CN106974910B - Pharmaceutical composition and purposes containing Sorafenib and GSK2656157 - Google Patents
Pharmaceutical composition and purposes containing Sorafenib and GSK2656157 Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
- A61K31/33—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
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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Abstract
The invention belongs to biomedicine fields, and in particular to the application of pharmaceutical composition and pharmaceutical composition of the present invention containing Sorafenib and GSK2656157 in the preparation treatment cancer of the esophagus, lung cancer and liver cancer.The pharmaceutical composition of Sorafenib and GSK2656157 of the present invention can effectively improve the side-effect problem of Sorafenib, improve the bioavilability of drug, simultaneously, Sorafenib Tosylate and combining for GSK2656157 can make drug effect generate synergistic effect in treatment lung cancer, liver cancer and the cancer of the esophagus, hence it is evident that use better than single medicine.
Description
Technical field
The invention belongs to biomedicine fields, and in particular to the pharmaceutical composition containing Sorafenib and GSK2656157 inhibitor
Object and purposes.
Background technique
World Health Organization's survey report shows that global cancer condition is got worse, and the number of 20 years from now on new patients will
Increase to 15,000,000 by current annual 10000000, dead number also will increase to 1000 by annual 6,000,000 due to cancer
Ten thousand.With the improvement of living standards, the change of dietary structure, the disease incidence of the cancer of the esophagus is in rise year by year trend；Wherein primary
Liver cancer is the canceration occurred in liver cell and intrahepatic biliary epithelium cell, is one of most common malignant tumour of the mankind；Lung cancer is
Common malignant tumour is derived from bronchiolar epitheliums at different levels, is divided into cell lung cancer and non-small cell lung cancer.Though the treatment of these cancers
So based on operation, but due to the general non-evident sympton of early stage patient, in diagnosed cancer patient for the first time, much it has been
Advanced stage, lose operation excision chance, therefore non-operative treatment (such as chemotherapy) have in the comprehensive treatment of tumors it is particularly significant
Status.Chemotherapy is that proliferation, the infiltration, transfer of cancer cell are prevented using chemicals, until final one kind for killing cancer cell
Therapeutic modality.It is a kind of systemic treatment means, and operation, radiotherapy are together, and 3 big treatment means of referred to as cancer.
The anti-tumor drug listed at present is more, such as alkylating agent drug, antimetabolite, antitumor antibiotics, is immunized
Regulator etc., but the disadvantages of the big generally existing selectivity of drug is low, is more toxic, and patient does not tolerate.With to tumour
The Study on Molecular Mechanism of occurrence and development is more and more clearer, and molecular targeted therapy Several Kinds of Malignancy has received widespread attention and height
Degree is paid attention to.Molecular targeted agents selectivity is high, wide spectrum is effective, and it is current tumour that safety, which is better than cytotoxic chemotherapy agents,
The new direction of therapy field development.
Sorafenib (Sorafenib) is targeted drug more than one, the cell that it is mediated by inhibition RAF/MEK/ERK
Signal transduction pathway and the proliferation for directly inhibiting tumour cell, block tumor neogenetic blood further through EGFR and PDGFR is acted on
The formation of pipe, inhibits tumour growth indirectly.The drug has apparent inhibition to make the Several Kinds of Malignancy including liver cancer
With, but the control line for phase that tumour can only get nowhere is in 6 months, and it is larger to human toxicity, is easy to lead after taking
Fash, blood pressure is caused to increase, palm or foot bottom is rubescent, pain, swelling or the ill symptoms such as blister occurs.How to further increase
Lower toxic side effect is kept while Sorafenib anti-tumor activity, undoubtedly and clinical test at present solution for study
Problem.
At present have by Sorafenib and other drugs combination in vivo with the example of extracorporeal anti-tumor.Such as Chinese patent Shen
Please CN102438608A disclose the combination between anti-angiogenic medicine AVE8062 and Sorafenib, and confirm that the combination can be effective
Treating cancer, especially solid tumor especially have inhibitory effect to sarcoma, lung cancer, oophoroma, liver cancer or kidney.It is Chinese special
Benefit application CN102836160A discloses the combination between lymph cancer drug ABT-263 and Sorafenib, and confirms the combination
Kinds cancer can effectively be treated.But toxic side effect of above-mentioned composition when being used in combination is stronger.
More and more evidences show that the drug susceptibility of er stress and tumour cell is closely related, and PERK/
EIF2 α access is the important sensing pathway in er stress downstream.GSK2606414 be one kind take orally it is biologically active, have
Effect, selective PERK inhibitor is 100 times at least higher than other eIF2AKs of test selectivity.
Currently, having no report associated with GSK2606414 and Sorafenib.
Summary of the invention
In order to solve the technical problems existing in the prior art, the purpose of the present invention is to provide one kind containing Sorafenib and
The pharmaceutical composition of GSK2656157 improves Sorafenib to the inhibitory effect of tumour, and effectively improves Sorafenib
Toxic side effect.
The pharmaceutical composition containing Sorafenib and GSK2656157 that the present invention provides a kind of, described pharmaceutical composition include
A effective amount of Sorafenib Tosylate and a effective amount of GSK2656157.
The Sorafenib Tosylate, No. CAS is 475207-59-1, the GSK2656157, and No. CAS is
1337532-29-2, structural formula are as follows:
As the optimal embodiment of the present invention, in described pharmaceutical composition Sorafenib Tosylate and
The molar concentration rate of GSK2656157 be 5~40: 1~10, it is preferable that in described pharmaceutical composition Sorafenib Tosylate and
The molar concentration rate of GSK2656157 is 10: 5, and structural formula is as follows:
Preferably, heretofore described pharmaceutical composition can be prepared into ejection preparation or mouth according to this field routine techniques
Heretofore described pharmaceutical composition is preferably prepared into oral preparation by formulation, the present invention, and the oral preparation is preferably mouth
Take capsule.According to dosage form, the content of pharmaceutical composition of the present invention in the formulation can be 1~99% in mass,
Preferably 5~90%；The auxiliary material of this field routine can be used in the auxiliary material that preparation uses, and to get along well, pharmaceutical composition of the present invention occurs
Reaction or premised on not influencing the curative effect of drug of the present invention；The preparation method of preparation can use the preparation method of this field routine
It is prepared.
The dosage of pharmaceutical composition in the present invention according to the dosage form of administration object, administration route or drug not
It is same to carry out variation appropriate, but to guarantee that the pharmaceutical composition can reach effective blood concentration in the mammalian body
Premised on.
Aforementioned pharmaceutical compositions can effective treating cancer, especially lung cancer, the cancer of the esophagus or liver cancer, be more particularly for treating
The cancer of the esophagus.
Another object of the present invention is to provide use of the above-mentioned pharmaceutical composition in preparation prevention and/or treatment tumour
On the way.Wherein, the tumour is lung cancer, the cancer of the esophagus or liver cancer, it is highly preferred that the tumour is the cancer of the esophagus.
Compared with prior art, pharmaceutical composition of the present invention has the advantage that
The present invention effectively improves Sorafenib containing the pharmaceutical composition of Sorafenib Tosylate and GSK2656157
Side-effect problem, improve the bioavilability of drug, meanwhile, the joint of Sorafenib Tosylate and GSK2656157
Drug effect can be made to generate synergistic effect in treatment lung cancer, liver cancer and the cancer of the esophagus, hence it is evident that use better than single medicine, this point exists
It is confirmed in antitumor action of the present invention and test result.Particularly, as Sorafenib Tosylate and GSK2656157
When molar concentration rate 10: 5, this synergistic effect is very good, and drug is minimum to the toxic side effect of normal cell.
Detailed description of the invention
Fig. 1 shows that the influence to growth of tumour cell is used alone in Sorafenib Tosylate and GSK2656157；
Fig. 2 shows Sorafenib Tosylate, cis-platinum, 5 FU 5 fluorouracil respectively with GSK2656157 synergy to swollen
The influence of tumor cell growth；
Fig. 3 shows Sorafenib Tosylate and influence of the GSK2656157 synergy to apoptosis of tumor cells；
Fig. 4 shows the shadow that Sorafenib Tosylate and GSK2656157 synergy form tumor cell clone
It rings.
Specific embodiment:
The following describes the present invention further through the description of specific embodiments, but it is to limit of the invention that this, which is not,
System, those skilled in the art's basic thought according to the present invention can make various modifications or improvements, but without departing from this
The basic thought of invention, is all within the scope of the present invention.
The composition of raw materials of embodiment 1, pharmaceutical composition of the present invention
Composition 1: Sorafenib Tosylate and GSK2656157, Sorafenib Tosylate and GSK2656157's
Molar concentration rate 10: 5.
Composition 2: Sorafenib Tosylate and GSK2656157, Sorafenib Tosylate and GSK2656157's
Molar concentration rate 5: 1.
Composition 3: Sorafenib Tosylate and GSK2656157, Sorafenib Tosylate and GSK2656157's
Molar concentration rate 40: 10.
Embodiment 2, antitumor action and test
Research 1: the influence (Fig. 1) to tumor cell proliferation is used alone in Sorafenib Tosylate and GSK2656157
1.1 experimental method
Cell is inoculated into 96 orifice plates with the quantity of every 3000~6000 cells in hole, it, will after cell adherent (for 24 hours)
Sorafenib Tosylate and GSK2656157 drug are diluted to certain gradient concentration respectively, and every concentration sets 5 multiple holes, point experiment
Group and zeroing group dosing.Cell viability detection is carried out using mtt assay after 48h, 10 μ lMTT solution are added in every hole, continue to cultivate 4h,
It is careful to absorb liquid in hole, crystal in hole is avoided contact with, every hole is added the DMSO of 100 μ l, rocks in being protected from light on constant speed shaking table.
Object to be crystallized after completely dissolution, reads OD value (wavelength 570nm, reference wavelength 630nm) in microplate reader, measures absorbance A value.
The calculation formula of cell viability (CellViability) are as follows: cell viability=OD experimental group/OD control group.According to each concentration
Inhibiting rate can map to obtain dose response histogram, mapping software Graphpad.
It will be seen from figure 1 that Sorafenib Tosylate and GSK2656157 have certain growth to press down tumour cell
Production is used, and wherein Sorafenib Tosylate is at 10 μM to four plants of tumour cell Eca-109, E C9706, A549 and HepG2
Survival rate is respectively 31%, 48%, 45% and 74%, and GSK26 56157 distinguishes in 5 μM of survival rates to four plants of tumour cells
It is 60%, 76%, 74% and 73%.
Research 2:Sorafenib Tosylate and GSK2656157 combine the influence (Fig. 2A) to tumor cell proliferation
Tumour Eca-109, EC9706, A549 and HepG2 cell are inoculated into the quantity of 3000-6000, every hole cell
96 orifice plates add blank control group, Sorafenib Tosylate list medicine group, the mono- medicine group of GSK2656157 and connection after cell is adherent
It shares medicine group drug (+5 μM of GSK2656157 of 10 μM of Sorafenib Tosylates), after cultivating 48h, 10 μ l concentration are added in every hole
For the MTT solution of 5mg/ml, continue to cultivate 4h, then discards the DMSO that 100 μ l are added in the every hole of culture solution, kept away on constant speed shaking table
Light rocks.Object to be crystallized after completely dissolution, reads OD value (wavelength 570nm, 6 30nm of reference wavelength) in microplate reader, reads every
The light absorption value in hole calculates cell survival and inhibiting rate after two medicines share.
To the combination effect of tumour cell when evaluating two kinds of combination therapies using Jin Shi amendment type, the specific steps are,
According to growth inhibition ratio (%)=(1-OD experimental group/OD control group) × 100% formula, A medicine is calculated under certain conditions
Inhibiting rate to tumour cell is EA, and calculating B medicine is under certain conditions EB to the inhibiting rate of tumour cell, then calculates two
The inhibiting rate that person is administered in combination is EC, is calculated by the following formula drug combination index q value, q=EC/ (EB+EA-EB*EA), when
Value>1.15 q are synergistic effect, and 0.85<q<1.15 are additive effect, and q<0.85 is antagonistic effect.Referred to by above-mentioned drug combination
Several calculating further judges the final drug effect of two kinds of combination therapies.Through calculating Sorafenib Tosylate with
GSK2656157 drug combination is respectively 1.27,1.23 in Eca-109, EC9706, the q value of A549 and HepG2 tumour cell,
1.16 1.18.Show that 10 μM of Sorafenib Tosylates and 5 μM of GS K2656157 are used in combination with very in tumour cell
Good synergistic effect.
Research 3:Sorafenib Tosylate, cis-platinum, 5 FU 5 fluorouracil combine with GSK2656157 thin to the cancer of the esophagus respectively The influence (Fig. 2 B) of born of the same parents' proliferation
According to research 2 described in method, explore Sorafenib Tosylate, cis-platinum, 5 FU 5 fluorouracil respectively with
GSK2656157 combines the influence to esophagus carcinoma proliferation.Esophageal carcinoma Eca-109 cell line bed board, is grouped as follows: control group, first
Benzene sulfonic acid Sorafenib group, GSK2656157 group, Sorafenib Tosylate+GSK2656157 group, cis-platinum group, cis-platinum+
GSK2656157 group, 5 FU 5 fluorouracil group, 5 FU 5 fluorouracil group+GSK2656157 group.By calculating, 10 μM of toluenesulfonic acid ropes are drawn
Non- Buddhist nun and q value of 5 μM of 157 drug combinations of GSK2656 in Eca-109 are 1.27；0.5 μ g/ml cis-platinum and 5 μM
Q value of the GSK2656157 drug combination in Eca-109 is 0.85；2 μ g/ml 5 FU 5 fluorouracils and 5 μM of GSK265615 7
Q value of the drug combination in Eca-109 is 0.75.Show that Sorafenib Tosylate and GSK265615 7 are inhibiting the cancer of the esophagus
The effect that is used in combination in cell growth is better than cis-platinum, 5 FU 5 fluorouracil and GSK2656 157 and is used in combination.
Research 4: Sorafenib Tosylate and GSK2656157 combine the influence (Fig. 3) to apoptosis of tumor cells
By Eca-109 cell respectively with every hole 2 × 105The density of a cell is seeded to 6 orifice plates.After cell is adherent, press
2 grouping administration of research, after being jointly processed by 48h.Using Western blot method detection through Sorafenib Tosylate with
GSK2656157 individually handle and Combined Treatment after the intracellular apoptotic proteins PARP of esophageal cancer cell Eca-1 09 expression
Situation.Western blot method is carried out according to research 2.
As a result as shown in figure 3, in Eca-109 cell, when with Sorafenib Tosylate and GSK265 6157 individually and
When drug combination processing, the shearing bar band of apoptosis marker protein PARP is obviously raised, and joint group is compared with each single medicine group
Expression has apparent difference, this illustrates that Sorafenib Tosylate can significantly cause to eat with G SK2656157 drug combination
Apoptosis occurs for pipe cancer cell.
Research 5: Sorafenib Tosylate and GSK2656157 combine the influence (Fig. 4) formed to tumor cell clone
By Eca-109 and EC9706 cell inoculation to 6 orifice plates, after cell is adherent overnight, blank control group, 10 μM is added
Sorafenib Tosylate, 5 μM of GSK2656157 and drug combination group drug are incubated for 7 days, detect cell plates Clone formation
Situation.As a result as shown in figure 4, drug combination has apparent association to cell clonal formation compared with control group and single medicine group
Same inhibiting effect, drug combination group is not it is observed that apparent cell clone.
Embodiment 3, drug combination acute toxicity test
This experiment studies Sorafenib Tosylate and GSK2656157 composition of medicine pair using kunming mice as research object
The influence of the acute toxicity of mouse is further researched and developed and is mentioned for Sorafenib Tosylate and GSK2656157 pharmaceutical composition
It is referred to for preliminary secure estimate.
Acute toxicity test is tried by maximum tolerated dose method in GB1519.3-2003 " food acute toxicity test "
It tests.18 cleaning small white mouses are taken, are randomly divided into 3 groups: blank control group (A group), Sorafenib Tosylate and GSK2656157
(molar concentration rate 10: 5) combination group (B group), Sorafenib Tosylate independent medication group (C group), every group 6 (N=6),
Male and female each 3.According to the acute toxicity grading criteria in assessment, mouse fasting 10h before testing, only with 0.5ml/
Gastric infusion, for 24 hours interior administration 2 times, consumption per day 15g/Kg, the physiological saline of blank control group mouse stomach-filling same dose.It gives
It is whether dead in observation mouse 72h after medicine, and the changes of weight in one week future.All test results are with " x ± s " table
Show, with t method of inspection testing significance of difference, the results are shown in Table 1.
As known from Table 1, weight of the mouse during nursing is ever-increasing, and Sorafenib Tosylate is individually for medicine group
(C group) has significant decline relative to blank control group (A group) weight, and Sorafenib Tosylate and GSK2656157 are combined
For group (B group) relative to blank control group (A group) though weight is declined, amplitude is little.Illustrate, Sorafenib Tosylate and
Toxicity has reduction, i.e. toluenesulfonic acid rope compared with the toxicity of Sorafenib Tosylate independent medication associated with GSK2656157 combination group
La Feini and SK2656157 combination can make Sorafenib Tosylate reduce the toxic side effect of human body.
The changes of weight situation (N=6) of mouse during 1 medication of table
Note: compared with A group,**P < 0.01.
By above-mentioned mouse, after weighing, dissection, the heart that detects by an unaided eye, liver,spleen,kidney, brain and thymus gland situation, note are put to death
Record observation result.As the result is shown: Sorafenib Tosylate independent medication group and Sorafenib Tosylate and
Each organ of GSK2656157 combination group mouse has different degrees of lesion.
Each internal organs of taking-up are removed into the remained blood and connective tissue of organ surface with brine, are used
Blotting paper is dried, correct amount, is calculated organ index (organ index=organ weights body/weight * 100%), be the results are shown in Table 2.
From table 2 it can be seen that compared with blank control group, Sorafenib Tosylate independent medication group mice organs index
There is significant difference；Sorafenib Tosylate and GSK2656157 combination group mice organs index differential be not significant.
2 each group mice organs index (N=6) of table
Note: compared with A group,*P < 0.05,**P < 0.01.
Organ index can the approximate physical signs for reflecting the internal organs, the disease of reflection animal total nutritional status and internal organs
Become situation.Organ coefficient shows there is the variation such as congestion and edema hypertrophy when increasing, organ coefficient shows that internal organs may when reducing
There is the variation such as atrophy degeneration.The present invention judges whether Viscera in Mice occurs lesion according to organ index.
Serum total cholesterol, triglycerides be reflect organism in blood lipid level important indicator, serum glutamic pyruvic transminase,
Glutamic-oxalacetic transaminease is the index that predominantly detects of liver function, and urea nitrogen and creatinine are that renal function predominantly detects index.The present invention
The side effect that Sorafenib and GSL2656157 combination drug are investigated by the Serum Indexes of mouse, the results are shown in Table 3.
As shown in Table 3, the Biochemical Indices In Serum of Sorafenib Tosylate independent medication group has significantly compared with the control group
Property ground difference, and difference is not compared with the control group for Sorafenib Tosylate and the Serum Indexes of GSK2656157 combination group mouse
Significantly, it influences to be significantly less than Sorafenib Tosylate independent medication group.
The Biochemical Indices In Serum (N=6) of 3 each group mouse of table
Note: compared with A group,*P < 0.05,**P < 0.01.
Claims (5)
1. the pharmaceutical composition containing Sorafenib and GSK2656157, which is characterized in that described pharmaceutical composition includes effective quantity
Sorafenib Tosylate and a effective amount of GSK2656157, in described pharmaceutical composition Sorafenib Tosylate and
The molar concentration rate of GSK2656157 is 10: 5, and described pharmaceutical composition is intended for treatment lung cancer, the cancer of the esophagus or liver cancer.
2. pharmaceutical composition as described in claim 1, which is characterized in that described pharmaceutical composition is made into ejection preparation or mouth
Formulation.
3. pharmaceutical composition as claimed in claim 2, which is characterized in that described pharmaceutical composition is made into oral preparation.
4. purposes of the pharmaceutical composition in preparation tumor as described in claims 1 to 3 is any, the tumour are
Lung cancer, the cancer of the esophagus or liver cancer.
5. purposes as claimed in claim 4, which is characterized in that the tumour is the cancer of the esophagus.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102917588A (en) * | 2010-03-25 | 2013-02-06 | 葛兰素史密斯克莱有限责任公司 | Chemical compounds |
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2017
- 2017-03-02 CN CN201710121670.2A patent/CN106974910B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102917588A (en) * | 2010-03-25 | 2013-02-06 | 葛兰素史密斯克莱有限责任公司 | Chemical compounds |
Non-Patent Citations (3)
| Title |
|---|
| Bufalin enhances the anti-proliferative effect of sorafenib on human hepatocellular carcinoma cells through downregulation of ERK;Yang Gao等;《Mol Biol Rep》;20110527;第39卷;第1683-1689页 * |
| Expression of pERK and VEGFR-2 in advanced hepatocellular carcinoma and resistance to sorafenib treatment;Francesca V. Negri等;《Liver International》;20151231;第35卷;第2001-2008页 * |
| 索拉非尼联合顺铂对胃癌SGC7901细胞的抑制作用;孙艺 等;《现代生物医学进展》;20130331;第13卷(第10期);第1807-1810页，第1823页 * |
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