CN114939122B - Combined antitumor pharmaceutical composition derived from natural plants - Google Patents
Combined antitumor pharmaceutical composition derived from natural plants Download PDFInfo
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- CN114939122B CN114939122B CN202210651202.7A CN202210651202A CN114939122B CN 114939122 B CN114939122 B CN 114939122B CN 202210651202 A CN202210651202 A CN 202210651202A CN 114939122 B CN114939122 B CN 114939122B
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- rosavin
- tumor
- salvianolic acid
- pharmaceutical composition
- melanoma
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 10
- SNKFFCBZYFGCQN-VWUOOIFGSA-N Lithospermic acid B Natural products C([C@H](C(=O)O)OC(=O)\C=C\C=1C=2[C@H](C(=O)O[C@H](CC=3C=C(O)C(O)=CC=3)C(O)=O)[C@H](OC=2C(O)=CC=1)C=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 SNKFFCBZYFGCQN-VWUOOIFGSA-N 0.000 claims abstract description 37
- RINHYCZCUGCZAJ-UHAHJPEESA-N (2s,3r,4s,5s,6r)-2-[(e)-3-phenylprop-2-enoxy]-6-[[(2s,3r,4s,5s)-3,4,5-trihydroxyoxan-2-yl]oxymethyl]oxane-3,4,5-triol Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)CO[C@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC\C=C\C=2C=CC=CC=2)O1 RINHYCZCUGCZAJ-UHAHJPEESA-N 0.000 claims abstract description 36
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Classifications
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- 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
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
-
- 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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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The application provides a natural plant-derived combined anti-tumor pharmaceutical composition, which comprises Salvianolicacid B and Rosavin bulk drugs, wherein the weight ratio of Salvianolic acid B to Rosavin is as follows: 1-16:5. experiments prove that the Salvianolic acid B and Rosavin combined application of natural plant sources can effectively inhibit the proliferation of tumors such as melanoma and the like; the anti-tumor effect is obviously better than that of Salvianolic acid B or Rosavin which are used independently, the biological safety is good, no obvious toxic or side effect is caused, and the application prospect is wide.
Description
Technical Field
The invention belongs to the field of antitumor drugs, and in particular relates to a Salvianolic acid B and Rosavin combined antitumor pharmaceutical composition derived from natural plant sources.
Background
Salvianolic acid B the aromatic acid component of radix Salviae Miltiorrhizae has slightly bitter and astringent taste, and is effective in eliminating dampness. Is soluble in water, is one of the salvianolic acids which are studied more, and has important pharmacological actions on organs such as heart, brain, liver, kidney and the like. The product has effects of promoting blood circulation for removing blood stasis, dredging meridian passage, and can be used for treating ischemic apoplexy due to blood stasis blocking channels and collaterals, manifested by numbness of limbs, weakness, spasm pain, or movement disturbance, facial distortion, etc.
Rosavin is a natural component in the traditional Chinese medicine rhodiola rosea, and is mainly used for activating blood, stopping bleeding, clearing lung-heat, relieving cough, treating hemoptysis, cough due to pneumonia and leucorrhea of women. Anti-hypoxia, anti-fatigue and anti-cold; can improve the strength and flexibility of the organism and can quickly recover from fatigue; regulating immune system, and has bidirectional regulating effect on brain and organ function.
Modern pharmacological studies show that Salvianolic acid B has the effects of promoting blood circulation to remove blood stasis and treating blood vessels, while Rosavin has the effects of resisting oxidation, scavenging free radicals and improving the immune function of the organism.
In view of the success of the combined use of the anti-angiogenesis medicine and the tumor immunosuppression medicine in the clinical anti-tumor performance, the combination of two links of the traditional Chinese medicine is promoted to be excavated whether the synergistic anti-tumor effect can be achieved.
Disclosure of Invention
To better address the above considerations, the present invention combines Salvianolic acid B having anti-angiogenic effect and Rosavin having immunomodulatory effect, which are natural plant sources, in order to evaluate the combined anti-tumor effect of the compositions. Wherein Salvianolic acid B and Rosavin have the following specific structural formulas:
according to an embodiment of the invention, the dose ratio of Salvianolic acid B to Rosavin is 1-16:5, preferably: 1:5,4:5,16: 5. according to an embodiment of the invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier and/or excipient.
According to an embodiment of the present invention, the pharmaceutical composition may be formulated into conventional preparations such as tablets, granules, capsules, sustained-release preparations, or the like by conventional methods.
The pharmaceutically acceptable carrier and/or excipient comprises filler, binder, correctant, antioxidant, etc.
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 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 flavoring agents that may be used 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 provides application of the combined anti-tumor drug in preparing a drug for treating tumors; the tumor comprises colon cancer, melanoma, lung cancer, breast cancer, gastric cancer, liver cancer, adrenocortical cancer, cholangiocarcinoma, esophageal cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostatic cancer and the like, and is preferably used for preparing medicines for treating melanoma.
The anti-tumor beneficial effects are as follows: salvianolic acid B and Rosavin have wide sources, are easy to obtain, and have no obvious toxic or side effects on human bodies. According to the invention, the anti-tumor effect of the single drug Salvianolic acid B or Rosavin is obviously improved through the combination of Salvianolic acid B and Rosavin, the obvious inhibiting effect on the weight of a tested mouse is avoided, and the lung injury of the mouse caused by modeling can be improved, so that Salvianolic acid B and Rosavin are adopted to be combined to improve the anti-tumor curative effect, and the combined mode possibly plays a larger role in the future tumor treatment.
Specifically, in a mouse melanoma model, salvianolic acid B (80 mg/kg) and Rosavin (100 mg/kg) are combined, so that the tumor inhibition rate can be effectively increased, the tumor inhibition rate of subcutaneous transplantation tumor of a melanoma cell B16F10 mouse is 83.21%, the tumor inhibition rate is increased by 35.64% compared with 80mg/kg Salvianolic acid B alone, the tumor inhibition rate is increased by 10.97% compared with 100mg/kgRosavin alone, and the drug safety is good from the aspect of weight data.
Drawings
Fig. 1: salvianolic acid B and Rosavin at different concentrations and their combined use have an effect on the size of melanoma tumor volume, wherein graph a is a photograph of melanoma and graph B is a plot of the size of melanoma tumor volume;
fig. 2: salvianolic acid B and Rosavin, and their combination effect on the rate of melanoma inhibition in mice;
fig. 3: salvianolic acid B and Rosavin, and their combination effects on mouse body weight.
Detailed Description
The technical scheme of the invention will be further described in detail below with reference to specific embodiments. It is to be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the invention.
Unless otherwise indicated, the starting materials and reagents used in the following examples were either commercially available or may be prepared by known methods.
Example 1: mixing Salvianolic acid B g and Rosavin 50g, adding starch, granulating, adding appropriate amount of lubricant, tabletting, and making into tablet.
Example 2: mixing Salvianolic acid B g and Rosavin 50g, adding dextrin, granulating, adding appropriate amount of lubricant, and making into capsule.
Example 3: mixing Salvianolic acid B g and 50g of Rosavin, adding dextrin, granulating, and making into granule.
Example 4: the influence of the invention on the C57BL/6 subcutaneous melanoma animal model
1. Experimental materials
1.1 test drug
Name: rosavin; the content is as follows: HPLC is more than or equal to 98%; providing units: chengduremia Biotechnology Co., ltd., lot number RFS-L02411802020; the preparation method comprises the following steps: the gastric lavage administration is carried out according to a system of 0.1ml/10g, the administration volume is 0.2ml, 600mg Rosavin is taken and dissolved in 30ml physiological saline containing 0.3% CMCNA, namely, the administration dosage is 100mg/kg, and 25mg/kg is diluted proportionally.
Name: salvianolic acid B; the content is as follows: HPLC is more than or equal to 98%; providing units: nanjing Jin Yi Cupressaceae technology Co., ltd., CAS number: 121521-90-2; the preparation method comprises the following steps: the administration is carried out by lavage according to a system of 0.1ml/10g, the administration volume is 0.2ml, 480mg Salvianolic acid B is dissolved in 30ml physiological saline containing 0.3% CMCNA, namely the administration dosage is 80mg/kg, and the administration dosage is diluted according to a proportion for 20 mg/kg.
1.2 test animals
Source, strain: c57BL6 mice, company: the Jiangsu Jiyaokang biotechnology Co Ltd, production license number: SCXK 2018-0008. Week-old: 6 weeks of age; gender: and (5) male.
1.3 groups of experimental animals and dose settings are shown in Table 1.
TABLE 1 grouping and group setting of animals
1.4. Statistical method
Experimental data were analyzed using SPSS software (version 20.00), all data expressed in SD or SEM. Group difference analysis was performed using Prism 9.0 (Graph Pad Software Inc, san Diego, CA). The difference of P <0.05 is statistically significant.
1.5 Experimental procedure
1.5.1 Establishment of C57BL/6 subcutaneous melanoma animal model: B16F10 melanoma cells were resuspended in PBS to adjust cell concentration to 1 x 10 6 /mL. 200 mu L of cell suspension was inoculated to the right of C57BL/6 miceGroin measurement, and tumor volume reaching 50-100mm 3 At this time, model mice were randomly divided into 9 groups (n=10), and were dosed for about 2 weeks in the above-described experimental animal group and dose setting, and the body weight was weighed every 3 days during this period, and tumor volumes were measured and calculated (tumor volume=1/2×a×b 2 A is the major diameter of the tumor and b is the minor diameter of the tumor), and a tumor growth curve is plotted. About 2 weeks of treatment, mice were sacrificed, tumor tissues were dissected and organ tissues were photographed and weighed and saved as needed for subsequent experiments.
Based on the measured results, the relative tumor volume (relative tumor volume, RTV) is calculated as: rtv=vt/V0. Where V0 is the tumor volume measured at the time of divided cage administration (i.e., d 0), and Vt is the tumor volume at each measurement. The evaluation index of the anti-tumor activity is relative tumor proliferation rate T/C (%), and the calculation formula is as follows:
T RTV : treatment group RTV; c (C) RTV : negative control RTV
The tumor inhibition rate calculation formula is as follows:
T weight : average tumor weight in treatment group; c (C) weight : average tumor weight of the negative control group.
1.5.2 experimental results
1.5.2.1 Salvianolic acid B and Rosavin combined have inhibitory effect on B16F10 melanoma subcutaneous graft tumor volume, as shown in Table 2 and FIG. 1, the effect of different concentrations of Salvianolic acid B and Rosavin and the combined group on B16F10 subcutaneous graft melanoma volume proliferation can be seen that the combined administration of group C4, namely Salvianolic acid B (80 mg/kg) and Rosavin (100 mg/kg), shows the best anti-tumor effect. Wherein in fig. 1, a is a photograph of melanoma, and B is a volume size of melanoma.
1.5.2.2 Salvianolic acid B and Rosavin combined administration can effectively increase the tumor inhibition rate of B16F10 melanoma subcutaneous transplantation tumor, as shown in Table 3 and FIG. 2, salvianolic acid B (80 mg/kg) and Rosavin (100 mg/kg) combined administration can effectively increase the tumor inhibition rate of B16F10 melanoma cell B16F10 subcutaneous transplantation tumor by 83.21 percent, which is 35.64 percent higher than that of 80mg/kg Salvianolic acid B alone, and 10.97 percent higher than that of 100mg/kg Rosavin alone. In FIG. 2, the control group is 0 and is not shown.
Table 2 different concentrations of Salvianolic acid B and Rosavin and combinations thereof for melanoma tumor volume (mm) 3 ) Influence of size
Table 3: salvianolic acid B and Rosavin, and effects of their combination on the rate of melanoma inhibition in mice
| Control group | S1 | S2 | R1 | R2 | C1 | C2 | C3 | C4 | |
| Tumor inhibition rate | 0 | 0.50215857 | 0.47567937 | 0.50442346 | 0.72238849 | 0.55461794 | 0.56328993 | 0.78787519 | 0.83209532 |
1.5.2.3Salvianolic acid B and Rosavin were good in drug safety, as shown in table 4 and fig. 3, salvianolic acid B and Rosavin at different concentrations and the combination group had no significant effect on experimental animal body weight (p < 0.05) compared to the blank group (K). M is a control group.
Table 4:Salvianolic acid B and Rosavin and their combination effect on mouse body weight (g)
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, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (4)
1. The natural plant-derived combined anti-tumor pharmaceutical composition is characterized by comprising Salvianolic acid B and Rosavin bulk drugs, wherein the weight ratio of Salvianolic acid B to Rosavin is as follows: 4:5.
2. the pharmaceutical composition of claim 1, further comprising a pharmaceutically acceptable carrier and/or excipient.
3. The pharmaceutical composition according to claim 2, wherein the conventional formulation is formulated by conventional methods, the formulation being one of a tablet, a granule, a capsule or a sustained release formulation.
4. Use of a pharmaceutical composition according to claim 1 for the preparation of a medicament for the treatment of a tumor, wherein the tumor is melanoma.
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| CN110590872A (en) * | 2019-09-27 | 2019-12-20 | 天圆(宁波)生物医药科技有限公司 | Synthesis method of rhodiola rosea active ingredient roservine or roseoline |
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| CN101455673A (en) * | 2007-12-13 | 2009-06-17 | 上海药谷药业有限公司 | Use of cinnamyl-(6'-O-alpha-L- arabopyranose)- O-beta-D-glucopyranoside in preparing antidepressant medicine |
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