CN106491603A - A kind of pharmaceutical composition and its application containing capsaicin and Sorafenib - Google Patents
A kind of pharmaceutical composition and its application containing capsaicin and Sorafenib Download PDFInfo
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- CN106491603A CN106491603A CN201611112946.2A CN201611112946A CN106491603A CN 106491603 A CN106491603 A CN 106491603A CN 201611112946 A CN201611112946 A CN 201611112946A CN 106491603 A CN106491603 A CN 106491603A
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- sorafenib
- capsaicin
- pharmaceutical composition
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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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
Abstract
The invention belongs to field of antineoplastic medicaments, and in particular to a kind of pharmaceutical composition containing capsaicin and Sorafenib.In described pharmaceutical composition, the mol ratio of capsaicin and Sorafenib is 5:1～10:1.Sorafenib is unique hepatocarcinoma system chemotherapeutics in current global range, but its curative effect needs further to be improved.The pharmaceutical composition can substantially suppress hepatoma cell proliferation, inducing apoptosis of tumour cell, and both use in conjunction show good synergism.
Description
Technical field
The present invention relates to field of antineoplastic medicaments, and in particular to a kind of pharmaceutical composition containing capsaicin and Sorafenib and
Which is applied.
Background technology
Primary hepatocarcinoma is one of common malignant tumor in world wide, and its M ＆ M is in rise year by year
Gesture, seriously threatens the health of the mankind.In China, due to there is more serious hepatitis b virus infected grade carcinogenic risk
Factor, the M ＆ M situation of hepatocarcinoma are particularly severe.According to the statistical report that World Health Organization (WHO) issues for 2014,
Chinese hepatocarcinoma neopathy number of cases in 2012 accounts for the 55% of global new cases sum more than 400,000.Hepatocarcinoma onset is hidden, most
Is lost in middle and advanced stage the best opportunity of operative treatment when patient makes a definite diagnosis first.Radio-frequency (RF) ablation, TACE etc.
Local treatment is also restricted in terms of reply micro metastasis.Therefore, system chemotherapy is the treatment meanss that clinically needs badly.
Targeted drug Sorafenib (sorafinib) is in recent years should in multiple state approvals such as the U.S., European Union and China
For clinical hepatocarcinoma and renal carcinoma system chemotherapeutics.Sorafenib plays antitumor action by double mechanism：On the one hand logical
Suppression tumor cell RAF/MEK/ERK signal transduction pathway is crossed, directly suppresses tumour growth；On the other hand, it can pass through suppression again
Vascular endothelial growth factor receptor (VEGFR) processed and platelet derived growth factor receptor (PDGFR) and block tumor neogenetic blood
The formation of pipe, suppresses the growth of tumor cell indirectly.Sorafenib is a milestone in the treatment of hepatocarcinoma molecular targeted agents
The discovery of formula, late plays irreplaceable therapeutical effect in hepatocarcinoma comprehensive therapy scheme.Even so, Sorafenib
Clinical efficacy still can not be of great satisfaction.It is different degrees of congenital resistance to that clinical practice finds that hepatocarcinoma is present to Sorafenib
Medicine, the case of the patient only 43% treated through Sorafenib can obtain short-term control.Therefore explore and can strengthen Suo Lafei
The medicine of Buddhist nun's curative effect, the particularly naturally occurring integration of edible and medicinal herbs material little to human body toxic and side effects, with highly important meaning
Justice.
CN103933039A discloses Sorafenib and a kind of compositionss of natural drug silibinin, and the two is suppressing liver
There is in terms of growth of cancer cells propagation synergism.CN102836160A discloses Sorafenib and a kind of chemosynthesis small molecule
The compositionss of substance A BT-263, the two drug combination have collaboration and potentiation on antitumous effect.
Fructus Capsici is a kind of vegetable and flavoring agent that people extensively eat, and its pungent sense comes from capsaicin class contained therein
Material, including capsaicin (capsaicin), Dihydrocapsaicin (dihydrocasaicin), nordihydrocapsaicin
(nordihydrocapsaicin) etc..Capsaicin is content highest component in Capsaicinoids, accounts for the 69% of total amount.
Capsaicin has many pharmacologically actives, can be used for analgesia and antiinflammatory etc..Recent studies indicate that, capsaicin also has certain
Anti-tumor activity, has to malignant cells such as hepatocarcinoma, cancer of pancreas, breast carcinoma, carcinoma of prostate, pulmonary carcinoma and bladder cancer and suppresses to increase
Grow and apoptosis-induced effect.The antitumor action of capsaicin is relevant with following factors：Increase permeability of cell membrane, suppress line grain
Body is breathed；Raise antioncogene p53 expression and suppress intracellular signal transduction pathway JNK；Increase the content of reactive oxygen species.
CN104447777A discloses a kind of capsaicin-camptothecin cancer therapy drug conjugate, and the conjugate in vivo can
Capsaicin and camptothecine are directly discharged in the way of hydrolyzing enough, and the two has antitumor action of collaboration.
CN104983900A disclose Fructus Capsici extract and grasp seed procyanidins be used in combination can the nausea and vomiting that causes of prophylaxis of cancer chemotherapy,
Simultaneously work as the effect for aiding in suppressing tumor.
At present, the report that capsaicin and Sorafenib drug combination are treated malignant tumor there is no.
Content of the invention
Goal of the invention：For solving problems of the prior art, the present invention proposes one kind containing capsaicin and Sorafenib
Pharmaceutical composition and its application, improve antitumous effect.
Technical scheme：For realizing that above-mentioned technical purpose, the present invention propose a kind of medicine containing capsaicin and Sorafenib
Compositionss, wherein, in described pharmaceutical composition, capsaicin is 5 with the mol ratio of Sorafenib:1～10:1.
Preferably, in the pharmaceutical composition containing capsaicin and Sorafenib, capsaicin and Sorafenib mole
Than for 10:1.
Wherein, the pharmaceutical composition containing capsaicin and Sorafenib also includes pharmaceutically acceptable carrier, described
The pharmaceutical carrier that pharmaceutically acceptable carrier can be known to the skilled person.
The invention allows for purposes of the aforementioned pharmaceutical compositions on the medicine for being used for treating malignant tumor is prepared.
Wherein, the malignant tumor is any one in primary hepatocarcinoma and renal carcinoma.
The pharmaceutical composition of the present invention can be with conventional various oral dosage forms in pharmaceuticss.On above-mentioned pharmaceuticss often
Various peroral dosage forms can be tablet, capsule, granule, oral liquid etc..
In addition, also the single active medicine or pharmaceutical composition in pharmaceutical composition can be made slow control conventionally
Release formulation, such as slow releasing tablet, micropill or controlled release tablet.
Pharmacology test shows that the pharmaceutical composition containing capsaicin and Sorafenib of the present invention has Synergistic treatment primary
Property the malignant tumor such as hepatocarcinoma function, described malignant tumor is preferably primary hepatocarcinoma and renal carcinoma.
Beneficial effect：Compared with prior art, the Pharmaceutical composition containing capsaicin and Sorafenib of the invention is anti-swollen
Tumor effect is significantly stronger than single medicine, and capsaicin and Sorafenib are used in combination and drug effect can be made to produce synergism.Especially, when
Capsaicin is 10 with the mol ratio of Sorafenib:When 1, the synergism of the two is best.
Description of the drawings
Fig. 1 Sorafenibs combine inhibitory action of the capsaicin to tumor cell proliferation
Fig. 2 Sorafenibs combine impact of the capsaicin to tumor cell form
Fig. 3 Sorafenibs combine impact of the capsaicin to 3/7 activity of tumor cell Caspase
Specific embodiment
Tumor cell line source used by following examples is as follows：Hepatoma carcinoma cell PLC/PRF/5 and kidney cancer cell OS-RC-2
Derive from American Type Culture Collection committee of Chinese Academy of Sciences cell bank.
Medicine and reagent：Sorafenib is purchased from Selleck Chemicals companies of the U.S.；Capsaicin is purchased from Britain Tocris
Company.Two kinds of medicines are dissolved with dimethyl sulfoxide (DMSO), are preserved in -80 DEG C, and (DMSO is dense to be diluted to working concentration during experiment
Degree<0.5%).MTT(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)、
Hoechst33258, Propidium Iodide (PI) and 3/7 detectable of Caspase are purchased from U.S. ThermoFisher
Company.
1 Sorafenib of embodiment is with capsaicin to tumor cell half-inhibition concentration (IC50) measure.
The present embodiment determines capsaicin and Sorafenib to hepatoma carcinoma cell PLC/PRF/5 and kidney cancer cell OS- using mtt assay
The inhibitory action of RC-2.Cell is with 5 × 104The concentration of/mL is inoculated in 96 well culture plates, and per 100 μ L of hole, overnight incubation treats cell
Medicine is added after adherent.Sorafenib arranges 5 drug level, is 0.3,1,3,10,30 μM respectively；Capsaicin arranges 5 medicines
Thing concentration, is 10,30,100,300,1000 μM respectively.After cell is incubated 72 hours in incubator with drug solution, add per hole
Entering 10 μ L MTT solution (5mg/mL), 37 DEG C are incubated 4 hours, abandon culture medium, 150 μ L DMSO being added per hole, 37 DEG C of placements 1 are little
When, the absorbance (OD) in each hole is then determined with microplate reader at 490nm, calculates suppression ratio of the medicine to cell.Carbazole alkaloid
Rate computing formula is：Suppression ratio (%)=(matched group OD value test group OD values)/(matched group OD value blank group OD values) ×
100%.
As a result show, Sorafenib and capsaicin can dose-dependently suppress the propagation of tumor cell.Sorafenib
7.6 and 17.0 μM are respectively to the half-inhibition concentration of PLC/PRF/5 and OS-RC-2 cells.Capsaicin to PLC/PRF/5 and
The half-inhibition concentration of OS-RC-2 cells propagation is respectively 137.0 and 169.8 μM.
2 Sorafenib of embodiment combines inhibitory action of the capsaicin to tumor cell proliferation.
By PLC/PRF/5 the and OS-RC-2 cells of exponential phase with 5 × 104The concentration of/mL is inoculated in the culture of 96 holes
Plate, per 100 μ L of hole, overnight incubation adds medicine after cell attachment.Experiment packet is as follows：Negative control group, capsaicin group, rope
La Feini groups, capsaicin and Sorafenib administering drug combinations group.Capsaicin group gives 10,50,100 μM of capsaicin respectively；Suo La
Non- Buddhist nun's group gives 10 μM of Sorafenib；Drug combination group presses 1:1、5:1、10:1 ratio is simultaneously introduced capsaicin and Suo Lafei
Buddhist nun's (drug combination group 1：10 μM of 10 μM+Sorafenib of capsaicin；Drug combination group 2：10 μM of 50 μM+Sorafenib of capsaicin；Connection
Share medicine group 3：10 μM of 100 μM+Sorafenib of capsaicin).After cell is incubated 72 hours in incubator with drug solution, per hole
10 μ L MTT solution (5mg/mL) being added, 37 DEG C are incubated 4 hours, abandon culture medium, 150 μ L DMSO being added per hole, 37 DEG C are placed 1
Hour, the absorbance in each hole is then determined with microplate reader at 490nm, calculates the suppression ratio of drug on tumor cell propagation.With
Chou-Talalay association indexs method judges that the type that Sorafenib interacts with capsaicin (antagonism, is added or cooperates with effect
Should).With the medication combined effect index of CompuSyn computed in software (combination index, CI), when CI values are in 0.90-
It is judged to summation action when in the range of 1.10, is judged to synergism when CI values are less than 0.90, judges when CI values are more than 1.1
For antagonism.
Experimental result as shown in figure 1, capsaicin concentration can not significantly increase Sorafenib when being 10 μM to PLC/PRF/5 and
Inhibitory action (the drug combination group 1, p of OS-RC-2 cells>0.05), but Sorafenib can be then remarkably reinforced at 50 and 100 μM
Antiproliferative effect (drug combination group 2 and group 3, p<0.01), prompting capsaicin is 5 with the mol ratio of Sorafenib:1～10:1
When, the curative effect of pharmaceutical composition can be substantially better than single medicine.The joint effect index CI of two kind medicines is further calculated, as a result
As follows：In PLC/PRF/5 cells, capsaicin is 5 with the mol ratio of Sorafenib:1 and 10:When 1, CI values are respectively 1.09 Hes
0.55, point out the former the latter is cooperative effect for additive effect；OS-RC-2 cells, capsaicin and Sorafenib mole
Than for 5:1 and 10:When 1, CI values are respectively 0.43 and 0.32, point out the interaction of medicine under both ratios to be collaboration
Effect, but the cooperative effect of the latter becomes apparent from.Result above shows, the mol ratio of capsaicin and Sorafenib is 5:When 1
The Graft Versus Tumor that can be added or be cooperateed with, when its mol ratio is 10:When 1 two kinds of cells are presented with the antitumor of collaboration
Effect.
3 capsaicin of embodiment combines impact of the Sorafenib to tumor cell form.
By PLC/PRF/5 the and OS-RC-2 cells of exponential phase with 1 × 105The concentration of/mL is inoculated in the culture of 96 holes
Plate, per 100 μ L of hole, overnight incubation adds medicine after cell attachment.Experiment packet is as follows：Negative control group, capsaicin group, rope
La Feini groups, capsaicin and Sorafenib administering drug combinations group.Capsaicin group gives 100 μM of capsaicin；Sorafenib group gives 10 μ
M Sorafenibs；Drug combination group gives 100 μM of capsaicin and 10 μM of Sorafenibs simultaneously.Cell is incubated in incubator with medicine
The form of inverted phase contrast microscope observation of cell is used after educating 24 hours.
Photo of the hepatocarcinoma PLC/PRF/5 cell after different pharmaceutical process is as shown in Figure 2 A：Negative control group cell is certainly
Bottom hole is so spread in, and outward appearance is soft full, and form is normal；Sorafenib treatment group, cell shrinkage, part cell take off wall, kytoplasm
Middle black particle shape material increases and occurs cavity, points out cell to occur the sign of apoptosis under medicine effect；Capsaicin Treatment
Group, in cell, particulate material increases, and part cell film has the phenomenon of shrinkage；Capsaicin and Sorafenib Combined Treatment
Group, the de- wall of a large amount of cells are rounded, and apoptosis pointed out by part cell breakage.After renal carcinoma OS-RC-2 cell is through drug treating
The change of form is similar to PLC/PRF/5 cells.This test result indicate that, capsaicin combine Sorafenib to tumor cell outward appearance
The impact of form is maximum, and points out cell to may have occurred apoptosis under the process of medicine.
4 Sorafenib of embodiment combines capsaicin inducing apoptosis of tumour cell.
Thin to PLC/PRF/5 using the double dye method detection Sorafenibs of Hoechst 33258 and PI, capsaicin and the two combination
The impact of born of the same parents' apoptosis.By PLC/PRF/5 cells with 5 × 104The concentration of/mL is inoculated in 24 well culture plates, per hole 2mL, cultivates
Night adds medicine after cell attachment.Dosage Regimen is as follows：Capsaicin group gives 100 μM of capsaicin；Sorafenib group is given
Give 10 μM of Sorafenibs；Drug combination group gives 100 μM of capsaicin and 10 μM of Sorafenibs simultaneously.Cell is with medicine in incubator
Middle incubation 24 hours, collects cell, carries out Hoechst 33258 and PI dyeing respectively, then uses immunofluorescence microscopy,
In 5 different region random pictures, the cell number and total cell number that apoptosis occurs is counted, apoptosis rate is calculated.
The double dyes of Hoechst 33258 and PI test result indicate that, negative control group apoptosis rate is 0.41%, capsaicin
Group apoptosis rate is 4.22%, and Sorafenib group apoptosis rate is 9.76%, capsaicin and Sorafenib combination group cell
Apoptosis rate is 30.58%.Drug combination group apoptosis rate is significantly higher than Sorafenib group and capsaicin group (p<0.05).
5 capsaicin of embodiment combines impact of the Sorafenib to 3/7 activity of apoptosis-related protein Caspase
The activation of Caspase protein cascades can directly result in apoptosis.The present embodiment is detected peppery using fluorescence microscope
Green pepper element joint impact of the Sorafenib to 3/7 activity of hepatocarcinoma PLC/PRF/5 cell Caspase.By PLC/PRF/5 cells with 2.5
×105The concentration of/mL is inoculated in 24 well culture plates, and per 400 μ L of hole, overnight incubation adds medicine after cell attachment.Administration side
Case design is as follows：Capsaicin group drug level is 100 μM；Sorafenib group drug level is 10 μM；Drug combination group adds simultaneously
Enter capsaicin and Sorafenib (concentration is ibid).Cell is incubated in incubator 24 hours with medicine, abandons culture medium, is added
3/7 detectable CellEvent of CaspaseTMCaspase-3/7Green Detection Reagent, 37 DEG C are incubated 20 points
Clock, fluorescence microscope.The cell shows green fluorescence of the activation of Caspase 3/7, takes 5 visuals field at random per hole, counts simultaneously
Average.
As a result as shown in figure 3, the cell number of drug combination group shows green fluorescence is significantly more than Sorafenib or capsaicin
Independent medication group (p<0.05), prompting drug combination can be with the Caspase 3/ in significantly more efficient activation PLC/PRF/5 cells
7, so as to induced apoptosis.
Claims (5)
1. a kind of pharmaceutical composition containing capsaicin and Sorafenib, it is characterised in that in described pharmaceutical composition capsaicin and
The mol ratio of Sorafenib is 5:1~10:1.
2. the pharmaceutical composition described in claim 1, it is characterised in that the mol ratio of wherein capsaicin and Sorafenib is 10:
1.
3. the pharmaceutical composition described in claim 1 and 2, it is characterised in that described pharmaceutical composition also includes pharmaceutically connecing
The carrier that receives.
4. the pharmaceutical composition described in claim 1 and 2 prepare treatment malignant tumor medicine on purposes.
5. the pharmaceutical composition described in claim 1, prepare for treat primary hepatocarcinoma and renal carcinoma medicine on purposes.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611112946.2A CN106491603B (en) | 2016-12-07 | 2016-12-07 | Medicinal composition containing capsaicin and sorafenib and application thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611112946.2A CN106491603B (en) | 2016-12-07 | 2016-12-07 | Medicinal composition containing capsaicin and sorafenib and application thereof |
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| Publication Number | Publication Date |
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| CN106491603A true CN106491603A (en) | 2017-03-15 |
| CN106491603B CN106491603B (en) | 2020-01-14 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115006469A (en) * | 2022-06-27 | 2022-09-06 | 云南诺思普医疗科技有限公司 | Anti-lung cancer medicine containing capsicum and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009045504A1 (en) * | 2007-10-04 | 2009-04-09 | President And Fellows Of Harvard College | Methods and compositions for treating cancer and modulating signal transduction and metabolism pathways |
| CN101940569A (en) * | 2009-07-07 | 2011-01-12 | 鼎泓国际投资（香港）有限公司 | Medicament composition containing sorafenib, artemisinin and artemisinin derivative and application thereof in preparing medicament for treating cancer |
-
2016
- 2016-12-07 CN CN201611112946.2A patent/CN106491603B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009045504A1 (en) * | 2007-10-04 | 2009-04-09 | President And Fellows Of Harvard College | Methods and compositions for treating cancer and modulating signal transduction and metabolism pathways |
| CN101940569A (en) * | 2009-07-07 | 2011-01-12 | 鼎泓国际投资（香港）有限公司 | Medicament composition containing sorafenib, artemisinin and artemisinin derivative and application thereof in preparing medicament for treating cancer |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115006469A (en) * | 2022-06-27 | 2022-09-06 | 云南诺思普医疗科技有限公司 | Anti-lung cancer medicine containing capsicum and preparation method thereof |
| CN115006469B (en) * | 2022-06-27 | 2024-03-22 | 云南诺思普医疗科技有限公司 | Chilli lung cancer resisting medicine and preparation method thereof |
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| CN106491603B (en) | 2020-01-14 |
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