CN106075456A - A kind of pleasure that contains cuts down the pharmaceutical composition for Buddhist nun and application thereof - Google Patents
A kind of pleasure that contains cuts down the pharmaceutical composition for Buddhist nun and application thereof Download PDFInfo
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- CN106075456A CN106075456A CN201610266697.6A CN201610266697A CN106075456A CN 106075456 A CN106075456 A CN 106075456A CN 201610266697 A CN201610266697 A CN 201610266697A CN 106075456 A CN106075456 A CN 106075456A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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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
- A61K31/47—Quinolines; Isoquinolines
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Abstract
The invention belongs to field of pharmaceutical preparations, be specifically related to cut down the pharmaceutical composition for Buddhist nun containing happy.Specifically, the invention provides containing (1) 4 [3 chlorine 4 (cyclopropylaminocarbonyl) amino-benzene oxygen] 7 methoxyl group 6 quinoline formyl amine, its pharmaceutically acceptable salt or their solvate and the pharmaceutical composition of (2) calcium hydrogen phosphate, it is provided that the pharmaceutical preparation of the pharmaceutical composition containing the present invention and these compositionss or pharmaceutical preparation application in the medicine of preparation preventing and treating tumor-related illness.The pharmaceutical composition of the present invention and pharmaceutical preparation improve pleasure and cut down for Buddhist nun or its pharmaceutically acceptable salt or the dissolution of its solvate, improve its stability and have more universality.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to cut down the pharmaceutical composition for Buddhist nun containing happy.In more detail
Say, relate to improving and happy cut down for Buddhist nun or its pharmaceutically acceptable salt or the dissolution of its solvate and improve surely
Have more the pharmaceutical composition of universality qualitatively.
Background technology
Pleasure is cut down for Buddhist nun (lenvatinib), trade name LENVIMA, obtains FDA on February 13rd, 2015 and criticizes
Mutatis mutandis have Progressive symmetric erythrokeratodermia, the patient of differentiated thyroid carcinoma (DTC) in treatment.Its chemical name is 4-[3-
Chloro-4-(cyclopropylaminocarbonyl) amino-benzene oxygen]-7-methoxyl group-6-quinoline formyl amine, chemical structural formula is:
International patent application WO2006/030826 discloses to cut down pleasure and makes medicine group for Buddhist nun as active ingredient
During compound, under humidification, heating preservation condition, it may occur that decompose, additionally, when pharmaceutical composition moisture absorption,
Compositions surface can occur gelation, produces extremely strong viscosity, causes happy cutting down to delay for Buddhist nun's dissolution, affects medicine
The onset of thing and absorption.For overcoming problems, the LENVIMA of the Japanese Wei Cai company listedTMUse
Pleasure cuts down the compositions for Buddhist nun Yu calcium carbonate, and calcium carbonate is a kind of customary adjuvant in effervescent tablet, oral entrance stomach
In intestinal, substantial amounts of bubble can be produced under the effect of gastric acid so that pleasure is cut down for Buddhist nun intermolecular separate,
Stop its gelation.But, oral calcium carbonate may cause constipation and flatulence, be not suitable for old people and
The patient having the disease of stomach such as gastric ulcer directly takes and (sees " pharmaceutic adjuvant handbook " (Zheng Junmin etc. main translates) the
Four editions page 86 " calcium carbonate " parts), and such patient may account for sizable ratio in tumor patient.
Accordingly, it would be desirable to develop have more universality cut down the pharmaceutical composition for Buddhist nun containing happy, at the same time, it is desirable to so
Pharmaceutical composition dissolution more excellent and long-term preservation is more stable.
Summary of the invention
It is an object of the present invention to provide and improve happy cutting down for Buddhist nun or its pharmaceutically acceptable salt or its solvent
The dissolution of compound also improves a kind of pharmaceutical composition having more universality of stability, this pharmaceutical composition
Containing (1) 4-[3-chloro-4-(cyclopropylaminocarbonyl) amino-benzene oxygen]-7-methoxyl group-6-quinoline formyl amine, its
Pharmaceutically acceptable salt or their solvate and (2) calcium hydrogen phosphate.
It is a further object to provide the pharmaceutical preparation of the pharmaceutical composition containing the present invention.
It is also another object of the present invention to provide the pharmaceutical composition of the present invention at preparation preventing and treating tumor-related illness
Medicine in application.
For above-mentioned purpose, the present invention provides techniques below scheme:
The present invention provides a kind of pharmaceutical composition, and it contains (1) 4-[3-chloro-4-(cyclopropylaminocarbonyl) amino
Phenoxy group]-7-methoxyl group-6-quinoline formyl amine (happy cut down for Buddhist nun), its pharmaceutically acceptable salt or its solvent close
Thing and (2) calcium hydrogen phosphate.
In some preferred embodiments, in the pharmaceutical composition of the present invention, described calcium hydrogen phosphate is two
Water calcium hydrogen phosphate or calcium phosphate dibasic anhydrous.In a specific embodiment, the compositions that the present invention provides
(happy containing (1) 4-[3-chloro-4-(cyclopropylaminocarbonyl) amino-benzene oxygen]-7-methoxyl group-6-quinoline formyl amine
Cut down for Buddhist nun), its pharmaceutically acceptable salt or its solvate and (2) dicalcium phosphate dehydrate.At another
In specific embodiment, the compositions that the present invention provides contains (1) 4-[the chloro-4-of 3-(cyclopropylaminocarbonyl)
Amino-benzene oxygen]-7-methoxyl group-6-quinoline formyl amine (happy cut down for Buddhist nun), its pharmaceutically acceptable salt or it is molten
Agent compound and (2) calcium phosphate dibasic anhydrous.
In other embodiments, the pharmaceutical composition of the present invention also can comprise disintegrating agent.Preferably, institute
State disintegrating agent selected from corn starch, part alphalysed starch, hydroxypropyl starch, carboxymethyl cellulose, carboxymethyl
Sodium cellulosate, carboxymethylcellulose calcium, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, low replacement hydroxyl
One or more in propyl cellulose, polyvinylpolypyrrolidone.It is highly preferred that described disintegrating agent is selected from crosslinking carboxylic
One or more in sodium carboxymethylcellulose pyce, low-substituted hydroxypropyl cellulose and polyvinylpolypyrrolidone.
In some preferred embodiments, in the pharmaceutical composition of the present invention, described pharmaceutically acceptable
Salt be hydrochlorate, hydrobromate, tosilate, sulfate, mesylate or esilate；Enter
Preferably, described pharmaceutically acceptable salt is mesylate or esilate to one step.
In some preferred embodiments, in the pharmaceutical composition of the present invention, described solvate refers to
Hydrate, dimethyl sulfoxide compound or acetic acid compound.
In some specific embodiments, the pharmaceutical composition of the present invention also can comprise excipient, binding agent,
Fluidizer, lubricant etc..Such as, described excipient be selected from lactose monohydrate, white sugar, glucose, fructose,
Starch, potato starch, corn starch, wheaten starch, rice starch, crystalline cellulose, microcrystalline Cellulose,
Radix Glycyrrhizae powder, PEARLITOL 25C, erithritol, maltose alcohol, Sorbitol, trehalose, silicic acid anhydride, silicic acid
Calcium, calcium phosphate, anhydrous calcium phosphate and calcium sulfate etc..Preferably, described excipient is selected from lactose monohydrate, micro-
One or more in crystalline cellulose and PEARLITOL 25C.Described binding agent is selected from gelatin, starch, Arab
Glue, Tragacanth, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvidone, first
Base cellulose, part alphalysed starch, alphalysed starch, polyvinyl alcohol, sodium alginate, pulullan polysaccharide, glycerol
Deng.Preferably, described binding agent is hydroxypropyl cellulose.Described lubricant is selected from magnesium stearate, tristearin
Acid, calcium stearate, sodium stearyl fumarate, Pulvis Talci, Polyethylene Glycol etc..Preferably, described lubricant is
One or more in magnesium stearate, sodium stearyl fumarate and Pulvis Talci.Described fluidizer is selected from Pulvis Talci
And micropowder silica gel.
In other specific embodiments, the pharmaceutical composition of the present invention also can comprise antioxidant, rectify
Taste agent, coloring agent and spice etc..Such as, described antioxidant can be sodium ascorbate, Cys,
Sodium sulfite, tocopherol, soybean lecithin etc..Described correctives can be citric acid, ascorbic acid, wine
Stone acid, malic acid, aspartame, acesulfame potassium, thaumatin, saccharin sodium, glycyrrhizin dipotassium,
Sodium glutamate, 5'-inosinic acid sodium, GMP etc..Described coloring agent can be titanium oxide, three oxidations two
Ferrum, Yellow ferric oxide, alkermes, carmine, riboflavin, edible Sunset Yellow FCF, edible blueness
No. 2 etc..Described spice can be Fructus Citri Limoniae oil, orange oil, menthol, Oleum menthae, Borneolum Syntheticum, vanillin etc..
In some embodiments, in the pharmaceutical composition of the present invention, cut down the gauge for Buddhist nun with happy, described
The happy weight ratio cut down for Buddhist nun or its pharmaceutically acceptable salt or its solvate and calcium hydrogen phosphate is about
1:0.2-50, preferably from about 1:0.5-25, more preferably from about 1:1-12.5.In some specific embodiments, at this
In the pharmaceutical composition of invention, cutting down the gauge for Buddhist nun with happy, described pleasure cuts down for Buddhist nun or it is pharmaceutically acceptable
The weight ratio of salt or its solvate and calcium hydrogen phosphate is about 1:1-5, e.g., from about 1:1-2, about 1:2-3, about 1:3-4
Deng.
The present invention also provides for a kind of pharmaceutical preparation, and it comprises the pharmaceutical composition of the present invention.
In some preferred embodiments, the pharmaceutical preparation of the present invention is tablet, granule, powder, delays
Release agent, drop pill, capsule.In a specific embodiment, described slow releasing agent is slow-release micro-pill.
In some embodiments, the pharmaceutical composition of the present invention is cut down for Buddhist nun or it is pharmaceutically acceptable by happy
Salt or its solvate, calcium hydrogen phosphate, disintegrating agent, binding agent, lubricant and excipient composition, wherein with
Happy cutting down the gauge for Buddhist nun, described pleasure is cut down and is accounted for described medicine for Buddhist nun or its pharmaceutically acceptable salt or its solvate
About the 5% of compositions accounts for the pact of described pharmaceutical composition to about 95% (w/w), described calcium hydrogen phosphate
5% to about 95% (w/w), described disintegrating agent account for described pharmaceutical composition 0% to about 60% (weight/
Weight), described binding agent accounts for 0% to about 30% (w/w) of described pharmaceutical composition, described excipient
Account for 0% to about 90% (w/w) of described pharmaceutical composition, and described lubricant accounts for described drug regimen
The 0% of thing is to about 30% (w/w).In some specific embodiments, the pharmaceutical composition of the present invention
By happy cut down for Buddhist nun or its pharmaceutically acceptable salt or its solvate, calcium hydrogen phosphate, disintegrating agent, binding agent,
Lubricant and excipient composition, wherein cut down the gauge for Buddhist nun with happy, described pleasure cut down for Buddhist nun or its pharmaceutically can connect
The salt being subject to or its solvate account for about 5% to about 70% (w/w) of described pharmaceutical composition, described phosphorus
Acid hydrogen calcium accounts for about 5% to about 70% (w/w) of described pharmaceutical composition, and described disintegrating agent accounts for described medicine
About the 2% of compositions to about 40% (w/w), described binding agent account for about the 1% of described pharmaceutical composition to
About 20% (w/w), described excipient accounts for about 15% to about 80% (weight/weight of described pharmaceutical composition
Amount), and described lubricant accounts for about 0.5% to about 10% (w/w) of described pharmaceutical composition.Separately
In some specific embodiments, the pharmaceutical composition of the present invention is cut down for Buddhist nun or it is pharmaceutically acceptable by happy
Salt or its solvate, calcium hydrogen phosphate, disintegrating agent, binding agent, lubricant and excipient composition, wherein with
Happy cutting down the gauge for Buddhist nun, described pleasure is cut down and is accounted for described medicine for Buddhist nun or its pharmaceutically acceptable salt or its solvate
About the 10% of compositions accounts for described pharmaceutical composition to about 50% (w/w), described calcium hydrogen phosphate
About 10% to about 40% (w/w), described disintegrating agent accounts for about the 3% to about 30% of described pharmaceutical composition
(w/w), described binding agent accounts for about 2% to about 10% (w/w) of described pharmaceutical composition, described
Excipient accounts for about 20% to about 70% (w/w) of described pharmaceutical composition, and described lubricant accounts for institute
State about 0.5% to about 5% (w/w) of pharmaceutical composition.
In some preferred embodiments, the pharmaceutical composition of the present invention by happy cut down for Buddhist nun or its pharmaceutically may be used
The salt accepted or its solvate, calcium hydrogen phosphate, disintegrating agent, binding agent, lubricant and excipient composition,
Wherein cutting down the gauge for Buddhist nun with happy, described pleasure is cut down and is accounted for for Buddhist nun or its pharmaceutically acceptable salt or its solvate
About the 10% of described pharmaceutical composition is to about 25% (w/w), and described calcium hydrogen phosphate accounts for described medicine group
About the 30% of compound to about 35% (w/w), described disintegrating agent account for about the 5% of described pharmaceutical composition to
About 30% (w/w), described binding agent accounts for about 2% to about 8% (w/w) of described pharmaceutical composition,
Described excipient accounts for about 20% to about 45% (w/w) of described pharmaceutical composition, and described lubricant
Account for about 1% to about 4% (w/w) of described pharmaceutical composition.It is further preferred that the medicine of the present invention
Compositions by happy cut down for Buddhist nun or its pharmaceutically acceptable salt or its solvate, calcium hydrogen phosphate, disintegrating agent,
Binding agent, lubricant and excipient composition, wherein cut down the gauge for Buddhist nun with happy, and described pleasure is cut down for Buddhist nun or its medicine
On, acceptable salt or its solvate account for about 10% to about 25% (weight/weight of described pharmaceutical composition
Amount), described calcium hydrogen phosphate accounts for about 30% to about 35% (w/w) of described pharmaceutical composition, described disintegrate
Agent accounts for about 5% to about 30% (w/w) of described pharmaceutical composition, and described binding agent accounts for described drug regimen
About the 2% of thing is to about 8% (w/w), and described excipient accounts for about the 20% of described pharmaceutical composition to about
45% (w/w), and described lubricant accounts for about 1% to about 4% (weight/weight of described pharmaceutical composition
Amount), wherein said calcium hydrogen phosphate is calcium phosphate dibasic anhydrous or dicalcium phosphate dehydrate, and described disintegrating agent takes selected from low
For hydroxypropyl cellulose and polyvinylpolypyrrolidone, described binding agent is hydroxypropyl cellulose, and described excipient is selected from
One or more in microcrystalline Cellulose, mannitol and lactose monohydrate, described lubricant is selected from Pulvis Talci, hard
One or more in fatty acid magnesium, sodium stearyl fumarate.
In some embodiments, the pharmaceutical preparation of the present invention is prepared from by the pharmaceutical composition of the present invention.
Such as, in the case of granule, can cut down for Buddhist nun adding excipient, binding agent, collapsing to pleasure as required
Solution agent, wetting agent etc. are stirred granulation, extrusion granulator, rotation is pelletized, one-step palletizing etc. of spraying manufactures,
Directly dry granulation also may be used.Prepare additionally, may be used without micropill medicine-feeding mode.Additionally, also dependent on needs
Carry out granulate, pulverizing.And then, it is possible to state addition excipient in granule, disintegrating agent further up, glue
Mixture, antioxidant, coloring agent etc. carry out tabletting and make tablet or direct encapsulating capsule.In the reality that some are concrete
Executing in scheme, the method for the pharmaceutical preparation of the preparation present invention comprises the following steps:
(1). pleasure is cut down for Buddhist nun or its pharmaceutically acceptable salt or its solvate, calcium hydrogen phosphate, disintegrating agent
(if necessary), binding agent (if necessary) and excipient (if necessary) mixing；
(2). mixture step 1 obtained is dried；With
(3). add excipient (if necessary) and lubricant (if necessary) and mix.
Also can by happy cut down for Buddhist nun or its pharmaceutically acceptable salt or its solvate and excipient, binding agent,
The direct pressing such as disintegrating agent, fluidizer is in flakes or encapsulating capsule.
In some preferred embodiments, the present invention provides a kind of pharmaceutical preparation, and it comprises the medicine of the present invention
Compositions, described pharmaceutical composition by happy cut down for Buddhist nun or its pharmaceutically acceptable salt or its solvate,
Calcium hydrogen phosphate, disintegrating agent, binding agent, lubricant and excipient composition, wherein cut down the gauge for Buddhist nun with happy,
Described pleasure is cut down and is accounted for about the 10% of described pharmaceutical composition for Buddhist nun or its pharmaceutically acceptable salt or its solvate
To about 25% (w/w), described calcium hydrogen phosphate accounts for about 30% to about 35% (weight of described pharmaceutical composition
Amount/weight), described disintegrating agent accounts for about 5% to about 30% (w/w) of described pharmaceutical composition, described viscous
Mixture accounts for about 2% to about 8% (w/w) of described pharmaceutical composition, and described excipient accounts for described medicine group
About the 20% of compound is to about 45% (w/w), and described lubricant accounts for about the 1% of described pharmaceutical composition
To about 4% (w/w).It is further preferred that the present invention provides a kind of pharmaceutical preparation, it comprises the present invention
Pharmaceutical composition, described pharmaceutical composition is closed for Buddhist nun or its pharmaceutically acceptable salt or its solvent by happy cutting down
Thing, calcium hydrogen phosphate, disintegrating agent, binding agent, lubricant and excipient composition, wherein cut down the amount for Buddhist nun with happy
Meter, described pleasure cuts down the pact accounting for described pharmaceutical composition for Buddhist nun or its pharmaceutically acceptable salt or its solvate
10% to about 25% (w/w), described calcium hydrogen phosphate accounts for about the 30% to about 35% of described pharmaceutical composition
(w/w), described disintegrating agent accounts for about 5% to about 30% (w/w) of described pharmaceutical composition, described
Binding agent accounts for about 2% to about 8% (w/w) of described pharmaceutical composition, and described excipient accounts for described medicine
About the 20% of compositions is to about 45% (w/w), and described lubricant accounts for the pact of described pharmaceutical composition
1% to about 4% (w/w), wherein said calcium hydrogen phosphate is calcium phosphate dibasic anhydrous or dicalcium phosphate dehydrate,
Described disintegrating agent is selected from low-substituted hydroxypropyl cellulose and polyvinylpolypyrrolidone, and described binding agent is hydroxy propyl cellulose
Element, one or more in microcrystalline Cellulose, mannitol and lactose monohydrate of described excipient, described profit
One or more in Pulvis Talci, magnesium stearate, sodium stearyl fumarate of lubrication prescription.
In a specific embodiment, the pharmaceutical composition of the present invention by happy cut down for Buddhist nun or its pharmaceutically may be used
The salt accepted or its solvate, calcium hydrogen phosphate, disintegrating agent, binding agent, lubricant and excipient composition,
Wherein cutting down the gauge for Buddhist nun with happy, described pleasure is cut down and is accounted for for Buddhist nun or its pharmaceutically acceptable salt or its solvate
About the 10% of described pharmaceutical composition is to about 25% (w/w), and described calcium hydrogen phosphate accounts for described medicine group
About 33% (w/w) of compound, described disintegrating agent accounts for about 5% to about 30% (weight of described pharmaceutical composition
Amount/weight), described binding agent accounts for about 2% to about 8% (w/w) of described pharmaceutical composition, described tax
Shape agent accounts for about 20% to about 45% (w/w) of described pharmaceutical composition, and described lubricant accounts for described
About the 1% of pharmaceutical composition is to about 4% (w/w).
In some preferred embodiments, the method for preparation said medicine preparation comprises the following steps:
(1). pleasure is cut down for Buddhist nun or its pharmaceutically acceptable salt or its solvate, calcium hydrogen phosphate, disintegrating agent,
Binding agent and excipient mixing；
(2). mixture step 1 obtained is dried and sieves；With
(3). add excipient and lubricant and mix.
The pharmaceutical composition of the present invention and pharmaceutical preparation can be used for treatment and/or prophylaxis of tumours relevant disease.One
In a little embodiments, the present invention provides described pharmaceutical composition or pharmaceutical preparation for treatment and/or prophylaxis of tumours
The method of relevant disease, described method includes giving treatment to patient in need and/or preventing effective dose
The pharmaceutical composition of the present invention or pharmaceutical preparation.In other embodiments, the present invention provides described medicine
Compositions or pharmaceutical preparation application in the medicine that preparation is used for treatment and/or prophylaxis of tumours relevant disease.?
In some embodiments, according to the present invention, described tumor-related illness can be thyroid carcinoma, non-small cell
Property pulmonary carcinoma, melanoma, hypopharyngeal carcinoma, esophageal carcinoma, gastric cancer, colorectal cancer, hepatocarcinoma, renal cell carcinoma,
Cancer of pancreas, bladder cancer, breast carcinoma, uterus carcinoma, ovarian cancer, carcinoma of prostate, carcinoma of testis, Gastrointestinal Stromal
Tumor, sarcoma, osteosarcoma, hemangioma, malignant lymphoma, myelomatosis, neuroma, neuroglia
Tumor etc..
In this article, described compound " 4-[3-chloro-4-(cyclopropylaminocarbonyl) amino-benzene oxygen]-7-methoxyl group
-6-quinoline formyl amine " or its pharmaceutically acceptable salt contain their any crystal formation, hydrate and solvate.
Accompanying drawing explanation
Fig. 1 represents that the compound A's in the preparation obtained by comparative example 1, comparative example 2 and embodiment 1-6 is molten
Going out curve chart, wherein, 1 represents the dissolution of the compound A in the preparation that comparative example 1 (ordinary recipe) obtains
Curve chart；2 represent that the dissolution of the compound A in the preparation that comparative example 2 (calcium carbonate listing prescription) obtains is bent
Line chart；3 represent that the dissolution of the compound A in the preparation that embodiment 1 (10% calcium phosphate dibasic anhydrous) obtains is bent
Line chart；4 represent that the dissolution of the compound A in the preparation that embodiment 2 (25% calcium phosphate dibasic anhydrous) obtains is bent
Line chart；5 represent that the dissolution of the compound A in the preparation that embodiment 3 (33% calcium phosphate dibasic anhydrous) obtains is bent
Line chart；6 represent that the dissolution of the compound A in the preparation that embodiment 4 (10% dicalcium phosphate dehydrate) obtains is bent
Line chart；7 represent that the dissolution of the compound A in the preparation that embodiment 5 (25% dicalcium phosphate dehydrate) obtains is bent
Line chart；8 represent that the dissolution of the compound A in the preparation that embodiment 6 (33% dicalcium phosphate dehydrate) obtains is bent
Line chart.
Fig. 2 represents adding of the compound A in the preparation obtained by comparative example 1, comparative example 2 and embodiment 1-6
7 days stripping curve figures of speed, wherein, 1 represents in the preparation that comparative example 1 (ordinary recipe accelerates 7 days) obtains
The stripping curve figure of compound A；2 represent what comparative example 2 (calcium carbonate listing prescription accelerates 7 days) obtained
The stripping curve figure of the compound A in preparation；3 represent embodiment 1 (10% calcium phosphate dibasic anhydrous accelerates 7 days)
The stripping curve figure of the compound A in the preparation obtained；4 represent that (25% calcium phosphate dibasic anhydrous adds embodiment 2
Speed 7 days) the stripping curve figure of compound A in the preparation that obtains；5 represent embodiment 3 (33% anhydrous phosphorus
Acid hydrogen calcium accelerates 7 days) the stripping curve figure of compound A in the preparation that obtains；6 represent embodiment 4 (10%
Dicalcium phosphate dehydrate accelerates 7 days) the stripping curve figure of compound A in the preparation that obtains；7 represent enforcement
The stripping curve figure of the compound A in the preparation that example 5 (25% dicalcium phosphate dehydrate accelerates 7 days) obtains；8
The dissolution of the compound A in the preparation that expression embodiment 6 (33% dicalcium phosphate dehydrate accelerates 7 days) obtains
Curve chart.
Fig. 3 represents the stripping curve figure of the compound A in the preparation obtained by embodiment 7 and embodiment 8,
Wherein, the stripping curve figure of the compound A in the preparation that 1 expression embodiment 7 (dry granulation) obtains, 2
The stripping curve figure of the compound A in the preparation that expression embodiment 8 (micropill medicine-feeding) obtains.
Fig. 4 represents the compound A's in the preparation obtained by comparative example 3, comparative example 4 and embodiment 9-11
Stripping curve figure.Wherein, 1 represents that the compound A's in the preparation that comparative example 3 (conventional tablet) obtains is molten
Go out curve chart；2 dissolutions representing the compound A in the preparation that comparative example 4 (calcium carbonate listing prescription) obtains
Curve chart；3 represent the compound A's in the preparation that embodiment 9 (10% calcium phosphate dibasic anhydrous tablet) obtains
Stripping curve figure；4 represent the compound in the preparation that embodiment 10 (25% calcium phosphate dibasic anhydrous tablet) obtains
The stripping curve figure of A；5 represent in the preparation that embodiment 11 (33% calcium phosphate dibasic anhydrous tablet) obtains
The stripping curve figure of compound A.
Detailed description of the invention
The most representational embodiment and experimental example are in order to the present invention is better described, not for limiting this
The protection domain of invention.
Preparation example
Prepare happy cutting down with reference to the method disclosed in international patent application WO2002/032872 to cut down for Buddhist nun for Buddhist nun, pleasure
Mesylate, happy cutting down crystallize for Buddhist nun's mesylate c-type, with reference in international patent application WO2006/030826
Disclosed method preparation is happy cuts down other crystallizations for Buddhist nun's mesylate, such as A, B, F, I crystallization and A ' and B '
Crystalline polymorph etc., and confirmed by mass spectrum and X ray diffracting spectrum.WO2002/032872 and
Two documents of WO2006/030826 are incorporated herein by reference with their full content.
Comparative example 1
Pleasure is cut down for Buddhist nun's mesylate c-type crystallization (hereinafter referred to as compound A), PEARLITOL 25C (France Luo Gaite
Company), hydroxypropyl cellulose (HPC, Tso Tat Co., Ltd., Japan), low-substituted hydroxypropyl cellulose (L-HPC,
Shin-Etsu Chemial Co., Ltd) and microcrystalline Cellulose PH-101 (Anhui Shanhe Medical Accessary Material Co., Ltd.),
With the prescription ratio of table 1, use wet granulator, with purified water as wetting agent, wet granulation.Use stream
Changing bed to be further dried, be formed as the moisture granule less than 2%, 20 mesh arrange.Then, with table 1
Prescription ratio, (Germany's JRS pharmaceutic adjuvant is public to add microcrystalline Cellulose PH-102 in the granule that granulate is crossed
Department) and Pulvis Talci (Guilin Gui Guang Talcum development corporation, Ltd.), use mixer mixing, the granule that will obtain
100mg fills to No. 4 hard capsules, manufactures the capsule containing compound A.
Table 1
| Comparative example 1 | |
| Compound A | 12.5 |
| PEARLITOL 25C | 13.5 |
| Hydroxypropyl cellulose | 3 |
| Low-substituted hydroxypropyl cellulose | 25 |
| Microcrystalline Cellulose PH-101 | 38 |
| Microcrystalline Cellulose PH-102 | 5 |
| Pulvis Talci | 3 |
| Amount to | 100 |
Unit: weight %
Comparative example 2
By compound A, PEARLITOL 25C (Roquette Freres of France), winnofil (Whiten F, Bai Shi
Calcium Co., Ltd.), hydroxypropyl cellulose (HPC, Tso Tat Co., Ltd., Japan), low substituted hydroxy-propyl fiber
(mountains and rivers, Anhui is medicinal auxiliary for element (L-HPC, Shin-Etsu Chemial Co., Ltd) and microcrystalline Cellulose PH-101
Material company limited), with the prescription ratio of table 2, use wet granulator, with purified water as wetting agent, wet method
Pelletize.Employing fluid bed is further dried, and is formed as the moisture granule less than 2%, and 30 mesh arrange.So
After, with the prescription ratio of table 2, in the granule that granulate is crossed, add microcrystalline Cellulose PH-102 (Germany JRS
Pharmaceutic adjuvant company) and Pulvis Talci (Guilin Gui Guang Talcum development corporation, Ltd.), use mixer mixing, will
The granule 100mg obtained fills to No. 4 hard capsules, manufactures the capsule containing compound A.
Table 2
| Comparative example 2 | |
| Compound A | 12.5 |
| Winnofil | 33 |
| PEARLITOL 25C | 8.5 |
| Hydroxypropyl cellulose | 3 |
| Low-substituted hydroxypropyl cellulose | 25 |
| Microcrystalline Cellulose PH-101 | 10 |
| Microcrystalline Cellulose PH-102 | 5 |
| Pulvis Talci | 3 |
| Amount to | 100 |
Unit: weight %
Comparative example 3
By compound A, lactose monohydrate (Mei Jile group of Germany), hydroxypropyl cellulose (HPC, Japan's letter
More), low-substituted hydroxypropyl cellulose (L-HPC, Shin-Etsu Chemial Co., Ltd), sodium stearyl fumarate (moral
JRS pharmaceutic adjuvant company of state) and microcrystalline Cellulose PH-102 (Germany JRS pharmaceutic adjuvant company), with table 3
Prescription ratio, use multifunctional mini-mixer (Xinyi, Shenzhen spy Science and Technology Ltd.) mix homogeneously, granule
With ZP-10A rotary tablet machine (Beijing Gylongli Sci.&Tech. Co., Ltd.) 8mm shallow arc stamping, prepare
Tablet use the water-soluble coating solution of yellow (Opadry, Shanghai Colorcon Coating Technology Co., Ltd) coating,
Manufacturing the tablet containing compound A, tablet weight is 200mg.
Table 3
| Comparative example 3 | |
| Compound A | 12.5 |
| Lactose monohydrate | 38 |
| Hydroxypropyl cellulose | 3 |
| Low-substituted hydroxypropyl cellulose | 5 |
| Microcrystalline Cellulose PH-102 | 40.5 |
| Sodium stearyl fumarate | 1 |
| Amount to | 100 |
Unit: weight %
Comparative example 4
By compound A, lactose monohydrate (Germany Mei Jile group), winnofil (you are strange for Japan's calcium),
Hydroxypropyl cellulose (HPC, Shin-Etsu Chemial Co., Ltd of Japan), low-substituted hydroxypropyl cellulose
(Germany's JRS pharmaceutic adjuvant is public for (L-HPC, Shin-Etsu Chemial Co., Ltd of Japan), sodium stearyl fumarate
Department) and microcrystalline Cellulose PH-102 (German JRS pharmaceutic adjuvant company), with the prescription ratio of table 4, make
With multifunctional mini-mixer (Xinyi, Shenzhen spy Science and Technology Ltd.) mix homogeneously, granule rotates pressure with ZP-10A
Sheet machine (Beijing Gylongli Sci.&Tech. Co., Ltd.) 8mm shallow arc stamping, prepared tablet uses yellow water
Molten coating solution (Opadry, Shanghai Colorcon Coating Technology Co., Ltd) coating, manufactures containing compound A
Tablet, tablet weight is 200mg.
Table 4
| Comparative example 4 | |
| Compound A | 12.5 |
| Winnofil | 33 |
| Lactose monohydrate | 28 |
| Hydroxypropyl cellulose | 3 |
| Low-substituted hydroxypropyl cellulose | 5 |
| Microcrystalline Cellulose PH-102 | 17.5 |
| Sodium stearyl fumarate | 1 |
| Amount to | 100 |
Unit: weight %
Embodiment 1～3
By compound A, PEARLITOL 25C (France Roquette Freres), calcium phosphate dibasic anhydrous (Merck KGaA),
Hydroxypropyl cellulose (HPC, Tso Tat Co., Ltd., Japan), low-substituted hydroxypropyl cellulose (L-HPC, letter
More chemical industry Co., Ltd.) and microcrystalline Cellulose PH-101 (Anhui Shanhe Medical Accessary Material Co., Ltd.), with
The prescription ratio of table 5, uses wet granulator, with purified water as wetting agent, wet granulation.Use fluidisation
Bed is further dried, and is formed as the moisture granule less than 2%, and 30 mesh arrange.Then, with the place of table 5
Side's ratio, adds microcrystalline Cellulose PH-102 (Germany JRS pharmaceutic adjuvant company) in the granule that granulate is crossed
With Pulvis Talci (Guilin Gui Guang Talcum development corporation, Ltd.), use mixer mixing, the granule 100mg that will obtain
Fill to No. 4 hard capsules, manufacture the capsule containing compound A.
Table 5
| Embodiment 1 | Embodiment 2 | Embodiment 3 | |
| Compound A | 12.5 | 12.5 | 12.5 |
| Calcium phosphate dibasic anhydrous | 10 | 25 | 33 |
| PEARLITOL 25C | 8.5 | 8.5 | 8.5 |
| Hydroxypropyl cellulose | 3 | 3 | 3 |
| Low-substituted hydroxypropyl cellulose | 25 | 25 | 25 |
| Microcrystalline Cellulose PH-101 | 33 | 18 | 10 |
| Microcrystalline Cellulose PH-102 | 5 | 5 | 5 |
| Pulvis Talci | 3 | 3 | 3 |
| Amount to | 100 | 100 | 100 |
Unit: weight %
Embodiment 4～6
By compound A, PEARLITOL 25C (Roquette Freres of France), dicalcium phosphate dehydrate (Huzhou prospect Pharmaceutical
Company limited), hydroxypropyl cellulose (HPC, Tso Tat Co., Ltd., Japan), low-substituted hydroxypropyl cellulose
(L-HPC, Shin-Etsu Chemial Co., Ltd) and the microcrystalline Cellulose PH-101 (mountains and rivers, Anhui pharmaceutic adjuvant
Company limited), with the prescription ratio of table 6, use wet granulator, with purified water as wetting agent, wet method system
Grain.Employing fluid bed is further dried, and is formed as the moisture granule less than 2%, and 30 mesh arrange.Then,
With the prescription ratio of table 6, (JRS is medicinal in Germany to add microcrystalline Cellulose PH-102 in the granule that granulate is crossed
Adjuvant company) and Pulvis Talci (Guilin Gui Guang Talcum development corporation, Ltd.), use mixer mixing, will obtain
Granule 100mg fill in No. 4 hard capsules, manufacture the capsule containing compound A.
Table 6
| Embodiment 4 | Embodiment 5 | Embodiment 6 | |
| Compound A | 12.5 | 12.5 | 12.5 |
| Dicalcium phosphate dehydrate | 10 | 25 | 33 |
| PEARLITOL 25C | 8.5 | 8.5 | 8.5 |
| Hydroxypropyl cellulose | 3 | 3 | 3 |
| Low-substituted hydroxypropyl cellulose | 25 | 25 | 25 |
| Microcrystalline Cellulose PH-101 | 33 | 18 | 10 |
| Microcrystalline Cellulose PH-102 | 5 | 5 | 5 |
| Pulvis Talci | 3 | 3 | 3 |
| Amount to | 100 | 100 | 100 |
Unit: weight %
Embodiment 7
By compound A, lactose monohydrate (Mei Jile group of Germany), dicalcium phosphate dehydrate (Huzhou prospect Pharmaceutical
Company limited), PVP K30 (Huzhou Zhanwang Pharmaceutical Co., Ltd.), polyvinylpolypyrrolidone XL (PVPP-XL,
International Specialty Products company of the U.S.) and microcrystalline Cellulose PH-101 (Anhui Shanhe Medical Accessary Material Co., Ltd.), with table
The prescription ratio of 7, uses dry granulating machine, is pressed into granule, and 20 mesh arrange.Then, with the place of table 7
Side's ratio, adds microcrystalline Cellulose PH-102 (Germany JRS pharmaceutic adjuvant company) in the granule that granulate is crossed
With magnesium stearate (Anhui Shanhe Medical Accessary Material Co., Ltd.), use mixer mixing, the granule that will obtain
100mg fills to No. 4 hard capsules, manufactures the capsule containing compound A.
Table 7
Unit: weight %
Embodiment 8
Compound A is swollen in purified water, in fluid bed (wound will electromechanics development in science and technology company limited), with
Blank MCC micropill (Anhui Shanhe Medical Accessary Material Co., Ltd.) is carrier, uses capsule core medicine-feeding method preparationization
Compound A micropill, uses HPLC method to measure the content of compound A, pours into capsule according to theoretical loading amount.
Embodiment 9～11
By compound A, lactose monohydrate (Mei Jile group of Germany), calcium phosphate dibasic anhydrous (Huzhou prospect Pharmaceutical
Company limited), hydroxypropyl cellulose (HPC, Japan SHIN-ETSU HANTOTAI), low-substituted hydroxypropyl cellulose (L-HPC,
Shin-Etsu Chemial Co., Ltd), sodium stearyl fumarate (Germany JRS pharmaceutic adjuvant company) and microcrystalline cellulose
Element PH-102 (Germany JRS pharmaceutic adjuvant company), with the prescription ratio of table 8, uses multifunctional mini-mixer (deep
Zhen Shi Xinyi spy Science and Technology Ltd.) mix homogeneously, granule is with ZP-10A rotary tablet machine (Beijing traditional Chinese medicines dragon
Vertical Science and Technology Ltd.) 8mm shallow arc stamping, prepared tablet use the water-soluble coating solution of yellow (Opadry,
Shanghai Colorcon Coating Technology Co., Ltd) coating, manufacture the tablet containing compound A, tablet weight is 200mg.
Table 8
| Embodiment 9 | Embodiment 10 | Embodiment 11 | |
| Compound A | 12.5 | 12.5 | 12.5 |
| Calcium phosphate dibasic anhydrous | 10 | 25 | 33 |
| Lactose monohydrate | 28 | 28 | 28 |
| Hydroxypropyl cellulose | 3 | 3 | 3 |
| Low-substituted hydroxypropyl cellulose | 5 | 5 | 5 |
| Microcrystalline Cellulose PH-102 | 40.5 | 25.5 | 17.5 |
| Sodium stearyl fumarate | 1 | 1 | 1 |
| Amount to | 100 | 100 | 100 |
Unit: weight %
Experimental example 1
Use with a batch of compound A, by compound A and calcium phosphate dibasic anhydrous 1:1, compound A with
Calcium carbonate 1:1 precision weighing, is placed in cillin bottle, vortex 3min, is respectively placed in high temperature 60 DEG C, high humidity
Uncovered placement under the conditions of 92.5%RH, illumination 4500lux, in sampling in the 10th day, uses HPLC mensurationization
The catabolite (having related substance) of compound A, compares the stability of three.Related substance summary sheet is had to see table 9.
Table 9
Result shows, under the conditions of above three, calcium phosphate dibasic anhydrous all can significantly inhibit the product of degradation impurity
Raw, produced impurity content is all less than 1 ‰；And the ability of calcium carbonate suppression impurity generation is more weak, and
Retention time is all to produce the content impurity more than 1 ‰ at 23.2min.Especially under high temperature, illumination condition,
Calcium phosphate dibasic anhydrous is substantially better than calcium carbonate.
Experimental example 2
By embodiment 1～6 and the capsule of comparative example 1～2, correct described in Pharmacopeia of Japan according to the 15th edition
Dissolution laboratory method (paddle method 50rpm, test liquid: pH 1.2 hydrochloric acid), the stripping property of compound A is carried out
Research (n=6 seed lac capsule).Experimental result is as shown in Figure 1.Result shows, is not added with calcium carbonate or anhydrous phosphorus
In the comparative example 1 of acid hydrogen calcium or dicalcium phosphate dehydrate, the dissolution of compound A is insufficient, containing anhydrous phosphoric acid hydrogen
The embodiment 1 of calcium or dicalcium phosphate dehydrate～6 and comparative example calciferous 2 all can substantially suppress gelation,
Dissolution is complete.It addition, from experimental result it can be seen that the use 33% calcium phosphate dibasic anhydrous group (5 of the present invention
Minute dissolution rate 85%) or the dissolution rate of 33% dicalcium phosphate dehydrate group (5 minutes dissolution rates 84%) bright
Show and be better than 10% calcium phosphate dibasic anhydrous group (5 minutes dissolution rates 76%), 25% calcium phosphate dibasic anhydrous group (5 points
Clock dissolution rate 75%), 10% dicalcium phosphate dehydrate group (5 minutes dissolution rates 71%), 25% dicalcium phosphate dehydrate
Group (5 minutes dissolution rates 64%).
Experimental example 3
By embodiment 1～6 and the capsule of comparative example 1～2, at temperature 40 DEG C, the acceleration bar of relative humidity 75%
Preserve one week under part, according to the 15th edition dissolution laboratory method corrected described in Pharmacopeia of Japan (paddle method, reality
Test liquid: pH 1.2 hydrochloric acid), the stripping property of compound A is studied.Experimental result is as shown in Figure 2.Knot
Fruit shows, is not added with in the comparative example 1 of calcium carbonate or calcium phosphate dibasic anhydrous or dicalcium phosphate dehydrate, compound A
Dissolution insufficient, embodiment containing calcium phosphate dibasic anhydrous or dicalcium phosphate dehydrate 1～6 and ratio calciferous
Relatively example 2 all can dissolution complete, but containing calcium phosphate dibasic anhydrous or embodiment 1～6 dissolution of dicalcium phosphate dehydrate
Rapider, dissolution is the most slack-off under acceleration conditions.It addition, from experimental result it can be seen that the present invention
Use 33% calcium phosphate dibasic anhydrous group (5 minutes dissolution rates 94%) or 33% dicalcium phosphate dehydrate group (5 minutes
Dissolution rate 92%) dissolution rate be substantially better than 10% calcium phosphate dibasic anhydrous group (5 minutes dissolution rates 88%),
25% calcium phosphate dibasic anhydrous group (5 minutes dissolution rates 85%), 10% dicalcium phosphate dehydrate group (5 minutes dissolution rates
75%), 25% dicalcium phosphate dehydrate group (5 minutes dissolution rates 73%).
Experimental example 4
Compound A capsule embodiment 7～8 prepared, corrects described in Pharmacopeia of Japan according to the 15th edition
Dissolution laboratory method (paddle method 50rpm, test liquid: pH 1.2 hydrochloric acid), the stripping property of compound A is carried out
Research.Result shows, both can discharge rapidly completely (Fig. 3), and this explanation calcium phosphate dibasic anhydrous can show
Write the dissolving out capability improving compound A, and do not affected by its adjuvant, dosage form.
Experimental example 5
By embodiment 9～11 and the tablet of comparative example 3,4, correct Pharmacopeia of Japan according to the 15th edition and remembered
The dissolution laboratory method (paddle method 50rpm tests liquid: pH 1.2 hydrochloric acid) carried, enters the stripping property of compound A
Row research (n=6 seed lac capsule).Result shows, is not added with in the comparative example 3 of calcium carbonate or calcium phosphate dibasic anhydrous,
The dissolution of compound A is insufficient, embodiment containing calcium phosphate dibasic anhydrous 9～11 and comparative example calciferous 4
All energy dissolutions are complete, but embodiments of the invention 9～11 dissolution is more rapidly (Fig. 4), and this illustrates anhydrous phosphoric acid
Hydrogen calcium can significantly improve the dissolving out capability of the compound A in tablet.It addition, from experimental result it can be seen that
The dissolution rate of the use 33% calcium phosphate dibasic anhydrous group (5 minutes dissolution rates 94%) of the present invention is substantially better than
10% calcium phosphate dibasic anhydrous group (5 minutes dissolution rates 85%) and (dissolution in 5 minutes of 25% calcium phosphate dibasic anhydrous group
Rate 84%).
Although below the present invention being described in detail, however it is understood by skilled practitioners that the most inclined
On the premise of the spirit and scope of the present invention, the present invention can be carried out various modifications and changes.The present invention's
Interest field is not limited to the detailed description made above, and should belong to claims.
Claims (10)
1. a pharmaceutical composition, it contains
(1) 4-[3-chloro-4-(cyclopropylaminocarbonyl) amino-benzene oxygen]-7-methoxyl group-6-quinoline formyl amine or its
Pharmaceutically acceptable salt；With
(2) calcium hydrogen phosphate.
Pharmaceutical composition the most according to claim 1, wherein said calcium hydrogen phosphate is dicalcium phosphate dehydrate
Or calcium phosphate dibasic anhydrous.
Pharmaceutical composition the most according to claim 1 and 2, it contains disintegrating agent further, it is preferable that
Described disintegrating agent is carboxymethyl cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, carboxymethyl starch
Sodium, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, corn starch, portion
Divide one or more in alphalysed starch and hydroxypropyl starch.
4., according to the pharmaceutical composition described in any one of claim 1-3, it comprises excipient further, glues
Mixture and lubricant.
5. according to the pharmaceutical composition described in any one of claim 1-4, wherein said pharmaceutically acceptable
Salt is hydrochlorate, hydrobromate, tosilate, sulfate, mesylate or esilate.
Pharmaceutical composition the most according to claim 5, wherein said pharmaceutically acceptable salt is 4-[3-
Chloro-4-(cyclopropylaminocarbonyl) amino-benzene oxygen]-7-methoxyl group-6-quinoline formyl amine mesylate.
7., according to the pharmaceutical composition described in any one of claim 1-6, it is by 4-[3-chloro-4-(cyclopropylamino
Carbonyl) amino-benzene oxygen]-7-methoxyl group-6-quinoline formyl amine or its pharmaceutically acceptable salt, calcium hydrogen phosphate,
Disintegrating agent, binding agent, lubricant and excipient composition, wherein with 4-[3-chloro-4-(cyclopropylaminocarbonyl) ammonia
Phenoxyl] gauge of-7-methoxyl group-6-quinoline formyl amine, described 4-[3-chloro-4-(cyclopropylaminocarbonyl) amino
Phenoxy group]-7-methoxyl group-6-quinoline formyl amine or its pharmaceutically acceptable salt account for the pact of described pharmaceutical composition
5% to about 70% (w/w), described calcium hydrogen phosphate accounts for about 5% to about 70% (weight of described pharmaceutical composition
Amount/weight), described disintegrating agent accounts for about 2% to about 40% (w/w) of described pharmaceutical composition, described viscous
Mixture accounts for about 1% to about 20% (w/w) of described pharmaceutical composition, and described excipient accounts for described medicine group
About the 15% of compound is to about 80% (w/w), and described lubricant accounts for the pact of described pharmaceutical composition
0.5% to about 10% (w/w)；Preferably, described 4-[3-chloro-4-(cyclopropylaminocarbonyl) aminobenzene oxygen
Base]-7-methoxyl group-6-quinoline formyl amine or its pharmaceutically acceptable salt account for about the 10% of described pharmaceutical composition
To about 50% (w/w), described calcium hydrogen phosphate accounts for about 10% to about 40% (weight of described pharmaceutical composition
Amount/weight), described disintegrating agent accounts for about 3% to about 30% (w/w) of described pharmaceutical composition, described viscous
Mixture accounts for about 2% to about 10% (w/w) of described pharmaceutical composition, and described excipient accounts for described medicine group
About the 20% of compound is to about 70% (w/w), and described lubricant accounts for the pact of described pharmaceutical composition
0.5% to about 5% (w/w)；It is highly preferred that described 4-[3-chloro-4-(cyclopropylaminocarbonyl) aminobenzene
Epoxide]-7-methoxyl group-6-quinoline formyl amine or its pharmaceutically acceptable salt account for the pact of described pharmaceutical composition
10% to about 25% (w/w), described calcium hydrogen phosphate accounts for about the 30% to about 35% of described pharmaceutical composition
(w/w), described disintegrating agent accounts for about 5% to about 30% (w/w) of described pharmaceutical composition, described
Binding agent accounts for about 2% to about 8% (w/w) of described pharmaceutical composition, and described excipient accounts for described medicine
About the 20% of compositions is to about 45% (w/w), and described lubricant accounts for the pact of described pharmaceutical composition
1% to about 4% (w/w).
8. a pharmaceutical preparation, it comprises according to the pharmaceutical composition described in any one of claim 1-7.
Pharmaceutical preparation the most according to claim 8, its be tablet, granule, powder, slow releasing agent,
Drop pill or capsule, it is preferable that described slow releasing agent is slow-release micro-pill.
10. according to the pharmaceutical composition described in any one of claim 1-7 or according to claim 8 or claim 9
Pharmaceutical preparation preparation for treatment and/or prophylaxis of tumours relevant disease medicine in application.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106551935A (en) * | 2015-09-24 | 2017-04-05 | 江苏奥赛康药业股份有限公司 | Containing happy pharmaceutical composition cut down for Buddhist nun and preparation method thereof |
| CN112190583A (en) * | 2019-07-08 | 2021-01-08 | 成都苑东生物制药股份有限公司 | Levatinib pharmaceutical composition and preparation method thereof |
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| CN102600149A (en) * | 2012-02-02 | 2012-07-25 | 西藏易明西雅生物医药科技有限公司 | Pharmaceutical composition for treating diabetes |
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| CN106551935A (en) * | 2015-09-24 | 2017-04-05 | 江苏奥赛康药业股份有限公司 | Containing happy pharmaceutical composition cut down for Buddhist nun and preparation method thereof |
| CN106551935B (en) * | 2015-09-24 | 2020-04-14 | 江苏奥赛康药业有限公司 | Pharmaceutical composition containing lenvatinib and preparation method thereof |
| CN112190583A (en) * | 2019-07-08 | 2021-01-08 | 成都苑东生物制药股份有限公司 | Levatinib pharmaceutical composition and preparation method thereof |
| CN112190583B (en) * | 2019-07-08 | 2021-10-29 | 成都苑东生物制药股份有限公司 | Levatinib pharmaceutical composition and preparation method thereof |
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