CN105801476A - Crystal form II of Apatinib mesylate as well as preparation method and application of crystal form II - Google Patents
Crystal form II of Apatinib mesylate as well as preparation method and application of crystal form II Download PDFInfo
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- CN105801476A CN105801476A CN201610226830.5A CN201610226830A CN105801476A CN 105801476 A CN105801476 A CN 105801476A CN 201610226830 A CN201610226830 A CN 201610226830A CN 105801476 A CN105801476 A CN 105801476A
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- mesylate
- buddhist nun
- handkerchief
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a crystal form II of Apatinib mesylate. The crystal form II is characterized in that Cu-Kalpha 1 rays are adopted for radiation, X-ray powder diffraction represented by a 2theta angle has diffraction peaks when the 2theta angle is 5.02 degrees, 10.28 degrees, 11.13 degrees, 13.75 degrees, 15.65 degrees, 18.18 degrees, 20.35 degrees, 20.86 degrees, 21.58 degrees and 24.96 degrees, and an error range of a 2theta value is plus or minus 0.2. The crystal form II of Apatinib mesylate has the advantages of good stability, low hygroscopicity and high solubility.
Description
Technical field
The present invention relates to the molecular targeted antitumor drug nicotinamide derivant Ah handkerchief first sulphur for Buddhist nun
Hydrochlorate, is specifically related to Ah handkerchief for Buddhist nun's mesylate II crystal formation and its preparation method and application.
Background technology
Nicotinamide derivant Ah handkerchief replaces Buddhist nun (Apatinib), and molecular formula is C24H23N5O, changes
Formal name used at school is referred to as N-[4-(1-cyan cyclopentyl) phenyl]-2-(4-picolyl) amino-3-pyridinecarboxylic
Amine, is a kind of molecular targeted antitumor drug.It is as the typical little molecule blood vessel endothelium of one
Somatomedin tyrosine kinase inhibitor, can be used for treat advanced Non-small cell lung, gastric cancer,
The tumor disease such as hepatocarcinoma and breast carcinoma.
Chinese invention patent CN101676267 discloses above-mentioned nicotinamide derivant mesylate
(molecular formula C24H23N5O·CH4O3S, as shown in formula (I)) preparation method and application.
According to described in CN101676267 method obtain nicotinamide derivant mesylate (see
Description page 5 embodiment 0026,0027, hereinafter referred to as " Ah handkerchief replaces Buddhist nun's mesylate I crystal ")
For anhydride, it is needle-like solid, and it has hygroscopicity.Such as those skilled in the art institute
Knowing, particularly hygroscopic solid is difficult to make preparation under medicine processing conditions, and is easily converted to
, there is the potential risk that crystal formation is unstable in solvate.It addition, needle-like solid because of portable greatly
Amount electrostatic, thus seem very thickness, poor fluidity, cause the cost of production process to increase.
Accordingly, it would be desirable to have the crystalline substance of the nicotinamide derivant mesylate of superior physicochemical characteristics
Type so that it is be conducive to using in medicine processing and pharmaceutical composition.
Polymorphism refers to that solid matter exists two or more different spatial arrangements side
Formula, thus there is the phenomenon of the solid state of multiple different physicochemical properties, it is compound
Build-in attribute.There is two or more different crystal forms state of matter in effective ingredient, claims
For polymorph in pharmaceuticals.Due to arrangement architecture or model of action between same drug different crystal forms
Difference, its bioavailability is likely to exist difference, additionally its stability, mobility, can
Compressibility is likely to can difference.
Summary of the invention
Problem to be solved by this invention is the instability solving existing Ah handkerchief for Buddhist nun's mesylate
Property, strong hygroscopicity etc. be unfavorable for its problem used in medicine is processed.
In order to solve above-mentioned technical problem, the invention provides a kind of Ah handkerchief for Buddhist nun's mesylate
Novel crystal forms (hereinafter referred to as " Ah handkerchief replaces Buddhist nun's mesylate II crystal formation "), it is characterised in that use
Cu-Kα1X radiation x, the X-ray powder diffraction represented with 2 θ angles 5.02,10.28,11.13,
13.75, having diffraction maximum at 15.65,18.18,20.35,20.86,21.58,24.96, wherein 2 θ values are by mistake
Difference scope is ± 0.2.
Ah handkerchief according to the present invention replaces Buddhist nun's mesylate II crystal formation, has and Figure of description Fig. 1 base
XRPD collection of illustrative plates identical in basis.
Ah handkerchief according to the present invention for Buddhist nun's mesylate II crystal formation be anhydrous crystal forms, be respectively provided with
Substantially the same for Figure of description Fig. 2-6 DSC collection of illustrative plates, TGA collection of illustrative plates, infrared spectrum, draw
Graceful spectrum and dynamic water absorption collection of illustrative plates.
Present invention also offers and a kind of prepare Ah handkerchief for the method for Buddhist nun's mesylate II crystal formation, including with
Lower step:
Ah handkerchief is added organic solvent for Buddhist nun's mesylate with the ratio of 1:30 to 1:200g/mL
In, it is heated to the first temperature and stirs, filter, then at the second temperature solvent flashing, by institute
Obtain solid drying under reduced pressure thus obtain Ah handkerchief for Buddhist nun's mesylate A crystal formation crystal.
Present invention also offers the another kind of preparation Ah handkerchief method for Buddhist nun's mesylate II crystal formation, including
Following steps:
Ah handkerchief is added organic solvent for Buddhist nun's mesylate with the ratio of 1:30 to 1:200g/mL
In, it is heated to the first temperature and stirs, filters, being then slowly cooled to room temperature, again filter,
By gained solid drying under reduced pressure thus obtain Ah handkerchief for Buddhist nun's mesylate A crystal formation crystal.
In the Ah handkerchief's above-mentioned preparation method for Buddhist nun's mesylate II crystal formation, described organic solvent is
Alcohols solvent or a combination thereof, i.e. any one alcohols solvent or two or more alcohols solvent are to appoint
The mixed solvent of meaning ratio.
In the Ah handkerchief's above-mentioned preparation method for Buddhist nun's mesylate II crystal formation, described alcohols solvent bag
Include methanol, ethanol, isopropanol, normal propyl alcohol, isobutanol and n-butyl alcohol.
In the Ah handkerchief's above-mentioned preparation method for Buddhist nun's mesylate II crystal formation, described first temperature is
50 to 80 DEG C, preferably 60 to 80 DEG C, more preferably 65 to 75 DEG C, most preferably 70 DEG C.
In the Ah handkerchief's above-mentioned preparation method for Buddhist nun's mesylate II crystal formation, described second temperature is
40 to 70 DEG C, more preferably 45 to 60 DEG C, most preferably 50 DEG C.
In the Ah handkerchief's above-mentioned preparation method for Buddhist nun's mesylate II crystal formation, Ah handkerchief replaces Buddhist nun's methanesulfonic acid
Salt is preferably 1:50 to 1:150g/mL with the ratio of described organic solvent, more preferably 1:120
g/mL。
It should be understood that those of ordinary skill in the art can be according to its knowledge and experience, to this
The temperature used in bright method and the consumption of agents useful for same are adjusted, and these schemes adjusted are also
Comprise in the method for the invention.
Having the Ah handkerchief of the present invention for the compositions of Buddhist nun's mesylate II crystal formation is a kind of little molecule blood
Endothelial tube somatomedin tyrosine kinase inhibitor, it is possible to be used for treating advanced Non-small cell lung,
Gastric cancer, hepatocarcinoma and breast carcinoma and the disease such as any other type of entity or liquid tumors.
Therefore, present invention also offers above-mentioned Ah handkerchief for Buddhist nun's mesylate II crystal formation preparation for
Application in the medicine for the treatment of tumor.In some embodiments, described tumor include non-little carefully
Born of the same parents' pulmonary carcinoma, gastric cancer, hepatocarcinoma and breast carcinoma.
Present invention also offers pharmaceutical composition, it comprises the Ah handkerchief according to the present invention for Buddhist nun's first sulphur
Hydrochlorate II crystal formation and one or more pharmaceutically acceptable carriers, excipient or diluent.
Ah handkerchief according to the present invention is a kind of anhydrous crystal forms for Buddhist nun's mesylate II crystal formation, has excellent
Elegant stability, agent of low hygroscopicity and high-dissolvability, can answer in the medicine for the treatment of late tumor
With.
Accompanying drawing explanation
Fig. 1 replaces the XRPD collection of illustrative plates of Buddhist nun's mesylate II crystal formation for the Ah handkerchief that the present invention provides.
Fig. 2 replaces the DSC collection of illustrative plates of Buddhist nun's mesylate II crystal formation for the Ah handkerchief that the present invention provides.
Fig. 3 replaces the TGA collection of illustrative plates of Buddhist nun's mesylate II crystal formation for the Ah handkerchief that the present invention provides.
Fig. 4 replaces the infrared spectrum of Buddhist nun's mesylate II crystal formation for the Ah handkerchief that the present invention provides.
Fig. 5 replaces the Raman spectrum of Buddhist nun's mesylate II crystal formation for the Ah handkerchief that the present invention provides.
The Ah handkerchief that Fig. 6 provides for the present invention replaces Buddhist nun for Buddhist nun's mesylate II crystal formation with existing Ah handkerchief
The comparison of the dynamic water absorption collection of illustrative plates of mesylate I crystal.
Detailed description of the invention
Below according to embodiment, and combine accompanying drawing, describe the present invention in detail.Detailed from hereafter
In thin description, aforementioned aspect of the present invention and other aspects of the present invention will be apparent from.This
Bright scope is not limited to the following example.
Embodiment 1 to 6 Ah handkerchief is for the preparation of Buddhist nun's mesylate II crystal formation
Weighing 500mg Ah handkerchief replaces Buddhist nun's mesylate raw material in container, is separately added into molten according to table 1
Agent (analytical pure) and heating, keeps heating-up temperature to stir 2 hours.Filter, after filtering
Solution is maintained at volatilization temperature, makes solvent volatilize, obtains white solid.Then by gained solid
Drying under reduced pressure 12 hours, thus obtain Ah handkerchief for Buddhist nun's mesylate II crystal formation crystal.Weigh and calculate it
Yield, result illustrates in Table 1.
Table 1 Ah handkerchief is for the preparation of Buddhist nun's mesylate II crystal formation
Embodiment 7 to 12 Ah handkerchief is for the preparation of Buddhist nun's mesylate II crystal formation
Weighing 1.0g Ah handkerchief replaces Buddhist nun's mesylate raw material in container, is separately added into molten according to table 2
Agent (analytical pure) and heating, keeps heating-up temperature to stir 2 hours.Filter, after filtering
Solution be slowly cooled to room temperature, separate out white solid.The most again filter, by gained solid
Drying under reduced pressure 12 hours, thus obtain Ah handkerchief for Buddhist nun's mesylate II crystal formation crystal.Weigh and calculate
Its yield, result illustrates in table 2.
Table 2 Ah handkerchief is for the preparation of Buddhist nun's mesylate II crystal formation
Embodiment 13 characterizes Ah handkerchief for Buddhist nun's mesylate II crystal formation by XRPD
The measurement of X-ray powder diffraction (XRPD) collection of illustrative plates, uses Germany Brooker company D8
Advance X-ray diffractometer, at room temperature detects, and concrete collection information is as follows: ray
Source is Cu-K α1Ray, sweep limits (2 θ scope) from 3 ° to 40 °, scanning speed be 12 °/point
Clock, scanning step 0.02, slit width 0.01.Microscope slide is used directly to suppress sample at test board
Product process.Thereafter XRPD collection of illustrative plates all uses similar measuring method.
Measure according to the Ah handkerchief prepared by method described in embodiment 1 for Buddhist nun's mesylate II crystal formation
XRPD collection of illustrative plates, 2 θ be 5.02,10.28,11.13,13.75,15.65,18.18,20.35,
20.86, there is feature Cu-K α at 21.58,24.961Diffraction maximum, as shown in Figure 1.Wherein 2 θ value
Range of error is ± 0.2.After testing, 2 θ value range of error can also be ± 0.15.Come from this spectrogram
The concrete list at distinctive X-ray diffraction peak illustrate in table 3.
XRPD diffraction maximum list in table 3 Fig. 1
| Numbering | 2θ±0.2(°) |
| 1 | 5.02 |
| 2 | 10.28 |
| 3 | 11.13 |
| 4 | 13.75 |
| 5 | 15.65 |
| 6 | 18.18 |
| 7 | 20.35 |
| 8 | 20.86 |
| 9 | 21.58 |
| 10 | 24.96 |
Buddhist nun's mesylate II crystal formation is replaced according to Ah handkerchief prepared by method described in embodiment 2-12, its
XRPD collection of illustrative plates is essentially identical with collection of illustrative plates shown in accompanying drawing 1.
It will be understood by those skilled in the art that these diffraction maximums do not represent A Pa for Buddhist nun mesylate II
The detailed situation of diffraction maximum shown by crystal formation.2 θ values of X-ray powder diffraction figure are can be along with machine
Device and along with sample prepare in change and batch between change and slightly change, cited value
It is not intended as absolute value.It will also be appreciated that the relative intensity at peak may become with orientation effect,
Therefore the intensity shown in the XRPD trace contained by the present invention is exemplary, is not used to definitely
Relatively.
Embodiment 14 characterizes Ah handkerchief for Buddhist nun's mesylate II crystal formation by DSC-TGA
Use Q2000 and the Q500 thermal analyzer of TA company of the U.S. respectively, survey at standard conditions
Try according to the Ah handkerchief prepared by method described in embodiment 1 for Buddhist nun's mesylate II crystal formation DSC and
TGA collection of illustrative plates.DSC test condition is programming rate 10 DEG C/min, and temperature range 25 DEG C is to 210
℃.TGA test condition is programming rate 10 DEG C/min, temperature range 30 DEG C to 400 DEG C.?
DSC and the TGA collection of illustrative plates arrived is respectively as shown in accompanying drawing Fig. 2 and Fig. 3.Result shows, the present invention's
A Pa is anhydrous crystal forms for Buddhist nun's mesylate II crystal formation.Detection is according to method system described in embodiment 2-12
Standby Ah handkerchief replaces Buddhist nun's mesylate II crystal formation, obtains DSC collection of illustrative plates and TGA collection of illustrative plates and the above results base
This is identical.
Embodiment 15 replaces Buddhist nun's mesylate II crystal formation by infrared spectrum characterization Ah handkerchief
Use Nicolet-Magna FT-IR 750 infrared spectrometer of U.S. Buddhist nun usury company, in room
The lower detection of temperature replaces the red of Buddhist nun's mesylate II crystal formation according to the Ah handkerchief prepared by method described in embodiment 1
External spectrum, detection range is: 4000～350cm-1.Gained infrared spectrum is as shown in accompanying drawing Fig. 4.
Detect the Ah handkerchief prepared according to method described in embodiment 2-12 and replace Buddhist nun's mesylate II crystal formation, obtain
Infrared spectrum is essentially identical with collection of illustrative plates shown in accompanying drawing 4.
Embodiment 16 replaces Buddhist nun's mesylate II crystal formation by Raman Characterization Ah handkerchief
Use the DXR micro-Raman spectroscopy of power & light company of the U.S., at room temperature detect according to reality
Execute described in example 1 Raman spectrum for Buddhist nun's mesylate II crystal formation of the Ah handkerchief prepared by method, detect model
Enclosing (Raman shift) is: 3500～50cm-1.Gained Raman spectrum is as shown in figure 5 of the drawings.Inspection
Surveying the Ah handkerchief prepared according to method described in embodiment 2-12 and replace Buddhist nun's mesylate II crystal formation, obtain draws
Graceful spectrum is essentially identical with collection of illustrative plates shown in accompanying drawing 5.
Embodiment 17 replaces Buddhist nun's mesylate II crystal formation by dynamic water absorption representation Ah handkerchief
Use the dynamic water adsorption instrument (Intrinsic DVS) of SMS company of Britain, detect respectively
Ni Jia is replaced for Buddhist nun's mesylate II crystal formation and A Pa according to the Ah handkerchief prepared by method described in embodiment 1
The dynamic water absorption collection of illustrative plates of sulfonate I crystal.The dynamic water absorption collection of illustrative plates obtained is at accompanying drawing Fig. 6
Shown in.Detect the Ah handkerchief prepared according to method described in embodiment 2-12 brilliant for Buddhist nun mesylate II
Type, the dynamic water obtained absorption collection of illustrative plates is essentially identical with collection of illustrative plates shown in accompanying drawing 6.
The result of dynamic water absorption shows, the Ah handkerchief that the present invention provides is for Buddhist nun's mesylate II crystal formation
There is more preferable stability.Existing commercially available medicinal Ah handkerchief is easily subject to the external world for Buddhist nun's mesylate I crystal
Environmental effect, in the environment of relative humidity (RH) >=20%, the content that absorbs water is more than 3%.
And the Ah handkerchief of the present invention is respectively less than for Buddhist nun's mesylate II crystal formation hygroscopic capacity in bigger humidity range
0.2%, and long-time at ambient temperature place without turning a brilliant phenomenon, this be more beneficial for crude drug and
The preparation of pharmaceutical preparation and storage.
Embodiment 18 Ah handkerchief replaces Buddhist nun mesylate I for Buddhist nun's mesylate II crystal formation with existing Ah handkerchief
The dissolubility of crystal formation compares
At 25 DEG C, Ah handkerchief is replaced Buddhist nun's mesylate I crystal for Buddhist nun's mesylate II crystal formation with Ah handkerchief
It is completely dissolved in respectively in ultra-pure water.Use ultraviolet-visible spectrophotometer (Varian CARY
50), each solution concentration is tested with ultraviolet spectrophotometry, until concentration is not further added by, with this
Calculate the dissolubility of different crystal forms.Acquired results illustrates in table 4.
Table 4 Ah handkerchief compares with the dissolubility of I crystal for Buddhist nun's mesylate II crystal formation
| Crystal formation | Dissolubility (mg/mL) |
| II | 0.4849 |
| I | 0.1317 |
From dissolubility relatively, the Ah handkerchief of the present invention has ratio Ah handkerchief for Buddhist nun's mesylate II crystal formation
For Buddhist nun's higher dissolubility of mesylate I crystal.
Although those skilled in the art is it should be understood that for illustrative purposes, retouch herein
State the detailed description of the invention of the present invention, but it can be carried out various amendment without departing from this
Bright spirit and scope.Therefore, detailed description of the invention and the embodiment of the present invention is not to be construed as
Limit the scope of the present invention.The present invention is limited only by the appended claims.The application quotes
All documents be fully incorporated herein by reference.
Claims (10)
1. the Ah handkerchief of a formula (I) is for the II crystal formation of Buddhist nun's mesylate, it is characterised in that
Use Cu-K α1X radiation x, the X-ray powder diffraction represented with 2 θ angles 5.02,
10.28, have at 11.13,13.75,15.65,18.18,20.35,20.86,21.58,24.96
Diffraction maximum, wherein 2 θ value range of error are ± 0.2.
2. Ah handkerchief as claimed in claim 1 is for Buddhist nun's mesylate II crystal formation, it is characterised in that
It has the XRPD collection of illustrative plates substantially the same with Figure of description Fig. 1.
3. Ah handkerchief as claimed in claim 1 is for Buddhist nun's mesylate II crystal formation, it is characterised in that
Described A Pa is anhydrous crystal forms for Buddhist nun's mesylate II crystal formation, and is respectively provided with attached with description
Substantially the same for figure Fig. 2-6 DSC collection of illustrative plates, TGA collection of illustrative plates, infrared spectrum, Raman spectrum and
Dynamic water absorption collection of illustrative plates.
4. preparation Ah handkerchief as described in any one of claims 1 to 3 is brilliant for Buddhist nun mesylate II
The method of type, it is characterised in that comprise the following steps:
Ah handkerchief is added organic solvent for Buddhist nun's mesylate with the ratio of 1:30 to 1:200g/mL
In, it is heated to the first temperature and stirs, filter, then at the second temperature solvent flashing, by institute
Obtain solid drying under reduced pressure thus obtain Ah handkerchief for Buddhist nun's mesylate II crystal formation crystal.
5. preparation Ah handkerchief as described in any one of claims 1 to 3 is brilliant for Buddhist nun mesylate II
The method of type, it is characterised in that comprise the following steps:
Ah handkerchief is added organic solvent for Buddhist nun's mesylate with the ratio of 1:30 to 1:200g/mL
In, it is heated to the first temperature and stirs, filters, being then slowly cooled to room temperature, again filter,
By gained solid drying under reduced pressure thus obtain Ah handkerchief for Buddhist nun's mesylate II crystal formation crystal.
6. the method as described in claim 4 or 5, it is characterised in that described organic solvent is
Alcohols solvent or a combination thereof, described alcohols solvent include methanol, ethanol, isopropanol, normal propyl alcohol,
Isobutanol and n-butyl alcohol.
7. the method as described in claim 4 or 5, it is characterised in that described first temperature is
50 to 80 DEG C, described second temperature is 40 to 70 DEG C.
8. the Ah handkerchief as described in any one of claims 1 to 3 exists for Buddhist nun's mesylate II crystal formation
Preparation application in the medicine treating tumor.
Apply the most as claimed in claim 8, wherein said tumor include nonsmall-cell lung cancer,
Gastric cancer, hepatocarcinoma and breast carcinoma.
10. a pharmaceutical composition, it comprises as described in any one of claims 1 to 3
A Pa replaces Buddhist nun's mesylate II crystal formation, and one or more pharmaceutically acceptable carrier, taxes
Shape agent or diluent.
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| Application Number | Priority Date | Filing Date | Title |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108250139A (en) * | 2016-12-28 | 2018-07-06 | 上海宣创生物科技有限公司 | A Pa is for Buddhist nun's B crystal form and its preparation method and application |
| CN108250137A (en) * | 2016-12-28 | 2018-07-06 | 上海宣创生物科技有限公司 | A Pa is for Buddhist nun's C crystal form and its preparation method and application |
| CN108250138A (en) * | 2016-12-28 | 2018-07-06 | 上海宣创生物科技有限公司 | A Pa is for Buddhist nun's A crystal forms and its preparation method and application |
| WO2020051173A1 (en) | 2018-09-05 | 2020-03-12 | Assia Chemical Industries Ltd | New crystalline polymorphs of rivoceranib and rivoceranib mesylate |
| CN111773220A (en) * | 2020-06-10 | 2020-10-16 | 首都医科大学附属北京世纪坛医院 | New medicinal application of apatinib or pharmaceutically acceptable salts thereof |
| US11208484B2 (en) * | 2016-10-10 | 2021-12-28 | Suzhou Suncadia Biopharmaceuticals Co., Ltd. | Use of combination of anti-PD-1 antibody and VEGFR inhibitor in preparation of drug for treating cancers |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US11208484B2 (en) * | 2016-10-10 | 2021-12-28 | Suzhou Suncadia Biopharmaceuticals Co., Ltd. | Use of combination of anti-PD-1 antibody and VEGFR inhibitor in preparation of drug for treating cancers |
| US20220119528A1 (en) * | 2016-10-10 | 2022-04-21 | Suzhou Suncadia Biopharmaceuticals Co., Ltd. | Use of Combination of Anti-PD-1 Antibody and VEGFR Inhibitor in Preparation of Drug for Treating Cancers |
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| CN108250139A (en) * | 2016-12-28 | 2018-07-06 | 上海宣创生物科技有限公司 | A Pa is for Buddhist nun's B crystal form and its preparation method and application |
| CN108250137A (en) * | 2016-12-28 | 2018-07-06 | 上海宣创生物科技有限公司 | A Pa is for Buddhist nun's C crystal form and its preparation method and application |
| CN108250138A (en) * | 2016-12-28 | 2018-07-06 | 上海宣创生物科技有限公司 | A Pa is for Buddhist nun's A crystal forms and its preparation method and application |
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| US11434202B2 (en) | 2018-09-05 | 2022-09-06 | Assia Chemical Industries Ltd. | Crystalline polymorphs of Rivoceranib and Rivoceranib mesylate |
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