CN106974910A - Pharmaceutical composition and purposes containing Sorafenib and GSK2656157 - Google Patents
Pharmaceutical composition and purposes containing Sorafenib and GSK2656157 Download PDFInfo
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- CN106974910A CN106974910A CN201710121670.2A CN201710121670A CN106974910A CN 106974910 A CN106974910 A CN 106974910A CN 201710121670 A CN201710121670 A CN 201710121670A CN 106974910 A CN106974910 A CN 106974910A
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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
- A61K31/33—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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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract
The invention belongs to biomedicine field, and in particular to the application of pharmaceutical composition and pharmaceutical composition of the present invention containing Sorafenib and GSK2656157 in the treatment cancer of the esophagus, lung cancer and liver cancer is prepared.The pharmaceutical composition of Sorafenib and GSK2656157 of the present invention can effectively improve the side-effect problem of Sorafenib, improve the bioavilability of medicine, simultaneously, Sorafenib Tosylate and combining for GSK2656157 can make the effect of drug effect generation Synergistic in treatment lung cancer, liver cancer and the cancer of the esophagus, hence it is evident that be used better than single medicine.
Description
Technical field
The invention belongs to biomedicine field, and in particular to the drug regimen containing Sorafenib and GSK2656157 inhibitor
Thing and purposes.
Background technology
World Health Organization's survey report shows that global cancer condition is increasingly serious, 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 because of cancer
Ten thousand.With the improvement of living standards, the change of dietary structure, the incidence of disease of the cancer of the esophagus is in ascendant trend year by year；Wherein primary
Liver cancer, to occur the canceration in liver cell and intrahepatic biliary epithelium cell, is one of most common malignant tumour of the mankind；Lung cancer is
Common malignant tumour, comes 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 first, in being a lot
In late period, the chance of surgery excision is lost, therefore non-operative treatment (such as chemotherapy) has particularly significant in the complex treatment of tumour
Status.Chemotherapy is using the propagation of chemicals prevention cancer cell, infiltration, transfer, until final one kind for killing cancer cell
Therapeutic modality.It is a kind of systemic treatment means, and operation, radiotherapy are together, and referred to as 3 big treatment means of cancer.
The antineoplastic that has listed is more at present, such as alkylating agent medicine, antimetabolite, antitumor antibiotics, immune
Conditioning agent etc., but big drug generally existing is selectively low, toxicity is larger, the shortcomings of patient does not tolerate.With to tumour
The Study on Molecular Mechanism developed is more and more clearer, and molecular targeted therapy Several Kinds of Malignancy is of great interest and height
Degree is paid attention to.Molecular targeted agents selectivity is high, wide spectrum is effective, and its security is better than cytotoxic chemotherapy agents, is current tumour
The new direction of therapy field development.
Sorafenib (Sorafenib) is targeted drug more than one, and it is believed by suppressing the cell of RAF/MEK/ERK mediations
Number conduction path and the propagation for directly suppressing tumour cell, tumor neogenetic blood vessels are blocked further through EGFR and PDGFR is acted on
Formation, suppress tumour growth indirectly.The medicine has obvious inhibitory action to the Several Kinds of Malignancy including liver cancer,
But the control line for phase that tumour can only get nowhere is in 6 months, and it is larger to human toxicity, and skin is easily caused after taking
Rash, blood pressure rise, palm or foot bottom is rubescent, pain, swelling or the ill symptomses such as blister occur.How rope drawing is further improved
Relatively low toxic side effect is kept while non-Buddhist nun's antitumor activity, is also undoubtedly asking for current clinical test solution for study
Topic.
Current example by Sorafenib and other drugs combination in vivo with extracorporeal anti-tumor.Such as Chinese patent Shen
Please CN102438608A disclose combination between anti-angiogenic medicine AVE8062 and Sorafenib, and confirm that the combination can be effective
Treating cancer, particularly solid tumor, especially have inhibition to sarcoma, lung cancer, oophoroma, liver cancer or kidney.It is Chinese special
Profit 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.
Increasing evidence shows that the drug susceptibility of er stress and tumour cell is closely related, and PERK/
EIF2 α paths are the important sensing pathway in er stress downstream.GSK2606414 be it is a kind of orally have bioactivity, have
Effect, selectivity PERK inhibitor, other eIF2AKs selectivity than test are at least high 100 times.
At present, have no and reported associated with GSK2606414 and Sorafenib.
The content of the invention
In order to solve technical problem present in prior art, it is an object of the invention to provide one kind containing Sorafenib and
GSK2656157 pharmaceutical composition, improves inhibition of the Sorafenib to tumour, and effectively improve Sorafenib
Toxic side effect.
The invention provides a kind of pharmaceutical composition containing Sorafenib and GSK2656157, described pharmaceutical composition is included
The Sorafenib Tosylate of effective dose and the GSK2656157 of effective dose.
Described first Sorafenib Tosylate, No. CAS is 475207-59-1, the GSK2656157, and No. CAS is
1337532-29-2, its structural formula is as follows：
As the optimal embodiment of the present invention, Sorafenib Tosylate and GSK2656157 in described pharmaceutical composition
Molar concentration rate be 5~40: 1~10, it is preferable that Sorafenib Tosylate and GSK2656157 in described pharmaceutical composition
Molar concentration rate be 10: 5, its structural formula is as follows：
Preferably, heretofore described pharmaceutical composition according to this area routine techniques can be prepared into ejection preparation or mouth
Heretofore described pharmaceutical composition is preferably prepared into oral formulations by formulation, the present invention, and the oral formulations are 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 that preparation is used can be occurred using the conventional auxiliary material in this area with pharmaceutical composition of the present invention of getting along well
Reaction or premised on not influenceing the curative effect of medicine of the present invention；The preparation method of preparation can be using the conventional preparation method in this area
Prepared.
The dosage of pharmaceutical composition in the present invention according to the dosage form of administration object, method of administration or medicine not
It is same to carry out appropriate change, but to ensure that the pharmaceutical composition can reach effective blood concentration in mammalian body
Premised on.
Aforementioned pharmaceutical compositions can effectively treating cancer, particularly lung cancer, the cancer of the esophagus or liver cancer, be more particularly for treatment
The cancer of the esophagus.
Another object of the present invention is to provide use of the above-mentioned pharmaceutical composition in prevention and/or treatment tumour is prepared
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：
Pharmaceutical composition of the invention containing Sorafenib Tosylate and GSK2656157 effectively improves Sorafenib
Side-effect problem, improve the bioavilability of medicine, meanwhile, Sorafenib Tosylate and GSK2656157's combines
Drug effect can be made to produce the effect of Synergistic in treatment lung cancer, liver cancer and the cancer of the esophagus, hence it is evident that used better than single medicine, this point is at this
It is confirmed in invention antitumor action and result of the test.Especially, rubbing as Sorafenib Tosylate and GSK2656157
During your concentration ratio 10: 5, this synergy is very good, and medicine is minimum to the toxic side effect of normal cell.
Brief description of the drawings
Fig. 1 shows that the influence to growth of tumour cell is used alone with GSK2656157 for Sorafenib Tosylate；
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 is formed with GSK2656157 synergy to tumor cell clone
Ring.
Embodiment：
Below by way of the description of embodiment, the invention will be further described, but this is not the limit to the present invention
System, those skilled in the art are according to the basic thought of the present invention, and various modifications may be made or improves, but without departing from this
The basic thought of invention, 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 rubs
That concentration ratio 10: 5.
Composition 2：Sorafenib Tosylate and GSK2656157, Sorafenib Tosylate and GSK2656157's rubs
That concentration ratio 5: 1.
Composition 3：Sorafenib Tosylate and GSK2656157, Sorafenib Tosylate and GSK2656157's rubs
That concentration ratio 40: 10.
Embodiment 2, antitumor action and experiment
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, after after cell attachment (24h), by first
Benzene sulfonic acid Sorafenib is diluted to certain gradient concentration respectively with GSK2656157 medicines, and 5 multiple holes are set per concentration, point experimental group
And zeroing group dosing.Cell viability detection is carried out using mtt assay after 48h, 10 μ lMTT solution are added per hole, continues to cultivate 4h, it is small
The heart absorbs liquid in hole, it is to avoid crystal in contact hole, and 100 μ l DMSO is added per hole, is rocked in lucifuge on constant speed shaking table.Treat
After crystal fully dissolves, OD values (wavelength 570nm, reference wavelength 630nm) are read on ELIASA, absorbance A value is measured.Carefully
The calculation formula of born of the same parents' vigor (CellViability) is：Cell viability=OD experimental groups/OD control groups.According to the suppression of each concentration
Rate processed, which can map, obtains dose response block diagram, and mapping software is Graphpad.
It will be seen from figure 1 that Sorafenib Tosylate and GSK2656157 have certain growth suppression to tumour cell
Make and use, wherein Sorafenib Tosylate is in 10 μM of depositing to four plants of tumour cells Eca-109, EC9706, A549 and HepG2
Motility rate is respectively 31%, 48%, 45% and 74%, and GSK2656157 is respectively in 5 μM of survival rates to four plants of tumour cells
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 every 3000-6000 cell in hole
96 orifice plates, after after cell attachment, plus blank control group, Sorafenib Tosylate list medicine group, the mono- medicine groups of GSK2656157 and connection
Share after medicine group medicine (+5 μM of GSK2656157 of 10 μM of Sorafenib Tosylates), culture 48h, 10 μ l concentration are added per hole
For 5mg/ml MTT solution, continue to cultivate 4h, then discard the DMSO that nutrient solution adds 100 μ l per hole, kept away on constant speed shaking table
Light rocks.After thing to be crystallized fully dissolves, OD values (wavelength 570nm, reference wavelength 630nm) are read on ELIASA, are read every
The light absorption value in hole, calculates cell survival and inhibiting rate after two medicines are shared.
To the combination effect of tumour cell when evaluating two kinds of combination therapies using Jin Shi amendment types, concretely comprise the following steps,
According to the formula of growth inhibition ratio (%)=(1-OD experimental groups/OD control groups) × 100%, A medicines are calculated under certain conditions
Inhibiting rate to tumour cell is EA, and it is EB to calculate inhibiting rate of the B medicines under certain conditions to tumour cell, then calculates two
The inhibiting rate of person's administering drug combinations be EC, by below equation calculate drug combination index q values, q=EC/ (EB+EA-EB*EA), when
Q values>1.15 be cooperative effect, 0.85<q<1.15 be additive effect, q<0.85 is antagonistic effect.Referred to by above-mentioned drug combination
Several calculating determines whether the final drug effect of two kinds of combination therapies.Through calculating Sorafenib Tosylate with
GSK2656157 drug combinations are in Eca-109, EC9706, and the q values of A549 and HepG2 tumour cells are respectively 1.27,1.23,
1.16,1.18.Show that 10 μM of Sorafenib Tosylates and 5 μM of GS K2656157 are used in combination in tumour cell with very
Good synergy.
Research 3：Sorafenib Tosylate, cis-platinum, 5 FU 5 fluorouracil combine thin to the cancer of the esophagus with GSK2656157 respectively The influence (Fig. 2 B) of born of the same parents' propagation
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 groups, Sorafenib Tosylate+GSK2656157 groups, cis-platinum group, cis-platinum+
GSK2656157 groups, 5 FU 5 fluorouracil group, 5 FU 5 fluorouracil group+GSK2656157 groups.By calculating, 10 μM of toluenesulfonic acid ropes are drawn
Non- Buddhist nun is 1.27 with q value of 5 μM of GSK2656157 drug combinations in Eca-109；0.5 μ g/ml cis-platinums and 5 μM
Q value of the GSK2656157 drug combinations in Eca-109 is 0.85；2 μ g/ml 5 FU 5 fluorouracils and 5 μM of GSK2656157 join
It is 0.75 to share q value of the medicine in Eca-109.Show that Sorafenib Tosylate is suppressing esophageal cancer cell with GSK2656157
The effect that is used in combination in growth is better than cis-platinum, 5 FU 5 fluorouracil and GSK2656157 and is used in combination.
Research 4：Sorafenib Tosylate and GSK2656157 combine the influence (Fig. 3) to apoptosis of tumor cells
By Eca-109 cells respectively with every hole 2 × 105The density of individual cell is seeded to 6 orifice plates.After after cell attachment, press
The packet administration of research 2, is jointly processed by after 48h.Using Western blot methods detection through Sorafenib Tosylate with
GSK2656157 individually handle and Combined Treatment after the intracellular apoptotic proteins PARP of esophageal cancer cell Eca-109 expression feelings
Condition.Western blot methods are carried out according to research 2.
As a result as shown in figure 3, in Eca-109 cells, when with Sorafenib Tosylate and GSK2656157 individually and
During drug combination processing, apoptosis marker protein PARP shearing bar band is substantially raised, and joint group is compared with each single medicine group
Expression has obvious difference, and this explanation Sorafenib Tosylate can significantly cause oesophagus with GSK2656157 drug combinations
Apoptosis occurs for cancer cell.
Research 5：The influence (Fig. 4) of Sorafenib Tosylate and GSK2656157 combinations to tumor cell clone formation
Eca-109 and EC9706 cells are inoculated into 6 orifice plates, after cell attachment is stayed overnight, add blank control group, 10 μM
Sorafenib Tosylate, 5 μM of GSK2656157 and drug combination group medicine, are incubated 7 days, detect cell plates Clone formation
Situation.As a result as shown in figure 4, compared with control group and single medicine group, drug combination has obvious association to cell clonal formation
Same inhibitory action, drug combination group is not it is observed that obvious cell clone.
Embodiment 3, drug combination acute toxicity test
This experiment is using kunming mice as research object, research Sorafenib Tosylate and GSK2656157 composition of medicine pair
The influence of the acute toxicity of mouse, is that further research and development are carried for Sorafenib Tosylate and GSK2656157 pharmaceutical compositions
For preliminary secure estimate reference.
GB1519.3-2003 is pressed in acute toxicity test《Food acute toxicity test》Middle maximum tolerated dose method is tried
Test.18 cleaning small white mouses are taken, 3 groups are randomly divided into：Blank control group (A groups), Sorafenib Tosylate and GSK2656157
(molar concentration rate is 10: 5) combination group (B groups), Sorafenib Tosylate independent medication group (C groups), every group 6 (N=6),
Each 3 of male and female.Acute toxicity grading criteria in assessment, mouse fasting 10h before experiment, with 0.5ml/ only
Administration 2 times in gastric infusion, 24h, consumption per day is 15g/Kg, the physiological saline of blank control group mouse stomach same dose.Give
After medicine, observe whether dead in mouse 72h, and the changes of weight in following one week.All result of the tests are with " x ± s " tables
Show, with t method of inspection testing significance of differences, the results are shown in Table 1.
As known from Table 1, body weight of the mouse during feeding is ever-increasing, and Sorafenib Tosylate individually supplies medicine group
(C groups) has significant decline relative to blank control group (A groups) body weight, and Sorafenib Tosylate and GSK2656157 are combined
Group (B groups) is relative to blank control group (A groups) though body weight has declined, and 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 groups
La Feini and SK2656157 combinations can make Sorafenib Tosylate reduce the toxic side effect of human body.
The changes of weight situation (N=6) of mouse during the medication of table 1
Note：Compared with A groups,**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 a result show：Sorafenib Tosylate independent medication group and Sorafenib Tosylate and
Each organ of GSK2656157 combination group mouse has different degrees of lesion.
By each internal organs of taking-up, with brine, the remained blood and connective tissue of organ surface are removed, is used
Blotting paper is dried, correct amount, is calculated organ index (organ index=organ weights body/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 differentials be not notable.
The each group mice organs index (N=6) of table 2
Note：Compared with A groups,*P<0.05,**P ＜ 0.01.
Organ index can approximately reflect the disease of the physical signs of the internal organs, the total nutritional status of reflection animal and internal organs
Change situation.Organ coefficient shows there is the change such as congestion and edema hypertrophy when increasing, organ coefficient shows that internal organs may when reducing
There is the change 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 renal functions predominantly detects index.The present invention
The side effect of Sorafenib and GSL2656157 combination drugs is investigated by the Serum Indexes of mouse, 3 are the results are shown in Table.
As shown in Table 3, the Biochemical Indices In Serum of Sorafenib Tosylate independent medication group has significantly compared with control group
Property ground difference, and difference is not compared with control group for Sorafenib Tosylate and the Serum Indexes of GSK2656157 combination group mouse
Significantly, influence is significantly less than Sorafenib Tosylate independent medication group.
The Biochemical Indices In Serum (N=6) of each group mouse of table 3
Note：Compared with A groups,*P<0.05,**P ＜ 0.01.
Claims (9)
1. the pharmaceutical composition containing Sorafenib and GSK2656157, it is characterised in that described pharmaceutical composition includes effective dose
First Sorafenib Tosylate and effective dose GSK2656157.
2. pharmaceutical composition as claimed in claim 1, it is characterised in that Sorafenib Tosylate in described pharmaceutical composition
Molar concentration rate with GSK2656157 is 5~40: 1~10.
3. pharmaceutical composition as claimed in claim 2, it is characterised in that Sorafenib Tosylate in described pharmaceutical composition
Molar concentration rate with GSK2656157 is 10: 5.
4. the pharmaceutical composition as described in claims 1 to 3 is any, it is characterised in that described pharmaceutical composition is made into injection
Preparation or oral formulations.
5. pharmaceutical composition as claimed in claim 4, it is characterised in that described pharmaceutical composition is made into oral formulations.
6. pharmaceutical composition as claimed in claim 1, it is characterised in that described pharmaceutical composition be intended for treatment lung cancer,
The cancer of the esophagus or liver cancer.
7. purposes of the pharmaceutical composition in prevention and/or treatment tumour is prepared as described in claim 1~6 is any.
8. purposes as claimed in claim 7, it is characterised in that the tumour is lung cancer, the cancer of the esophagus or liver cancer.
9. purposes as claimed in claim 8, it is characterised in that the tumour is the cancer of the esophagus.
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| CN201710121670.2A CN106974910B (en) | 2017-03-02 | 2017-03-02 | Pharmaceutical composition and purposes containing Sorafenib and GSK2656157 |
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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 |
|---|
| FRANCESCA V. NEGRI等: "Expression of pERK and VEGFR-2 in advanced hepatocellular carcinoma and resistance to sorafenib treatment", 《LIVER INTERNATIONAL》 * |
| YANG GAO等: "Bufalin enhances the anti-proliferative effect of sorafenib on human hepatocellular carcinoma cells through downregulation of ERK", 《MOL BIOL REP》 * |
| 孙艺 等: "索拉非尼联合顺铂对胃癌SGC7901细胞的抑制作用", 《现代生物医学进展》 * |
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