CN103585113A - Apigenin polylactic acid sustained release microsphere and preparation method thereof - Google Patents
Apigenin polylactic acid sustained release microsphere and preparation method thereof Download PDFInfo
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Abstract
The invention discloses an apigenin polylactic acid sustained release microsphere and a preparation method of the apigenin polylactic acid sustained release microsphere. The preparation method comprises the following steps: dissolving hydroxyl-terminated racemic polylactic acid and soybean lecithin in an organic solvent; stirring the liquid, and slowly adding the apigenin mixed liquid subjected to ultrasonic treatment in an emulsifier aqueous solution to be emulsified; reducing the pressure, removing the solvent with steam, concentrating the volume; centrifuging at high speed, washing and drying the obtained mixed liquid to prepare the polylactic acid entrapped apigenin acid sustained release microsphere, wherein the microsphere particle size is 1-5 microns, the drug loading ratio is larger than 25%, the encapsulation efficiency is larger than 79%, and the sustained release time is more than 550 hours. According to the polylactic acid with good biocompatibility and biodegradability is taken as a clad material to prepare the apigenin polylactic acid sustained release microsphere, so that the microsphere is uniform in shape, smooth and adhesion-free on the surface, uniformly distributed in the particle size, and good in slow-release effect, can keep continuous release time in vitro 550 h above, conquers the defects that the drug is poor in water solubility and fat solubility, improves the oral administration availability, prolongs the drug action time and improves the drug therapeutic effect.
Description
Technical field
The present invention relates to a kind of medicament slow release preparation and preparation method thereof, specifically a kind of apigenin PLA Microspheres that apigenin forms and preparation method thereof that carried by polylactic acid bag.
Background technology
Apigenin is the flavone compound being extensively present in various fruits vegetable, beans and Folium Camelliae sinensis, has free radical, antiinflammatory and the anticancer bioactive of removing.It mainly passes through to control cancerous cell gene expression, thereby affects its protein active cell death inducing, and then multiple cancerous cell is played to the effect that suppresses its growth and promote apoptosis.Can be used as again treatment HIV and the antiviral drugs of other viral infection, the inhibitor of map kinase, antioxidant, tranquilizer, antihypertensive drugs etc. simultaneously.With other Flavonoid substances, as Quercetin, Rhizoma Kaempferiae flavone, compare there is low toxicity, without features such as mutagenicitys.After deliberation, apigenin also has the effect of cardioprotection and the effect for the treatment of Parkinson's disease.But because apigenin is water insoluble, hydrophilic and lipotropy are all very poor, and oral absorption is poor, have greatly limited its clinical practice.Therefore can be made into slow releasing preparation by applying biological degradation material, to improve its oral availability, there is certain feasibility.
At present, in the exploitation of medical product, fewer about the report of its medicament slow release preparation.Zhang Zhi state (preparation of apigenin chitosan microball and tablets in vitro research, practical medicine and clinical, the 33rd the 12nd phase of volume) etc. chitosan is pharmaceutical carrier, adopt emulsion-emulsion chemical crossline method to prepare apigenin chitosan microball, improved to a certain extent oral absorption, the prolong drug release time of apigenin, but because Viscosity of Chitosan is large, there is the easy adhesion problems of microsphere in preparation process.
Publication number is that CN 102274192 A disclose " a kind of carboxymethyl chitosan medicament-carrying microspheres and preparation method thereof ", it take carboxymethyl chitosan as matrix material, in solution, adopt first ionomer, the small-molecule drugs such as the coated apigenin of method of rear secondary cross-linking, but there is drug loading and the lower problem of envelop rate in it.
Polylactic acid (PLA) is owing to having good biocompatibility and biological degradability, in human body, final metabolism is water and carbon dioxide, can not be widely used as pharmaceutical carrier in vitals gathering, therefore adopt polylactic acid bag to carry apigenin and make apigenin PLA Microspheres preparation, can delay Slow release, greatly reduce administration frequency, improve bioavailability, overcome the poor shortcoming of intrinsic oral absorption.
Summary of the invention
The present invention is directed to apigenin poorly water-soluble, fat-soluble poor, poor and the low shortcoming of envelop rate of oral absorption, based on polylactic acid biocompatibility and the good feature of biological degradability, using it as host material, prepare apigenin PLA Microspheres, and by water solublity, fat-soluble good soybean lecithin joins in polylactic acid, make to prepare microsphere and can overcome that it is intrinsic poorly soluble, the shortcoming that oral absorption is poor, greatly reduce administration frequency, improve its bioavailability, with this, realize a kind of apigenin PLA Microspheres that the present invention will provide and preparation method thereof.
Object of the present invention is just being to provide a kind ofly take polylactic acid and as host material, prepares apigenin PLA Microspheres having compared with high drug load, envelop rate and preparation method thereof.This preparation method is emulsion dispersion-solvent evaporation method, polylactic acid and soybean lecithin are dissolved in organic solvent, and be scattered in wherein apigenin is ultrasonic, and high shear slowly joins in emulsifying agent by the mixed liquor after ultrasonic under stirring, emulsifying goes to emulsion on Rotary Evaporators, to remove the concentrated volume of solvent under reduced pressure after stirring, by the mixed liquor high speed centrifugation of gained, washing, dry, make apigenin PLA Microspheres again.Adopt microsphere that the method is prepared have spherical regular, particle surface smooth without adhesion, particle size distribution is even, embedding is good, drug loading and envelop rate is high, the feature of slow release long-acting.
Technical scheme of the present invention is: a kind of apigenin PLA Microspheres and preparation method thereof, wherein, a kind of apigenin PLA Microspheres, described in it, sustained-release micro-spheres is by polylactic acid bag, to carry apigenin to form, its particle diameter is 1-5 μ m, carrying drug ratio > 25%, envelop rate > 79%, slow-release time > 550h.
A preparation method for above-mentioned apigenin PLA Microspheres, is characterized in that: described preparation method follows these steps to carry out:
(1) medical grade terminal hydroxy group poly-dl-lactide (OH-PDLLA-OH) and 0.3 ~ 1.5g soybean lecithin of 0.2 ~ 1 g molecular weight 20000 ~ 100000 are dissolved in the organic solvent of 10mL, are made into the mixed solution that concentration is 0.02 ~ 0.1g/mLPDLLA and 0.03 ~ 0.15g/mL soybean lecithin;
(2) be scattered in above-mentioned polylactic acid mixed solution the apigenin of certain mass is ultrasonic, ultrasonic dispersion 2 ~ 5min at normal temperatures after mixing, the mass ratio of apigenin and polylactic acid is 1:2 ~ 8;
(3) in high shear mixing speed, be under 600 ~ 2000rpm, the mixed solution of step (2) ultrasonic emulsification gained is slowly added dropwise in the emulsifying agent of certain volume, after mixing, make O/W type emulsion; The profit volume ratio of mixed solution and emulsifier aqueous solution is 1:2 ~ 5;
(4) low whipping speed is to stir after 10min under 400rpm, and emulsion is gone on Rotary Evaporators and removes solvent under reduced pressure, and it is 10 ~ 20mL that emulsion is concentrated into volume;
(5) step (4) gained is dispersed with to the centrifugal 20 ~ 40min of emulsion of microsphere, centrifugal speed is 12000rpm, centrifugal rear mixture upper strata is liquid, lower floor is microspheres with solid, collect lower floor's microspheres with solid and with distilled water wash, dry after, obtaining mean diameter is the apigenin sustained-release micro-spheres of 1 ~ 5 μ m.
In technique scheme, described organic solvent is a kind of in ethyl acetate, acetone, dichloromethane and oxolane; Described emulsifying agent is the pluronic of concentration 0.25 ~ 0.35g/mL
f-68aqueous solution; Described microsphere particle is preserved under 4 ° of C drying regimes.
Above-mentioned provided a kind of apigenin PLA Microspheres and preparation method thereof is provided, compared with prior art, its that directly bring and beneficial effect that do not certainly lead to is: the present invention be take PDLLA as carrier, adopt emulsion dispersion-solvent evaporation method, by adding water solublity and fat-soluble good soybean lecithin, control the amount ratio of PDLLA and apigenin, the time of ultrasonic emulsification and mix and blend, the concentration of emulsifying agent and profit phase volume ratio, the apigenin sustained-release micro-spheres of preparation, spherical regular, particle surface is smooth without adhesion, particle size dispersion is even, size is between 1-5 μ m, drug loading higher (more than 25%), envelop rate high (more than 79%), drug release time is long, more than reaching 550h, has significant long-acting and slow releasing function.This preparation method has overcome apigenin water solublity, fat-soluble all poor, problems that oral absorption rate is low, and technique is simple, and the cycle is short, can fully guarantee realization and the long-acting slow-release performance of contained medication amount, greatly reduce administration frequency, improve its bioavailability.
Accompanying drawing explanation
Fig. 1 be in embodiment 1 5000 times of apigenin PLA Microspheres scanning electron microscope diagram.
Fig. 2 is the standard working curve of apigenin in embodiment 1.
Fig. 3 is the release in vitro curve of apigenin PLA Microspheres in embodiment 1.
The specific embodiment
The present invention is described in further detail below with reference to embodiment.Should be understood that these embodiment are only not used in and limit the scope of the invention for the present invention is described.In addition should be understood that those skilled in the art can make various changes or modifications the present invention after having read the content of the present invention's instruction, these equivalent form of values fall within the application's appended claims limited range equally.
Embodiment 1
Implement a kind of preparation method of apigenin PLA Microspheres, this preparation method follows these steps to carry out:
(1) preparation of apigenin PLA Microspheres
The OH-PDLLA-OH of 0.2 g molecular weight 20000 and 0.3g soybean lecithin are dissolved in 10mL dichloromethane, are made into the mixed solution that concentration is 0.02g/mL OH-PDLLA-OH and 0.03g/mL soybean lecithin; 0.07g apigenin is added in above-mentioned polylactic acid dichloromethane mixed solution, ultrasonic dispersion 5min at normal temperatures after mixing, apigenin and polylactic acid mass ratio are 1:3.High shear mixing speed is under 800rpm, above-mentioned suspension is slowly added dropwise to the pluronic of 30mL concentration 0.25g/mL
f-68in aqueous solution, after mixing, make O/W type emulsion.Then under low whipping speed 400rpm, this emulsion is stirred after 10 min, go to and on Rotary Evaporators, remove solvent under reduced pressure to be concentrated into volume be 10 mL, obtain being dispersed with the emulsion of microsphere.By this solution centrifugal 20min under 12000rpm in high speed centrifuge, centrifugal rear mixture upper strata is liquid, and lower floor is microspheres with solid, collects lower floor's microspheres with solid and with distilled water wash, dry after, obtain apigenin PLA Microspheres.
(2) form of microsphere and grain size
The microsphere photo of taking by scanning electron microscope (accompanying drawing 1), can see, the microsphere that institute obtains is spherical regular, and particle surface is smooth even without adhesion, particle size dispersion, and size is at 1 ~ 5 μ m.
(3) medicament contg and entrapment efficiency determination
The mensuration of A, apigenin maximum absorption wavelength
For determining Quantitative Determination of Apigenin determined by ultraviolet spectrophotometry wavelength, in research, with Shanghai essence 756MC ultraviolet-uisible spectrophotometer, the maximum absorption wavelength of apigenin is measured, determination step is: precision takes 20mg apigenin, dissolve with ethanol solution with 95%, 95% the alcoholic solution of take is blank, in 200 ~ 400nm catch cropping UV scanning, just can obtain maximum absorption wavelength is 340nm.
B, standard curve preparation
Precision takes 8mg apigenin, and the dissolve with ethanol solution with 95% is transferred to standardize solution in 100mL volumetric flask, obtains the apigenin contrast liquid of 0.08mg/mL.The accurate contrast liquid 0.05,0.1,0.15,0.2,0.25 of drawing, 0.3mL, in test tube, the ethanol with 95% is settled to 5mL respectively.According to spectrophotography, in the maximum absorption wave strong point of apigenin, measure absorbance.And take the apigenin concentration standard curve that mapping obtains apigenin alcoholic solution as vertical coordinate, absorbance as abscissa as shown in Figure 2.By linear regression, obtaining apigenin concentration A to the regression equation of absorbance C is: A=0.076 C-0.011[R
2=0.9996, RSD=0.0035%, n=6, P < 0.0001].
The calculating of C, drug loading and envelop rate
Precision takes 5 mg apigenin PLA Microspheres, and add 10 mL 95% ethanol in test tube, Ultrasonic Heating destroys after 1h, use microporous filter membrane sucking filtration, accurate filtrate 1 mL that draws, take 95% ethanol as blank, at 340 nm places, records, substitution regression equation also calculates, and just can obtain Quantitative Determination of Apigenin is 26%.The envelop rate that then just can calculate apigenin in microsphere preparation process according to following formula is 79%.
Drug loading=(microspheres quality that the drug quality ÷ in microsphere takes) * 100%
Envelop rate=(in microsphere in the actual content ÷ microsphere of apigenin the theoretical content of apigenin) * 100%
(4) extracorporeal releasing experiment
Take 20mg apigenin PLA Microspheres and be placed in bag filter (trapped molecular weight 8000), phosphate buffered solution 3 mL that add pH 7.4, clamp bag filter two ends, put in 100mL phosphate buffered solution, in constant temperature (37.0 ± 1.0) ℃ water-bath, magnetic stirring apparatus stirring at low speed.Respectively 1,3,7,21,35,61,107,145,168,264,323,470,550h equi-time point, respectively get 3 mL samples, measure its trap A, by the concentration of each time point apigenin of regression equation calculation.Solution after mensuration is refunded in former delivery systme, and each time point is surveyed 3 times, is averaged the drug level that is worth this time point, and does microsphere and add up release profiles outward, sees accompanying drawing 3.In initial 21h, drug release rate is 38.2%, and 550 h apigenins are afterwards slow sustained release from microsphere, and 550 h accumulative releasing degrees reach 73.5%, and can further discharge, and the microsphere of visible gained meets the requirement of slow release long-acting.
Embodiment 2
The OH-PDLLA-OH of 0.6 g molecular weight 70000 and 0.9g soybean lecithin are dissolved in 10mL ethyl acetate, are made into the mixed solution of 0.06g/mL OH-PDLLA-OH and 0.09g/mL soybean lecithin; 0.1g apigenin is added in above-mentioned polylactic acid ethyl acetate mixture, ultrasonic dispersion 3min at normal temperatures after mixing, apigenin and polylactic acid mass ratio are 1:6.High shear mixing speed is under 1500rpm, above-mentioned suspension is slowly added dropwise to the pluronic of 50mL 0.30g/mL
f-68in aqueous solution, after mixing, make O/W type emulsion.Then under low whipping speed 400rpm, stir after 10 min, go on Rotary Evaporators and remove solvent under reduced pressure, being concentrated into volume is 15 mL, obtains being dispersed with the emulsion of microsphere.By this solution centrifugal 30min under 12000rpm in high speed centrifuge, centrifugal rear mixture upper strata is liquid, and lower floor is microspheres with solid, collects lower floor's microspheres with solid and with distilled water wash, dry after, obtain apigenin sustained-release micro-spheres.Microsphere is spherical regular, and smooth surface is without adhesion, and particle diameter is 1-5 μ m, carrying drug ratio 27%, envelop rate 82%, slow-release time > 550h.
Embodiment 3
The OH-PDLLA-OH of 0.8 g molecular weight 100000 and 1.3g soybean lecithin are dissolved in 10mL acetone, are made into the mixed solution of 0.08g/mL OH-PDLLA-OH and 1.3g/mL soybean lecithin; 0.1g apigenin is added in above-mentioned polylactic acid acetone mixed solution, ultrasonic dispersion 2min at normal temperatures after mixing, apigenin and polylactic acid mass ratio are 1:8.High shear mixing speed is under 2000rpm, above-mentioned suspension is slowly added dropwise to the pluronic of 20mL 0.35g/mL
f-68in aqueous solution, after mixing, make O/W type emulsion.Then under low whipping speed 400rpm, stir after 10 min, this emulsion is gone on Rotary Evaporators and removes solvent under reduced pressure, being concentrated into volume is 20 mL, obtains being dispersed with the emulsion of microsphere.By this solution centrifugal 40min under 12000rpm in high speed centrifuge, centrifugal rear mixture upper strata is liquid, and lower floor is microspheres with solid, collects lower floor's microspheres with solid and with distilled water wash, dry after, obtain apigenin sustained-release micro-spheres.Microsphere is spherical regular, and smooth surface is without adhesion, and particle diameter is 1-5 μ m, carrying drug ratio 29%, envelop rate 83%, slow-release time > 550h.
Claims (5)
1. an apigenin PLA Microspheres, it is characterized in that: described sustained-release micro-spheres is by polylactic acid bag, to carry apigenin to form, and its particle diameter is 1-5 μ m, carrying drug ratio > 25%, envelop rate > 79%, slow-release time > 550h.
2. for a preparation method for apigenin PLA Microspheres as claimed in claim 1, it is characterized in that: described preparation method follows these steps to carry out:
(1) medical grade terminal hydroxy group poly-dl-lactide (OH-PDLLA-OH) and 0.3 ~ 1.5g soybean lecithin of 0.2 ~ 1 g molecular weight 20000 ~ 100000 are dissolved in the organic solvent of 10mL, are made into the mixed solution that concentration is 0.02 ~ 0.1g/mLPDLLA and 0.03 ~ 0.15g/mL soybean lecithin;
(2) be scattered in above-mentioned polylactic acid mixed solution the apigenin of certain mass is ultrasonic, ultrasonic dispersion 2 ~ 5min at normal temperatures after mixing, the mass ratio of apigenin and polylactic acid is 1:2 ~ 8;
(3) in high shear mixing speed, be under 600 ~ 2000rpm, the mixed solution of step (2) ultrasonic emulsification gained is slowly added dropwise in the emulsifying agent of certain volume, after mixing, make O/W type emulsion; The profit volume ratio of mixed solution and emulsifier aqueous solution is 1:2 ~ 5;
(4) low whipping speed is to stir after 10min under 400rpm, and emulsion is gone on Rotary Evaporators and removes solvent under reduced pressure, and it is 10 ~ 20mL that emulsion is concentrated into volume;
(5) step (4) gained is dispersed with to the centrifugal 20 ~ 40min of emulsion of microsphere, centrifugal speed is 12000rpm, centrifugal rear mixture upper strata is liquid, lower floor is microspheres with solid, collect lower floor's microspheres with solid and with distilled water wash, dry after, obtaining mean diameter is the apigenin sustained-release micro-spheres of 1 ~ 5 μ m.
3. preparation method according to claim 2, is characterized in that described organic solvent is a kind of in ethyl acetate, acetone, dichloromethane and oxolane.
4. preparation method according to claim 2, is characterized in that described emulsifying agent is the pluronic of concentration 0.25 ~ 0.35g/mL
f-68aqueous solution.
5. preparation method according to claim 2, is characterized in that described microsphere particle preserves under 4 ° of C drying regimes.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106902387A (en) * | 2017-03-18 | 2017-06-30 | 浙江臻我生物技术有限公司 | A kind of composition for skin filling and preparation method thereof |
| CN109010271A (en) * | 2018-09-25 | 2018-12-18 | 山东师范大学 | A kind of apiolin slow-release medicine carrier and preparation method thereof |
| CN109316371A (en) * | 2018-09-21 | 2019-02-12 | 珀莱雅化妆品股份有限公司 | A kind of preparation method of apiolin sustained release preparation |
| CN110698826A (en) * | 2019-11-01 | 2020-01-17 | 四川大学 | Preparation method of high-barrier polylactic acid film containing three-dimensional barrier network |
| CN113209372A (en) * | 2021-06-08 | 2021-08-06 | 青岛杰圣博生物科技有限公司 | Emulsification preparation method of polylactic acid soft tissue filling micro-rice grains |
Citations (1)
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| CN102274192A (en) * | 2011-08-09 | 2011-12-14 | 山西医科大学第一医院 | Carboxymethyl chitosan medicament-carrying microspheres and preparation method thereof |
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2013
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102274192A (en) * | 2011-08-09 | 2011-12-14 | 山西医科大学第一医院 | Carboxymethyl chitosan medicament-carrying microspheres and preparation method thereof |
Non-Patent Citations (1)
| Title |
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| HOSSEINKHANI H,ET AL: "in vitro sustained release and degradation study of biodegradable poly(D.L-lactic acid) microspheres loading theophylline", 《ADVANCED SCIENCE LETTERS》, vol. 2, no. 1, 31 March 2009 (2009-03-31), pages 70 - 77 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106902387A (en) * | 2017-03-18 | 2017-06-30 | 浙江臻我生物技术有限公司 | A kind of composition for skin filling and preparation method thereof |
| CN109316371A (en) * | 2018-09-21 | 2019-02-12 | 珀莱雅化妆品股份有限公司 | A kind of preparation method of apiolin sustained release preparation |
| CN109316371B (en) * | 2018-09-21 | 2021-09-03 | 珀莱雅化妆品股份有限公司 | Preparation method of apigenin sustained-release preparation |
| CN109010271A (en) * | 2018-09-25 | 2018-12-18 | 山东师范大学 | A kind of apiolin slow-release medicine carrier and preparation method thereof |
| CN109010271B (en) * | 2018-09-25 | 2021-06-25 | 山东师范大学 | Apigenin slow-release type drug carrier and preparation method thereof |
| CN110698826A (en) * | 2019-11-01 | 2020-01-17 | 四川大学 | Preparation method of high-barrier polylactic acid film containing three-dimensional barrier network |
| CN113209372A (en) * | 2021-06-08 | 2021-08-06 | 青岛杰圣博生物科技有限公司 | Emulsification preparation method of polylactic acid soft tissue filling micro-rice grains |
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