CN111110851A - Pharmaceutical composition of baicalein and tyrosine kinase inhibitor and application thereof - Google Patents
Pharmaceutical composition of baicalein and tyrosine kinase inhibitor and application thereof Download PDFInfo
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- CN111110851A CN111110851A CN202010063961.2A CN202010063961A CN111110851A CN 111110851 A CN111110851 A CN 111110851A CN 202010063961 A CN202010063961 A CN 202010063961A CN 111110851 A CN111110851 A CN 111110851A
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- baicalein
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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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
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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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
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Abstract
The invention relates to a pharmaceutical composition of baicalein and a tyrosine kinase inhibitor and application thereof, in particular to application of combination of baicalein and a tyrosine kinase inhibitor in treating lung cancer. The inventor combines baicalein and ocitinib, finds that the combination of the baicalein and the ocitinib produces synergistic effect, can effectively improve the effect of the medicament for treating the lung cancer, and provides a basis for clinical combined administration of the baicalein and the tyrosine kinase inhibitor.
Description
Technical Field
The application belongs to the field of medicines, and particularly relates to a pharmaceutical composition of baicalein and a tyrosine kinase inhibitor and application thereof.
Background
The baicalein is one of the main components of natural Chinese herbal medicine scutellaria baicalensis, is also an important flavonoid compound in the scutellaria baicalensis, is widely concerned by scholars at home and abroad due to multiple pharmacological actions, has the effects of resisting tumors, protecting heart and cerebral vessels, protecting nerves, treating or preventing diabetes and complications thereof, removing oxygen radicals, resisting oxidation, resisting bacteria and viruses and the like, and has good commercial development value.
Tyrosine Kinase Inhibitors (TKI) are compounds capable of inhibiting tyrosine kinase activity, can be used as competitive inhibitors combining adenosine triphosphate and tyrosine kinase, and have the action mechanism of inhibiting protein tyrosine residue phosphorylation, thereby blocking the conduction of downstream signal pathways, inhibiting the growth, the transfer and the like of tumor cells at expression positions, and playing a role in resisting tumors. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) can remarkably improve the survival period of advanced non-small cell lung cancer patients with epidermal growth factor receptor activation mutation. Drugs against EGFR-TKIs have been developed to the third generation, with oxitinib and loxitinib having new clinical advances. At present, how to improve the treatment effect of EGFR-TKIs and reduce drug resistance in clinic becomes a research hotspot, the EGFR-TKIs are combined with other drugs more and more, but the results are good or bad, and a random clinical research result shows that the clinical benefit of erlotinib treatment and platinum chemotherapy is very little even in a non-small cell lung cancer patient group with EGFR mutation; in another study, combination of afatinib and cetuximab resulted in almost complete tumor regression, while the therapeutic effect of each drug alone did not result in a significant response.
The combined treatment of tumors by Chinese and western medicines is one of the current research hotspots, the combined use of the Chinese patent medicine and the western medicine with the same or similar pharmacological effects can possibly play a role in synergy, the dosage of the western medicine is reduced, the treatment period is shortened, but certain risks exist, such as reduction of the curative effect, when the plum blossom glossogyne and the like are used in combination with the acid medicines such as vitamin C, aspirin and the like, the saponin active ingredients in the plum blossom glossogyne can be decomposed, so that the curative effect is reduced; the astragaloside IV in the Jinfukang oral liquid can obviously inhibit the activity of CYP3A4 and CYP2C9 and the like, so that the specific combination needs experimental verification and condition groping, thereby promoting the rationality of the combined use of Chinese and western medicines.
The application is based on the thought of the combined action of Chinese and western medicines, finds out the tyrosine kinase inhibitor combined with baicalein and a synergistic interval during combined use, and provides a basis for clinical combined medication of the baicalein and the tyrosine kinase inhibitor.
Disclosure of Invention
The invention aims to provide a pharmaceutical composition for treating tumors, which consists of baicalein and a tyrosine kinase inhibitor.
Further, tyrosine kinase inhibitors include the first generation products gefitinib, erlotinib; the second generation products of dacomitinib and afatinib; the third generation product of oxitinib and the like.
Preferably, the tyrosine kinase inhibitor comprises oxitinib.
Furthermore, the pharmaceutical composition also comprises pharmaceutic adjuvants.
The pharmaceutical excipients are selected from one or more of diluents, flavoring agents, lubricants, glidants, and optionally disintegrants and binders.
The diluent is selected from one or more of pregelatinized starch, mannitol, calcium hydrogen phosphate, microcrystalline cellulose 101 and xylitol;
the flavoring agent is selected from one or more of mint-flavored powdered essence, blackcurrant-flavored powdered essence, strawberry-flavored powdered essence and cream-flavored powdered essence;
the lubricant is selected from one or more of magnesium stearate, superfine silica gel powder, talcum powder and hydrogenated vegetable oil;
the glidant is selected from silicon dioxide;
the disintegrating agent is selected from one or more of dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl methylcellulose and cross-linked polyvinylpyrrolidone;
the adhesive is selected from one or more of starch slurry, polyvidone, gelatin and polyethylene glycol.
Further, the concentration ratio of the baicalein to the tyrosine kinase inhibitor is 1: 0.025-0.2.
Preferably, the concentration ratio of baicalein to the tyrosine kinase inhibitor is 1: 0.05-0.2; more preferably, the concentration ratio of baicalein to the tyrosine kinase inhibitor is 1: 0.05-0.067.
Further, the concentration ratio of baicalein to oxitinib is 1: 0.025-0.2.
Preferably, the concentration ratio of the baicalein to the ocitinib is 1: 0.05-0.2; more preferably, the concentration ratio of baicalein to ocitinib is 1: 0.05-0.067.
The invention aims to provide application of the pharmaceutical composition in preparing a medicine for treating tumors.
Preferably, the tumor is lung cancer, more preferably, the tumor is non-small cell lung cancer.
Further, the application of the pharmaceutical composition in preparing anti-tumor cell proliferation medicines.
Further, the concentration ratio of the baicalein to the tyrosine kinase inhibitor is 1: 0.025-0.2.
Preferably, the concentration ratio of baicalein to the tyrosine kinase inhibitor is 1: 0.05-0.2; more preferably, the concentration ratio of baicalein to the tyrosine kinase inhibitor is 1: 0.05-0.067.
Further, the concentration ratio of baicalein to oxitinib is 1: 0.025-0.2.
Preferably, the concentration ratio of the baicalein to the ocitinib is 1: 0.05-0.2; more preferably, the concentration ratio of baicalein to ocitinib is 1: 0.05-0.067.
The dosage form of the pharmaceutical composition of the present invention is not particularly limited, and the pharmaceutical composition may be prepared into one or more of tablets, capsules, pills, mixtures, gels, ointments, granules, powders, ointments, granules, pellets, oral liquids, dripping pills, injections or injections, or any other dosage forms.
The invention has the advantages that:
the combination of baicalein and tyrosine kinase inhibitor can obviously improve the anti-tumor cell proliferation capacity of the medicament, generate synergistic effect, effectively reduce the medicament cost, improve the clinical treatment effect and provide a theoretical basis for the clinical combination of Chinese and western medicaments.
Detailed Description
The present invention is further illustrated below with reference to specific examples, which are intended to be illustrative only and are not to be construed as limiting the invention. Those of ordinary skill in the art will understand that: various changes, modifications, substitutions and alterations can be made to the embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the claims and their equivalents. The following examples are examples of experimental methods not indicating specific conditions, and the detection is usually carried out according to conventional conditions or according to the conditions recommended by the manufacturers.
Example 1 Combined dosing experiment of baicalein and oxitinib in Lung cancer cells
1.1 Experimental methods
Cell culture:
digesting non-small cell lung cancer H1299 cells to prepare a cell suspension, inoculating 5000 cells per well into a 96-well plate, placing at 37 ℃ and 5% CO2The culture was carried out overnight in an incubator. On the next day, the cells were grouped, the control group was added with the corresponding medium, and the other groups were added with different drugs for further culture for 24 h.
Grouping experiments:
the administration concentration of the baicalein is as follows: control group 0. mu.M, group 125. mu.M, group 2 50. mu.M, group 3 100. mu.M, group 4 200. mu.M;
the dosing concentrations of oxitinib were: control group 0. mu.M, group 5 1.25. mu.M, group 6 2.5. mu.M, group 7 5. mu.M, group 8 10. mu.M;
the concentrations administered for the combined administration were: control group 0 μ M baicalein +0 μ M ocitinib, group 9 50 μ M baicalein +0 μ M ocitinib, group 10 50 μ M baicalein +1.25 μ M ocitinib, group 11 50 μ M baicalein +2.5 μ M ocitinib, group 12 50 μ M baicalein +5 μ M ocitinib, and group 13 50 μ M baicalein +10 μ M ocitinib.
Determination of IC50 value and determination of efficacy of combination:
(1) calculation of median inhibitory concentration (IC50) values: half maximal inhibitory concentration (IC50) values were calculated using SPSS23.0 software based on the effect of different concentrations of drug on the cells.
(2) After 24 hours of administration, the cell activities of each group were measured by MTT method and the inhibition rate was calculated (inhibition rate ═ control OD value-administration OD value)/(control OD value) × 100%).
(3) And (3) judging the effect of the double-medicine combination:
calculation method for judging effect of combined medicationThe method comprises the following steps: and judging by adopting a gold positive mean q value method. The q value is obtained by the following formula: q ═ PA+B/(PA+PB-PA×PB). In the formula PA、PBAnd PA+BRespectively the treatment rates of the A medicine group, the B medicine group and the combination of the two medicines. q is less than 1, which indicates that the two medicines generate antagonism after being used together; q is more than 1, which indicates that the two drugs produce synergistic effect after being combined together, and q is 1, which indicates that the two drugs produce additive effect after being combined together.
1.2 results of the experiment
The results show that both baicalein and oxitinib have the effect of inhibiting the growth of tumor cells on H1299 cells. The half inhibition concentration (IC50) value was calculated by using SPSS23.0 software, and the average inhibition rates of baicalein at 25, 50, 100 and 200 μ M were 16.6 + -1.0%, 30.1 + -4.4%, 72.0 + -3.9% and 86.0 + -4.9%, respectively, and the half inhibition concentration (IC50) value was 68.4 + -6.4. When the combination is administrated, the ratio of the baicalein to the oxitinib is 1: 0.05-0.2 has synergistic effect.
TABLE 1 combination of baicalein and oxitinib in Lung cancer cells H1299
Example 2 Combined baicalein and oxitinib dosing experiments in H460 cells
2.1 Experimental methods
Cell culture: digesting non-small cell lung cancer H460 cells to prepare cell suspension, inoculating 5000 cells per well into a 96-well plate, placing at 37 ℃ and 5% CO2The culture was carried out overnight in an incubator. On the next day, the cells were grouped, the control group was added with the corresponding medium, and the other groups were added with different drugs for further culture for 24 h.
Grouping experiments:
the administration concentration of the baicalein is as follows: control group 0. mu.M, group 125. mu.M, group 2 50. mu.M, group 3 100. mu.M, group 4 200. mu.M;
the dosing concentrations of oxitinib were: control group 0. mu.M, group 5 2.5. mu.M, group 6 5. mu.M, group 7 7.5. mu.M, group 8 10. mu.M;
the concentrations administered for the combined administration were: control group 0 μ M baicalein +0 μ M ocitinib, group 9 100 μ M baicalein +0 μ M ocitinib, group 10 100 μ M baicalein +2.5 μ M ocitinib, group 11 100 μ M baicalein +5 μ M ocitinib, group 12 100 μ M baicalein +7.5 μ M ocitinib, and group 13 100 μ M baicalein +10 μ M ocitinib.
2.2 results of the experiment
The results show that both baicalein and oxitinib have the effect of inhibiting the growth of tumor cells on H460 cancer cells. The half inhibition concentration (IC50) value was calculated by using SPSS23.0 software, and the average inhibition rates of baicalein at 25, 50, 100 and 200 μ M were 4.1 + -4.5%, 22.9 + -3.1%, 43.4 + -1.4% and 64.9 + -2.0%, respectively, and the half inhibition concentration (IC50) value was 125.5 + -2.0. When the combination is administrated, each group shows synergistic effect, wherein the best effect is achieved when the ratio of the baicalein to the oxitinib is 1: 0.05.
TABLE 2 combination of baicalein and oxitinib in H460 cancer cells
| Inhibition ratio (%) | Q value | Ratio of | |
| Group 9 | 36.1±1.2％ | — | — |
| Group 10 | 41.8±3.6％ | 1.08 | 1：0.025 |
| Group 11 | 50.1±6.5％ | 1.18 | 1：0.05 |
| Group 12 | 61.4±3.3％ | 1.17 | 1：0.1 |
| Group 13 | 80.2±0.7％ | 1.13 | 1：0.2 |
Example 3 Combined baicalein and oxitinib dosing experiments in A549 cells
3.1 Experimental methods
Cell culture: digesting non-small cell lung cancer A549 cell, preparing into cell suspension, inoculating 5000 cells per well into 96-well plate, standing at 37 deg.C and 5% CO2The culture was carried out overnight in an incubator. On the next day, the cells were grouped, the control group was added with the corresponding medium, and the other groups were added with different drugs for further culture for 24 h.
Grouping experiments:
the administration concentration of the baicalein is as follows: control group 0. mu.M, group 125. mu.M, group 2 50. mu.M, group 3 100. mu.M, group 4 200. mu.M;
the dosing concentrations of oxitinib were: control group 0. mu.M, group 5 2.5. mu.M, group 6 5. mu.M, group 7 7.5. mu.M, group 8 10. mu.M;
the concentrations administered for the combined administration were: control group 0 μ M baicalein +0 μ M ocitinib, group 9 150 μ M baicalein +0 μ M ocitinib, group 10 150 μ M baicalein +2.5 μ M ocitinib, group 11 150 μ M baicalein +5 μ M ocitinib, group 12 150 μ M baicalein +7.5 μ M ocitinib, and group 13 150 μ M baicalein +10 μ M ocitinib.
2.2 results of the experiment
The results show that both baicalein and oxitinib have the effect of inhibiting the growth of tumor cells on H460 cancer cells. The half maximal inhibitory concentration (IC50) values were calculated using SPSS23.0 software. When the combination is administrated, each group shows synergistic effect, wherein the best effect is achieved when the ratio of the baicalein to the oxitinib is 1: 0.05.
TABLE 3 combination of baicalein and oxitinib in A549 cells
| Inhibition ratio (%) | Q value | Ratio of | |
| Group 9 | 27.4±6.2％ | — | — |
| Group 10 | 31.9±4.3％ | 0.91 | 1：0.017 |
| Group 11 | 43.1±5.8％ | 0.95 | 1：0.033 |
| Group 12 | 61.7±2.3％ | 1.19 | 1：0.05 |
| Group 13 | 74.0±0.9％ | 1.15 | 1：0.067 |
Claims (10)
1. A pharmaceutical composition for treating tumor comprises baicalein and tyrosine kinase inhibitor.
2. The pharmaceutical composition of claim 1, wherein the tyrosine kinase inhibitor is gefitinib, erlotinib, dacomitinib, afatinib, or oxitinib.
3. The pharmaceutical composition of claim 1, further comprising a pharmaceutical excipient selected from one or more of diluents, flavoring agents, lubricants, glidants, and optionally disintegrants and binders.
4. The pharmaceutical composition of claim 1, wherein the ratio of baicalein to tyrosine kinase inhibitor concentration is 1: 0.025-0.2, preferably, the concentration ratio of baicalein to tyrosine kinase inhibitor is 1: 0.05-0.2; more preferably, the concentration ratio of baicalein to the tyrosine kinase inhibitor is 1: 0.05-0.067.
5. The pharmaceutical composition of claim 2, wherein the ratio of baicalein to ocitinib is 1: 0.025-0.2; preferably, the concentration ratio of the baicalein to the ocitinib is 1: 0.05-0.2; more preferably, the concentration ratio of baicalein to ocitinib is 1: 0.05-0.067.
6. Use of a pharmaceutical composition according to any one of claims 1 to 5 for the preparation of a medicament for the treatment of tumors.
7. Use according to claim 6, wherein the pharmaceutical composition is for the manufacture of a medicament for the treatment of tumor cell proliferation.
8. Use according to claim 6, wherein the tumour is lung cancer, preferably non-small cell lung cancer.
9. The use of claim 6, wherein the ratio of baicalein to tyrosine kinase inhibitor concentration is 1: 0.025-0.2, preferably, the concentration ratio of baicalein to tyrosine kinase inhibitor is 1: 0.05-0.2; more preferably, the concentration ratio of baicalein to the tyrosine kinase inhibitor is 1: 0.05-0.067.
10. The use of claim 6, wherein the ratio of baicalein to ocitinib is 1: 0.025-0.2; preferably, the concentration ratio of the baicalein to the ocitinib is 1: 0.05-0.2; more preferably, the concentration ratio of baicalein to ocitinib is 1: 0.05-0.067.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107198685A (en) * | 2017-06-14 | 2017-09-26 | 山东大学 | A kind of pharmaceutical composition for treating clear-cell carcinoma and application |
| CN108669269A (en) * | 2018-05-25 | 2018-10-19 | 陕西省西安植物园 | Small green mandarin orange radix scutellariae leaf tea of one kind and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107198685A (en) * | 2017-06-14 | 2017-09-26 | 山东大学 | A kind of pharmaceutical composition for treating clear-cell carcinoma and application |
| CN108669269A (en) * | 2018-05-25 | 2018-10-19 | 陕西省西安植物园 | Small green mandarin orange radix scutellariae leaf tea of one kind and preparation method thereof |
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