CN105748413B - Hydroxycamptothecin nano crystal load microballoon and preparation method thereof - Google Patents
Hydroxycamptothecin nano crystal load microballoon and preparation method thereof Download PDFInfo
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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- 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
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- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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Abstract
The invention discloses hydroxycamptothecin nano crystal load microballoons and preparation method thereof, the preparation method liquefied carbon dioxide is continually introduced into sedimentation kettle through high-pressure pump, dimethyl sulfoxide (DMSO) and/or alcohol solvent are passed through by nozzle, after stabilization, stopping is passed through solvent, and hydroxycamptothecin and Zein solution are passed through by nozzle；Solvent is quickly sufficiently mixed with supercritical carbon dioxide and flows out recycling through settling the bottom of kettle, and the particles of solute of formation falls to sedimentation bottom portion；Obtain hydroxycamptothecin nano crystal and the coprecipitation mixture of Zein；In coprecipitation mixture ultrasonic disperse to ethanol-water solution；The Zein microballoon lotions for carrying hydroxycamptothecin nano crystal are prepared using dialysis apparatus built in ultrasound；Freeze-drying.The obtained microsphere features smooth surface of the present invention, drugloading rate and carrier medicine carrying efficiency are high, and particle diameter distribution is narrow, good dispersion；The present invention overcomes medicament nano crystal in stability, nanometer toxicity, the deficiency for controlling slow release and targeting etc..
Description
Technical field
The present invention relates to a kind of preparation of medicament nano crystal and load fields, are received more particularly to a kind of hydroxycamptothecin
Rice crystal load microballoon and preparation method thereof.
Background technology
Hydroxycamptothecin is a kind of micro alkaloid separated from the distinctive plant camptotheca acuminata in China, be at present from
The most strong a kind of alkaloid of antitumor activity in a monomer more than 20 separated in camplotheca acuminata.Hydroxycamptothecin is not soluble in water, mesh
The preceding hydroxy-camptothecin alkali preparation used clinically is its sodium-salt parenteral solution, and lactone ring structure is destroyed, and active anticancer is only
The 10% of hydroxycamptothecin.
It is the available strategy for improving poorly water soluble drugs curative effect to prepare medicament nano crystal, in many pharmaceutical dosage forms
To application.The reduction of grain size can increase the specific surface area of drug, enhance the water solubility and drug effect of drug.Meanwhile polymorphic is shadow
Ring another main cause of drug effect.There are the physics such as solubility, stability and bioavilability between same drug different crystal forms
The notable difference of property.The micronized of hydroxycamptothecin has obtained certain progress at present, research shows that hydroxycamptothecin is received
Meter Jing Ti has preferably water-soluble and better antitumous effect, the hydroxycamptothecin nano crystal of especially needle-shaped crystal form.
Chinese invention patent 2008100497076 discloses a kind of preparation method of nano-grade hydroxy camptothecine crystal freeze-dried powder preparation,
Hydroxycamptothecin average content is the 98.5% of labelled amount in sample, and said preparation inhibits and kill liver cancer and stomach cancer cell effect aobvious
Work is better than alkyl camptothecine injection.But for hydroxycamptothecin nano crystal due to high interface energy, stability is poor, easily occurs poly-
Collection, growth and transformation of crystal, and the addition of stabilizer can influence medicament nano Physical Properties of Crystals and bioavilability, and may
There are toxic side effects.Hydroxycamptothecin nano crystal grain size is small simultaneously, rapidly dissolvable and can not control sustained release, it is understood that there may be nanometer
Toxicity generates toxic side effect to organism.
Drug loading is prepared as to the release speed that delivery system (DDS) was adjusted and controlled drug in carrier material
Degree, protects the drug from the influence of internal enzyme and degrades, and reduces administration number of times and medicine irritation, improves curative effect and utilizes carrier
Material and the special compatibility of certain cell tissues play targeting conveying and therapeutic effect.In the prior art, about hydroxyl
The preparation research of base camptothecine transport system.But since hydroxycamptothecin is insoluble in the less toxic organic solvent such as ethyl alcohol, existing method
Using alkaline solution or toxic organic solvents in preparation process in preparation process, there are drug inactivation, toxic organic solvents
The problems such as residual, at the same in DDS hydroxycamptothecin mostly by molecular cluster or it is unbodied in the form of exist, do not have medicament nano crystal
Unique advantage.
Invention content
It is an object of the invention to be directed to the deficiency of technology, effectively avoid easily occurring in hydroxycamptothecin dispersion process poly-
The problems such as collection, direct carrying medicament nanocrystal thus obtained microsphere size distribution are uneven, it is high to provide a kind of carrier medicine carrying efficiency, dispersibility
Good, uniform in size, particle size is controllable, and high income and residual solvent are few, and it is brilliant that 70% mass of release carries medicine hydroxycamptothecin nano
The time of body is more than 72h, hydroxycamptothecin nano crystal load microballoon and preparation method thereof.
The present invention realizes the preparation of hydroxycamptothecin nano crystal load microballoon using two-step method.First it is situated between by dispersion of Zein
Matter prepares hydroxycamptothecin nano crystal dispersion；It is again carrier material to medicament nano crystal load using Zein.
The object of the invention is achieved through the following technical solutions：
A kind of preparation method of hydroxycamptothecin nano crystal load microballoon, includes the following steps：
(1) liquefied carbon dioxide is continually introduced into sedimentation kettle through high-pressure pump, and the temperature in the kettle for adjusting sedimentation kettle is 30-45 DEG C,
Pressure is 80-140bar；Dimethyl sulfoxide (DMSO) and/or alcohol solvent are passed through by nozzle, after stablizing, stopping is passed through solvent, passes through
Nozzle is passed through hydroxycamptothecin and Zein solution；Solvent is quickly sufficiently mixed with supercritical carbon dioxide and the bottom through settling kettle
Outflow recycling, the particles of solute of formation fall to sedimentation bottom portion；The co-precipitation for obtaining hydroxycamptothecin nano crystal and Zein mixes
Close object；The volume ratio of the dimethyl sulfoxide (DMSO) and ethyl alcohol is 1:0‐2:3；
(2) by the coprecipitation mixture ultrasonic disperse of hydroxycamptothecin nano crystal obtained by step (1) and Zein to ethyl alcohol-
In aqueous solution, hydroxycamptothecin nano crystal dispersion is obtained；
(3) the hydroxycamptothecin nano crystal dispersion obtained using step (2) is dialysis solution, using ultra-pure water as dialysis
Liquid prepares the Zein microballoon lotions for carrying hydroxycamptothecin nano crystal using dialysis apparatus built in ultrasound；
(4) the Zein microballoons emulsion freeze of gained dialysis rear bearing hydroxycamptothecin nano crystal is dried, obtains carrying hydroxyl
The Zein microsphere powders of camptothecine nanocrystal.
Further to realize the object of the invention, it is preferable that after step (1) hydroxycamptothecin and Zein solution are passed through,
Continue to be passed through carbon dioxide to remove remaining dimethyl sulfoxide (DMSO) and/or alcohol solvent.
Preferably, the time for continuing to be passed through carbon dioxide is 30-60min.
Preferably, the mass ratio of step (1) hydroxycamptothecin and Zein are 1:5‐1:25；Hydroxycamptothecin is in hydroxyl
The concentration 0.25-1.5mg/mL of camptothecine and Zein solution.
Preferably, step (1) prepares hydroxycamptothecin in hydroxycamptothecin nano crystal and Zein coprecipitation mixtures and receives
Rice uniform crystal dispersion is around Zein nano-particles.
Preferably, the time of the ultrasonic disperse is 15-30min.
Preferably, the volume fraction of ethyl alcohol is 60-90% in the ethanol-water solution.
Preferably, the temperature of dialysis apparatus regulation and control is 15-40 DEG C built in step (3) ultrasound；Ultrasonic power is 100-
200W；Ultrasonic time/intermittent time is 1-2s/2-4s；Dialysis time is 0.5-1.5h/ times；Number of repetition of dialysing is 2-4 times；
Bag filter molecular cut off is less than 19000Da.
Preferably, the sublimation drying is 12-48h, and condenser temperature is less than -30 DEG C in freeze-drying.
A kind of hydroxycamptothecin nano crystal loads microballoon, is made by above-mentioned preparation method；Hydroxycamptothecin is with nanocrystalline
The form of body is embedded in the microballoon of carrier material Zein formation, microsphere features smooth surface, and grain size is 1-5 μm；With mass percent
Meter, drug loading 3-15%, carrier medicine carrying efficiency 56-97%；Microballoon can realize the sustained release of hydroxycamptothecin nano crystal, release
The time that 70% mass carries medicine hydroxycamptothecin nano crystal is more than 72h.
Step (1) of the present invention prepares hydroxycamptothecin nano crystal and Zein coprecipitation mixtures, and Zein is situated between as dispersion
Matter prevents the aggregation of hydroxycamptothecin nano crystal, improves redispersibility, and hydroxycamptothecin nano crystal is equal in gained mixture
It is even to be scattered in around Zein nano-particles.
Solvent of the present invention is can dissolve each other, and can dissolve the liquids of drug and carrier material simultaneously with supercritical carbon dioxide
Matter.Inventor has found that preferred solvent is dimethyl sulfoxide (DMSO) or the mixture of dimethyl sulfoxide (DMSO) and ethyl alcohol by a large amount of preliminary experiment
The volume ratio of system, dimethyl sulfoxide (DMSO) and ethyl alcohol is 1:0‐2:3.
The mass ratio of present invention control hydroxycamptothecin and Zein are 1:5‐1:25th, hydroxycamptothecin in hydroxycamptothecin and
A concentration of 0.25-1.5mg/mL of Zein solution, sample introduction flow rate are 0.5-1.5mg/mL, carbon dioxide flow rate 10-40g/
min。
Volume fraction of ethanol is 60%-90% in step (2) ethanol-water system, and Zein solution concentrations are 0.25-
20mg/mL, ultrasonic disperse time are more than 15min, it is ensured that the alcohol-water that hydroxycamptothecin nano crystal is dispersed in Zein is molten
In liquid.
Chinese invention patent CN104225607A proposes dialysis apparatus built in a kind of preparation ultrasound of new Zein microballoons,
Using Zein microsphere features smooth surfaces obtained by the device, grain size is 1-2 μm, and particle diameter distribution is narrow and good dispersion.Based on patent
The method of CN104225607A reports, for alcohol-water-soluble enzymatic hydrolysis system, can be proportionally added into drug in preparation process and Zein matches
It is set to the Zein microballoons that carrying medicament is prepared in dialysis solution.But hydroxycamptothecin solubility in ethanol-water system is extremely low,
Cannot load directly be realized using the technology.Simultaneously as nanocrystal surface can be high, easily assemble in dispersion process, directly
Connect carrying medicament nanocrystal thus obtained microsphere size distribution unevenness.
Supercritical carbon dioxide anti-solvent technology is with reaction condition is adjusted, dissolvent residual is low, the grain size and grain of particle
The advantages that degree distribution is controllable, suitable for preparing medicament nano crystal and DDS insoluble in supercritical carbon dioxide.Using the technology
It can be prepared that grain size is small and the single medicament nano crystal of crystal form, but nanocrystal such as has aggregation, is difficult to disperse at the drawbacks.Separately
Outside, DDS can directly be prepared using the technology, but most drugs molecule or nanocrystal are scattered in carrier material in gained DDS
Particle surface fails to load to inside carrier granular, is unfavorable for protection and the sustained release of drug.Due to hydroxycamptothecin and
Zein solubility in supercritical carbon dioxide is extremely low, and hydroxycamptothecin and Zein solution are passed through in supercritical carbon dioxide,
Particles of solute is precipitated by supercritical carbon dioxide extracting in solvent.Meanwhile relative to Zein, hydroxycamptothecin is in solvent is selected
Solubility is very low, first reaches supersaturation precipitation and forms nanocrystal, is scattered between the Zein nano-particles being precipitated later.So it adopts
The aggregation of hydroxycamptothecin nano crystal using Zein as decentralized medium, can be prevented with the technology, improves redispersibility.
Compared with prior art, the invention has the advantages that：
(1) carrier material used in hydroxycamptothecin transport system synthesizes macromolecule with polylactic acid, polyethylene glycol etc. at present
Based on system and hydrophilic natural macromolecular.The former is unfavorable for degradation and absorption in vivo, and the latter is unfavorable for drug
Sustained release.For the present invention using the hydrophobicity natural biological macromolecular Zein of plant origin as carrier material, gained drug bearing microsphere is simultaneous
Have biocompatibility and delay the advantage that drug discharges in vivo.
(2) present invention prepares hydroxycamptothecin nano crystal dispersion, avoids carrier material using Zein as decentralized medium
Influence of the use of outer dispersant to medicament nano Physical Properties of Crystals and bioavilability, while using supercritical carbon dioxide
Anti-solvent technology can meet dissolvent residual requirement.
(3) present invention can be in the proportioning and ultrasound by medicament nano crystal size, medicament nano crystal and carrier material
The operating parameter of dialysis is put, the micro-structures such as drugloading rate, granule size and the pattern of Effective Regulation final product meet different medicines
Object delivery requirements.
(4) preparation process of the present invention is easy to operate, mild condition, and products obtained therefrom particle has drugloading rate and carrier medicine carrying efficiency
The advantages such as height, good dispersion, uniform in size, particle size are controllable, high income and residual solvent are few.
(5) hydroxycamptothecin nano crystal load microballoon prepared by the present invention, hydroxycamptothecin is in the form of nanocrystal
It is carried in Zein microballoons, except having nanocrystal in addition to the advantage in terms of water-soluble and drug effect, it is defeated in drug to be also equipped with microballoon
Send, control the advantage of the fermentation such as sustained release and targeting.
Description of the drawings
Fig. 1 is the scanning electron microscope (SEM) photograph of 3 gained hydroxycamptothecin nano crystal of embodiment and Zein coprecipitation mixtures；
Fig. 2 is the scanning electron microscope (SEM) photograph that 3 gained hydroxycamptothecin nano crystal of embodiment loads microballoon；
Fig. 3 is 3 gained hydroxycamptothecin nano crystal of embodiment and Zein coprecipitation mixture (a) and carries hydroxycamptothecin
The In-vitro release curves of the Zein microballoons (b) of nanocrystal；
Fig. 4 is the scanning electron microscope (SEM) photograph for the Zein microballoons that hydroxycamptothecin nano crystal is carried obtained by comparative example.
Specific embodiment
To be best understood from the present invention, the invention will be further described in conjunction with the accompanying drawings and embodiments, but it should be recognized that
The range of protection of the presently claimed invention is not limited to the range that example below is stated.
A kind of method of hydroxycamptothecin nano crystal load microballoon, including hydroxycamptothecin nano crystal dispersion
It prepares (a) and hydroxycamptothecin nano crystal loads (b) two parts.
(a) supercritical carbon dioxide anti-solvent technology is selected in part, and main preparation process is liquefied carbon dioxide through high pressure
Pump is continually introduced into sedimentation kettle, adjusts the sedimentation temperature in the kettle (30-45 DEG C) of kettle and pressure (80-140bar)；Through sample introduction after stabilization
Pump is passed through pure solvent (dimethyl sulfoxide (DMSO) and/or ethyl alcohol) 15min, kettle internal solvent and two to set sample introduction flow rate (F) by nozzle
After content of carbon oxide reaches stable state, by pure solvent be changed to a certain concentration (C) drug and carrier solution (hydroxycamptothecin and
Zein) sample introduction；Solvent is quickly sufficiently mixed with supercritical carbon dioxide and flows into solvent recovery unit recycling through bottom portion, and molten
Matter particle is precipitated and falls to the metallic filtering film in sedimentation bottom portion.After sample solution is passed through, sampling pump is closed, continues to lead to
Enter carbon dioxide about 40min to remove remaining organic solvent；After the completion of washing, instrument is closed in pressure release, is taken out sedimentation kettle, is received
Collect the obtained coprecipitation mixture product for obtaining hydroxycamptothecin nano crystal and Zein.
(b) dialysis built in ultrasound is selected in part, and main preparation process is the hydroxycamptothecin nano crystal that will be obtained
It is scattered in ethanol-water solution with the coprecipitation mixture of Zein and dialysis solution is made, pipette dialysis that 10mL obtains with molten
Liquid is placed in prior processed length in 15mm bag filters, then to fix bag filter and ultrasonic amplitude transformer, by what is fixed
Bag filter is put into dialyzate (ultra-pure water), opens ultrasonic generator, sets ultrasonic power, ultrasonic time/intermittent time, dialysis
Time and number of repetition obtain hydroxycamptothecin nano crystal load microballoon lotion.Then, sample freezing is dry after gained is dialysed
It is dry, obtain hydroxycamptothecin nano crystal load microsphere powder.
Embodiment 1-8
A kind of preparation method for the Zein microballoons for carrying hydroxycamptothecin nano crystal.Include the following steps：
(1) co-precipitation that hydroxycamptothecin nano crystal and Zein are prepared using supercritical carbon dioxide anti-solvent technology is mixed
Close object：Using dimethyl sulfoxide (DMSO) and/or ethyl alcohol as solvent, operating condition is set according to table 1：The mass ratio of hydroxycamptothecin and Zein
(MR), the volume ratio of dimethyl sulfoxide (DMSO) and ethyl alcohol (VR), sample introduction flow rate (F), operating pressure (P) and temperature (T), hydroxycamptothecin
A concentration of 1mg/mL, carbon dioxide flow rate control are 20g/min.
(2) dialysis solution is prepared, by the coprecipitation mixture of hydroxycamptothecin nano crystal obtained by step (1) and Zein point
It is a concentration of 5mg/mL of Zein in solvent that be scattered to 20mL volume fraction of ethanol, which be 70% alcohol-water, ultrasonic disperse 15 minutes.
(3) the microballoon lotion for carrying medicament nano crystal, the drug of step (2) configuration are prepared using dialysis apparatus built in ultrasound
Nanocrystal dispersion is dialysis solution, using ultra-pure water as dialyzate.Dialysis apparatus operation temperature built in ultrasound is set as 20
DEG C, ultrasonic power 125W, ultrasonic time/intermittent time be 1s/2s, be set as 1h total times, after the 1h that dialyses, replace dialysis
Liquid, then the 1h that dialyses obtain hydroxycamptothecin nano crystal load microballoon lotion.(dialysis apparatus regulation and control parameter also may be used built in ultrasound
It is adjusted in following range；Temperature is 15-40 DEG C；Ultrasonic power is 100-200W；Ultrasonic time/intermittent time is 1-2s/2-
4s；Dialysis time is 0.5-1.5h/ times；Number of repetition of dialysing is 2-4 times.)
(4) drying of hydroxycamptothecin nano crystal load microballoon emulsion freeze for 24 hours, obtains hydroxy-camptothecin after gained is dialysed
Alkali nanocrystal loads microsphere powder.
Table 1
Each embodiment all according to listed operating parameter numerical value in table 1, is performed in strict accordance with above-mentioned steps, obtains carrying hydroxyl happiness
Drugloading rate, carrier medicine carrying efficiency and the granularity of the Zein microsphere powders of tree alkali nanocrystal are shown in Table 1, and (drugloading rate is hydroxy-camptothecin in product
The mass ratio of alkali actual amount and product population, carrier medicine carrying efficiency are that hydroxycamptothecin actual amount adds with initial hydroxyl groups camptothecine in product
Enter the mass ratio of amount).It is received it can be seen that changing operating condition and can prepare the load hydroxycamptothecin of different drugloading rates and grain size less than 5 μm
Meter Jing Ti Zein microballoons.Fig. 1 is sweeping for 3 step 1 gained hydroxycamptothecin nano crystal of embodiment and Zein coprecipitation mixtures
Retouch electron microscope, it is seen that needle-shaped hydroxycamptothecin nano crystal is dispersed in around Zein nano-particles, and particularly Zein can make
For decentralized medium prevent gained hydroxycamptothecin nano crystal aggregation, significantly improve hydroxycamptothecin nano crystal ethyl alcohol-
Redispersibility in aqueous solution.
Fig. 2 is the scanning electron microscope (SEM) photograph that 3 gained hydroxycamptothecin nano crystal of embodiment loads microballoon, it is seen that needle-shaped hydroxyl happiness
Tree alkali nanocrystal is successfully carried on inside Zein microballoons, and covering property is good, and gained sample is smooth microballoon, and granular size is uniform
(substantially at 0.84-3.7 μm), and good dispersion.Fig. 3 is co-precipitated for 3 gained hydroxycamptothecin nano crystal of embodiment and Zein
(dissolution medium is pH=7.4 phosphoric acid to the In-vitro release curves of mixture (a) and hydroxycamptothecin nano crystal load microballoon (b)
Salt buffer solution, temperature are 37 DEG C, and release profiles abscissa is the time, and ordinate is the cumulative release amount of drug).It is it can be seen that opposite
In the dispersion of medicament nano crystal, by medicament nano crystal load to support material internal, drug can be delayed to release well
It puts, the time of 70% drug of release is more than 80h.
Comparative example：
According to document (Jiang, Y.；Sun,W.；Wang,W.,Recrystallization and micronization
of10‐hydroxycamptothecin by supercritical antisolvent
Process.Ind.Eng.Chem.Res.2012,51,2596-2602) report, first using supercritical carbon dioxide anti-solvent skill
Art prepares the aciculiform hydroxycamptothecin nano crystal that particle size is 223nm；It is by 70% alcohol-water of volume fraction of ethanol
Solvent, the Zein solution of a concentration of 5mg/mL of configuration 20mL, and add in hydroxycamptothecin nano crystal obtained by 5mg, ultrasonic disperse
15min；Hydroxycamptothecin nano crystal load microballoon lotion is prepared using dialysis apparatus built in ultrasound, setting operation temperature is 20
DEG C, ultrasonic power 125W, ultrasonic time/intermittent time be 1s/2s, total time be set as 1h, start to dialyse, after 1h, replace
Dialyzate, then the 1h that dialyses；The drying of hydroxycamptothecin nano crystal load microballoon emulsion freeze for 24 hours, obtains hydroxyl after gained is dialysed
Base camptothecine nanocrystal loads microsphere powder.Fig. 4 is the scanning that hydroxycamptothecin nano crystal obtained by comparative example loads microballoon
Electron microscope, it is seen that since nanocrystal surface can be high, easily assemble in dispersion process, it is direct using dialysis apparatus built in ultrasound
Carrying medicament nanocrystal thus obtained microsphere size distribution is very uneven, seriously affects performance.
During hydroxycamptothecin nano crystal is prepared, inventor has found the present invention, adds in Zein as decentralized medium,
The aggregation of gained hydroxycamptothecin nano crystal can be prevented, avoids the use of the outer dispersant of carrier material to medicament nano crystal object
The influence of rationality matter and bioavilability.Particularly the coprecipitation mixture of hydroxycamptothecin nano crystal and Zein can significantly change
Kind redispersibility of the hydroxycamptothecin nano crystal in ethanol-water solution, can be prepared table through dialysis apparatus built in ultrasound
Face is smooth, particle diameter distribution is narrow, good dispersion, covering property are good, and drugloading rate and the high hydroxycamptothecin nano crystal of carrier medicine carrying efficiency are born
Carry microballoon.
Claims (10)
1. hydroxycamptothecin nano crystal loads the preparation method of microballoon, it is characterised in that includes the following steps：
(1) liquefied carbon dioxide is continually introduced into sedimentation kettle through high-pressure pump, and the temperature in the kettle for adjusting sedimentation kettle is 30-45 DEG C, pressure
For 80-140bar；Dimethyl sulfoxide (DMSO) and/or alcohol solvent are passed through by nozzle, after stablizing, stopping is passed through solvent, passes through nozzle
It is passed through hydroxycamptothecin and Zein solution；Solvent is quickly sufficiently mixed with supercritical carbon dioxide and the bottom through settling kettle is flowed out
Recycling, the particles of solute of formation fall to sedimentation bottom portion；Obtain hydroxycamptothecin nano crystal and the coprecipitation mixture of Zein；
The volume ratio of the dimethyl sulfoxide (DMSO) and ethyl alcohol is 1:0‐2:3；
(2) it is the coprecipitation mixture ultrasonic disperse of hydroxycamptothecin nano crystal obtained by step (1) and Zein is molten to alcohol-water
In liquid, hydroxycamptothecin nano crystal dispersion is obtained；
(3) the hydroxycamptothecin nano crystal dispersion obtained using step (2) is dialysis solution, using ultra-pure water as dialyzate,
The Zein microballoon lotions for carrying hydroxycamptothecin nano crystal are prepared using dialysis apparatus built in ultrasound；
(4) the Zein microballoons emulsion freeze of gained dialysis rear bearing hydroxycamptothecin nano crystal is dried, obtains carrying hydroxy-camptothecin
The Zein microsphere powders of alkali nanocrystal.
2. the preparation method of hydroxycamptothecin nano crystal load microballoon according to claim 1, which is characterized in that step
(1) after hydroxycamptothecin and Zein solution are passed through, continue to be passed through carbon dioxide with remove remaining dimethyl sulfoxide (DMSO) and/or
Alcohol solvent.
3. the preparation method of hydroxycamptothecin nano crystal load microballoon according to claim 2, which is characterized in that described
The time for continuing to be passed through carbon dioxide is 30-60min.
4. the preparation method of hydroxycamptothecin nano crystal load microballoon according to claim 1, which is characterized in that step
(1) mass ratio of the hydroxycamptothecin and Zein are 1:5‐1:25；Hydroxycamptothecin is in hydroxycamptothecin and Zein solution
A concentration of 0.25-1.5mg/mL.
5. the preparation method of hydroxycamptothecin nano crystal load microballoon according to claim 1, which is characterized in that step
(1) it prepares hydroxycamptothecin nano crystal in hydroxycamptothecin nano crystal and Zein coprecipitation mixtures and is dispersed in Zein
Around nano-particle.
6. the preparation method of hydroxycamptothecin nano crystal load microballoon according to claim 1, it is characterised in that：It is described
The time of ultrasonic disperse is 15-30min.
7. the preparation method of hydroxycamptothecin nano crystal load microballoon according to claim 1, it is characterised in that：It is described
The volume fraction of ethyl alcohol is 60-90% in ethanol-water solution.
8. the preparation method of hydroxycamptothecin nano crystal load microballoon according to claim 1, it is characterised in that：Step
(3) temperature of dialysis apparatus regulation and control is 15-40 DEG C built in the ultrasound；Ultrasonic power is 100-200W；During ultrasonic time/interval
Between be 1-2s/2-4s；Dialysis time is 0.5-1.5h/ times；Number of repetition of dialysing is 2-4 times.
9. the preparation method of hydroxycamptothecin nano crystal load microballoon according to claim 1, it is characterised in that：It is described
Sublimation drying is 12~48h, and condenser temperature is less than -30 DEG C in freeze-drying.
10. a kind of hydroxycamptothecin nano crystal loads microballoon, which is characterized in that it is by any one of the claim 1-9 systems
Preparation Method is made；Hydroxycamptothecin is embedded in the form of nanocrystal in the microballoon of carrier material Zein formation, microsphere surface
Smooth, grain size is 1-5 μm；By percentage to the quality, drug loading 3-15%, carrier medicine carrying efficiency 56-97%；Discharge 70% matter
The time of loading gage medicine hydroxycamptothecin nano crystal is more than 72h.
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