CN113244232A - Oroxylin and sorafenib combined anti-tumor drug and application thereof - Google Patents
Oroxylin and sorafenib combined anti-tumor drug and application thereof Download PDFInfo
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- CN113244232A CN113244232A CN202011589573.4A CN202011589573A CN113244232A CN 113244232 A CN113244232 A CN 113244232A CN 202011589573 A CN202011589573 A CN 202011589573A CN 113244232 A CN113244232 A CN 113244232A
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- sorafenib
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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
- A61K31/35—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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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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 application provides an anti-tumor pharmaceutical composition containing effective amounts of oroxylin and sorafenib. The combination of oroxylin and sorafenib can obviously improve the anti-tumor effect of low-dose sorafenib, and can not generate obvious inhibition effect on the body weight of a subject. Has wide application prospect.
Description
Technical Field
The invention belongs to the field of antitumor drugs, and particularly relates to a combined antitumor drug containing oroxylin and sorafenib and application thereof.
Background
Oroxylin A is one of active components of radix Scutellariae, has obvious antitumor effect, and is a natural antitumor drug with wide application prospect. However, oroxylin has wide pharmacological action, the mechanism of the anti-tumor action of oroxylin is not completely clarified at present, and documents show that oroxylin can play the anti-tumor action by inducing apoptosis of tumor cells and also has the action of inhibiting growth of tumor blood vessels.
At present, first-line medicaments for treating liver cancer in clinic are mainly targeted medicaments of sorafenib, chemical medicaments of 5-fluorouracil, adriamycin and the like. However, these drugs have large toxic and side effects and are easy to develop drug resistance. It is known that sorafenib doses of 400mg or less than 400mg twice daily are well tolerated. When doses reached 600mg and 800mg twice daily, there was a significant increase in skin and gastrointestinal toxicity. The dose-limiting toxicity of 800mg twice daily was III degree diarrhea and fatigue, and the dose-limiting toxicity of 600mg twice daily was III degree rash. Most patients receiving 600-800 mg twice daily eventually lose to 400mg due to adverse reactions. Thus, the maximum tolerated dose for oral administration of sorafenib was 400mg twice daily. The treatment effect and the toxic and side effect of the sorafenib are closely related to the dosage, and the toxic and side effect is small if the dosage is low; however, lowering the dose may also result in a reduction in the therapeutic effect. How to improve the anti-tumor effect of sorafenib under low dose is a technical problem to be solved urgently.
Disclosure of Invention
In order to improve the technical problems, the invention provides a combined anti-tumor pharmaceutical composition which comprises effective amounts of oroxylin and sorafenib.
According to an embodiment of the invention, the weight ratio of oroxylin to sorafenib may be (1-10):1, e.g. (2-8):1, (3-7):1, (4-6):1, illustratively 3:1, 4:1, 5:1, 6:1, 7: 1.
According to an embodiment of the present invention, the effective amount of sorafenib in the combined antitumor drug composition is less than 400 mg/day for human patients, such as 100-.
According to an embodiment of the present invention, the effective amount of oroxylin in the combined anti-tumor pharmaceutical composition is less than 1800 mg/day, such as 200-.
According to an embodiment of the present invention, wherein sorafenib may be in the form of a pharmaceutically acceptable salt, such as hydrochloride, phosphate, formate, acetate, citrate, maleate, malate, mesylate, benzensulfonate, and the like.
According to an embodiment of the present invention, the combined antitumor pharmaceutical composition further comprises a pharmaceutically acceptable carrier and/or excipient.
According to an embodiment of the present invention, the combined anti-tumor pharmaceutical composition may be prepared into conventional formulations, such as tablets, granules, capsules, sustained-release formulations, and the like, by conventional methods.
The pharmaceutically acceptable carriers or excipients include, but are not limited to, fillers, disintegrants, binders, wetting agents, lubricants, flavoring agents, antioxidants, and the like.
Examples of fillers useful in the present invention include, but are not limited to, microcrystalline cellulose, lactose, mannitol, starch, or dextrin, or a combination of two or more thereof.
Examples of disintegrants that can be used in the invention include, but are not limited to, sodium carboxymethyl starch, croscarmellose sodium, sodium carboxymethyl starch, hydroxypropyl starch, crospovidone, low substituted hydroxypropyl cellulose, or corn starch, or a combination of two or more thereof.
Examples of binders useful in the present invention include, but are not limited to, hypromellose, povidone, methylcellulose, or sodium carboxymethylcellulose, or a combination of two or more thereof.
Examples of wetting agents useful in the present invention include, but are not limited to, water or aqueous ethanol.
Examples of lubricants useful in the present invention include, but are not limited to, magnesium stearate, talc, or aerosil, or a combination of two or more thereof.
Examples of flavoring agents useful in the present invention include, but are not limited to, sucrose, stevioside, or aspartame, or a combination of two or more thereof.
Examples of antioxidants useful in the present invention include, but are not limited to, sodium sulfite, sodium bisulfite or sodium metabisulfite, or a combination of two or more thereof.
The invention also provides application of the combined anti-tumor medicine in preparing a medicine for treating cancer. Preferably, the cancer is liver cancer.
Advantageous effects
Oroxylin is a natural medicinal component, has wide source, is easy to obtain, and has no obvious toxic or side effect on human bodies. The invention remarkably improves the anti-tumor effect of the low-dose sorafenib by combining the oroxylin and the sorafenib, and does not generate obvious inhibition effect on the weight of a subject. Therefore, the lower dose of sorafenib can reduce the toxic reaction, and the combined use of oroxylin can improve the curative effect, and the combined use mode can play a larger role in the future tumor treatment.
Specifically, in a mouse liver cancer model, the oroxylin (300mg/kg) and the sorafenib (60mg/kg) are jointly administrated, so that the tumor inhibition rate can be effectively increased, the tumor inhibition rate of human liver cancer cell HuH-7 nude mouse transplanted tumor reaches 71.02%, and the tumor inhibition rate is increased by 19.06% compared with that of the individual use of 60mg/kg of sorafenib. Compared with a blank control group, the sorafenib 120mg/kg group has significant influence on the weight of the experimental animal, and other groups have no statistical difference on the influence on the weight of the experimental animal.
Detailed Description
The technical solution of the present invention will be further described in detail with reference to specific embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.
By constructing a human hepatoma cell HuH-7 nude mouse transplantation tumor model, the fact that oroxylin combined with low-dose sorafenib can obviously improve the anti-tumor effect of the low-dose sorafenib is found, and no obvious inhibition effect is generated on the weight of an experimental animal.
Example 1
1. Experimental Material
1.1 test drugs
Name: oroxylin
The content is as follows: 99.52 percent
Providing a unit: college of pharmacy of Chinese university
The preparation method comprises the following steps: the oroxylin bulk drug is dispersed in 0.5 percent CMC-Na after being pulverized by airflow to prepare a suspension with the drug concentration of 15mg/ml, the administration volume is 0.4ml/20g, namely the administration dose is 300 mg/kg. Diluting with medium-low dosage multiple ratio.
1.2 Positive control drugs
Name: sorafenib
The manufacturer: bayer medicine industry (Huiyang)
Specification: 200 mg/tablet
The preparation method comprises the following steps: the tablets of the above specifications were ground into powder. 12.74mg of drug powder (containing 56.51%) is weighed, 1.2ml of 0.5% CMC-Na is used for shaking uniformly before drug administration, so that a solution with the sorafenib concentration of 6mg/ml is obtained, the administration volume is 0.4ml/20g, and the administration dose is 120 mg/kg. 6.37mg of medicine powder (containing 56.51%) is weighed, 1.2ml of 0.5% CMC-Na is used for shaking evenly before administration, so as to obtain a solution with the sorafenib concentration of 3mg/ml, the administration volume is 0.4ml/20g, namely the administration dose is 60 mg/kg.
1.3 Experimental animals
Source, species, strain: BALB/c nude mice, obtained from Kyowa Kavens laboratory animals Co., Ltd. (laboratory animal production license: SCXK (threo) 2016-0010).
The age in days: 4-5 weeks
Sex: female
1.4 Experimental animal grouping and dose setting
| Group of | Medicine | Dosage form | Mode of administration | Number of animals |
| Negative control group | Physiological saline | -- | p.o. | 12 |
| Positive control group | Sorafenib | 120mg/kg | Once in p.o.2 days | 6 |
| Positive control group | Sorafenib | 60mg/kg | Once in p.o.2 days | 6 |
| Drug treatment group | Oroxylin | 300mg/kg | Once in p.o.2 days | 6 |
| Combination therapy group | Oroxylin + sorafenib | 300mg/kg+60mg/kg | Once in p.o.2 days | 6 |
1.5 transplantation tumor
The human liver cancer HuH-7 nude mouse transplantation tumor is established by inoculating a human liver cancer HuH-7 cell strain under axillary fossa of a nude mouse. The cell inoculation amount is 5 multiplied by 106One/only.
2. Experimental methods
Taking human liver cancer HuH-7 cell strain in logarithmic growth phase, preparing into 5 × 10 cell strain under aseptic condition7The cell suspension was inoculated in 0.1ml under the right axilla of the nude mouse. Measuring the diameter of the transplanted tumor of the nude mouse by using a vernier caliper until the tumor grows to 100-300 mm3Animals were then randomized into groups. The antitumor effect of the test object is dynamically observed by using a method for measuring the tumor size. Tumor diameter was measured 1 time every 3 days. After 21 days, the mice were sacrificed and the tumor mass was surgically removed and weighed. The formula for Tumor Volume (TV) is: TV 1/2 × a × b2Wherein a and b represent length and width, respectively.
Calculating Relative Tumor Volume (RTV) according to the measurement result, wherein the calculation formula is as follows: RTV ═ Vt/V0. Wherein V0When administered separately from the cage (i.e. d)0) Measurement of the resulting tumor volume, VtFor the tumor volume at each measurement. The evaluation index of the antitumor activity is relative tumor proliferation rate T/C (%), and the calculation formula is as follows:
TRTV: treatment group RTV; cRTV: negative control group RTV.
The tumor inhibition rate calculation formula is as follows:
Tweight: mean tumor weight in treatment group; cweight: negative control group mean tumor weight.
3. Results of the experiment
3.1 Sorafenib combined with oroxylin has effect of inhibiting growth of human hepatoma cell HuH-7 nude mouse xenograft tumor
As shown in Table 1, oroxylin is administrated by gavage at 300mg/kg, 1 time every 2 days, and after 24 days of administration, the tumor inhibition rate of human hepatoma cell HuH-7 nude mouse transplanted tumor is 63.59%. The sorafenib is administrated by gavage at 60mg/kg and 120mg/kg respectively, 1 time every 2 days, and after 24 days of administration, the tumor inhibition rates of human hepatoma cell HuH-7 nude mouse transplanted tumor are 51.98% and 71.11% respectively.
The oroxylin and sorafenib are co-administered at 300mg/kg and 60mg/kg respectively, and the tumor inhibition rate of human hepatoma cell HuH-7 nude mouse transplanted tumor is 71.02% as above. The tumor inhibition rate of the combined drug group is increased by 19.06 percent compared with that of the single drug group of sorafenib 60 mg/kg.
Compared with a blank control group, the sorafenib 120mg/kg group has a significant influence on the body weight of the experimental animal (p is less than 0.05), and other groups have no statistical difference on the influence on the body weight of the experimental animal.
TABLE 1 oroxylin and Sorafenib in combination with inhibition of human hepatoma cell HuH-7 nude mouse xenograft tumor growth (X + -SD)
Note: compared with the blank control group, the composition of the composition,*P<0.05，**P<0.01; compared with the sorafenib 60mg/kg group,#P<0.05。
when oroxylin is combined with sorafenib, the clinically planned effective dose of the sorafenib in mice is 60mg/kg, and the reduced effective dose of human bodies is 321.12mg/60kg, which is obviously lower than the dose of the current sorafenib tablets, namely 800 mg/day; the mouse clinical planned effective dose of oroxylin is 300mg/kg, the effective dose is 1605.6mg/60kg in a conversion mode, the half-life period of oroxylin is long, and oral administration twice a day can be supported, for example, 800 mg/time/day and 2 times/day can be realized.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (8)
1. A combined anti-tumor pharmaceutical composition comprising an effective amount of oroxylin and sorafenib.
2. The pharmaceutical composition according to claim 1, wherein the weight ratio of oroxylin to sorafenib is (1-10):1, such as (2-8):1, (3-7):1, (4-6):1, illustratively 3:1, 4:1, 5:1, 6:1, 7: 1.
3. The pharmaceutical composition according to claim 1 or 2, wherein the effective amount of sorafenib is lower than 400 mg/day for a human patient; for example, 390 mg/day for 100-.
4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the effective amount of oroxylin is less than 1800 mg/day, such as 200-.
5. The pharmaceutical composition according to any one of claims 1-4, wherein sorafenib can be in the form of a pharmaceutically acceptable salt, such as a hydrochloride, phosphate, formate, acetate, citrate, maleate, malate, mesylate or besylate salt.
6. The pharmaceutical composition according to any one of claims 1-5, further comprising a pharmaceutically acceptable carrier and/or excipient.
7. The pharmaceutical composition according to claim 6, which is prepared into conventional preparations such as tablets, granules, capsules or sustained-release preparations by conventional methods.
8. Use of a pharmaceutical composition according to any one of claims 1 to 7 for the manufacture of a medicament for the treatment of cancer; preferably, the compound is used for preparing the medicine for treating liver cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011589573.4A CN113244232A (en) | 2020-12-28 | 2020-12-28 | Oroxylin and sorafenib combined anti-tumor drug and application thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011589573.4A CN113244232A (en) | 2020-12-28 | 2020-12-28 | Oroxylin and sorafenib combined anti-tumor drug and application thereof |
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| CN113244232A true CN113244232A (en) | 2021-08-13 |
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| CN202011589573.4A Pending CN113244232A (en) | 2020-12-28 | 2020-12-28 | Oroxylin and sorafenib combined anti-tumor drug and application thereof |
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- 2020-12-28 CN CN202011589573.4A patent/CN113244232A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| LIBIN WEI等: ""Oroxylin A activates PKM1/HNF4 alpha to induce hepatoma differentiation and block cancer progression"", 《CELL DEATH AND DISEASE》 * |
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Effective date of registration: 20210928 Address after: Room 303, building B, phase I, Zhongdan Ecological Life Science Industrial Park, No. 3-1, xinjinhu Road, Jiangbei new area, Nanjing, Jiangsu 210031 Applicant after: Nanjing Qinling Pharmaceutical Technology Co.,Ltd. Address before: Nanjing City, Jiangsu Province, Tong Lane 210009 No. 24 Applicant before: CHINA PHARMACEUTICAL University |
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