CN111728960B - Application of bisoprolol fumarate and docetaxel in preparation of antitumor drugs - Google Patents
Application of bisoprolol fumarate and docetaxel in preparation of antitumor drugs Download PDFInfo
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- CN111728960B CN111728960B CN202010630747.0A CN202010630747A CN111728960B CN 111728960 B CN111728960 B CN 111728960B CN 202010630747 A CN202010630747 A CN 202010630747A CN 111728960 B CN111728960 B CN 111728960B
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- docetaxel
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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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
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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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention relates to application of bisoprolol fumarate and docetaxel in preparation of antitumor drugs, wherein the combination of bisoprolol fumarate and docetaxel serving as chemotherapeutic drugs has an obvious synergistic effect, can increase the sensitivity of tumors to the chemotherapeutic drugs, and can play a role of 'killing two birds with one stone' simultaneously in patients with angina, arrhythmia and hypertension combined cancers.
Description
Technical Field
The invention relates to the technical field of antitumor drugs, and particularly discloses application of bisoprolol fumarate and docetaxel in preparation of an antitumor drug.
Background
Malignant tumors (also called cancers) are mainly caused by diseases caused by uncontrolled cell growth and proliferation mechanism, and further local invasion of normal tissues, even metastasis to other parts through lymphatic system and internal circulation system. Liver cancer is one of common tumors, the liver cancer proportion of Chinese accounts for half of the world, and liver cancer is a serious disease which jeopardizes the life of Chinese. The tumor therapy applied in clinic is mainly through surgery, physical therapy, chemotherapy and biological therapy. Chemotherapy is one of the main means for treating liver cancer, and especially plays a major role in the systemic treatment of late-stage liver cancer. The chemotherapy drug resistance phenomenon is an important reason for the failure of late-stage liver cancer treatment, so that finding a new drug treatment method, improving the sensitivity of chemotherapy drugs and reversing or reducing the occurrence of chemotherapy drug resistance is of great significance for the treatment of liver cancer. The search for safe, low-toxicity and small-side-effect drugs and chemotherapy sensitization are important means for treating tumors and solving chemotherapy drug resistance.
Bisoprolol Fumarate (Bisoprolol Fumarate), chemical name: (±) 1- [4- [ [2- (1-methylethoxy) ethoxy ] methyl ] -phenoxy ] -3[ (1-methylethyl) amino ] -2-propanol fumarate of the formula:
bisoprolol fumarate is a long-acting beta 1 receptor blocker with high cardiac selectivity. Is clinically used for treating angina, arrhythmia and hypertension. It has high affinity to beta 1 receptor of bronchial and vascular smooth muscle, resulting in blood vessel expansion and lowering blood pressure. The oral liquid blocks a neuroendocrine system, more importantly, the oral liquid aims at a myocardial remodeling mechanism, prevents and delays the development of myocardial remodeling, improves myocardial compliance and obviously improves left ventricular diastolic function, so that an enlarged left ventricular cavity is gradually recovered to be normal, the bisoprolol fumarate is used for treating hypertension for a long time, the systolic and diastolic functions can be improved while the blood pressure is reduced, ventricular remodeling is reversed, and the oral liquid has the effects of oxidation resistance and apoptosis resistance, so that the cardiac function is comprehensively protected. Clinical research shows that the medicine has high oral absorption rate, long half-life period of 10-12 hr and lasting medicine effect. On the basis of a large number of experimental researches, the inventor finds that bisoprolol fumarate has a certain sensitization effect on docetaxel serving as a chemotherapeutic drug, and is expected to develop a pharmaceutical composition for treating tumors.
Disclosure of Invention
The invention aims to solve the technical problem of drug resistance of antitumor drugs in the prior art, and provides application of bisoprolol fumarate and chemotherapeutic drugs in preparation of antitumor drugs.
The technical scheme of the invention can be realized by the following technical measures:
the invention provides application of a composition containing bisoprolol fumarate and docetaxel in preparing a medicament for resisting tumors.
The invention also provides application of bisoprolol fumarate in preparation of a chemotherapeutic drug sensitization drug, and preferably, the chemotherapeutic drug is docetaxel.
When the bisoprolol fumarate is used for any one of the applications, the dosage range of the bisoprolol fumarate is 1-200 mg/day according to the body weight of a medicine receiving object, and the preferable dosage range is 5-150 mg/day.
In any of the above uses of the invention, the mass ratio of bisoprolol fumarate to docetaxel is 1 to 10, preferably, the mass ratio of bisoprolol fumarate to docetaxel is 1.
In some embodiments, in the pharmaceutical composition, the bisoprolol fumarate and docetaxel are packaged separately. In some embodiments, in the pharmaceutical composition, the bisoprolol fumarate and docetaxel are packaged together. In some embodiments, the pharmaceutical composition is a single administration formulation, wherein the pharmaceutical composition comprises 1-5mg bisoprolol fumarate and 5-10mg docetaxel.
The invention also provides a pharmaceutical composition for treating tumors, which comprises a chemotherapeutic drug docetaxel and bisoprolol fumarate for combined use with the chemotherapeutic drug.
The bisoprolol fumarate is a liquid preparation, a granule, a tablet, a medicinal granule, a capsule, a sustained-release agent, a dropping pill, an orally disintegrating preparation or an injection, and is prepared from the bisoprolol fumarate and a pharmaceutically acceptable carrier. The chemotherapeutic drug docetaxel can be in the dosage forms of liquid preparation, injection, freeze-dried powder and the like. The chemotherapy drug docetaxel can be injected into abdominal cavity or intravenous injection. Bisoprolol fumarate and the chemotherapeutic drug can be administered simultaneously, separately or sequentially, and the combination of the two drugs has obvious synergistic effect on tumors.
In some embodiments, the pharmaceutical composition of the present invention may be in the form of injection or lyophilized powder (which may be reconstituted prior to use to meet injection requirements).
In some embodiments, the pharmaceutical composition of the invention further comprises a pharmaceutically acceptable pharmaceutical excipient. Such pharmaceutically acceptable pharmaceutical excipients include, but are not limited to, solvents, solubilizers, solubilizing agents, emulsifiers, colorants, stabilizers, glidants, suspending agents, antioxidants, pH adjusters, diluents, and the like. For pharmaceutically acceptable pharmaceutical excipients, see, for example, handbook of pharmaceutical excipients (4 th edition), monograph of r.c. ro, zheng folk translation, 2005, chemical industry press.
Tumors in which bisoprolol fumarate in combination with docetaxel may act include: liver cancer, non-small cell lung cancer, head and neck tumor, gastric cancer, pancreatic cancer, melanoma, breast cancer, and ovarian cancer.
Compared with the prior art, the invention has the following beneficial effects:
(1) The bisoprolol fumarate and the chemotherapeutic drug docetaxel have obvious synergistic effect and can increase the sensitivity of tumors to the chemotherapeutic drug.
(2) The antitumor effect obtained by the combined use of the bisoprolol fumarate and the chemotherapy medicament docetaxel is obviously superior to that of single bisoprolol fumarate or docetaxel, the obvious synergistic effect is achieved, the basis is provided for clinical combined application of the bisoprolol fumarate and the docetaxel for resisting tumors, and the bisoprolol fumarate and docetaxel are potential high-efficiency low-toxicity tumor medicaments.
(3) The bisoprolol fumarate and the chemotherapy drug docetaxel are combined to greatly reduce the dosage of each drug, reduce the toxic and side effects, obviously enhance the drug effect and overcome the single drug resistance of tumor cells.
(4) In the prior art, docetaxel and other anticancer drugs are usually not taken simultaneously in the form of pharmaceutical compositions, and are mostly taken sequentially in sequence, but the pharmaceutical composition of docetaxel and bisoprolol fumarate can be simultaneously prepared into an injection, and the administration is simultaneously carried out to treat liver cancer, so that the use of patients is greatly facilitated, and the compliance of cancer treatment is improved.
(5) Bisoprolol fumarate is a common drug for clinically treating angina, arrhythmia and hypertension, and the bisoprolol fumarate and a chemotherapeutic drug docetaxel can play a role of killing two birds with one stone simultaneously in patients with the diseases and cancers.
Detailed Description
Example 1 Effect of the pharmaceutical composition of the present invention on the growth of human hepatoma Huh7 cell nude mouse transplanted tumors
1 materials and methods
1.1 cell lines
The hepatoma cell strain Huh7 cell strain is purchased from the China center for type culture Collection of Wuhan university.
1.2 drugs and reagents
RPMI1640 medium, newborn calf serum, 0.25% trypsin, gibco, 1ml (40 mg) of docetaxel injection, purchased from Zingible pharmaceutical Co., ltd; bisoprolol fumarate tablets (2.5 mg) were purchased from Beijing Huasu pharmaceutical Co., ltd, and the other reagents were domestic analytical purifiers.
1.3 human hepatoma nude mouse transplantation tumor treatment experiment
100 SPF-grade BALB/c-nu mice are purchased from the experimental animals of Schlekschada, hunan, 6-week-old, and the body mass is 18g-20g. Taking Huh7 cells in logarithmic growth phase, and adjusting the concentration of the Huh7 cells to 3 multiplied by 10 by using sterile PBS 7 mL, 0.1mL of PBS suspension of the above Huh7 cells was subcutaneously inoculated on the back of BALB/c-nu mice to a volume of 75mm for subcutaneous transplantation 3 On the left and right, the mice were divided into 7 groups of 12 mice each based on the principle of tumor volume and weight balance of tumor-bearing mice. Groups of mice were dosed according to the following dosing schedule:
model control group: injecting physiological saline with the same quantity into the abdominal cavity;
docetaxel group: injecting 10mg/kg into abdominal cavity;
bisoprolol fumarate group: injecting 10mg/kg into abdominal cavity;
bisoprolol fumarate + docetaxel group a: 1mg/kg bisoprolol fumarate and 5mg/kg docetaxel are injected into the abdominal cavity;
bisoprolol fumarate + docetaxel B group: 5mg/kg bisoprolol fumarate and 5mg/kg docetaxel are injected into the abdominal cavity;
bisoprolol fumarate + docetaxel group C: 1mg/kg bisoprolol fumarate and 10mg/kg docetaxel are injected into the abdominal cavity;
bisoprolol fumarate + docetaxel group D: 5mg/kg bisoprolol fumarate and 10mg/kg docetaxel are injected into the abdominal cavity;
the drug is administered 1 time every other day, 8 times in total, and the longest diameter and the shortest diameter of the transplanted tumor are measured by vernier calipers every 4 days during the drug administration. Mice were sacrificed by dislocation 48h after the last administration, the transplanted tumors were excised, and the tumor weights were weighed. Tumor weight inhibition ratio IR (%) = (1-tumor weight average value of experimental group/tumor weight average value of control group) × 100%. The effect of the drug on inhibiting tumor growth of human liver cancer Huh7 cell nude mice is reflected by comparing tumor weights.
1.4 statistical treatment
Data are presented as means ± standard deviation, and anova was performed using SPSS15.0 software.
2 results
The test results are shown in table 1:
TABLE 1 Effect of the pharmaceutical compositions of the present invention on the growth of human hepatoma Huh7 cell nude mouse transplantable tumors
| Group of | Tumor weight/mg | Tumor inhibition rate/%) |
| Model control group | 426.50 ± 92.15 | —— |
| Docetaxel group | 241.50 ± 55.12 * | 43.38 |
| Bisoprolol fumarate group | 425.65±33.75 | 0 |
| 1mg/kg bisoprolol fumarate +5mg/kg docetaxel | 150 ± 71.88 **# | 64.79 |
| 5mg/kg bisoprolol fumarate +5mg/kg docetaxel | 145.75 ± 65.33 **# | 65.83 |
| 1mg/kg bisoprolol fumarate +10mg/kg docetaxel | 90.55±20.51 **# | 78.77 |
| 5mg/kg bisoprolol fumarate +10mg/kg docetaxel | 87.37±44.27 **# | 79.51 |
* Compared with the model control group, p is less than 0.05, ** p is less than 0.01 compared with the model control group;
# compared with docetaxel group, p is less than 0.01.
The test result shows that:
(1) Compared with a model control group, the docetaxel group has significant difference (p is less than 0.05) in the inhibition effect of the human liver cancer Huh7 cell nude mouse transplanted tumor growth, the bisoprolol fumarate single drug group has no inhibition effect on the human liver cancer Huh7 cell nude mouse transplanted tumor growth, and the bisoprolol fumarate and docetaxel groups have significant difference (p is less than 0.01) in the inhibition effect of the human liver cancer Huh7 cell nude mouse transplanted tumor growth.
(2) Compared with a docetaxel single medicine group, the bisoprolol fumarate and docetaxel groups have very significant difference (p is less than 0.01) in the inhibition effect on the growth of human liver cancer Huh7 cell nude mouse transplanted tumor, and show synergistic effect.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (8)
1. A pharmaceutical composition for treating liver cancer, which comprises bisoprolol fumarate and docetaxel in a mass ratio of 1.
2. The pharmaceutical composition for treating liver cancer according to claim 1, wherein, in the pharmaceutical composition, the bisoprolol fumarate and docetaxel are separately packaged.
3. The pharmaceutical composition for treating liver cancer according to claim 1, wherein, in the pharmaceutical composition, the bisoprolol fumarate and docetaxel are packaged together.
4. The pharmaceutical composition for treating liver cancer according to any one of claims 1-3, wherein the pharmaceutical composition is a single administration formulation, wherein the pharmaceutical composition comprises 1-5mg bisoprolol fumarate and 5-10mg docetaxel.
5. The pharmaceutical composition for treating liver cancer according to claim 4, wherein the pharmaceutical composition is in the form of injection or lyophilized powder.
6. Use of a pharmaceutical composition according to any one of claims 1 to 5 for the manufacture of a medicament for use against liver cancer.
7. The bisoprolol fumarate is applied to the preparation of a chemotherapeutic drug sensitization drug, wherein the chemotherapeutic drug is docetaxel.
8. The use according to claim 7, wherein the mass ratio of bisoprolol fumarate to docetaxel is 1.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107872977A (en) * | 2015-04-30 | 2018-04-03 | 拜耳制药股份公司 | The combination product of IRAK4 inhibitor and BTK inhibitor |
| CN109288831A (en) * | 2018-11-08 | 2019-02-01 | 杭州师范大学 | A kind of docetaxel and elemene molecular compatibility pharmaceutical composition and its application |
| WO2019195819A1 (en) * | 2018-04-06 | 2019-10-10 | North Carolina State University | Cell assembly-mediated delivery of checkpoint inhibitors for cancer immunotherapy |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20170128417A1 (en) * | 2014-07-01 | 2017-05-11 | Vicus Therapeutics, Llc | Combination drug therapies for cancer and methods of making and using them |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107872977A (en) * | 2015-04-30 | 2018-04-03 | 拜耳制药股份公司 | The combination product of IRAK4 inhibitor and BTK inhibitor |
| WO2019195819A1 (en) * | 2018-04-06 | 2019-10-10 | North Carolina State University | Cell assembly-mediated delivery of checkpoint inhibitors for cancer immunotherapy |
| CN109288831A (en) * | 2018-11-08 | 2019-02-01 | 杭州师范大学 | A kind of docetaxel and elemene molecular compatibility pharmaceutical composition and its application |
Non-Patent Citations (1)
| Title |
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| The β‑adrenergic receptor to chemotherapeutics in diverse antagonist propranolol offsets resistance mechanisms sarcoma subtypes: a pilot study;Letizia Porcelli et al.;《Scientific Reports》;20200626;第10卷;第1-12页 * |
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