CN105434360A - Hollow drug carrying microsphere used for pulmonary drug delivery and preparation method thereof - Google Patents
Hollow drug carrying microsphere used for pulmonary drug delivery and preparation method thereof Download PDFInfo
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Abstract
The present invention provides a hollow drug carrying microsphere used for pulmonary drug delivery and a preparation method thereof. The method is as follows: dissolving a drug in water to form an inner aqueous phase W1; dissolving a biodegradable polymer material into an organic solvent to form an oil phase O; adding the inner aqueous phase W1 into the oil phase O for emulsification for formation of W1 / O emulsion; adding the W1 / O emulsion into an external aqueous phase W2containing a stabilizer to form W1 / O / W2 pre-emulsion; passing the W1 / O / W2 pre-emulsion through a microporous membrane for emulsification to obtain W1 / O / W2 emulsion; and removing an organic solvent of the oil phase of the W1 / O / W2 emulsion to solidify the oil phase, and then washing and freeze-drying to obtain the hollow drug carrying microsphere. According to the method, by use of a membrane emulsification technology, controlled particle size and narrow particle size distribution of the drug carrying microsphere can be ensured. The particle size distribution of the drug carrying microsphere is between 0.5-5mum, the drug loading amount is 1%-13%, the encapsulation efficiency is 50%-82%, and the drug carrying microsphere has good biocompatibility, can instantly release or continuously release 5 hours-30 days, and drug dosage and side effects can be reduced.
Description
Technical field
The invention belongs to drug world, be specifically related to a kind of hollow medicine carrying microballoons for pulmonary administration and preparation method thereof.
Background technology
At present, medicine carrying microballoons occupies very important status in new medicinal preparation, and it refers to medicine dispersion or is attracted to the miniature spherical body formed in macromolecular material, and microsphere diameter is generally 1-500 μm (being generally 5-250 μm).Difference according to route of administration can be divided into drug administration by injection, oral administration, pulmonary administration and percutaneous drug delivery etc.Compared with other administration route, pulmonary administration (is about 140m greatly because it has absorption area
2), absorption site blood flow enriches, and can avoid the first pass effect of liver, enzymatic activity is lower, the advantage such as thin and film permeability high (film thickness is only 0.1-0.2 μm) of epithelial barrier, has great importance to the treatment of pulmonary disease and even Formulations for systemic administration.But the difficult point of pulmonary administration technology is how to realize the effective deposition of medicine in pulmonary and the controllable release of medicine.
Guaranteeing that medicine carrying microballoons is in pulmonary effectively deposition, researcher both domestic and external has attempted a lot of method for this reason.Chinese patent (publication number CN101361716A) adopts the medicine carrying microballoons prepared of stirrings-solvent evaporation method, and its particle size distribution is wider, because particle diameter heterogeneity certainly will cause preparation repeatability and treat the problem of poor repeatability, is difficult to be applied to clinical.And Chinese patent (CN1813684A) can make narrow particle size distribution although prepare nano drug-carrying technology, but easily occur to assemble between granule when being applied to pulmonary to be engulfed by pulmonary alveolar macrophage.In order to overcome the problems referred to above, (the Edwards such as Edwards, D.A., Ben-Jebria, A., andLanger, R. (1998) Recentadvancesinpulmonarydrugdeliveryusinglarge, porousinhaledparticles, Journalofappliedphysiology85,379-385.) prepare macropore medicine carrying microballoons, because it has lower grain density and larger particle volume, thus effectively can improve the time of staying in the aerosol of drug particles and lung.But the macropore on microsphere can strengthen the prominent generation releasing phenomenon, the envelop rate of medicine reduces simultaneously, and medicine easily runs off.Research is had to point out (Imai, Y., Miki, T., Ishikawa, T., Aoki, T., andYamaguchi, T. (2012) Depositionofmicrometerparticlesinpulmonaryairwaysduringi nhalationandbreathholding, JournalofBiomechanics45,1809-1815.), be less than 0.5 μm and be greater than 5 μm microsphere all cannot long time sedimentation at alveolar surface and then play drug effect.
And the Co ntrolled release of medicine is also the major issue of restriction pulmonary administration microsphere application, selects have certain hydrophilic polymeric material not only can improve the bioavailability of medicine, also can improve the attachment of microsphere and alveolar surface simultaneously.
Summary of the invention
The object of this invention is to provide a kind of hollow medicine carrying microballoons for pulmonary administration and preparation method thereof.
Hollow medicine carrying microballoons for pulmonary administration provided by the present invention prepares according to the method comprised the steps:
1) medicine is soluble in water, aqueous phase W in being formed
1;
2) biodegradable polymer material is dissolved in organic solvent, forms oil phase O;
3) by described interior aqueous phase W
1join in described oil phase O, emulsifying, form W
1/ O emulsion;
4) by described W
1/ O emulsion joins the outer aqueous phase W containing stabilizing agent
2in, form W
1/ O/W
2pre-emulsion;
5) by described W
1/ O/W
2pre-emulsion, by porous membrane emulsiilcation, obtains W
1/ O/W
2emulsion;
6) by described W
1/ O/W
2organic solvent in emulsion in oil phase is removed, and oil phase is solidified, then through washing and lyophilization, obtains hollow medicine carrying microballoons.
Said method step 1) in, described medicine is water miscible macromolecular drug, and described water miscible medicine specifically can be: polypeptide, protein, polysaccharide, nucleic acid and vaccine.
Said method step 2) in, described biodegradable polymer material is selected from following at least one: the amphipathic condensation material that polylactic acid, PLGA, condensing model, polycaprolactone and above-mentioned at least one polymer and Polyethylene Glycol copolymerization obtain.Wherein, described condensing model specifically can be poly sebacic polyanhydride, poly-adipic anhydride and gathers [two (to the carboxyphenoxy) propane of 1,3-and decanedioic acid copolymer].
The molecular weight of above-mentioned biodegradable polymer is 10,000-5 ten thousand.
Described biodegradable polymer material specifically can be: molecular weight is the polylactic acid of 10,000, molecular weight is the PLGA of 30,000, molecular weight is the poly sebacic polyanhydride of 10,000, molecular weight is the PLGA of 3.8 ten thousand and the copolymer of Polyethylene Glycol, molecular weight is the polycaprolactone of 50,000, molecular weight is the polylactic acid of 4.5 ten thousand and the copolymer of Polyethylene Glycol, molecular weight is the PLGA of 50,000 and the copolymer of Polyethylene Glycol, molecular weight be 4.5 ten thousand polycaprolactone and molecular weight be the PLGA of 3.5 and the copolymer of Polyethylene Glycol.
Described organic solvent is selected from following at least one: dichloromethane, chloroform, ethyl acetate and acetone.
Said method step 3) in, interior aqueous phase W
1be 1:5-15 with the volume ratio of oil phase O, specifically can be 1:5,1:7,1:8,1:10 and 1:15.
Described interior aqueous phase W
1in medicine and described oil phase O in the mass ratio of biodegradable polymer material be 1:6.25-50, specifically can be 1:6.25,1:10,1:12.5,1:15,1:20,1:25,1:40 and 1:50.
Said method step 3) in, described emulsifying is by aqueous phase W in obtaining
1carry out mechanical agitation with the system of oil phase O composition and realize, described churned mechanically condition is: 8000-12000rpm stirs 1-5min.
Said method step 4) in, described stabilizing agent is selected from following at least one: polyvinyl alcohol, polyvinylpyrrolidone, gelatin and dodecyl sodium sulfate.
Described stabilizing agent is at described outer aqueous phase W
2in mass concentration be 0.1wt%-5wt%; Be preferably 0.5wt%-2wt%, be more preferably 1wt%.
Described W
1/ O emulsion and described outer aqueous phase W
2volume ratio be 6-16:30-120.
Said method step 5) in, the aperture of described microporous membrane is 2.8 μm-8 μm, specifically can be 2.8 μm, 4.2 μm, 5.3 μm, 6.2 μm, 6.5 μm and 8.0 μm.The film thickness of described microporous membrane is 1-3mm, and the pressure of described film emulsifying is: 100kPa-150kPa, and the temperature of described film emulsifying is: 0 DEG C-30 DEG C.
Said method step 6) in, from described W
1/ O/W
2the method removing the organic solvent in oil phase in emulsion is selected from following at least one: solvent evaporation method and solvent extraction, is preferably solvent evaporation method.
Described solvent evaporation method can carry out in stirring or under leaving standstill; The condition of described stirring is that 50-500rpm stirs 3-12h.
The hollow medicine carrying microballoons for pulmonary administration prepared by said method also belongs to protection scope of the present invention.
The particle size distribution of the described hollow medicine carrying microballoons for pulmonary administration is between 0.5-5 μm, and particle diameter is adjustable.
The described hollow medicine carrying microballoons for pulmonary administration, while ensureing that drug powder enters alveolar, greatly can improve again the envelop rate of medicine carrying microballoons, and maximum envelop rate is 82%, energy sustained release 5 hours-30 days.This micro-sphere structure is particularly useful for the micro encapsulation of the higher medicine of the price such as albumen, nucleic acid.
The preparation method of narrow diameter distribution, size tunable is used in the preparation of pulmonary administration by the hollow medicine carrying microballoons for pulmonary administration provided by the invention first.Film emulsifying technology wherein ensure that the size tunable of medicine carrying microballoons and narrow particle size distribution.
Prepared product does not have loose structure due to surface, therefore can obtain higher drug loading.The degradation rate of microsphere can be controlled by the molecular weight and oil phase concentration controlling microsphere polymer material.
Preparation method of the present invention, compared with the existing technology of preparing for pulmonary administration microsphere, has the following advantages:
Preparation efficiency of the present invention is higher, and owing to adopting film emulsifying device to carry out emulsifying, thus the particle diameter of products obtained therefrom can control within the scope of 0.5-5 μm, avoids and adopts traditional deficiency being obtained suitable size microsphere by screening.
The invention provides a kind of hollow medicine carrying microballoons for pulmonary administration, its particle size distribution is between 0.5-5 μm, drug loading is 1%-13%, envelop rate is 50%-82%, adopt and there is good biocompatibility, can abrupt release or sustained release 5 hours-30 days, thus can reduce drug dose and side effect.
The present invention is directed to current pulmonary administration microsphere low at lung deposition efficiencies, the problems such as the low and drug controlled release of drug loading, invent a kind of method that size is applicable to the hollow medicine carrying microballoons of pulmonary administration, product prepared by the method has very high concordance, simultaneously operational approach and condition simple, process stabilizing, repeatability is high, is easy to suitability for industrialized production.Medicine loads, the biocompatibility of dispose procedure reduces side effects of pharmaceutical drugs to adopt Amphipathilic block polymer to improve.
Accompanying drawing explanation
Fig. 1 is the Electronic Speculum figure of microsphere prepared by embodiment 1.
Fig. 2 is the grain size distribution of microsphere prepared by embodiment 1.
Fig. 3 is the Electronic Speculum figure of microsphere prepared by embodiment 2.
Fig. 4 is the grain size distribution of microsphere prepared by embodiment 2.
Fig. 5 is the Electronic Speculum figure of microsphere prepared by embodiment 3.
Fig. 6 is the grain size distribution of microsphere prepared by embodiment 3.
Fig. 7 is the Electronic Speculum figure of microsphere prepared by embodiment 4.
Fig. 8 is the grain size distribution of microsphere prepared by embodiment 4.
Fig. 9 is the Electronic Speculum figure of microsphere prepared by embodiment 5.
Figure 10 is the grain size distribution of microsphere prepared by embodiment 5.
Figure 11 is the Electronic Speculum figure of microsphere prepared by embodiment 6.
Figure 12 is the grain size distribution of microsphere prepared by embodiment 6.
Figure 13 is the Electronic Speculum figure of microsphere prepared by embodiment 7.
Figure 14 is the grain size distribution of microsphere prepared by embodiment 7.
Figure 15 is the Electronic Speculum figure of microsphere prepared by embodiment 8.
Figure 16 is the grain size distribution of microsphere prepared by embodiment 8.
Figure 17 is the Electronic Speculum figure of microsphere prepared by embodiment 9.
Figure 18 is the grain size distribution of microsphere prepared by embodiment 9.
Figure 19 is the In-vitro release curves of medicine carrying microballoons in embodiment 10.
Figure 20 is the Electronic Speculum figure of microsphere prepared by comparative example.
Figure 21 is the grain size distribution of microsphere prepared by comparative example.
Detailed description of the invention
Below by specific embodiment, the present invention will be described, but the present invention is not limited thereto.
The experimental technique used in following embodiment if no special instructions, is conventional method; Reagent used in following embodiment, biomaterial etc., if no special instructions, all can obtain from commercial channels.
In following embodiment, carry out the mensuration of drug loading and envelop rate by the following method:
Weigh the medicine carrying microballoons in the following embodiment of 100mg, be dissolved in the sodium hydroxide of 1mL1mol/L, after microsphere dissolves completely, adopt BCA determination of protein concentration method, under 560nm wavelength, measure its ultraviolet absorption peak.Wherein, the total amount of contained drug amount/microsphere in drug loading=microsphere; Encapsulating and non-encapsulated total dose in the medication amount/system encapsulated in envelop rate=system.
Embodiment 1
By the molecular weight of 0.50g be 10,000 polylactic acid be dissolved in 5ml chloroform, and add the aqueous solution that 1ml contains 0.01g bovine serum albumin (for simulated albumin medicine), mechanical agitation 8000rpm stirs 1min, this emulsion is joined in the aqueous gelatin solution of the 5wt% of 40ml, again by the microporous membrane device of this emulsion by 5.3 μm, obtain final emulsion, then emulsion is at room temperature stirred 6h removing oil phase solvent, can product be obtained finally by washing, drying.Its drug loading is 1.2%, and envelop rate is 60%.
Its electron scanning micrograph is as Fig. 1, and particle size distribution is as Fig. 2.
As seen from Figure 1, the hollow medicine carrying microballoons sphericity of gained is better.
As shown in Figure 2, microspherulite diameter is between 1-5 μm.
Embodiment 2
By the molecular weight of 0.40g be 30,000 PLGA be dissolved in 6ml ethyl acetate, and add the aqueous solution that 0.4ml contains 0.04g bovine serum albumin, mechanical agitation 8000rpm stirs 2min, this emulsion is joined in the aqueous povidone solution of the 3wt% of 30ml, again by the microporous membrane device of this emulsion by 6.5 μm, obtain emulsion, then emulsion is at room temperature stirred 4h removing oil phase solvent, can product be obtained finally by washing, drying.Its drug loading is 6.8%, and envelop rate is 68%.
Its electron scanning micrograph is as Fig. 3, and particle size distribution is as Fig. 4.
As seen from Figure 3, the hollow medicine carrying microballoons sphericity of gained is better.
As shown in Figure 4, microspherulite diameter is between 1-5 μm.
Embodiment 3
Added by decanedioic acid (10.0g) in acetic anhydride (100mL), heat 50 DEG C of backflow 30min under nitrogen protection, distilling under reduced pressure obtains the crude product of prepolymer.By this crude product petroleum ether-ether (1:1) washing, filter, vacuum drying (35 DEG C) 24h.Subsequently decanedioic acid prepolymer is added in reactor, at 260 DEG C, react 3.5h.Nitrogen 1min is passed into therebetween every 15min.The crude product chloroform obtained dissolves, and then this solution is dripped normal hexane while stirring.Leach precipitate, use washed with diethylether.Product and 35 DEG C of vacuum drying 24h.
The molecular weight that 0.6g is obtained be 10,000 poly sebacic polyanhydride be dissolved in 15ml chloroform, and add the aqueous solution that 1ml contains 0.04g bovine serum albumin, mechanical agitation 8000rpm stirs 2min, this emulsion is joined in the sodium dodecyl sulfate aqueous solution of the 1.5%wt of 100ml, again by the microporous membrane device of this emulsion by 8.0 μm, obtain emulsion, then emulsion is at room temperature stirred 8h removing oil phase solvent, can product be obtained finally by washing, drying.Its drug loading is 4.15%, and envelop rate is 62.3%.
Its electron scanning micrograph is as Fig. 5, and particle size distribution is as Fig. 6.
As seen from Figure 5, the hollow medicine carrying microballoons sphericity of gained is better.
As shown in Figure 6, microspherulite diameter is between 1-5 μm.
Embodiment 4
Be that poly-(lactic acid-polyglycolic acid) of 3.8 ten thousand and the copolymer of Polyethylene Glycol are dissolved in 8ml dichloromethane by the molecular weight of 0.4g, and add the aqueous solution that 1ml contains 0.02g bovine serum albumin, mechanical agitation 8000rpm stirs 2min, this emulsion is joined in the polyvinyl alcohol water solution of the 1%wt of 80ml, again by the microporous membrane device of this emulsion by 5.3 μm, obtain emulsion, again emulsion is at room temperature stirred 8h and remove oil phase solvent, can product be obtained finally by washing, drying.Its drug loading is 4.0%, and envelop rate is 80.6%.
Its electron scanning micrograph is as Fig. 7, and particle size distribution is as Fig. 8.
As seen from Figure 7, the hollow medicine carrying microballoons sphericity of gained is better.
As shown in Figure 8, microspherulite diameter is between 1-5 μm.
Embodiment 5
By the molecular weight of 0.5g be 50,000 polycaprolactone be dissolved in 8ml acetone-dichloromethane, and add the aqueous solution that 1ml contains 0.02g bovine serum albumin, mechanical agitation 8000rpm stirs 2min, in the gelatin this emulsion being joined the 0.5%wt of 120ml and sodium dodecyl sulfate aqueous solution, again by the microporous membrane device of this emulsion by 2.8 μm, obtain emulsion, then emulsion is at room temperature stirred 4h removing oil phase solvent, can product be obtained finally by washing, drying.Its drug loading is 2.4%, and envelop rate is 60%.
Its electron scanning micrograph is as Fig. 9, and particle size distribution is as Figure 10.
As seen from Figure 9, the hollow medicine carrying microballoons sphericity of gained is better.
As shown in Figure 10, microspherulite diameter is between 0.5-5 μm.
Embodiment 6
Be that the polylactic acid of 4.5 ten thousand and the copolymer of Polyethylene Glycol are dissolved in 7ml chloroform by the molecular weight of 0.8g, and add the aqueous solution that 1ml contains 0.02g bovine serum albumin, mechanical agitation 10000rpm stirs 2min, in the polyvinyl alcohol this emulsion being joined the 1.5%wt of 120ml and sodium dodecyl sulfate aqueous solution, again by the microporous membrane device of this emulsion by 4.2 μm, obtain emulsion, then emulsion is at room temperature stirred 6h removing oil phase solvent, can product be obtained finally by washing, drying.Its drug loading is 1.97%, and envelop rate is 78.8%.
Its electron scanning micrograph is as Figure 11, and particle size distribution is as Figure 12.
As seen from Figure 11, the hollow medicine carrying microballoons sphericity of gained is better.
As shown in Figure 12, microspherulite diameter is between 0.5-5 μm.
Embodiment 7
Be that the PLGA of 50,000 and the copolymer of Polyethylene Glycol are dissolved in 7ml dichloromethane by the molecular weight of 0.6g, and add the aqueous solution that 1ml contains 0.03g bovine serum albumin, mechanical agitation 8000rpm stirs 2min, in the polyvinylpyrrolidone this emulsion being joined the 1.5%wt of 120ml and sodium dodecyl sulfate aqueous solution, again by the microporous membrane device of this emulsion by 6.2 μm, obtain emulsion, again emulsion is at room temperature stirred 8h and remove oil phase solvent, can product be obtained finally by washing, drying.Its drug loading is 3.2%, and envelop rate is 63.7%.
Its electron scanning micrograph is as Figure 13, and particle size distribution is as Figure 14.
As seen from Figure 13, the hollow medicine carrying microballoons sphericity of gained is better.
As shown in Figure 14, microspherulite diameter is between 1-5 μm.
Embodiment 8
By the molecular weight of 0.5g be 4.5 ten thousand polycaprolactone be dissolved in 7ml chloroform, and add the aqueous solution that 1ml contains 0.04g bovine serum albumin, mechanical agitation 8000rpm stirs 2min, this emulsion is joined in the polyvinyl alcohol water solution of the 1.5%wt of 120ml, again by the microporous membrane device of this emulsion by 5.3 μm, obtain emulsion, then emulsion is at room temperature stirred 6h removing oil phase solvent, can product be obtained finally by washing, drying.Its drug loading is 4.1%, and envelop rate is 51.2%.
Its electron scanning micrograph is as Figure 15, and particle size distribution is as Figure 16.
As seen from Figure 15, the hollow medicine carrying microballoons sphericity of gained is better.
As shown in Figure 16, microspherulite diameter is between 1-5 μm.
Embodiment 9
Be that the PLGA of 3.5 ten thousand and the copolymer of Polyethylene Glycol are dissolved in 10ml dichloromethane by the molecular weight of 0.5g, and add the aqueous solution that 1ml contains 0.08g bovine serum albumin, mechanical agitation 12000rpm stirs 3min, this emulsion is joined in the polyvinyl alcohol water solution of the 1.0%wt of 100ml, again by the microporous membrane device of this emulsion by 5.3 μm, obtain emulsion, again emulsion is at room temperature stirred 4h and remove oil phase solvent, can product be obtained finally by washing, drying.Its drug loading is 13%, and envelop rate is 81.3%.
Its electron scanning micrograph is as Figure 17, and particle size distribution is as Figure 18.
As seen from Figure 17, the hollow medicine carrying microballoons sphericity of gained is better.
As shown in Figure 18, microspherulite diameter is between 1-5 μm.
Embodiment 10
The medicine carrying microballoons product obtained in precise 100mg embodiment 4, adds the PBS buffer of 50mlpH7.2.Sample bottle is placed in 37 DEG C of water-bath constant temperature oscillator concussions.Regular taking-up 1.0ml supernatant, supplements the PBS buffer of same volume simultaneously.Protein content micro-BCA kit measurement in the supernatant taken out.After measured, in 30 days, microsphere sustained release BSA reaches 55%.As Figure 19.
Comparative example
Be that the PLGA of 3.5 ten thousand and the copolymer of Polyethylene Glycol are dissolved in 10ml dichloromethane by the molecular weight of 0.5g, and add the aqueous solution that 1ml contains 0.08g bovine serum albumin, mechanical agitation 8000rpm stirs 2min, this emulsion is joined in the polyvinyl alcohol water solution of the 1.0%wt of 100ml, again by this emulsion mechanical agitation 5min under rotating speed is 8000rpm, obtain emulsion, again emulsion is at room temperature stirred 4h and remove oil phase solvent, can product be obtained finally by washing, drying.Its drug loading is 5.67%, and envelop rate is 35.4%.
Its electron scanning micrograph is as Figure 20, and particle size distribution is as Figure 21.
As seen from Figure 20, the hollow medicine carrying microballoons surface of gained has micropore to exist, and rough surface.
As shown in Figure 21, microspherulite diameter is between 1-13 μm.
Claims (10)
1. prepare a method for hollow medicine carrying microballoons, comprise the steps:
1) medicine is soluble in water, aqueous phase W in being formed
1;
2) biodegradable polymer material is dissolved in organic solvent, forms oil phase O;
3) by described interior aqueous phase W
1join in described oil phase O, emulsifying, form W
1/ O emulsion;
4) by described W
1/ O emulsion joins the outer aqueous phase W containing stabilizing agent
2in, form W
1/ O/W
2pre-emulsion;
5) by described W
1/ O/W
2pre-emulsion, by porous membrane emulsiilcation, obtains W
1/ O/W
2emulsion;
6) by described W
1/ O/W
2organic solvent in emulsion in oil phase is removed, and oil phase is solidified, then through washing and lyophilization, obtains hollow medicine carrying microballoons.
2. method according to claim 1, is characterized in that: step 1) in, described medicine is water miscible medicine, and described water miscible medicine is: polypeptide, protein, polysaccharide, nucleic acid and vaccine.
3. method according to claim 1 and 2, it is characterized in that: step 2) in, described biodegradable polymer material is selected from following at least one: the amphipathic condensation material that polylactic acid, PLGA, condensing model, polycaprolactone and above-mentioned at least one polymer and Polyethylene Glycol copolymerization obtain;
The molecular weight of described biodegradable polymer is 10,000-5 ten thousand.
4. the method according to any one of claim 1-3, is characterized in that: step 2) in, described organic solvent is selected from following at least one: dichloromethane, chloroform, ethyl acetate and acetone.
5. the method according to any one of claim 1-4, is characterized in that: step 3) in, described interior aqueous phase W
1be 1:5-15 with the volume ratio of oil phase O; Described interior aqueous phase W
1in medicine and described oil phase O in the mass ratio of biodegradable polymer material be 1:6.25-50; Described emulsifying is by aqueous phase W in obtaining
1carry out mechanical agitation with the system of oil phase O composition and realize, wherein said churned mechanically condition is: 8000-12000rpm stirs 1-5min.
6. the method according to any one of claim 1-5, is characterized in that: step 4) in, described stabilizing agent is selected from following at least one: polyvinyl alcohol, polyvinylpyrrolidone, gelatin and dodecyl sodium sulfate; Described stabilizing agent is at described outer aqueous phase W
2in mass concentration be 0.1wt%-5wt%.
7. the method according to any one of claim 1-6, it is characterized in that: step 5) in, the aperture of described microporous membrane is 2.8 μm-8 μm, the film thickness of described microporous membrane is 1-3mm, the pressure of described film emulsifying is: 100kPa-150kPa, and the temperature of described film emulsifying is: 0 DEG C-30 DEG C.
8. the method according to any one of claim 1-7, is characterized in that: step 6) in, from described W
1/ O/W
2the method removing the organic solvent in oil phase in emulsion is selected from following at least one: solvent evaporation method and solvent extraction, is preferably solvent evaporation method, and described solvent evaporation method carries out in stirring or under leaving standstill; The condition of wherein said stirring is that 50-500rpm stirs 3-12h.
9. the hollow medicine carrying microballoons that method prepares according to any one of claim 1-8, is characterized in that: the particle size distribution of described hollow medicine carrying microballoons is between 0.5-5 μm.
10. hollow medicine carrying microballoons according to claim 9 is preparing the application in pulmonary administration medicine.
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| CN116262157A (en) * | 2022-12-29 | 2023-06-16 | 高颜苑科技(深圳)有限责任公司 | Preparation method of polypeptide slow-release microneedle based on hair growth |
| CN116262157B (en) * | 2022-12-29 | 2024-05-10 | 高颜苑科技(深圳)有限责任公司 | Preparation method of polypeptide slow-release microneedle based on hair growth |
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