derivatives thereof in the pharmaceutical composition is 3: 1-4: 1.
The pharmaceutically acceptable derivatives of paclitaxel in the pharmaceutical composition are docetaxel, paclitaxel, esmolol and dopamil.
The pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
The composition can be prepared into soft capsules, oral agents, injections, tablets and granules.
The composition can be prepared into tablets; the tablet is a double-layer tablet consisting of a tablet core and a quick release layer wrapping the tablet core, wherein the tablet core is a microcapsule prepared from paclitaxel or derivatives thereof and an excipient; the quick release layer is prepared from ibrutinib and auxiliary materials.
The excipient is cholesterol palmitate, propylene glycol and sodium stearate lactate; the auxiliary materials are selected from calcium monostearate, maltodextrin, monopalmitoyl glycerol and superfine silica gel powder.
The application of the pharmaceutical composition in the aspect of resisting tumor cells, in particular to the aspect of resisting non-small cell lung cancer.
Compared with the prior art, the invention has the following advantages: the paclitaxel and the ibrutinib are used together, so that the drug resistance of the ibrutinib is delayed, the toxic and side effects of the ibrutinib are reduced, and the drug effect of the ibrutinib is enhanced.
Detailed Description
The invention is further illustrated with reference to specific examples, without however being limited thereto.
Example 1
Determination of the concentration of ibrutinib in combination with paclitaxel and IC50 assay: this example uses the MTT method to analyze the drug sensitivity of a549 cells to ibrutinib and paclitaxel. A549 cells at 1 × 104The concentration of each mL is inoculated in a 96-well culture plate, 100 mu L of each well is added, and after overnight culture, drugs or control solution with different concentrations (20 mu L of each well) are added, wherein the ibutinib is provided with 8 concentration gradients which are respectively 10, 5, 2.5, 1.25, 0.625, 0.3125, 0.1500 and 0.0750 (the unit is mu mol/L); paclitaxel has 7 concentration gradients of 10, 5, 2.5,1.25, 0.625, 0.3125 and 0.1500 (units are all. mu. mol/L). Each drug concentration was set with 3 replicate wells, and the experiment was repeated 3 times with a drug-free control. And after 24h, 48h and 72h of culture, respectively adding 20 mu L of MTT solution into each hole, continuously culturing for 4h, respectively adding 130 mu L of dimethyl sulfoxide (DMSO) into each hole, fully and uniformly mixing on a vibrator, measuring an OD value at 490nm under a microplate reader, and calculating the concentration (IC50) of each drug required by 50% cell growth inhibition, thereby determining the concentration of the drug for the next step of experiment. The results are shown in table 1, and the inhibition effect of the two drugs on a549 cells is shown to be drug concentration and time-dependent. As can be seen from the results, the IC50 value of ibutinib on A549 cells is 2.38 +/-0.64 mu mol/L and the IC50 value of paclitaxel on A549 cells is 3.42 +/-0.46 mu mol/L after the cells are cultured for 72 hours.
TABLE 1 IC50 values (units: μmol/L, mean (x). + -. s) for A549 cells at various times
| Time (h) | Ibutinib (mu mol/L) | Taxol (mu mol/L) |
| 24 | 7.36±0.45 | 8.92±0.86 |
| 48 | 2.78±0.96 | 4.85±0.26 |
| 72 | 2.38±0.64 | 3.42±0.46 |
Example 2
Experiment of inhibition rate of ibutinib and paclitaxel pharmaceutical composition on A549 cell proliferation includes that logarithmic phase A549 cells are treated by 1 × 104The density per well was plated in 96-well plates at 50. mu.L/well and after 24h of incubation the drug was added (50. mu.L of either gazetinib, paclitaxel, combination or control per well). Wherein the concentration of the ibrutinib is respectively 0.01, 0.05, 0.1, 0.2, 0.4, 0.8 and 1.0 (the unit is mu mol/L), the concentration of the paclitaxel is respectively 0.01, 0.1 and 0.2, 0.4, 0.8, 1.6 and 2.0 (units are all μmol/L), the combined group concentrations are (0.01 μmol/L ibrutinib +0.01 μmol/L paclitaxel), (0.05 μmol/L ibrutinib +0.1 μmol/L paclitaxel), (0.1 μmol/L ibrutinib +0.2 μmol/L paclitaxel), (0.2 μmol/L ibrutinib +0.4 μmol/L paclitaxel), (0.4 μmol/L ibrutinib +0.8 μmol 1/L paclitaxel), (0.8 μmol/L ibrutinib +1.6 μmol/L paclitaxel) and (1.0 μmol/L ibrutinib +2.0 μmol/L paclitaxel), and each concentration is 4 replicates. Adding the drug, culturing for 72h, adding MTT 10 μ L with concentration of 5mg/L into each well, continuing culturing for 4h, adding DMSO80 μ L, shaking for 10min, measuring OD value of each well with enzyme labeling instrument (wavelength 490nm), and calculating cell proliferation inhibition rate according to the following formula:
judging the characteristic of the combination of the paclitaxel and the ibrutinib by using the q value, and calculating the formula:
wherein EA and EB are the single-use inhibition rates of paclitaxel and ibrutinib respectively, and EAB is the combined inhibition rate of the two medicines. When q is more than 1.15, the synergistic effect is obtained, q is more than or equal to 0.85 and less than or equal to 1.15, the additive effect is obtained, and q is less than 0.85, the antagonistic effect is obtained.
The research result shows that: after the A549 cells are treated by combination of paclitaxel and ibrutinib, the cell growth inhibition effect appears at 72h, and the cell inhibition rate is obviously increased compared with that of the paclitaxel or the ibrutinib which is singly used. The paclitaxel group has an inhibition rate of 10-25%, the ibrutinib group has an inhibition rate of 20-30%, and the combined group has an inhibition rate of 30-60%. Meanwhile, the q value of 2 mu mol/L paclitaxel and 1 mu mol/L ibutinib in 72h is 1.26, which shows a synergistic effect, and the q values of the other groups are 0.86-1.05, which shows an additive effect. In addition, the inhibition rate of the combination group increases with the increase of the drug concentration.
Example 3
In vitro inhibition experiments on various tumor cells with single drugs and combined drugs: the inhibition of the proliferation of lung tumor cells A549 and liver cancer cells HepG2 by ibutinib (1.5. mu. mol/L), paclitaxel (3.0. mu. mol/L) alone and two (0.5. mu. mol/L of ibutinib +1. mu. mol/L of paclitaxel) in combination were determined by the MTT method within 72 hours. The test results are shown in table 2, compared with the single drug, the combined drug (1.0 mu mol/L of ibutinib and 2.0 mu mol/L of paclitaxel) has better inhibition effect on lung tumor cells and liver cancer cells, and especially has better inhibition effect on lung tumor cells A549.
TABLE 2 inhibition of cancer cell proliferation by paclitaxel, ibrutinib and combinations thereof
By using
| Pharmaceutical composition | HepG2 | A549 |
| Control group 5-Fu (2. mu. mol/L, 100. mu.L) | 86.2％ | 81.3％ |
| Ibutotinib (1.5. mu. mol/L, 100. mu.L) | 46.8％ | 52.4％ |
| Taxol (3.0. mu. mol/L, 100. mu.L) | 42.3％ | 49.8％ |
| 1.0. mu. mol/L Ibutinib + 2.0. mu. mol/L paclitaxel (total 100. mu.L) | 91.4％ | 95.6％ |
Example 4
Experiment on the effect of the combined use of the pharmaceutical composition on apoptosis of A549 lung tumor cells: flow cytometry is adopted to analyze the influence of the individual use and the combined use of the ibrutinib and the paclitaxel on the apoptosis of A549 cells. A549 cells at 1 × 104The cells were inoculated in a 96-well plate at a concentration of 100. mu.L/well and cultured
Adding the medicine after night, (each well contains 100 mu L of ibrutinib, paclitaxel, combination or control liquid) ibrutinib is provided with 7 concentration gradients which are respectively 0.01, 0.05, 0.1, 0.2, 0.4, 0.8 and 1.0 (the unit is mu mol/L); paclitaxel is provided with 7 concentration gradients of 0.01, 0.1, 0.2, 0.4, 0.8, 1.6 and 2.0 (unit is mu mol/L); the concentrations of the combination group (ibrutinib + paclitaxel) were (0.01. mu. mol/L ibrutinib + 0.01. mu. mol/L kaempferol), (0.05. mu. mol/L ibrutinib + 0.1. mu. mol/L paclitaxel), (0.1. mu. mol/L ibrutinib + 0.2. mu. mol/L paclitaxel), (0.2. mu. mol/L ibrutinib + 0.4. mu. mol/L paclitaxel), (0.4. mu. mol/L ibrutinib + 0.8. mu. mol/L paclitaxel), (0.8. mu. mol/L ibrutinib + 1.6. mu. mol/L paclitaxel) and (1.0. mu. mol/L ibrutinib + 2.0. mu. mol/L paclitaxel), respectively. 3 repeated wells are set for each drug concentration, the experiment is repeated 3 times, a control group without the drug is set, and the apoptosis rate is measured after 72 hours.
The results of the study on the effect of ibutinib and paclitaxel on A549 cell apoptosis show that: when the ibutinib (the concentration is 1.5 mu mol/L) or the paclitaxel (the concentration is 3.0 mu mol/L) acts alone, the apoptosis rate is increased compared with that of a control group. Among them, the control group had an apoptosis rate of 3.6%, ibrutinib had an apoptosis rate of 15.3%, and paclitaxel had an apoptosis rate of 11.8%. The apoptosis rate of the combined medicine group (1.0 mu mol/L ibutinib +2.0 mu mol/L paclitaxel) is obviously increased to 60.5 percent, and compared with the single administration, the combined medicine group has obvious synergistic effect.
Claims (9)
1. The pharmaceutical composition is characterized by taking ibrutinib and paclitaxel or pharmaceutically acceptable derivatives thereof as effective components, wherein the mass ratio of ibrutinib to paclitaxel or pharmaceutically acceptable derivatives thereof is 1.5: 1-5: 1.
2. The pharmaceutical composition according to claim 1, wherein the mass ratio of ibrutinib to paclitaxel or pharmaceutically acceptable derivatives thereof is 2: 1-5: 1.
3. The pharmaceutical composition according to claim 1, wherein the mass ratio of ibrutinib to paclitaxel or pharmaceutically acceptable derivatives thereof in the pharmaceutical composition is 3: 1-4: 1.
4. The pharmaceutical composition of any one of claims 1-3, wherein the pharmaceutically acceptable derivative of paclitaxel in the pharmaceutical composition is docetaxel, paclitaxel, esbiotine, and dophenanthrene.
5. The pharmaceutical composition of any one of claims 1-3, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
6. The pharmaceutical composition according to any one of claims 1 to 3, wherein the composition is formulated as soft capsules, oral preparations, injections, tablets, granules.
7. The pharmaceutical composition of claim 6, wherein the composition is formulated as a tablet; the tablet is a double-layer tablet consisting of a tablet core and a quick release layer wrapping the tablet core, wherein the tablet core is a microcapsule prepared from paclitaxel or derivatives thereof and an excipient; the quick release layer is prepared from ibrutinib and auxiliary materials.
8. The pharmaceutical composition of claim 7, wherein the excipient is cholesterol palmitate, propylene glycol, sodium stearate; the auxiliary materials are selected from calcium monostearate, maltodextrin, monopalmitoyl glycerol and superfine silica gel powder.
9. Use of a pharmaceutical composition according to any one of claims 1 to 3 for combating tumour cells.
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| CN201811200402.0A CN111053777A (en) | 2018-10-16 | 2018-10-16 | Ibutinib pharmaceutical composition and application thereof |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20160022684A1 (en) * | 2014-07-25 | 2016-01-28 | Pharmacyclics Llc | Bet inhibitor and bruton's tyrosine kinase inhibitor combinations |
| CN106714909A (en) * | 2014-08-08 | 2017-05-24 | 药品循环有限责任公司 | Bruton's tyrosine kinase inhibitor combinations and uses thereof |
| CN106999495A (en) * | 2014-11-17 | 2017-08-01 | 药品循环有限责任公司 | TLR inhibitor and the combination of bruton's tyrosine kinase inhibitor |
| US20180071294A1 (en) * | 2013-08-12 | 2018-03-15 | Pharmacyclics Llc | Methods for the treatment of her2 amplified cancer |
| CN108024996A (en) * | 2015-07-31 | 2018-05-11 | 药品循环有限责任公司 | Bruton's tyrosine kinase inhibitor combines and its purposes |
-
2018
- 2018-10-16 CN CN201811200402.0A patent/CN111053777A/en not_active Withdrawn
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20180071294A1 (en) * | 2013-08-12 | 2018-03-15 | Pharmacyclics Llc | Methods for the treatment of her2 amplified cancer |
| US20160022684A1 (en) * | 2014-07-25 | 2016-01-28 | Pharmacyclics Llc | Bet inhibitor and bruton's tyrosine kinase inhibitor combinations |
| CN106714909A (en) * | 2014-08-08 | 2017-05-24 | 药品循环有限责任公司 | Bruton's tyrosine kinase inhibitor combinations and uses thereof |
| CN106999495A (en) * | 2014-11-17 | 2017-08-01 | 药品循环有限责任公司 | TLR inhibitor and the combination of bruton's tyrosine kinase inhibitor |
| CN108024996A (en) * | 2015-07-31 | 2018-05-11 | 药品循环有限责任公司 | Bruton's tyrosine kinase inhibitor combines and its purposes |
Non-Patent Citations (2)
| Title |
|---|
| DANIEL MASSÓ-VALLÉS: "Ibrutinib repurposing: from B-cell malignancies to solid tumors", 《ONCOSCIENCE》 * |
| 王业东: "激酶类抑制剂对紫杉醇羟化途径的选择性抑制以及药物相互作用研究", 《中国优秀硕士学位论文全文数据库（电子期刊）》 * |
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Application publication date: 20200424 |