CN108210468B - A kind of preparation method of Sorafenib Tosylate oral administration nanometer preparation - Google Patents
A kind of preparation method of Sorafenib Tosylate oral administration nanometer preparation Download PDFInfo
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Abstract
The invention discloses a kind of preparation method of Sorafenib Tosylate oral administration nanometer preparation, include the following steps: 1) to prepare Sorafenib Tosylate solution and excipient substance aqueous solution respectively；2) it obtained Sorafenib Tosylate solution will be prepared is separately added into high gravity rotating packed bed with excipient substance aqueous solution and recrystallize, control system temperature is 0~40 DEG C, obtains Sorafenib Tosylate nano suspending liquid；3) gained Sorafenib Tosylate nano suspending liquid is freeze-dried, obtains Sorafenib Tosylate oral administration nanometer preparation.The Sorafenib Tosylate oral administration nanometer preparation that the preparation method obtains has than Sorafenib Tosylate bulk pharmaceutical chemicals with faster dissolution rate, and it can faster reach higher blood concentration, the bioavilability for effectively improving Sorafenib Tosylate is more advantageous to the performance of drug effect.
Description
Technical field
The present invention relates to field of pharmaceutical preparations.More particularly, to a kind of Sorafenib Tosylate oral administration nanometer preparation
Preparation method.
Background technique
Sorafenib Tosylate (Sorafenib Tosylate), chemical name are 4- { 4- [3- (the chloro- 3- fluoroform of 4-
Base-phenyl)-uride]-phenoxy group }-pyridine-2-carboxylic acids methylamine -4- toluene fulfonate, molecular formula is
C21H16ClF3N4O3.C7H8O3S molecular structural formula is as follows:
Sorafenib Tosylate is a kind of new oral multiple target point molecular targeted agents, and being mainly used for treatment cannot perform the operation
Liver cancer, clear-cell carcinoma and thyroid cancer, trade name Nexavar (Nexavar).By inhibit tumour cell CRAF,
The target areas such as BRAF, c-Kit, FLT-3 and the target areas such as tumor vascular CRAF, VEGFR-2, VEGFR-3, PDGFR- β, toluene
Sulfonic acid Sorafenib, which has, inhibits RAF/MEK/ERK signal transduction pathway, inhibits the proliferation of tumour cell, and directly inhibition tumour is raw
Long effect also has and inhibits vascular endothelial growth factor, platelet derived growth factor and its receptor, and blocks tumor neogenetic
The growth of the indirect inhibition tumour cell of the formation of blood vessel.Sorafenib Tosylate be practically insoluble in water (60 μ g/mL,
PH=6), belong to BCS (biopharmaceutics classification system) II class drug, i.e. low solubility is hypertonic
Permeability, the dissolution rate of such drug are the speed limit processes absorbed.
Improve insoluble drug dissolution rate, improve the lower bioavilability of drug, can by by insoluble drug at
Salt, micronization is prepared into emulsion or from microemulsion using non-aqueous solvent/cosolvent, cyclodextrin encapsulated, not using thermodynamics
Stable crystal form is prepared into the Chang Fangfa such as solid dispersions.For example, having in the prior art with vinyl acetate groups
The excipient substance of (VA group) is cosolvent, improves degree of super saturation of the Sorafenib in dissolution medium；Either using molten
Melt-solvent method prepares Sorafenib Tosylate solid dispersions, solvent volatilization-cooling method prepares sorafenib organogel,
Inclusion compound is made in Sorafenib and hydroxypropyl-β-cyclodextrin and oral or injection Sorafenib self-emulsifying microemulsion is administered
System increases the solubility of Sorafenib Tosylate, to improve the hydrophily of Sorafenib Tosylate so as to improve toluene
Bioavilability of the sulfonic acid Sorafenib in human body.But these methods are complex, and imitate to the improvement of bioavilability
Fruit is limited.The report of its bioavilability is improved currently, having no by preparing Sorafenib Tosylate nanometer formulation.
According to Ostwald-Freundrich equation, drug-eluting rate and size of pharmaceutical particles are in inverse ratio, with drug
Grain specific surface area is directly proportional, therefore reduces drug granule partial size, effectively increases drug specific surface area, can greatly improve its dissolution
Rate reduces individual difference to significantly improve the bioavilability of drug, reduces toxic side effect.Liquid-phase precipitation crystallisation is
Obtain receiving the most general method of micro- drug granule in pharmaceuticals industry.Due to the limitation of agitating paddle in traditional crystallizer, cause
Mixing is uneven in equipment, or even the appearance in mixing dead zone, and inhomogenous so as to cause each point concentration distribution in device, nucleation process exists
It is carried out in micro heterogeneous, so that prepared drug granule size distribution is uneven, poor reproducibility between batch.
Therefore, in view of the above problems, needing to provide the new improvement Sorafenib Tosylate of one kind in the biology benefit of human body
The method of expenditure.
Summary of the invention
The first purpose of this invention is to provide a kind of preparation method of Sorafenib Tosylate oral administration nanometer preparation,
For improving the dissolution rate and bioavilability of Sorafenib Tosylate preparation.
Second object of the present invention is to provide that Sorafenib Tosylate that the preparation method is prepared is oral receives
Metric system agent.
In order to achieve the above first purpose, the present invention adopts the following technical solutions:
A kind of preparation method of Sorafenib Tosylate oral administration nanometer preparation, includes the following steps:
1) Sorafenib Tosylate solution and excipient substance aqueous solution are prepared respectively；
2) obtained Sorafenib Tosylate solution will be prepared and excipient substance aqueous solution is separately added into hypergravity rotation
Packed bed is recrystallized, and control system temperature is 0~40 DEG C, obtains Sorafenib Tosylate nano suspending liquid；
3) gained Sorafenib Tosylate nano suspending liquid is freeze-dried, obtains Sorafenib Tosylate oral administration nanometer
Preparation.
In the present invention, it is creative by high-gravity technology be used to improve Sorafenib Tosylate preparation dissolution rate and
In bioavilability.The rotation that high-gravity technology relies on high gravity rotating packed bed internal rotor generates simulation Elevated Gravity,
It realizes that object phase flows in Elevated Gravity with porous media generation to contact, liquid crushing is generated at nanoscale film, silk and drop
Phase interface that is huge and quickly updating improves 1~3 order of magnitude in the tower that interphase mass transfer speed ratio can be made traditional, and greatly
The microcosmic mixing of reinforcing and mass transport process.To which in high gravity rotating packed bed, nucleation process is in microcosmic uniform environment
It carries out, to keep nucleation process controllable.Meanwhile, it is capable to increase substantially the conversion ratio and selectivity of reaction, reduce significantly anti-
The volume of device is answered, technique, process are simplified, realizes the energy-efficient of process, reduces disposal of pollutants.
In the present invention, in high gravity rotating packed bed the control of system temperature for obtained nanometer formulation granularity it is big
The drug-eluting rate of small, epigranular degree and product plays an important role.When system temperature is 0~40 DEG C, it is prepared into
The nanometer formulation partial size arrived is small and uniform, and drug-eluting rate is fast.Preferably, in step 2), the system temperature is 5~20
DEG C, foregoing advantages are best at this time.
According to the dissolution properties of Sorafenib Tosylate, solvent is preferably able to dissolution Sorafenib Tosylate, simultaneously
For the lower solvent of toxicity.Preferably, in step 1), the solvent in Sorafenib Tosylate solution prepared is selected from first
One or more of alcohol, dehydrated alcohol, dimethyl sulfoxide and acetone.
Interaction between excipient substance and drug influences the nucleation rate and growth speed of Sorafenib Tosylate
Rate preferably facilitates to increase drug nucleation rate, reduces the excipient substance of crystal growth rate.Preferably, the excipient substance
Excipient substance in aqueous solution be polyethylene glycol, poloxamer, polyvinylpyrrolidone, hydroxypropyl methyl cellulose, mannitol,
The mixture of one or more of lauryl sodium sulfate, chitosan, sodium alginate and lactose.
Preferably, in step 1), the concentration of the Sorafenib Tosylate solution is 2g/L~50g/L；The drug
The concentration of auxiliary material aqueous solution is 2g/L~100g/L.The excessive concentration of excipient substance aqueous solution will appear arch formation because of its drug
The concentration of particle agglomeration, excipient substance aqueous solution is too low, then cannot effectively increase drug nucleation rate, reduces crystal growth speed
Rate.With this condition, the Sorafenib Tosylate solubility in Sorafenib Tosylate solution is high, and facilitates drug
Grain is uniformly dispersed and crystal growth.It is highly preferred that the concentration of the Sorafenib Tosylate solution is 10g/L~30g/L；
The concentration of the excipient substance aqueous solution is 3g/L~50g/L.
In the present invention, degree of supersaturation is to prepare Sorafenib Tosylate nano particle chief motivation, biggish satiety
Be conducive to reduce nano particle diameter with degree and help to control particle size distribution.Preferably, in step 1), the first
The volume ratio of benzene sulfonic acid Sorafenib solution and the excipient substance aqueous solution is 1:1~1:20.
Preferably, in step 2), the Sorafenib Tosylate and drug in the Sorafenib Tosylate solution are auxiliary
The mass ratio for expecting the excipient substance in aqueous solution is 1:0.5~1:10, can guarantee the dissolution rate of preparation at this time, moreover it is possible to which meeting should
The functional requirements of preparation.It is highly preferred that aforementioned mass ratio is 1:0.5~1:3；Most preferably, aforementioned mass ratio is 1:2~1:
3。
In the present invention, the adding speed of Sorafenib Tosylate solution and pharmaceutic adjuvant aqueous solution is excessive or too small can
Influence the partial size and particle size uniformity of particle in gained suspension.Preferably, in step 2), Sorafenib Tosylate solution
The speed that high gravity rotating packed bed is added is 1mL/min~300mL/min；Hypergravity rotary filling is added in pharmaceutic adjuvant aqueous solution
The speed for filling bed is 1mL/min~300mL/min.
In the present invention, high gravity rotating packed bed revolving speed influences liquid flowing state, to influence the nucleation and life of particle
Long rate.Preferably, in step 2), the high gravity rotating packed bed revolving speed is 500rpm~2840rpm, and what is obtained at this time is outstanding
The partial size of particle is more uniform in supernatant liquid.
Preferably, the high gravity rotating packed bed is outer circulation high gravity rotating packed bed.For example, outer circulation hypergravity
The structure composition and device parameter of rotary packed bed can with document (Chen J F.et al., IND ENG CHEM RES, 2015,
54 (33): 946-951.) it is consistent.
Preferably, the Sorafenib Tosylate oral administration nanometer preparation exists in the form of unformed；The toluene sulphur
The partial size of sour Sorafenib oral administration nanometer preparation is 50~900nm；More preferably 50~200nm.
The Sorafenib Tosylate oral administration nanometer preparation that preparation method of the invention is prepared can also simultaneously with one kind
Or several pharmaceutically acceptable excipient combine, and are used to prepare tablet, capsule or granular preparation.
To reach above-mentioned second purpose, the toluenesulfonic acid Suo Lafei that the present invention also protects above-mentioned preparation method to be prepared
Buddhist nun's oral administration nanometer preparation.It should be noted that tablet, being combined with for capsule or granular preparation one or more of can pharmaceutically connect
The aforementioned nanometer formulation for the excipient received is also within the scope of the present invention.
Unless otherwise specified, the raw material in the present invention can be obtained by commercially available purchase.
Beneficial effects of the present invention are as follows:
In the present invention, creative will take orally high gravity rotating packed bed technical application in Sorafenib Tosylate is received
In the preparation of metric system agent, the temperature that further selection recrystallization and control recrystallize, to obtain the toluene sulphur of Nano grade
Sour Sorafenib oral preparation, after being further freeze-dried, so that obtained preparation has than Sorafenib Tosylate original
Material medical instrument has faster dissolution rate, and the dissolution rate in 3min quickly plays curative effect, and can faster reach up to 88% or more
To higher blood concentration, the bioavilability of Sorafenib Tosylate is effectively improved, is more advantageous to the performance of drug effect.
The preparation method is that an entirety, only under the stringent cooperation of each condition of the invention, could obtain has this hair
The fast nanoscale Sorafenib Tosylate oral preparation of bright middle dissolution rate.
Detailed description of the invention
Specific embodiments of the present invention will be described in further detail with reference to the accompanying drawing.
Fig. 1 shows the scanning electron microscope (SEM) photograph of 1 Sorafenib Tosylate raw material of embodiment.
Fig. 2 shows the scanning electron microscope (SEM) photographs of particulate matter in 1 nano suspending liquid of embodiment.
Fig. 3 shows the scanning electron microscope (SEM) photograph of 1 gained Sorafenib Tosylate oral administration nanometer preparation water redisperse of embodiment.
Fig. 4 shows Sorafenib Tosylate oral administration nanometer preparation, physical mixed powder and the first that embodiment 1 is prepared
X-ray diffraction (XRD) figure of benzene sulfonic acid Sorafenib bulk pharmaceutical chemicals.
Fig. 5 shows Sorafenib Tosylate oral administration nanometer preparation, physical mixed powder and the first that embodiment 1 is prepared
The dissolution curve of benzene sulfonic acid Sorafenib bulk pharmaceutical chemicals.
Specific embodiment
In order to illustrate more clearly of the present invention, the present invention is done further below with reference to preferred embodiments and drawings
It is bright.Similar component is indicated in attached drawing with identical appended drawing reference.It will be appreciated by those skilled in the art that institute is specific below
The content of description is illustrative and be not restrictive, and should not be limited the scope of the invention with this.
Embodiment 1
A kind of preparation of Sorafenib Tosylate oral administration nanometer preparation, steps are as follows:
Sorafenib Tosylate (scanning electron microscope (SEM) photograph is as shown in Figure 1) and methanol are made into the toluene sulphur that concentration is 15g/L
Sour Sorafenib methanol solution 50mL；Polyvinylpyrrolidone and deionized water are made into the excipient substance aqueous solution of 3.75g/L
500mL；Outer circulation high gravity rotating packed bed is opened, adjusts revolving speed to 2272rpm；Feed pump is opened, toluenesulfonic acid rope is drawn
Non- Buddhist nun's methanol solution and excipient substance aqueous solution are delivered in high gravity rotating packed bed simultaneously carries out recrystallization reaction, and controls
Sorafenib Tosylate methanol solution feed rate is 2mL/min, excipient substance aqueous solution feed rate is 20mL/min, control
The temperature of reaction system processed is 10 DEG C；By obtained nano suspending liquid (Fig. 2 shows the scanning electron microscope (SEM) photographs of particulate matter in suspension)
It is freeze-dried, obtains Sorafenib Tosylate oral administration nanometer preparation, the partial size of gained preparation is 80nm or so.
Fig. 3 is the scanning electron microscope (SEM) photograph of gained Sorafenib Tosylate oral administration nanometer preparation water redisperse, as we know from the figure
It is freeze-dried to be dried to obtain nano-powder water point property is good again, it is identical as grain diameter 80nm in suspension.
As a comparison, Sorafenib Tosylate method moderate progress physics is prepared as described above with pharmaceutic adjuvant to mix
It closes, obtains physical mixed powder.
Fig. 4 is gained Sorafenib Tosylate oral administration nanometer preparation, physical mixed powder and Sorafenib Tosylate
X-ray diffraction (XRD) figure of raw material.This technique obtains Sorafenib and is in unformed state as we know from the figure.
The dissolution rate of Sorafenib Tosylate preparation is tested:
Test method are as follows: take Sorafenib Tosylate oral administration nanometer preparation obtained above, the object of certain mass respectively
Reason mixed powder and Sorafenib Tosylate bulk pharmaceutical chemicals are separately added into 300mL water pH6.8 phosphate buffer solution and (add 0.5%
SDS (lauryl sodium sulfate)) in, it sets in 37 DEG C of water-baths, revolving speed 100rpm is slowly stirred, and is sampled respectively in predetermined point of time
4mL is filtered with 0.45 micrometer syringe into centrifuge tube, and the dissolution blank medium of isothermal equivalent is added after the completion of every sub-sampling.To make
Measure obtained absorbance value within the specified scope, the corresponding blank medium of the clear solution sampled dilutes certain times
Number measures the absorbance of prepared solution in maximum absorption wave strong point.Each sample is measured in parallel 3 times.With calibration curve method meter
Its corresponding concentration is calculated, corresponding dissolution curve is drawn out.
It is mixed that Fig. 5 shows Sorafenib Tosylate oral administration nanometer preparation, the physics being prepared using above-mentioned preparation method
Close the dissolution curve of powder and Sorafenib Tosylate bulk pharmaceutical chemicals.The toluenesulfonic acid rope being prepared as we know from the figure is drawn
Non- Buddhist nun's oral administration nanometer preparation effectively improves the dissolution rate of drug, and the drug dissolution of 3min reaches 93%.
Embodiment 2
A kind of preparation of Sorafenib Tosylate oral administration nanometer preparation, steps are as follows:
Sorafenib Tosylate and dimethyl sulfoxide are made into the Sorafenib Tosylate dimethyl that concentration is 20g/L
Sulfoxide solution 500mL；Hydroxypropyl methyl cellulose and deionized water are made into the excipient substance aqueous solution 500mL of 45g/L；It opens
Outer circulation high gravity rotating packed bed adjusts revolving speed to 2840rpm；Feed pump is opened, by Sorafenib Tosylate dimethyl
Sulfoxide solution and excipient substance aqueous solution are delivered in high gravity rotating packed bed simultaneously carries out recrystallization reaction, and controls toluene
Sulfonic acid Sorafenib dimethyl sulphoxide solution feed rate is 200mL/min, excipient substance aqueous solution feed rate is 200mL/
Min, the temperature for controlling reaction system is 10 DEG C；Obtained material is freeze-dried, it is oral to obtain Sorafenib Tosylate
Nanometer formulation.The partial size of gained nanometer formulation is 120nm or so.If the dissolution rate test result of embodiment 1 is shown, it is prepared into
To Sorafenib Tosylate oral administration nanometer preparation effectively improve the dissolution rate of drug, the drug dissolution of 3min reaches
To 92%.
Embodiment 3
A kind of preparation of Sorafenib Tosylate oral administration nanometer preparation, steps are as follows:
Sorafenib Tosylate and dimethylformamide are made into the Sorafenib Tosylate diformazan that concentration is 30g/L
Base formamide solution 50mL；Hydroxypropyl methyl cellulose and dodecyl sodium sulfate that mass ratio is 1:1 are matched with deionized water
At the excipient substance aqueous solution 1000mL of 4.5g/L；Outer circulation high gravity rotating packed bed is opened, adjusts revolving speed to 800rpm；It opens
Feed pump is opened, Sorafenib Tosylate dimethyl formamide solution and excipient substance aqueous solution are delivered to hypergravity rotation simultaneously
Turn to carry out recrystallization reaction in packed bed, and controlling Sorafenib Tosylate methanol solution feed rate is 10mL/min, medicine
Object auxiliary material aqueous solution feed rate is 200mL/min, and the temperature for controlling reaction system is 10 DEG C；Obtained material is freezed
It is dry, obtain Sorafenib Tosylate oral administration nanometer preparation.The partial size of gained nanometer formulation is 200nm or so.Such as embodiment 1
Dissolution rate test result shows that the Sorafenib Tosylate oral administration nanometer preparation being prepared effectively improves drug
The drug dissolution of dissolution rate, 3min reaches 91%.
Embodiment 4
A kind of preparation of Sorafenib Tosylate oral administration nanometer preparation, steps are as follows:
It is molten that Sorafenib Tosylate and methanol are made into the Sorafenib Tosylate dimethyl sulfoxide that concentration is 15g/L
Liquid 50mL；Polyvinylpyrrolidone and dodecyl sodium sulfate and deionized water that mass ratio is 1:1 are made into the drug of 5g/L
Auxiliary material aqueous solution 750mL；Outer circulation high gravity rotating packed bed is opened, adjusts revolving speed to 2000rpm；Feed pump is opened, by first
Benzene sulfonic acid Sorafenib methanol solution and excipient substance aqueous solution are delivered in high gravity rotating packed bed simultaneously to be recrystallized
Reaction, and controlling Sorafenib Tosylate methanol solution feed rate is 10mL/min, excipient substance aqueous solution feed rate
For 150mL/min, the temperature for controlling reaction system is 0 DEG C；Obtained material is freeze-dried, toluenesulfonic acid Suo Lafei is obtained
Buddhist nun's oral administration nanometer preparation.The partial size of gained nanometer formulation is 170nm or so.If the dissolution rate test result of embodiment 1 is shown,
The Sorafenib Tosylate oral administration nanometer preparation being prepared effectively improves the dissolution rate of drug, and the drug of 3min is molten
Out-degree reaches 90%.
Embodiment 5
A kind of preparation of Sorafenib Tosylate oral administration nanometer preparation, steps are as follows:
Sorafenib Tosylate and dimethylformamide are made into the Sorafenib Tosylate diformazan that concentration is 15g/L
Base formamide solution 50mL；Hydroxypropyl methyl cellulose and dodecyl sodium sulfate that mass ratio is 1:1 are matched with deionized water
At the excipient substance aqueous solution 1000mL of 5.25g/L；Outer circulation high gravity rotating packed bed is opened, adjusts revolving speed to 2000rpm；
Feed pump is opened, Sorafenib Tosylate dimethyl formamide solution and excipient substance aqueous solution are delivered to hypergravity simultaneously
Recrystallization reaction is carried out in rotary packed bed, and control Sorafenib Tosylate methanol solution feed rate be 10mL/min,
Excipient substance aqueous solution feed rate is 200mL/min, and the temperature for controlling reaction system is 0 DEG C；Obtained material is carried out cold
It is lyophilized dry, obtains Sorafenib Tosylate oral administration nanometer preparation.The partial size of gained nanometer formulation is 150nm or so.Such as embodiment 1
Dissolution rate test result show that the Sorafenib Tosylate oral administration nanometer preparation being prepared effectively improves drug
Dissolution rate, the drug dissolution of 3min reaches 88%.
Embodiment 6
A kind of preparation of Sorafenib Tosylate oral administration nanometer preparation, steps are as follows:
The dimethyl sulfoxide that Sorafenib Tosylate and volume ratio are 1:1 is made into the first that concentration is 20g/L with methanol
Benzene sulfonic acid Sorafenib dimethyl sulphoxide solution 500mL；Hydroxypropyl methyl cellulose and deionized water are made into the drug of 45g/L
Auxiliary material aqueous solution 500mL；Outer circulation high gravity rotating packed bed is opened, adjusts revolving speed to 2500rpm；Feed pump is opened, by first
Benzene sulfonic acid Sorafenib dimethyl sulphoxide solution and excipient substance aqueous solution, which are delivered to simultaneously in high gravity rotating packed bed, to carry out
Recrystallization reaction, and controlling Sorafenib Tosylate dimethyl sulphoxide solution feed rate is 200mL/min, excipient substance water
Solution feed rate is 200mL/min, and the temperature for controlling reaction system is 20 DEG C；Obtained material is freeze-dried, is obtained
Sorafenib Tosylate oral administration nanometer preparation.The partial size of gained nanometer formulation is 100nm or so.Such as the dissolution speed of embodiment 1
Degree test result shows that the Sorafenib Tosylate oral administration nanometer preparation being prepared effectively improves the dissolution speed of drug
Degree, the drug dissolution of 3min reach 92%.
Comparative example 1
Embodiment 1 is repeated, difference is, temperature of reaction system is changed to 60 DEG C, remaining condition is constant, toluene sulphur obtained
Sour Sorafenib oral preparation partial size is 400nm or so.Dissolution rate test result are as follows: the drug dissolution of 3min is only
75%.
Comparative example 2
Embodiment 1 is repeated, difference is, by recrystallization reaction in traditional batch reactor, remaining condition is constant, obtained
Sorafenib Tosylate oral preparation partial size is 1 μm or so.Dissolution rate test result are as follows: the drug dissolution of 3min is only
81%.
Comparative example 3
Embodiment 1 is repeated, difference is, the concentration of polyvinylpyrrolidone in excipient substance aqueous solution is changed to 150g/
L, remaining condition is constant, and the partial size of Sorafenib Tosylate oral preparation obtained is 1 μm or so, and preparation granules are reunited now
As serious.Dissolution rate test result are as follows: the drug dissolution of 3min is only 67%.
Comparative example 4
Embodiment 1 is repeated, difference is, the revolving speed of outer circulation high gravity rotating packed bed is adjusted to 3000rpm, remaining
Part is constant, and the partial size of Sorafenib Tosylate oral preparation obtained is to be distributed between 60~400nm, and preparation granules are big
It is small different.Dissolution rate test result are as follows: the drug dissolution of 3min is only 70%.
Obviously, the above embodiment of the present invention be only to clearly illustrate example of the present invention, and not be pair
The restriction of embodiments of the present invention may be used also on the basis of the above description for those of ordinary skill in the art
To make other variations or changes in different ways, all embodiments can not be exhaustive here, it is all to belong to this hair
The obvious changes or variations that bright technical solution is extended out are still in the scope of protection of the present invention.
Claims (7)
1. a kind of preparation method of Sorafenib Tosylate oral administration nanometer preparation, which comprises the steps of:
1) medicine that the Sorafenib Tosylate solution and concentration that compound concentration is 2g/L~50g/L respectively are 2g/L~100g/L
Object auxiliary material aqueous solution, wherein the excipient substance in the excipient substance aqueous solution is polyethylene glycol, poloxamer, polyethylene pyrrole
One of pyrrolidone, hydroxypropyl methyl cellulose, mannitol, lauryl sodium sulfate, chitosan, sodium alginate and lactose or
Several mixtures；
2) obtained Sorafenib Tosylate solution will be prepared and excipient substance aqueous solution is separately added into hypergravity rotation and fills
Bed is recrystallized, and control system temperature is 5~20 DEG C, and high gravity rotating packed bed revolving speed is 500rpm~2840rpm, obtains first
Benzene sulfonic acid Sorafenib nano suspending liquid；
3) gained Sorafenib Tosylate nano suspending liquid is freeze-dried, obtains Sorafenib Tosylate oral administration nanometer system
Agent.
2. preparation method according to claim 1, which is characterized in that in step 1), the toluenesulfonic acid rope prepared is drawn
Solvent in non-Buddhist nun's solution is selected from one or more of methanol, dehydrated alcohol, dimethyl sulfoxide and acetone.
3. preparation method according to claim 1, which is characterized in that in step 1), the Sorafenib Tosylate is molten
The volume ratio of liquid and the excipient substance aqueous solution is 1:1~1:20.
4. preparation method according to claim 1, which is characterized in that in step 2), Sorafenib Tosylate solution adds
The speed for entering high gravity rotating packed bed is 1mL/min~300mL/min；Hypergravity rotation filling is added in pharmaceutic adjuvant aqueous solution
The speed of bed is 1mL/min~300mL/min.
5. preparation method according to claim 1, which is characterized in that the Sorafenib Tosylate oral administration nanometer preparation
Partial size be 50~900nm.
6. preparation method according to claim 1, which is characterized in that the Sorafenib Tosylate oral administration nanometer preparation
Partial size be 50~200nm.
7. the Sorafenib Tosylate oral administration nanometer system that preparation method as described in any one of claims 1 to 6 is prepared
Agent.
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