CN108210468A - 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 methods of Sorafenib Tosylate oral administration nanometer preparation, include the following steps：1) Sorafenib Tosylate solution and excipient substance aqueous solution are prepared respectively；2) the Sorafenib Tosylate solution that preparation obtains is separately added into high gravity rotating packed bed with excipient substance aqueous solution to 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 preparation method obtain Sorafenib Tosylate oral administration nanometer preparation with than Sorafenib Tosylate bulk pharmaceutical chemicals with faster dissolution rate, and it can faster reach higher blood concentration, the bioavilability of Sorafenib Tosylate is effectively improved, 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 technology
Sorafenib Tosylate (Sorafenib Tosylate), chemical name are 4- { 4- [3- (the chloro- 3- fluoroforms of 4-
Base-phenyl)-uride]-phenoxy group }-pyridine-2-carboxylic acids methylamine -4- toluene fulfonates, molecular formula is
C21H16ClF3N4O3.C7H8O3S molecular structural formulas are 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, directly inhibits tumour life
Long effect also has and inhibits vascular endothelial growth factor, platelet derived growth factor and its receptor, and blocks tumor neogenetic
The indirect growth for inhibiting 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 drugs, 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 relatively low bioavilability of drug, can by by insoluble drug into
Salt, micronizing using non-aqueous solvent/cosolvent, are prepared into emulsion or from microemulsion, cyclodextrin encapsulated, using thermodynamics not
Stable crystal form is prepared into the Chang Fangfa such as solid dispersions.For example, have in the prior art with vinyl acetate groups
The excipient substance of (VA groups) 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 to improve the hydrophily of Sorafenib Tosylate, increases the solubility of Sorafenib Tosylate, so as to improve toluene
Sulfonic acid Sorafenib is in the bioavilability of human body.But these methods are complex, and the improvement of bioavilability is imitated
Fruit is limited.At present, it has no and improves the report of its bioavilability by preparing Sorafenib Tosylate nanometer formulation.
According to Ostwald-Freundrich equations, 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 grain size, effectively increases drug specific surface area, can greatly improve its dissolution
Rate so as to significantly improve the bioavilability of drug, reduces individual difference, 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 mixes the appearance in 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 a kind of biology profit of new improvement Sorafenib Tosylate in human body
The method of expenditure.
Invention content
First of the present invention is designed to provide a kind of preparation method of Sorafenib Tosylate oral administration nanometer preparation,
For improving the dissolution rate of Sorafenib Tosylate preparation and bioavilability.
Second object of the present invention, which is to provide the Sorafenib Tosylate that the preparation method is prepared to take orally, to be received
Metric system agent.
To reach above-mentioned first purpose, the present invention uses following technical proposals：
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 for 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 is flowed with porous media generation in Elevated Gravity to contact, liquid crushing is generated into nano level film, silk and drop
Huge and quick newer boundary improves 1~3 order of magnitude, and greatly in the tower that interphase mass transfer speed ratio can be made traditional
The microcosmic mixing of reinforcing and mass transport process.So as to which in high gravity rotating packed bed, nucleation process is in microcosmic uniform environment
It carries out, so as to make nucleation process controllable.Meanwhile, it is capable to increase substantially the conversion ratio and selectivity of reaction, significantly reduce anti-
The volume of device is answered, simplifies technique, flow, realizes the energy-efficient of process, reduces disposal of pollutants.
In the present invention, the control of system temperature is for the big of the obtained granularity of nanometer formulation in high gravity rotating packed bed
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 grain 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 dissolving Sorafenib Tosylate, simultaneously
The solvent relatively low for toxicity.Preferably, in step 1), the solvent in the Sorafenib Tosylate solution prepared is selected from first
One or more of alcohol, absolute ethyl alcohol, dimethyl sulfoxide (DMSO) and acetone.
Interaction between excipient substance and drug influences the nucleation rate of Sorafenib Tosylate and growth speed
Rate preferably contributes to increase drug nucleation rate, reduces the excipient substance of crystal growth rate.Preferably, the excipient substance
Excipient substance in aqueous solution is 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), a concentration of 2g/L~50g/L of the Sorafenib Tosylate solution；The drug
A concentration of 2g/L~100g/L of auxiliary material aqueous solution.The excessive concentration of excipient substance aqueous solution will appear arch formation because of its drug
Particle agglomeration, the concentration of excipient substance aqueous solution is too low, then cannot effectively increase drug nucleation rate, reduces crystal growth speed
Rate.On this condition, the Sorafenib Tosylate solubility in Sorafenib Tosylate solution is high, and contributes to drug
Grain is uniformly dispersed and crystal growth.It is highly preferred that a concentration of 10g/L~30g/L of the Sorafenib Tosylate solution；
A concentration of 3g/L~50g/L of the excipient substance aqueous solution.
In the present invention, degree of supersaturation is to prepare Sorafenib Tosylate nano particle chief motivation, larger 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, it 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 grain size and particle size uniformity of particle in gained suspension.Preferably, in step 2), Sorafenib Tosylate solution
The speed for adding in high gravity rotating packed bed is 1mL/min~300mL/min；Pharmaceutic adjuvant aqueous solution adds in hypergravity rotary filling
The speed for filling bed is 1mL/min~300mL/min.
In the present invention, high gravity rotating packed bed rotating speed influences liquid flowing state, so as to influence the nucleation of particle and life
Long rate.Preferably, in step 2), the high gravity rotating packed bed rotating speed is 500rpm~2840rpm, and what is obtained at this time is outstanding
The grain 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):It is 946-951.) consistent.
Preferably, the Sorafenib Tosylate oral administration nanometer preparation exists in the form of unformed；The toluene sulphur
The grain size of sour Sorafenib oral administration nanometer preparation is 50~900nm；More preferably 50~200nm.
The Sorafenib Tosylate oral administration nanometer preparation that is prepared of preparation method of the present invention 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 present invention also protects the toluenesulfonic acid Suo Lafei that above-mentioned preparation method is 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, it is creative high gravity rotating packed bed technology will be applied to take orally in Sorafenib Tosylate receive
In the preparation of metric system agent, further selection recrystallizes and controls the temperature of recrystallization, so as 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 more than 88%
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 present invention, could obtain has this hair
The fast nanoscale Sorafenib Tosylate oral preparation of bright middle dissolution rate.
Description of the drawings
The specific embodiment of the present invention is described in further detail below in conjunction with the accompanying drawings.
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 with reference to preferred embodiments and drawings
It is bright.Similar component is indicated with identical reference numeral in attached drawing.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, step are as follows：
Sorafenib Tosylate (scanning electron microscope (SEM) photograph is as shown in Figure 1) and methanol are made into the toluene sulphur of a concentration of 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 rotating speed to 2272rpm；Feed pump is opened, toluenesulfonic acid rope is drawn
Non- Buddhist nun's methanol solution and excipient substance aqueous solution, which are delivered to simultaneously in high gravity rotating packed bed, carries out recrystallization reaction, and control
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 grain 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 with grain diameter 80nm in suspension.
As a comparison, Sorafenib Tosylate is prepared as described above method moderate progress physics 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 test of Sorafenib Tosylate preparation：
Test method is：Sorafenib Tosylate oral administration nanometer preparation obtained above, the object of certain mass are taken respectively
Reason mixed powder and Sorafenib Tosylate bulk pharmaceutical chemicals are separately added into 300mL water pH6.8 phosphate buffer solutions and (add 0.5%
SDS (lauryl sodium sulfate)) in, it puts in 37 DEG C of water-baths, rotating 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, adds the dissolution blank medium of isothermal equivalent after the completion per sub-sampling.To make
Obtained absorbance value is measured in prescribed limit, the corresponding blank medium of the clear solution sampled dilutes certain times
Number, in the absorbance of solution prepared by maximum absorption wave strong point measure.Each sample parallel determination 3 times.With calibration curve method meter
Its corresponding concentration is calculated, draws out corresponding stripping curve.
Fig. 5 shows to mix using Sorafenib Tosylate oral administration nanometer preparation, physics that above-mentioned preparation method is prepared
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, step are as follows：
Sorafenib Tosylate and dimethyl sulfoxide (DMSO) are made into the Sorafenib Tosylate dimethyl of a concentration of 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 rotating speed to 2840rpm；Feed pump is opened, by Sorafenib Tosylate dimethyl
Sulfoxide solution and excipient substance aqueous solution, which are delivered to simultaneously in high gravity rotating packed bed, carries out recrystallization reaction, and control 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 are 10 DEG C；Obtained material is freeze-dried, Sorafenib Tosylate is obtained and takes orally
Nanometer formulation.The grain size of gained nanometer formulation is 120nm or so.Dissolution rate test result such as embodiment 1 is shown, 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, step are as follows：
Sorafenib Tosylate and dimethylformamide are made into the Sorafenib Tosylate diformazan of a concentration of 30g/L
Base formamide solution 50mL；It is 1 by mass ratio:1 hydroxypropyl methyl cellulose and dodecyl sodium sulfate is matched with deionized water
Into the excipient substance aqueous solution 1000mL of 4.5g/L；Outer circulation high gravity rotating packed bed is opened, adjusts rotating 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 control Sorafenib Tosylate methanol solution feed rate as 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 grain 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
Dissolution rate, the drug dissolution of 3min reach 91%.
Embodiment 4
A kind of preparation of Sorafenib Tosylate oral administration nanometer preparation, step are as follows：
The Sorafenib Tosylate dimethyl sulfoxide (DMSO) that Sorafenib Tosylate is made into a concentration of 15g/L with methanol is molten
Liquid 50mL；It is 1 by mass ratio:1 polyvinylpyrrolidone and dodecyl sodium sulfate is made into the drug of 5g/L with deionized water
Auxiliary material aqueous solution 750mL；Outer circulation high gravity rotating packed bed is opened, adjusts rotating 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 are recrystallized simultaneously
Reaction, and Sorafenib Tosylate methanol solution feed rate is controlled as 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, obtains toluenesulfonic acid Suo Lafei
Buddhist nun's oral administration nanometer preparation.The grain size of gained nanometer formulation is 170nm or so.Dissolution rate test result such as embodiment 1 shows,
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, step are as follows：
Sorafenib Tosylate and dimethylformamide are made into the Sorafenib Tosylate diformazan of a concentration of 15g/L
Base formamide solution 50mL；It is 1 by mass ratio:1 hydroxypropyl methyl cellulose and dodecyl sodium sulfate is matched with deionized water
Into the excipient substance aqueous solution 1000mL of 5.25g/L；Outer circulation high gravity rotating packed bed is opened, adjusts rotating 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 for 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 grain 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, step are as follows：
It is 1 by Sorafenib Tosylate and volume ratio:1 dimethyl sulfoxide (DMSO) is made into the first of a concentration of 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 rotating speed to 2500rpm；Feed pump is opened, by first
Benzene sulfonic acid Sorafenib dimethyl sulphoxide solution and excipient substance aqueous solution are delivered in high gravity rotating packed bed and carry out simultaneously
Recrystallization reaction, and Sorafenib Tosylate dimethyl sulphoxide solution feed rate is controlled as 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 grain 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 lies in be changed to 60 DEG C, remaining condition is constant, toluene sulphur obtained by temperature of reaction system
Sour Sorafenib oral preparation grain size is 400nm or so.Dissolution rate test result is：The drug dissolution of 3min is only
75%.
Comparative example 2
Embodiment 1 is repeated, difference lies in react recrystallization in traditional batch reactor, remaining condition is constant, obtained
Sorafenib Tosylate oral preparation grain size is 1 μm or so.Dissolution rate test result is：The drug dissolution of 3min is only
81%.
Comparative example 3
Embodiment 1 is repeated, difference lies in be changed to 150g/ by the concentration of polyvinylpyrrolidone in excipient substance aqueous solution
L, remaining condition is constant, and the grain size of Sorafenib Tosylate oral preparation obtained is 1 μm or so, and preparation granules are reunited now
As serious.Dissolution rate test result is：The drug dissolution of 3min is only 67%.
Comparative example 4
Embodiment 1 is repeated, difference lies in, the rotating speed of outer circulation high gravity rotating packed bed is adjusted to 3000rpm, remaining
Part is constant, and the grain size of Sorafenib Tosylate oral preparation obtained is is distributed between 60~400nm, and preparation granules are big
It is small to differ.Dissolution rate test result is：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 for those of ordinary skill in the art, may be used also on the basis of the above description
To make other variations or changes in different ways, all embodiments can not be exhaustive here, it is every to belong to this hair
The obvious changes or variations that bright technical solution is extended out are still in the row of protection scope of the present invention.
Claims (10)
1. a kind of preparation method of Sorafenib Tosylate oral administration nanometer preparation, which is characterized in that include 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 and fills
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 system
Agent.
2. preparation method according to claim 1, which is characterized in that in step 2), the system temperature is 5~20 DEG C.
3. 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, absolute ethyl alcohol, dimethyl sulfoxide (DMSO) and acetone.
4. preparation method according to claim 1, which is characterized in that the excipient substance in the excipient substance aqueous solution is
Polyethylene glycol, poloxamer, polyvinylpyrrolidone, hydroxypropyl methyl cellulose, mannitol, lauryl sodium sulfate, shell gather
The mixture of one or more of sugar, sodium alginate and lactose.
5. preparation method according to claim 1, which is characterized in that in step 1), the Sorafenib Tosylate is molten
A concentration of 2g/L~50g/L of liquid；A concentration of 2g/L~100g/L of the excipient substance aqueous solution.
6. 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.
7. 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；Pharmaceutic adjuvant aqueous solution adds in hypergravity rotation filling
The speed of bed is 1mL/min~300mL/min.
8. preparation method according to claim 1, which is characterized in that in step 2), the high gravity rotating packed bed turns
Speed is 500rpm~2840rpm.
9. preparation method according to claim 1, which is characterized in that the Sorafenib Tosylate oral administration nanometer preparation
Grain size be 50~900nm；Preferably 50~200nm.
10. the Sorafenib Tosylate oral administration nanometer system being prepared such as claim 1~9 any one of them preparation method
Agent.
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| WO2023155307A1 (en) * | 2022-02-21 | 2023-08-24 | 北京睿创康泰医药研究院有限公司 | Sorafenib or donafenib oral preparation with low dose and high drug exposure, and application thereof |
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