CN106138061A - Prevention or weaken the complex of pulmonary fibrosis and preparation thereof and purposes - Google Patents
Prevention or weaken the complex of pulmonary fibrosis and preparation thereof and purposes Download PDFInfo
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Abstract
The present invention relates to complex of a kind of biguanides and EGFR-TKI or ALK-TKI and application thereof, this complex can be used for preventing or slowing down interstitial pneumonia, the interstitial pneumonia that particularly EGFR-TKI or ALK-TKI produces when treating nonsmall-cell lung cancer, it can avoid the complication that EGFR-TKI or ALK-TKI produces when treating nonsmall-cell lung cancer, it is effectively improved the therapeutic effect of EGFR-TKI or ALK-TKI, reduces generation and the development of complication for patients.
Description
Technical field
The invention belongs to field of medical application, particularly to preventing or weakening the compound of pulmonary fibrosis
Thing and preparation thereof and purposes.
Background technology
Pulmonary carcinoma is the malignant tumor that M & M is the highest in global range;Non-small cell lung
Cancer (Non Small Cell Lung Cancer, NSCLC) accounts for the 80%~85% of all cases of lung cancer.
EGF-R ELISA (Epidermal growth factor receptor, EGFR) and
Anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase (anaplasticlymphoma kinase, ALK) is NSCLC's
Occur evolution plays an important role.EGFR tyrosine kinase inhibitor (Tyrosine
Kinase inhibitor, TKI) and targeted drug that ALK-TKI is representative to specific NSCLC
Patient achieves significant curative effect, but occurs serious complication in TKI therapeutic process--
Matter pneumonia;Although its sickness rate is low, but once occur often patient to be produced detrimental effects.
Gefitinib (gefitnib, Iressa) is the EGFR-TKI of representative, is at present by many
State ratifies and is widely used in progress or the little molecular targeted agents of intractable NSCLC, has height
Selectivity and hypotoxic advantage, in nearly late result and the quality of life of improving advanced NSCLC
In effect demonstrate encouraging prospects.III recent phase clinical study results shows, right
The NSCLC patient of EGFR sudden change, a line uses targeted drug Erlotinib, routinizes with a line
Treatment is compared, and can improve the Progression free survival time of nearly 3 times.
Interstitial pneumonia is gefitinib and the rare but fatal untoward reaction of Erlotinib.Japan
Scholar Okamoto et al reports the first and causes serious interstitial pneumonia because taking gefitinib
And the case of death.Dyspnea i.e. occurs, although giving heavy dose of class after patient medication 8d
Steroid hormone is treated, but still dead after being administered 13d.The research of U.S. FDA finds, in U.S.
State uses the incidence rate of patient's interstitial lung disease of gefitinib to be 1%, the most about 1/3 patient
Die from interstitial pneumonia.Prevention interstitial pneumonia caused by EGFR-TKIs is to improve such patient
The key of prognosis.17-hydroxy-11-dehydrocorticosterone is one for the treatment of most important measure of this kind of interstitial pneumonia, but
Curative effect is unsatisfactory and side effect is bigger.Therefore, if a kind of new, effective measures can be found
The generation of prevention interstitial pneumonia, then for strengthening the safety of TKI, improving patient's prognosis all
To there is important scientific meaning and clinical value.
Showing after deliberation, pulmonary fibrosis is the pathological change that interstitial pneumonia is most basic, its morbidity
Mechanism mainly includes fibroblastic gathering and extracellular matrix excess deposition etc..The most clinical
Upper majority is the generation by preventing or weaken pulmonary fibrosis, prevents the generation of interstitial pneumonia.
Metformin is a kind of classical medicine treating diabetes, economic security, better tolerance,
Owing to its blood sugar lowering mechanism is the picked-up of suppression gastrointestinal tract glucose, increase surrounding tissue to islets of langerhans
The sensitivity of element, suppresses the gluconeogenesis that liver, kidney are excessive, therefore to normal person without hypoglycemic activity;
Along with going deep into of research, prior art discloses many metformin and become answering of subassembly with other
Compound;Such as, CN103271907 discloses a kind for the treatment of being made up of berberine and metformin
The compositions of diabetes;CN103860532 discloses and a kind of is made up of memantine and metformin
For treating the compositions of dementia of the Alzheimer type disease;Additionally, now technology also disclose by
Metformin and meglitinides or the compound formed with DPP-4 inhibitor etc..But
It is that prior art yet there are no about the biguanides based on metformin and gefitinib etc.
EGFR-TKI or ALK-TKI combination is used for preventing or weakening pulmonary fibrosis thus for treating interstitial
The report of property pneumonia.
Summary of the invention
The invention provides a kind of for preventing or weakening by EGFR-TKI or ALK-TKI treatment non-
The complex of the pulmonary fibrosis produced during small cell lung cancer and preparation thereof.
The present invention provides a kind of complex preventing or weaken pulmonary fibrosis, wherein, this complex
Including the biguanides that parts by weight are 2-4 part and the TKI of 2-5 part;Described TKI is selected from
EGFR-TKI or ALK-TKI.
Further improving, biguanides is selected from metformin and salt, phenformin or chlorine
Guanidine;Described EGFR-TKI selected from gefitinib, Erlotinib, Conmana, Afatinib,
AZD9291, CO-1686 or HM61713;For Buddhist nun or color is auspicious replaces selected from gram azoles for described ALK-TKI
Buddhist nun.
When biguanides is metformin, and EGFR-TKI is gefitinib, and, diformazan is double
The parts by weight of guanidine are 3 parts, when the parts by weight of gefitinib are 2 parts, to pulmonary fibrosis
Weaken effect the most obvious.
Another aspect of the present invention provides the oral formulations being made up of complex and adjuvant, is preferably
Tablet.
This tablet is the bilayer tablet being made up of the release layer of label and parcel label, described label
It is made up with excipient of metformin;Described release layer is made up of gefitinib and adjuvant.
Preferably, adjuvant is Powderd cellulose, beta-schardinger dextrin-, arabic gum, polyvinylpolypyrrolidone
And micropowder silica gel;Excipient be lactose, polyethylene maleic anhydride, ethylene glycol monostearate,
Polyvinylpolypyrrolidone and myristyl alcohol;The weight portion of described bilayer tablet is as follows:
Label:
Release layer:
After the present invention is by making bilayer tablet by complex, after making the entrance of this tablet internal,
Gefitinib first plays a role, and afterwards, metformin slowly plays a role, and both play and i.e. control
Treat the effect of nonsmall-cell lung cancer, the generation of pulmonary fibrosis can also be prevented or weaken simultaneously.Will
After gefitinib mixes with Powderd cellulose and beta-schardinger dextrin-, it is possible to decrease gefitinib medicine is at water
Precipitation in solution, improves the bioavailability of gefitinib;Simultaneously by metformin and slow release
After material polyethylene maleic anhydride and ethylene glycol monostearate make slow release label, label is made to exist
1, the cumulative defaultlogic of 2,6,12 and 24 hours respectively reach 30-32%, 65-67%,
80-82%, 85-88% and more than 90%, release is steady, the effect of slow release to make this double-layer tablet have
Really, and 24h release can be reached obtain purpose.
Another aspect of the present invention provides the purposes of this complex, and it is in preparation prevention or weakens lung
Application in Fibrotic medicine.The most described pulmonary fibrosis be by EGFR-TKI or
ALK-TKI produces when treating nonsmall-cell lung cancer.
The complex that the present invention provides can be additionally used in preparation prevention or slows down the medicine of interstitial pneumonia
Thing, described interstitial pneumonia is produced when being and treated nonsmall-cell lung cancer by EGFR-TKI or ALK-TKI
Raw complication.
Another aspect of the present invention additionally provides the application of tablet, this tablet can be used for preparation prevention or
Weaken the medicine of pulmonary fibrosis.Preferably, pulmonary fibrosis is to be controlled by EGFR-TKI or ALK-TKI
Produce when treating nonsmall-cell lung cancer.
The beneficial effects of the present invention is, the present invention provides answering of a kind of biguanides and TKI
Compound and application thereof, this complex can be used for preventing or weakening pulmonary fibrosis, particularly EGFR-TKI
Or the pulmonary fibrosis that ALK-TKI produces when treating nonsmall-cell lung cancer, thus play prevention or subtract
The generation of weak interstitial pneumonia, it can avoid EGFR-TKI or ALK-TKI to treat non-small cell lung
The complication produced during cancer, is effectively improved the therapeutic effect of EGFR-TKI or ALK-TKI, subtracts
The generation of few complication for patients and development.
Accompanying drawing explanation
Fig. 1 is the result that immunofluorescence technique detection fibers index α-actin expresses;
Fig. 2 is the table of western blot technology for detection Fibrosis Markers α-actin and COL1A1
Reach, the result of the expression of detection TGF-β downstream key signal pathway protein;
Fig. 3 is HE dyeing and the result of Masson dyeing;
Fig. 4 is the result of Elisa method detection hydroxyproline content;
Fig. 5 is the result that SABC detection α-actin expresses;
Fig. 6 is western blot detection COL1A1, α-actin and TGF-β downstream key signal
The result of the expression of pathway protein.
Specific embodiment mode
1 one kinds of complex prevented or weaken pulmonary fibrosis of embodiment
This complex includes metformin and the gefitinib of 2 weight portions of 3 weight portions.
2 one kinds of bilayer tablets of embodiment
Label:
Release layer:
3 one kinds of bilayer tablets of embodiment
Label:
Release layer:
Zoopery
Experimental example 1 metformin is obviously reduced gefitinib stimulates the research of the pulmonary fibrosis caused
1.1 experimental technique
Lung fibroblast strain HFL-1 is divided into 6 groups, respectively matched group, P9-CM group,
P9-CM+ gefitinib group, P9-CM+ gefitinib+metformin group, R9-CM group, R9-CM+
Metformin group;
Matched group is without special handling;P9-CM group gives at the conditioned medium of PC-9 cell
Reason cell 48h;PC-9+ gefitinib group gives the PC-9 processed from gefitinib 30 μMs
The conditioned medium of cell processes cell 48h;PC-9+ gefitinib+metformin group give from
At the conditioned medium associating metformin 20 μMs of the PC-9 cell that gefitinib 30 μMs processes
Reason cell 48h;R9-CM group gives to process cell 48h from the conditioned medium of PC-9GR cell;
R9-CM+ metformin group gives to combine metformin from the conditioned medium of PC-9GR cell
20 μMs process cell 48h;
After 48h, use the expression of immunofluorescence technique detection fibers index α-actin;Adopt
With western blot technology for detection Fibrosis Markers α-actin, COL1A1 and TGF-β
The expression of downstream key signal pathway protein.
2.2 experimental result
From figure 1 it appears that compared with matched group, through P9-CM group, R9-CM group and
After the HFL-1 cell 48h that P9-CM+ gefitinib group processes, the expression of α-actin albumen is bright
Aobvious increase;Compare with P9-CM group, through the HFL-1 cell that P9-CM+ gefitinib group processes
After 48h, the expression of α-actin albumen the most substantially increases, it follows that, gefitinib is not only
The content of pulmonary fibrosis mark α-actin albumen can be significantly improved, and can be further
Improve the content of the HFL-1 intracellular α-actin albumen after P9-CM group processes;With
P9-CM+ gefitinib group compares, after P9-CM+ gefitinib+metformin group processes
HFL-1 cell, the expression of α-actin albumen significantly reduces;Compare with R9-CM group, pass through
HFL-1 cell after the process of R9-CM+ metformin group, the expression of α-actin albumen is significantly dropped
Low;It follows that the condition that metformin not only can be obviously reduced from PC-9 cell strain is trained
The pulmonary fibrosis mark that foster base and the conditioned medium from PC-9GR cell strain cause
The expression of α-actin albumen;And gefitinib can be obviously reduced and sting the pulmonary fibrosis caused
The expression of mark α-actin albumen.
From figure 2 it can be seen that compared with matched group, non-through R9-CM group and P9-CM+ Ji
For Buddhist nun's group process HFL-1 cell 48h after, COL1A1, α-actin, pSmad2, pSmad3,
The expression of pSTAT3, pAKT and dpERK1/2 albumen substantially increases;Compare with P9-CM group, warp
After crossing the HFL-1 cell 48h that P9-CM+ gefitinib group processes, COL1A1, α-actin,
The expression of pSmad2, pSmad3, pSTAT3, pAKT and dpERK1/2 albumen substantially increases;With
P9-CM+ gefitinib group compares, after P9-CM+ gefitinib+metformin group processes
In HFL-1 cell, COL1A1, α-actin, pSmad2, pSmad3, pSTAT3, pAKT
Expression with dpERK1/2 albumen substantially reduces;Compare with R9-CM group, through R9-CM+ diformazan
Biguanide group process after HFL-1 cell in, COL1A1, α-actin, pSmad2, pSmad3,
The expression of pSTAT3, pAKT and dpERK1/2 albumen substantially reduces;It follows that metformin
Can be obviously reduced gefitinib and lung that the conditioned medium from PC-9GR cell strain causes is fine
Dimensionization mark α-actin and the expression of COL1A1 albumen, significantly inhibit TGF-β signal and lead to
The expression of key downstream, road albumen, significantly inhibits the key mechanism of pulmonary fibrosis.
1.3 conclusion
From showing that metformin can be obviously reduced the lung fiber that gefitinib causes above
Change.
Experimental example 2 metformin is obviously reduced the pulmonary fibrosis that the bleomycin that gefitinib increases the weight of causes
Research
2.1 experiment material
6 week old health male SD rats 75 are (dynamic purchased from the experiment of great Ping hospital of Third Military Medical University
Thing center), body weight 200g-210g;
Gefitinib, purchased from Tocris Bioscience company of Britain;
Metformin, purchased from sigma company of the U.S.;
HE and Masson staining kit, is stepped Newbiotics Inc by Foochow and produces;
Enzyme-linked Immunosorbent Assay (enzyme linked immunosorbent assay, ELISA) tries
Agent box, is produced by Wuhan You Ersheng company.
The preparation of 2.2 animal models and packet
After 75 SD rat adaptabilities are fed one week, it is divided into by the method for table of random number
Matched group, bleomycin group, metformin group, gefitinib group and gefitinib metformin
Combination group, often organizes each 15;
By 75 SD rats respectively with after 1% pentobarbital sodium intraperitoneal injection of anesthesia, lie on the back fixing
On Mus plate, ethanol disinfection after cervical region unhairing, longitudinal incision throat skin, sudden and violent after chorista
Leak pipe;
Wherein, matched group injects physiological saline solution 200 μ l, and remaining each group is injected to tracheal strips
Bleomycin (5mg/kg, 5g/L), rapidly that animal is upright after injection, rotate, make medicinal liquid
It is evenly distributed in lung;
Each experimental group rat started also to need continuous gavage 21 days in intratracheal injection the same day, wherein,
Matched group and bleomycin group give normal saline 2ml gavage, and gefitinib group gives Ji Fei and replaces
Buddhist nun's 200mg/kg gavage;Metformin group gives metformin 300mg/kg gavage;Ji Fei replaces
Buddhist nun's co-administrated metformin group gives gefitinib 200mg/kg associating metformin 300mg/kg and fills
Stomach;After intratracheal injection the 21st day, kill Mus and take lung;
2.3 observation index
The dyeing of left pneumolith wax slice row HE and Masson dyeing;SABC detection α-actin
Expression;Take right lung Elisa method detection hydroxyproline content;Western blot detects
COL1A1, α-actin and the expression of TGF-β downstream key signal pathway protein.
2.4 experimental result
From figure 3, it can be seen that after HE staining, compared with matched group, through rich next mould
After element group and gefitinib group process the lung of mice, lung septal thickening, pulmonary interstitial edema and fiber
Change capillary injection amount all to dramatically increase;Compare with bleomycin group, through gefitinib group
After processing the lung of mice, lung septal thickening, pulmonary interstitial edema and fibrosis capillary injection amount
Also dramatically increase;Compare with bleomycin group, after the lung that metformin group processes mice,
Lung septal thickening, pulmonary interstitial edema and fibrosis capillary injection amount all significantly reduce;With Ji
Non-compare for Buddhist nun's group, after the lung that gefitinib co-administrated metformin group processes mice, between lung
Every thickening, pulmonary interstitial edema and fibrosis capillary injection amount all significantly reduce;It follows that
Metformin can significantly reduce lung septal thickening, pulmonary interstitial edema and fibrosis capillary injection,
It is obviously reduced lung injury degree;Can draw through masson dyeing, compared with matched group, warp
After crossing the lung of bleomycin group and gefitinib group process mice, lung fibrosis degree increases the weight of;
Compare with bleomycin group, after the lung that gefitinib group processes mice, lung fibrosis
Degree also increases the weight of;Compare with bleomycin group, after the lung that metformin group processes mice,
Lung fibrosis degree substantially weakens;Compare with gefitinib group, through gefitinib diformazan
After biguanide combination group processes the lung of mice, lung fibrosis degree substantially weakens;It follows that
Metformin has been obviously reduced the fibrosis of lung tissue.
Figure 4, it is seen that compare with matched group, through bleomycin group and gefitinib
After group processes the lung of mice, the content of hydroxyproline dramatically increases;Compare with bleomycin group,
After the lung that gefitinib group processes mice, the content of hydroxyproline also dramatically increases;With rich
Bleomycin group compares, and after the lung that metformin group processes mice, the content of hydroxyproline shows
Write and reduce;Compare with gefitinib group, process mice through gefitinib co-administrated metformin group
Lung after, the content of hydroxyproline significantly reduces;It follows that metformin can significantly reduce
The content of hydroxyproline, is obviously reduced tissue collagen deposition.
From figure 5 it can be seen that compared with matched group, process mice through bleomycin group
After lung, the expression of α-actin albumen substantially increases;Compared with bleomycin group, non-through Ji
Organize the lung of process mice for Buddhist nun after, the expression of α-actin albumen the most substantially increases, it follows that,
Gefitinib can increase the weight of the table of the pulmonary fibrosis mark α-actin albumen that bleomycin causes
Reach;Compare with bleomycin group, after the lung that metformin group processes mice, α-actin
The expression of albumen substantially reduces;Compare with gefitinib group, join through gefitinib metformin
Process the lung of mice by group after, the expression of α-actin albumen significantly reduces;It follows that two
First biguanide not only can be obviously reduced the pulmonary fibrosis mark α-actin egg that bleomycin causes
White expression;And the lung fiber that the bleomycin that gefitinib increases the weight of causes can be obviously reduced
Change the expression of mark α-actin albumen.
From fig. 6 it can be seen that compared with matched group, through bleomycin group and gefitinib
Group process mice lung after, COL1A1, α-actin, pSmad2, pSTAT3, pAKT and
The expression of dpERK1/2 albumen substantially increases;Compare with bleomycin group, through gefitinib group
After processing the lung of mice, COL1A1, α-actin, pSmad2, pSmad3, pSTAT3 and pAKT
The expression of albumen substantially increases;Compared with bleomycin group, process mice through metformin group
Lung after, COL1A1, α-actin, pSmad2, pSTAT3, pAKT and dpERK1/2 albumen
Expression substantially reduce;Compared with gefitinib group, through gefitinib co-administrated metformin group
After processing the lung of mice, COL1A1, α-actin, pSmad2, pSTAT3, pAKT and dpERK1/2
The expression of albumen substantially reduces;Cause it follows that metformin can be obviously reduced bleomycin
Pulmonary fibrosis mark α-actin and the expression of COL1A1 albumen;And can significantly subtract
The pulmonary fibrosis mark α-actin that the bleomycin that weak gefitinib increases the weight of causes and
The expression of COL1A1 albumen;And significantly inhibit the table of TGF-β signal path key downstream albumen
Reach, significantly inhibit the key mechanism of pulmonary fibrosis.
2.5 conclusion
From showing that metformin can be obviously reduced the lung fiber that bleomycin causes above
Change;And it is obviously reduced the pulmonary fibrosis that the bleomycin that gefitinib increases the weight of causes.
Claims (9)
1. the complex prevented or weaken pulmonary fibrosis, it is characterised in that described complex includes
Parts by weight are biguanides and the TKI of 2-5 part of 2-4 part;Described TKI is selected from
EGFR-TKI or ALK-TKI.
2. complex as claimed in claim 1, it is characterised in that described biguanides is selected from two
First biguanide and salt, phenformin or proguanil;Described EGFR-TKI is selected from gefitinib, strategic point
Buddhist nun, Conmana, Afatinib, AZD9291, CO-1686 or HM61713 are replaced in Lip river;Institute
State ALK-TKI selected from gram azoles for Buddhist nun or Ceritinib.
3. complex as claimed in claim 2, it is characterised in that described biguanides is diformazan
Biguanide, described EGFR-TKI is gefitinib, and the parts by weight of described metformin are 3
Part, the parts by weight of described gefitinib are 2 parts.
4. contain the complex described in claim 3 and tablet that adjuvant is made, it is characterised in that institute
Stating tablet is by label and the bilayer tablet that forms of release layer of parcel label, described label by
Metformin is made with excipient;Described release layer is made up of gefitinib and adjuvant.
5. the application of the complex as described in claim 1-3 is arbitrary, it is characterised in that described compound
Thing prevents in preparation or weakens the application in the medicine of pulmonary fibrosis.
Apply the most as claimed in claim 5, it is characterised in that described pulmonary fibrosis is by EGFR-TKI
Or produce during ALK-TKI treatment nonsmall-cell lung cancer.
7. the application of the complex as described in claim 1-3 is arbitrary, it is characterised in that described compound
Thing prevents in preparation or slows down the application in the medicine of interstitial pneumonia, described interstitial pneumonia
The complication produced when being and treated nonsmall-cell lung cancer by EGFR-TKI or ALK-TKI.
8. the application of tablet as claimed in claim 4, it is characterised in that described tablet is pre-in preparation
Anti-or weaken the application in the medicine of pulmonary fibrosis.
Apply the most as claimed in claim 8, it is characterised in that described pulmonary fibrosis is by EGFR-TKI
Or produce during ALK-TKI treatment nonsmall-cell lung cancer.
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CN113143925A (en) * | 2021-04-16 | 2021-07-23 | 浙江大学智能创新药物研究院 | Application of metformin hydrochloride in preparation of preparation for treating crizotinib cardiotoxicity |
CN113143925B (en) * | 2021-04-16 | 2022-03-25 | 浙江大学智能创新药物研究院 | Application of metformin hydrochloride in preparation of preparation for treating crizotinib cardiotoxicity |
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