CN106994121A - A kind of pharmaceutical composition for treating cancer - Google Patents
A kind of pharmaceutical composition for treating cancer Download PDFInfo
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- CN106994121A CN106994121A CN201710057857.0A CN201710057857A CN106994121A CN 106994121 A CN106994121 A CN 106994121A CN 201710057857 A CN201710057857 A CN 201710057857A CN 106994121 A CN106994121 A CN 106994121A
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- VSMGSACHYCPUDG-UHFFFAOYSA-N CCc(c(NC(C1(C)CC1)=O)c1)ccc1-c(nc1cc2)c[n]1nc2-c1cccnc1C(F)(F)F Chemical compound CCc(c(NC(C1(C)CC1)=O)c1)ccc1-c(nc1cc2)c[n]1nc2-c1cccnc1C(F)(F)F VSMGSACHYCPUDG-UHFFFAOYSA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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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
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of pharmaceutical composition for treating cancer.Specifically, the invention discloses a kind of pharmaceutical composition and its preparation technology containing N- (2- ethyls -5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b] pyridazine -2- bases) phenyl) -1- methylcyclopropanecarboxamides or its pharmacologically acceptable salt and pregelatinized starch.The characteristics of pharmaceutical composition that the present invention is obtained has that dissolution is rapid, had good stability.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, and in particular to one kind contains N- (2- ethyls -5- (6- (2- (trifluoromethyl) pyrroles
Pyridine -3- bases) imidazo [1,2-b] pyridazine -2- bases) phenyl) -1- methylcyclopropanecarboxamides or its pharmacologically acceptable salt
Pharmaceutical composition and preparation method thereof, the characteristics of said composition has that dissolution is rapid, had good stability.
Background technology
Hedgehog signal paths are an important cellular physiological processes regulation paths.Experiment shows Hedgehog paths
Growth to tumour plays central role.Therefore, Hedgehog signal paths are effectively blocked to suppress tumour cell by medicine
Growth, the treatment to malignant tumour provides new approach.
CN103261198A disclose a kind of small-molecule active substance N- (2- ethyls -5- (6- (2- (trifluoromethyl) pyridine -
3- yls) imidazo [1,2-b] pyridazine -2- bases) phenyl) -1- methylcyclopropanecarboxamides, the chemical formula such as following formula of the active material
Shown in I：
The active material is oral type small molecule Hedgehog signal pathway inhibitors, can be clinically used for treating metastatic
Or Locally Advanced type basal-cell carcinoma.
During insoluble drug is prepared into pharmaceutical preparation, the dissolution rate of insoluble drug is mainly and preparation
Disintegration it is relevant with corrosion speed, and the pharmaceutic adjuvant such as suitable adhesive can play the beneficial effect of increase preparation dissolution.
In addition, in wet-granulation process, softwood processed is key technology, the general rule of thumb principle of quality of softwood be " it is hold agglomerating,
Light pressure dissipates " grasp, softwood is off quality easily to there is balling-up or the too many phenomenon of powder, cause mobility of particle compared with
Difference, particle size distribution is uneven, so as to cause drug content uneven, influences the dissolution of medicine.Therefore the use of adhesive is solid
Critical effect is played in the prilling of body preparation.
Pregelatinized starch, also referred to as partially pregelatinized starch, have an enormous advantage compared with traditional starch tool, and it is to utilize to add
Heat and Mechanical Method make partial starch breakage of particles in starch turn into a kind of jelly, and another part is still remained stationary state, and
And the ratio of strict control gelling starch, so as to maintain stablizing relatively for bonding and disintegrating property.Partially pregelatinized starch is simultaneously
Double action with bonding and disintegration, its cost is less than PVP and HPMC, and may replace the chemical synthesis auxiliary material such as PVP, HPMC is used for
Produce adhesive, disintegrant and the filler of the solid pharmaceutical preparations such as tablet and capsule.
It was found that the compound is equal in each Physiological Medium during the pharmaceutical composition of compound of formula I is prepared
It is almost insoluble, belong to insoluble drug, using conventional adhesive, such as starch slurry solution, the PVPP aqueous solution or hydroxypropyl first
When cellulose aqueous solution prepares composition grain, pelletization balling-up is serious, and medicine wetability is very poor, big in the particle of preparation
Grain is more, and mobility of particle is general, is unfavorable for production amplification.
The content of the invention
Had good stability the rapid pharmaceutical composition of dissolution, and the medicine simultaneously it is an object of the invention to provide one kind
Composition preparation technology is simple, is more suitable for industrialized production.
The pharmaceutical composition that the present invention is provided includes active pharmaceutical ingredient and pregelatinized starch.Wherein, active medicine into
It is divided into N- (2- ethyls -5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b] pyridazine -2- bases) phenyl) -1- methyl
Cyclopropane carboxamide or its pharmacologically acceptable salt, the content range of the active pharmaceutical ingredient can be 1-1000mg,
It is preferred that 25-500mg.The content range of pregelatinized starch can be the 1-90% of the gross weight based on composition, preferably 1-20%,
More preferably 1-10%, most preferably 2-5%.
The pharmaceutical composition that the present invention is provided can also contain filler, such as microcrystalline cellulose, calcium monohydrogen phosphate, pregelatinated
One or more in starch, lactose, mannitol etc..Gross weight based on composition, the filling agent content can be about 5-
80%.
The pharmaceutical composition that the present invention is provided can also contain disintegrant, and such as Ac-Di-Sol, carboxylic first form sediment
One or more in powder sodium, low-substituted hydroxypropyl cellulose or PVPP.Gross weight based on composition, the disintegration
Agent content can be about 1-30%.
The pharmaceutical composition that the present invention is provided can also contribute to tabletting or filling capsule comprising one or more lubricants.
Lubricant includes talcum powder, magnesium stearate, zinc stearate, sodium stearyl fumarate, Compritol 888 ATO, sldium lauryl sulfate, hydrogen
Change vegetable oil, cataloid etc..Gross weight based on composition, the content of lubricant can be about 0.5-5%.
In the pharmaceutical composition of the present invention, the particle size distribution range d (0.9) of the active component can be excellent less than 100 μm
Choosing is less than 50 μm.
Present invention also offers a kind of pharmaceutical composition, including：
1) 1-70wt% (N- (2- ethyls -5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b] pyridazine -
2- yls) phenyl) -1- methylcyclopropanecarboxamides；
2) 1-10wt% pregelatinized starch；
3) 5-80wt% filler, the one kind or many of the filler in lactose, mannitol and microcrystalline cellulose
Kind；
4) 1-30wt% disintegrant, the disintegrant is selected from Ac-Di-Sol, carboxyrnethyl starch sodium, low substitution
One or more in hydroxypropyl cellulose and PVPP；
5) 0.5-5wt% lubricant, the lubricant is selected from magnesium stearate, sodium stearyl fumarate, colloidal silica
With the one or more of talcum powder.
Preferably, pharmaceutical composition of the invention includes：
1) 10-70wt% (N- ((rattle away 2- ethyls -5- by 6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b]
Piperazine -2- bases) phenyl) -1- methylcyclopropanecarboxamides；
2) 2-5wt% pregelatinized starch；
3) 20-80wt% fillers, the filler includes microcrystalline cellulose and lactose；
4) 4-8wt% sodium carboxymethyl starch；
5) 0.5-2wt% magnesium stearate.
The pharmaceutical composition of the present invention is subjected to dissolution test, according to two annex dissolution determinations of Chinese Pharmacopoeia 2010 edition
Second method (paddle method), using the 0.1mol/L hydrochloric acid solutions of 2% lauryl sodium sulfate as dissolution medium, for medicine of the present invention
The unit dose of compositions, the dissolution medium is preferably 1000mL, and is carried out at 37 ± 0.5 DEG C with 75rpm oar speed
Dissolution test, dissolution rate of the active pharmaceutical ingredient in 45 minutes can reach more than 95%, the dissolution rate preferably in 40 minutes
More than 95%, the dissolution rate more preferably in 35 minutes is more than 95%, and the most preferably dissolution rate in 30 minutes is more than 95%.
Pregelatinized starch in the pharmaceutical composition of the present invention is preferably as adhesive, and pregelatinized starch can be small using temperature
In 50 DEG C, preferably 20-30 DEG C of wetting agent is configured to suspension to prepare pharmaceutical composition, wetting agent can for water, ethanol or
Ethanol water, preferably water.The pregelatinized starch liquid prepared compared to high-temperature moisture agent, the wetting agent that temperature is less than 50 DEG C is prepared
Pregelatinized starch liquid prevent material balling-up during pharmaceutical composition is prepared, the effect in terms of increase mobility of particle is more
It is good.
The pharmaceutical composition that the present invention is provided has drug-eluting complete rapidly, the advantage such as stability is good, is conducive to industry
Metaplasia is produced.Auxiliary material uses pregelatinized starch, can be obviously improved the phenomenon of mix wetting homogeneity difference in pelletization, preparation
Preferably, dissolution is complete rapidly after granulation for particle homogeneity, mobility.
There is the pharmaceutical composition of the present invention excellent Hedgehog signal paths to suppress inhibitory activity, can be used for and cancer
The treatment of relevant disease, particularly metastatic or Locally Advanced type basal-cell carcinoma.
Present invention also offers a kind of method for preparing pharmaceutical composition, including mixing (N- (2- ethyls -5- (6- (2- (three
Methyl fluoride) pyridin-3-yl) imidazo [1,2-b] pyridazine -2- bases) phenyl) -1- methylcyclopropanecarboxamides or its pharmacologically
Acceptable salt and pregelatinized starch, can be prepared into particle using the common method in this area, such as high-shearing granulation,
The methods such as fluid-bed marumerization prepare medicament composition granule, and then tabletting (coating) or filling capsule, prepare tablet or glue
Wafer.
Brief description of the drawings
Fig. 1 shows stripping curve of the tablet of embodiment 1 to 5 in 2%SDS 0.1mol/L hydrochloric acid solutions.
Fig. 2 shows stripping curve of the tablet of embodiment 6 to 8 in 2%SDS 0.1mol/L hydrochloric acid solutions.
Fig. 3 shows stripping curve of the tablet of embodiment 9 to 11 in 2%SDS 0.1mol/L hydrochloric acid solutions.
Fig. 4 shows stripping curve of the tablet of embodiment 12 to 14 in 2%SDS 0.1mol/L hydrochloric acid solutions.
Fig. 5 shows stripping curve of the tablet of embodiment 15 to 20 in 2%SDS 0.1mol/L hydrochloric acid solutions.
Fig. 6 show embodiment 6 tablet place 0 month, 3 months, 6 months after 2%SDS 0.1mol/L hydrochloric acid solutions
In stripping curve.
Fig. 7 show embodiment 10 tablet place 0 month, 3 months, 6 months after 2%SDS 0.1mol/L hydrochloric acid it is molten
Stripping curve in liquid.
Fig. 8 show embodiment 14 tablet place 0 month, 3 months, 6 months after 2%SDS 0.1mol/L hydrochloric acid it is molten
Stripping curve in liquid.
Embodiment
The present invention is further described by following examples and experimental example.These embodiments and experimental example are only used for
Bright property purpose, and the scope being not intended to limit the invention.
Embodiment 1 to 7
By N- (2- ethyls -5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2- that particle diameter d (0.9) is 45 μm
B] pyridazine -2- bases) phenyl) -1- methylcyclopropanecarboxamides (hereinafter referred to as compound A), microcrystalline cellulose, lactose, carboxylic first
Sodium starch, is mixed in the ratio in table 1, after being well mixed, respectively with the 5% hydroxypropyl methylcellulose aqueous solution, 5% and
The starch slurry solution of 8% aqueous povidone solution, 5% and 8% and the 5% and 8% pregelatinized starch aqueous solution
For adhesive, pelletized using high-shearing granulation machine, whole grain and drying process are carried out to softwood, then by dry particl (water
Divide to be less than and 3%) carry out dry whole grain, add magnesium stearate, mix.By obtained always mixed granulation.Prepare embodiment 1~7
Tablet.
Table 1
Unit：g；Specification：1000
Experimental example 1
The dry particl outward appearance in embodiment 1~7 is observed, and particle size distribution is carried out to it respectively.45 mesh sieves are placed
On the upside of 100 mesh sieves, first weighed material total amount, puts on 45 mesh sieves.Horizontality sieving is kept, left and right comes and goes, clapped when sieving
Beat 3min.Take by 45 mesh sieves and can not can calculate its proportion (%) by the particles of 100 mesh sieves, weighed weight.Separately
Outside, its carr index is determined respectively, as a result as shown in table 2.
Table 2
The as shown by data of table 2, during from HPMC E5, polyvinylpyrrolidone-K30 or starch slurry solution for adhesive, system
The balling-up of grain process is serious, and medicine wetability is very poor, and bulky grain is more in the particle of preparation, and mobility of particle is general, increases bonding
Agent concentration, mobility of particle and balling nothing are significantly improved.And select pregelatinized starch as adhesive, pelletization into
Ball phenomenon is improved, and mobility of particle is significantly improved.
Embodiment 8~14
It is 45 μm of compound A, filler, disintegrant by particle diameter d (0.9), is mixed in the ratio in table 3, is mixed
After uniform, 5% pregelatinized starch aqueous suspension is added, using high-shearing granulation mechanism grain, whole grain is carried out to softwood and dry
Dry processing, then carries out dry whole grain by dry particl (moisture is less than 3%), adds lubricant, mixing.By obtained always mixed particle pressure
Piece.Prepare the tablet of embodiment 8~14.
Table 3
Unit：g；Specification：1000
Experimental example 2
Empirically same method in example 1, carries out granulometry, and determine card respectively to the dry particl in embodiment 8~14
That index, as a result as shown in table 4.
Table 4
The as shown by data of table 4, the tablet of the embodiment 8~14 using pregelatinized starch as adhesive can be preferably
Improve the balling occurred in pelletization, obtained grain graininess is uniform, and good fluidity changes the kind of other excipient
Class, influence is little.
Experimental example 3：Dissolution is tested
According to two methods of annex dissolution determination second (paddle method) of Chinese Pharmacopoeia 2015 edition, respectively to embodiment 1~5,6~
8th, 9~11,12~14 tablet carries out dissolution determination.0.1mol/L hydrochloric acid using 2% lauryl sodium sulfate (SDS) is molten
Liquid 1000mL carries out dissolution test as dissolution medium, and at 37 ± 0.5 DEG C with 75rpm oar speed.As a result show, use hydroxyl
Third methylcellulose, polyvinylpyrrolidone-K30 or starch slurry solution are the tablet of the embodiment 1~5 of adhesive, and compound A exists
Dissolution only 80% or so during 45min, not exclusively, stripping curve figure is shown in Fig. 1 for dissolution；Mixed liquor after matching somebody with somebody using pregelatinized starch is cold
As the tablet of the embodiment 6~14 of adhesive, quickly and completely, stripping curve figure is shown in Fig. 2~4 for compound A dissolution.
Embodiment 15~20
By different grain size d (0.9) compound A, microcrystalline cellulose, lactose, carboxyrnethyl starch sodium, enter in the ratio in table 5
Row mixing, after being well mixed, is added 5% pregelatinized starch aqueous suspension, is pelletized using high-shearing granulation machine, to soft
Material carries out wet whole grain and drying process, and dry particl (moisture is less than 3%) then is carried out into dry whole grain, magnesium stearate, mixing is added.
By obtained always mixed granulation.Prepare the tablet of embodiment 15~20.
Table 5
Unit：g；Specification：1000
Experimental example 4：Dissolution is tested
According to two methods of annex dissolution determination second (paddle method) of Chinese Pharmacopoeia 2015 edition, to the tablet of embodiment 15~20
Carry out dissolution determination.0.1mol/L hydrochloric acid solutions 1000mL using 2%SDS is as dissolution medium, and at 37 ± 0.5 DEG C
Dissolution test is carried out with 75rpm oar speed.As a result show, can be in 45min when compound A granularities (d0.9) are below 100 μm
Interior dissolution is complete.Specifically, the tablet of embodiment 15~17, when granularity is below 50 μm, compound A dissolution is complete rapidly
Entirely；The tablet of embodiment 18~19, granularity is between 50 μm~100 μm, compared with embodiment 15~17, compound A dissolution
Completely, but speed slows down.And the tablet of embodiment 20, when granularity is more than 100 μm, compound A dissolution only 90% in 45min
Left and right, not exclusively, stripping curve figure is shown in Fig. 5 for dissolution.
Experimental example 5：Stability study
By the tablet in embodiment 6,10,14,40 DEG C ± 2 DEG C are placed in, in the environment of relative humidity 75% ± 5%, respectively
In 0 month, 3 months, sample within 6 months, observe its character, it is determined about material and content using HPLC methods.According to middle traditional Chinese medicines
Two methods of annex dissolution determination second (paddle method) of allusion quotation 2015 edition, using 2%SDS 0.1mol/L hydrochloric acid solutions 1000mL as
Dissolution medium, and dissolution determination is carried out to it with 75rpm oar speed respectively at 37 ± 0.5 DEG C.
Show (table 6 to 8) about material and assay result, during 0 to 6 month acceleration environment is investigated, embodiment
6th, in 10,14 tablet its character, content and relevant material is without significant changes, and sample is stable.
Dissolution determination result shows, compound A dissolution rate is under acceleration conditions in the tablet in embodiment 6,10,14
Still without being decreased obviously after placing 0 month, 3 months, 6 months, dissolution rate is quickly and completely (see Fig. 6 to 8).
Relevant material and the assay result of the embodiment 6 of table 6
Relevant material and the assay result of the embodiment 10 of table 7
Relevant material and the assay result of the embodiment 14 of table 8
Claims (14)
1. a kind of pharmaceutical composition, including：
1) active medicine, it is N- (2- ethyls -5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b] pyridazine -2-
Base) phenyl) -1- methylcyclopropanecarboxamides or its pharmacologically acceptable salt；And
2) pregelatinized starch.
2. pharmaceutical composition according to claim 1, it is characterised in that the content range of pregelatinized starch is based on combination
The 1-90% of thing gross weight meter, preferably 1-20%, more preferably 1-10%, most preferably 2-5%.
3. pharmaceutical composition according to claim 1, it is characterised in that the content range of the active medicine is 1-
1000mg, preferably 25-500mg.
4. pharmaceutical composition according to claim 1, it is characterised in that according to two annex dissolutions of Chinese Pharmacopoeia 2010 edition
Degree determines the second method (paddle method), and the 0.1mol/L hydrochloric acid solutions using 2% lauryl sodium sulfate are as dissolution medium, and 37
Dissolution test is carried out with 75rpm oar speed at ± 0.5 DEG C, dissolution rate of the active medicine in 45 minutes is excellent more than 95%
The dissolution rate being selected in 40 minutes is more than 95%, and the more preferably dissolution rate in 35 minutes is more than 95%, most preferably at 30 minutes
Interior dissolution rate is more than 95%.
5. pharmaceutical composition according to claim 1, it is characterised in that also comprising filler, the preferred crystallite of filler
One or more in cellulose, calcium monohydrogen phosphate, pregelatinized starch, lactose and mannitol, preferably its content are based on composition
The 5-80% of gross weight meter.
6. pharmaceutical composition according to claim 1, it is characterised in that also comprising disintegrant, the disintegrant is preferably crosslinked
One or more in sodium carboxymethylcellulose, carboxyrnethyl starch sodium, low-substituted hydroxypropyl cellulose and PVPP, preferably its
Content is the 1-30% based on composition total weight meter.
7. pharmaceutical composition according to claim 1, it is characterised in that also comprising lubricant, the lubricant preferably talc
Powder, magnesium stearate, zinc stearate, sodium stearyl fumarate, Compritol 888 ATO, sldium lauryl sulfate, hydrogenated vegetable oil and colloid
One or more in silica, preferably its content are the 0.5-5% based on composition total weight meter.
8. pharmaceutical composition according to claim 1, it is characterised in that the particle size distribution range d of the active medicine
(0.9) it is less than 100 μm, preferably smaller than 50 μm.
9. pharmaceutical composition according to claim 1, it is characterised in that the pregelatinized starch is less than 50 by using temperature
DEG C, preferably 20-30 DEG C of water is configured to suspension to prepare pharmaceutical composition.
10. a kind of pharmaceutical composition, including：
1) 1-70wt% (N- (2- ethyls -5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b] pyridazine -2-
Base) phenyl) -1- methylcyclopropanecarboxamides, its particle size distribution range d (0.9) is preferably smaller than 100 μm, more preferably less than 50 μm；
2) 1-10wt% pregelatinized starch；
3) 5-80wt% filler, one or more of the filler in lactose, mannitol and microcrystalline cellulose；
4) 1-30wt% disintegrant, the disintegrant is selected from Ac-Di-Sol, carboxyrnethyl starch sodium, low-substituted hydroxypropyl
One or more in base cellulose and PVPP；
5) 0.5-5wt% lubricant, the lubricant is selected from magnesium stearate, sodium stearyl fumarate, colloidal silica and cunning
The one or more of stone flour.
11. a kind of pharmaceutical composition, including：
1) 10-70wt% (N- (2- ethyls -5- (6- (2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b] pyridazine -2-
Base) phenyl) -1- methylcyclopropanecarboxamides, its particle size distribution range d (0.9) is preferably smaller than 100 μm, more preferably less than 50 μm；
2) 2-5wt% pregelatinized starch；
3) 20-80wt% fillers, the filler includes microcrystalline cellulose and lactose；
4) 4-8wt% sodium carboxymethyl starch；
5) 0.5-2wt% magnesium stearate.
12. the pharmaceutical composition according to any one of claim 1 to 11, it is oral solid formulation, preferred tablet and glue
Wafer.
13. purposes of the pharmaceutical composition in the medicine for preparing treating cancer described in any one of claim 1 to 12, the cancer
The preferred metastatic of disease or Locally Advanced type basal-cell carcinoma.
14. the method for the pharmaceutical composition described in any one of claim 1 to 12 is prepared, including mixing (N- (2- ethyl -5- (6-
(2- (trifluoromethyl) pyridin-3-yl) imidazo [1,2-b] pyridazine -2- bases) phenyl) -1- methylcyclopropanecarboxamides or its medicine
Acceptable salt and pregelatinized starch in Neo-Confucianism.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610052634 | 2016-01-26 | ||
| CN2016100526340 | 2016-01-26 |
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| CN106994121A true CN106994121A (en) | 2017-08-01 |
| CN106994121B CN106994121B (en) | 2021-07-02 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11655240B1 (en) | 2022-05-10 | 2023-05-23 | Beijing Grand Johamu Pharmaceutical Company, Ltd. | Crystal form of compound and fumaric acid, pharmaceutical composition and method for treating coronavirus-induced diseases |
| CN115252619A (en) * | 2022-05-27 | 2022-11-01 | 北京远大九和药业有限公司 | Pharmaceutical composition, preparation method thereof and application thereof in treating diseases caused by coronavirus |
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