CN101244277B - Medicine carrying fibroin microsphere and preparation thereof - Google Patents
Medicine carrying fibroin microsphere and preparation thereof Download PDFInfo
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- CN101244277B CN101244277B CN2008100185093A CN200810018509A CN101244277B CN 101244277 B CN101244277 B CN 101244277B CN 2008100185093 A CN2008100185093 A CN 2008100185093A CN 200810018509 A CN200810018509 A CN 200810018509A CN 101244277 B CN101244277 B CN 101244277B
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Abstract
The invention discloses a drug-loaded microsphere and the preparation method, belonging to the technical field of biomedicine, which comprises following steps: adopting water/oil/water multiple emulsion technology and self-assembly technology of protein to fully mix the water soluble medicine and regenerated silk fibroin solution; adding the mixture in oil phase with emulsifier with certain amount during stirring for emulsification; adding organic solvent and stirring, thereby the silk fibroin is denaturalized and Beta structured to form milky crystalline silk fibroin fine particle, and the medicine is embedded; removing supernatant liquid through centrifugal effect; adding organic solvent; further crystallizing the silk fibroin and embedding the medicine; removing solvent and residual oil phase through centrifugal effect and collecting the microsphere. The average particle size of the silk fibroin drug-loaded microsphere is between 5.84 to 86.27Mum, the embedding rate is 42 to 99%, the drug loading dosage is 2.5 to 8.5%. The drug-loaded microsphere has the advantages of applicability to requirements for different purposes and wide application prospect.
Description
Technical field
The present invention relates to a kind of medicine carrying microballoons and preparation method thereof, particularly a kind ofly make medicine carrying fibroin microsphere and preparation method thereof, belong to field of biomedicine technology, also belong to chemical field with natural silk.
Background technology
Medicine is introduced in the body with forms such as microgranule, microcapsule, liposome, albumin carriers, half-life that can prolong drug, make it slowly to discharge or regularly targeting discharge, improve the effect of medicine.The research of medicine carrying microballoons starts from 20th century the mid-1970s, it is to be the carrier parcel or to adsorb the spherical particle that medicine is made with natural or synthetic macromolecular material, microsphere is very little, be generally 1～500 μ m, the size of microsphere directly influences the availability of microsphere Chinese medicine, the drug loading and the interior targeting that distributes of body of microsphere.The medicine carrying microballoons application relates to pesticide, weaving, cosmetics, papermaking, food and biomedicine etc.
The preparation of microsphere can be adopted different method for preparing microsphere according to the different in kind of carrier material and medicine, and spray drying method, phase separation method etc. are arranged.Spray drying method wherein because baking temperature is higher, so its application is subjected to certain restriction, as protein medicaments, growth because of long etc.Phase separation method is used morely in the preparation of microsphere, and the carrier material of microsphere has synthetic macromolecular material and natural biological macromolecular material.The macromolecular material of synthetic has: polyester, polylactic acid (PLA), polylactic acid-hydroxide acetic acid copolymer (PLGA), polyacrylic resin (ACA), polymethyl methacrylate (PMMA) and polyamide-based etc.; Natural biological macromolecular material commonly used has: albumin, gelatin, sodium alginate, chitosan etc.
Though the synthetic macromolecular material can make the repeatability of product and the residue problem of mechanical property and other impurity more and more be paid close attention in today of bio-safety increasingly stringent by accurately regulating ratio of components.In recent years, the natural biological macromolecular material quite is subjected to people's attention owing to its unique biological compatibility, and particularly chitosan, sodium alginate all partly enter clinical experimental study.Though the application of chitosan is comparatively extensive, but the preparation of chitosan solution must will be carried out in acid medium, and its easily dissolving in acid medium, slow-release capability to medicine is poor, secondly chitosan is the product of de-acetyl chitin, and its some performances are relevant with deacetylation, use different catalyst and different solvents, can obtain the different chitosan of deacetylation, different its performance differences of deacetylation are bigger; During emulsifying one chemical crosslink technique that adopts in the chitosan drug-loading method for preparing microsphere, use chemical cross-linking agent.Sodium alginate is generally made the sodium alginate gel microsphere, but its drug loading is not satisfactory, and China is to natural seaweed acid heat purification with form authenticate technology.The emulsifying solidification method is mainly adopted in the preparation of albumin medicine carrying microballoons, method with heating or chemical crosslinking is solidified drop, make medicament-carried being restricted owing to temperature is higher, obtain difficultly because of albuminous again, these factors have all restricted the application of these natural macromolecular materials aspect the biological medicine carrier material significantly.
By the excretory fibroin albumen of domestic natural silk gland is a kind of natural macromolecular material.Because this albumen, non-immunogenicity nontoxic, harmless to human body, many researchs have shown that it can be used as Carrier Materials of Immobilized Enzyme, biosensor, operation suture thread, enzyme protective agent, functional cell culture matrix, anticoagulant material, artificial organ etc.In recent years, carry out the raw material of artificial skin, cosmetics and nutraceutical or as fixed enzyme vector with fibroin, or receive publicity with development and use that other natural biologic material constitutes the aspects such as complex carrier of medicine, the research that particularly with the fibroin albumen is pharmaceutical carrier is particularly active in recent years, be mainly film, gel, form of powder with fibroin albumen as pharmaceutical carrier, existing many experiments confirm that fully fibroin albumen is a kind of good bio-carrier material.Have the unexistent advantage of other macromolecular materials with fibroin albumen as pharmaceutical carrier, the fibroin albumen wide material sources, easy to prepare.Publication number CN1834240A discloses silk nano granular of a kind of immobilized enzyme and preparation method thereof, owing to adopt ultracentrifugal method that enzyme is fixed in the fibroin, therefore, fixed enzyme amount seldom is not suitable for the required bearing capacity of common drug.In the Chinese invention patent of publication number CN1293952A, chitosan and fibroin mixed microsphere and uses thereof and preparation method are disclosed, use complex carrier and cross-linking agent glutaraldehyde, utilize the crosslinked bag medicine microsphere that makes of glutaraldehyde and chitosan and fibroin, and the crosslinked action of glutaraldehyde, the breeding of pair cell and the integrity of biomacromolecule have side effect.
Summary of the invention
In order to overcome above-mentioned defective, the invention provides that a kind of to have excellent biological compatibility, drug loading height, production technology simple and preparation method thereof.
Realize that the technical scheme that the object of the invention is taked is: a kind of medicine carrying fibroin microsphere is provided, and it is carrier with the fibroin albumen, and water soluble drug is a drug model; Medicine is embedded in the top layer of fibroin microsphere, and drug loading is 2.5～8.5%, and mean diameter is 5.84～86.27 μ m, and is water insoluble.
The preparation method of above-mentioned medicine carrying fibroin microsphere, concrete steps are as follows:
(1) water soluble drug is dissolved in equably in the silk fibroin solution that concentration is 2.5～12%/wt;
(2) joining the mixed liquor of above-mentioned silk fibroin solution and medicine with Span or lecithin is in the oil phase of emulsifying agent, and oil phase is liquid paraffin or vegetable oil, and the ratio that emulsifying agent accounts for emulsion is 0.5～5%/wt, with 350～800rpm speed stirring and emulsifying;
(3) add water-miscible organic solvent, organic solvent is 1～6 times of silk fibroin solution by volume, and mixing speed is more than 100rpm, and the processing time is 30～60 minutes, obtains medicine carrying fibroin microsphere mixed liquor or suspension;
(4) through the centrifugal upper strata liquid of removing, obtain medicine carrying fibroin microsphere, add organic solvent again and handle more than 12 hours;
(5) remove organic solvent and residual oil phase, behind centrifuge washing, lyophilization or the vacuum drying, obtain medicine carrying fibroin microsphere.
In the technique scheme, described organic solvent is isopropyl alcohol, ethanol and acetone.
The method for preparing medicine carrying fibroin microsphere proposed by the invention is the method for a kind of separation of oil, fibroin albumen self assembly.Be raw material specifically with regenerated silk fibroin solution, by stirring fibroin is dispersed into droplet with the oil phase that contains a certain amount of emulsifying agent earlier, form milky emulsion, again certain amount of organic solvent is added in the emulsion, induce the fibroin protein degeneration, form crystallization fibroin granule, be embedded in the top layer of microgranule at fibroin granule forming process Chinese medicine; Emulsion is carried out centrifugalize, remove upper strata liquid, obtain the fibroin microsphere, add organic solvent again the fibroin microsphere is handled, allow the further crystallization of fibroin albumen, more medicine is embedded in the microgranule; Centrifugalize and collect microsphere again adds the organic solvent centrifuge washing, and 2-3 time repeatedly, use the deionized water centrifuge washing at last, the medicine carrying fibroin microsphere of acquisition hygrometric state through lyophilization or vacuum drying, promptly gets medicine carrying fibroin microsphere.The mean diameter of microsphere is 5.84～86.27 μ m.
Fibroin albumen is a fibrin, so regenerated silk directly stirs easy fibrosis, foaming under fair speed.Though can induce the fibroin albumen crystallization even add organic solvent under this situation, can not form the embedding of uniform fibroin granule and medicine.Under the effect of certain mixing speed and emulsifying agent, oil phase is dispersed into small uniform drop with the fibroin medicinal liquid earlier in the present invention, forms water/oil type emulsion; In this emulsion, add organic solvent again, impel the fibroin albumen degeneration, water-soluble fibroin is transformed into the beta sheet structure by random coil and α-Luo Xuanjiegou, forming the crystallinity particulate while of fibroin, medicine is gradually by embedding, form water/oil/water type emulsion, obtain the micron order medicine carrying fibroin microsphere by centrifugalize, therefore the microsphere drug loading of this moment is low, must the reuse organic solvent be handled by microsphere, could obtain higher, stable performance, the water-fast medicine carrying fibroin microsphere of drug loading.
The present invention has the following advantages:
1. utilize emulsifying agent and stirring action, oil phase is dispersed into uniform fine droplet with fibroin and medicament mixed liquid, utilizes organic solvent to mix with silk fibroin solution, makes the solubility fibroin albumen be converted into the beta sheet structure from random coil and α-Luo Xuanjiegou.In forming the particulate process of crystallinity fibroin, medicine does not use cross-linking agent gradually by embedding, but the drug loading of this moment is low.In order to obtain the higher medicine carrying fibroin microsphere of drug loading, with an organic solvent the microsphere of first acquisition is handled again, its drug loading of microsphere that washs the separation acquisition again is up to 2.5～8.5%, embedding rate is 41.46～99.08%, spherical in shape, the stable performance of electron microscope observation can at room temperature be preserved for a long time.
2. owing to do not use deleterious chemical reagent in preparation process, therefore, the medicine carrying fibroin microsphere that obtains is nontoxic, harmless to human body, and has excellent biological compatibility, is a kind of Green Product.The organic solvent used in preparation process filters or centrifugalize in process, and the recyclable heavy steaming of its waste liquid is recycling.Also because the support material fibroin of product is originated and enriched, produce conveniently, the equipment and the technology of preparing product are simple, workable.Therefore, will have vast market prospect.
Description of drawings
Fig. 1 is the electromicroscopic photograph figure of the medicine carrying fibroin microsphere that obtains by example 1 method of the present invention.
The specific embodiment
The invention will be further elaborated below in conjunction with embodiment and accompanying drawing.
Embodiment one:
0.1% the aqueous sodium carbonate that kind of eggs of silkworm cocoon cocoon shell 120g is joined 50 times of amounts boiled 30 minutes, taking-up washes with water totally, repeat above operation 1～2 time, guarantee sericin is all removed, fibroin fiber after will coming unstuck at last with deionized water wash clean after, 60 ℃ of following dry for standby.
Get in calcium chloride/ethanol/water ternary solution (mol ratio is 1: 2: 8) that the above-mentioned fibroin fiber 10g that comes unstuck is dissolved in 100ml, 70 ℃ of constant temperature magnetic agitation dissolvings.With the silk fibroin solution of above-mentioned acquisition dialyse, desalination, purification, obtain concentration and be 2.5～3.5% water-soluble fibroin solution, be condensed into 6% water-soluble fibroin solution.
Get the water soluble drug dexamethasone sodium phosphate that accounts for fibroin total amount 9.1%/wt add above-mentioned concentration be 6%/wt the water-soluble fibroin solution stirring evenly after, join in the liquid paraffin of the Span-80 that contains 2% (v/v), under 37 ℃ environmental condition, stirred 20 minutes under the 600rmpr mixing speed, form water/oil type emulsion, stirred 30 minutes after adding the isopropyl alcohol of 2 times of fibroin volumes again, make the fibroin albumen degeneration generate crystallinity fibroin granule.Through centrifugalize, remove upper strata liquid, add isopropyl alcohol again microsphere was handled 24 hours, make the top layer of the further embedding fibroin of medicine microgranule; Through centrifugalize, use the isopropyl alcohol centrifuge washing again, 2～3 times repeatedly, use deionized water wash at last, the medicine carrying fibroin microsphere that obtains through vacuum drying or lyophilization, is obtained the medicine carrying fibroin powder.After testing, drug loading is 8.36%, embedding rate 99.08%.
Referring to accompanying drawing 2, figure is the electromicroscopic photograph of the medicine carrying fibroin microsphere that obtains by this case method.As shown in Figure 2, the profile of medicine carrying fibroin microsphere is spherical in shape, and mean diameter is 5.84～86.27 μ m.
Embodiment two:
0.1% the aqueous sodium carbonate that waste silk 120g is joined 50 times of amounts boiled 30 minutes, taking-up washes with water totally, repeats above operation 1～2 time, guarantees sericin is all removed, fibroin fiber after will coming unstuck at last with deionized water wash clean after, 60 ℃ of following dry for standby.
Get in calcium chloride/ethanol/water ternary solution (mol ratio is 1: 2: 8) that the above-mentioned fibroin fiber 20g that comes unstuck is dissolved in 200ml, 72 ℃ of constant temperature magnetic agitation dissolvings.With the silk fibroin solution of above-mentioned acquisition dialyse, desalination, purification, obtain concentration and be 2.5～3.5% water-soluble fibroin solution.
Get the water soluble drug vitamin C that accounts for fibroin total amount 16.7%/wt join stir in the water-soluble fibroin solution that above-mentioned concentration is 2.5～3.5%/wt after, be added to again in the liquid paraffin of the Span-80 that contains 3% (v/v), under 37 ℃ environmental condition, under the 750rmpr mixing speed, stirred 20 minutes, form water/oil type emulsion, stirred 30 minutes after adding the isopropyl alcohol of 4 times of fibroin volumes again, make the fibroin albumen degeneration generate crystallinity fibroin granule.Through centrifugalize, remove upper strata liquid, adding isopropyl alcohol again handled 18 hours microsphere, make the further embedding fibroin of medicine microgranule top layer,, use the isopropyl alcohol centrifuge washing again through centrifugalize, 2～3 times repeatedly, use deionized water wash at last, the medicine carrying fibroin microsphere that obtains through vacuum lyophilization, is obtained the medicine carrying fibroin powder.
After testing, this medicine carrying fibroin microgranule mean diameter is at 5.84 μ m, embedding rate 41.46%, drug loading 6.91%.。
Embodiment three:
0.1% the aqueous sodium carbonate that waste silk 60g is joined 50 times of amounts boiled 30 minutes, took out to wash with water totally, repeated above operation 1～2 time, guaranteed sericin is all removed.Fibroin fiber after will coming unstuck at last with deionized water wash clean after, 60 ℃ of following dry for standby.
Get in the BrLi solution of 9.0mol/L that the fibroin fiber 10g that comes unstuck is dissolved in 100ml, 70 ℃ of constant temperature magnetic agitation dissolvings.With the silk fibroin solution of above-mentioned acquisition dialyse, desalination, purification, obtain concentration and be 2.5～3.5% water-soluble fibroin solution.
Get the water-soluble hormones class medicine that accounts for fibroin total amount 9.0%/wt add above-mentioned concentration be 2.5～3.5%/wt water-soluble fibroin solution stirring evenly after, be added to again in the olive oil that contains 0.8% (v/v) lecithin, under 37 ℃ environmental condition, under the 650rmpr mixing speed, stirred 30 minutes, form water/oil type emulsion, stirred 30 minutes after adding the acetone of 4 times of fibroin volumes again, make the fibroin albumen degeneration generate crystallinity fibroin granule.Through centrifugalize, remove upper strata liquid, adding acetone again handled 20 hours microsphere, make the further embedding fibroin of medicine microgranule top layer,, use the isopropyl alcohol centrifuge washing again through centrifugalize, 2～3 times repeatedly, use deionized water wash at last, the medicine carrying fibroin microsphere that obtains through vacuum lyophilization, is obtained the medicine carrying fibroin powder.
After testing, this medicine carrying fibroin microgranule mean diameter is at 9.96 μ m, embedding rate 75.59%, drug loading 6.87%.
Embodiment four:
0.1% the sodium bicarbonate aqueous solution that husks 50g is joined 50 times of amounts boiled 30 minutes, took out to wash with water totally, repeated above operation 1～2 time, guaranteed sericin is all removed.Fibroin fiber after will coming unstuck at last with deionized water wash clean after, 60 ℃ of following dry for standby.
Get in the BrLi solution of 10.0mol/L that the above-mentioned fibroin fiber 10g that comes unstuck is dissolved in 100ml, 75 ℃ of constant temperature magnetic agitation dissolvings.With the silk fibroin solution of above-mentioned acquisition dialyse, desalination, purification, obtain concentration and be 2.5～3.5% water-soluble fibroin solution.
Get the water solublity anti-inflammatory type medicine that accounts for fibroin total amount 10%/wt add above-mentioned concentration be 2.5～3.5%/wt the water-soluble fibroin solution stirring evenly after, be added to again in the olive oil that contains 1.0% (v/v) lecithin, under 37 ℃ environmental condition, under the 720rmpr mixing speed, stirred 20 minutes, form water/oil type emulsion, stirred 30 minutes after adding 4 times of fibroin volume of ethanol again, make the fibroin albumen degeneration generate crystallinity fibroin granule.Obtain wet fibroin microgranule through centrifugalize, adding ethanol again handled 22 hours microsphere, make the further embedding fibroin of medicine microgranule top layer, again through centrifugalize, use the isopropyl alcohol centrifuge washing, 2～3 times repeatedly, use the deionized water centrifuge washing at last 1 time, the medicine carrying fibroin microsphere that obtains through vacuum lyophilization, is obtained the medicine carrying fibroin powder.
After testing, this medicine carrying fibroin microgranule mean diameter is at 5.86 μ m, embedding rate 86.46%, drug loading 7.85%.
Claims (3)
1. medicine carrying fibroin microsphere, it is characterized in that: it is carrier with the fibroin albumen, and water soluble drug is a drug model; Medicine is embedded in the top layer of fibroin microsphere, and drug loading is 2.5～8.5%, and mean diameter is 5.84～86.27 μ m, and is water insoluble.
2. method for preparing medicine carrying fibroin microsphere is characterized in that concrete steps are as follows:
(1) water soluble drug is dissolved in equably in the silk fibroin solution that concentration is 2.5～12%/wt;
(2) joining the mixed liquor of above-mentioned silk fibroin solution and medicine with Span or lecithin is in the oil phase of emulsifying agent, and oil phase is liquid paraffin or vegetable oil, and the ratio that emulsifying agent accounts for emulsion is 0.5～5%/wt, with 350～800rpm speed stirring and emulsifying;
(3) add water-miscible organic solvent, organic solvent is 1～6 times of silk fibroin solution by volume, and mixing speed is more than 100rpm, and the processing time is 30～60 minutes, obtains medicine carrying fibroin microsphere mixed liquor or suspension;
(4) through the centrifugal upper strata liquid of removing, obtain medicine carrying fibroin microsphere, add organic solvent again and handle more than 12 hours;
(5) remove organic solvent and residual oil phase, behind centrifuge washing, lyophilization or the vacuum drying, obtain medicine carrying fibroin microsphere.
3. a kind of method for preparing medicine carrying fibroin microsphere according to claim 2 is characterized in that: described organic solvent is isopropyl alcohol, ethanol and acetone.
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Families Citing this family (15)
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| CN101743991B (en) * | 2009-12-22 | 2013-10-09 | 华南师范大学 | SF-embedded termite drug and preparation method and application thereof |
| CN102580106B (en) * | 2012-03-21 | 2013-07-10 | 浙江大学 | Method for preparing pH-sensitive type polyelectrolyte microcapsule administration carrier |
| CN103341175B (en) * | 2013-06-09 | 2015-09-30 | 浙江大学 | A kind of preparation method of fibroin microsphere |
| CN104592375A (en) * | 2014-12-16 | 2015-05-06 | 苏州丝美特生物技术有限公司 | Method for preparing fibroin microspheres by using polyethylene glycol |
| CN105963275B (en) * | 2016-05-31 | 2019-05-17 | 中国医学科学院生物医学工程研究所 | The controllable fibroin albumen micro-capsule of shell and preparation method |
| CN108553689B (en) * | 2018-04-13 | 2020-03-27 | 浙江大学 | Silk fibroin porous microsphere with nanofiber microstructure and preparation method thereof |
| CN108553690B (en) * | 2018-04-13 | 2020-08-07 | 浙江大学 | Porous strontium-doped fibroin microsphere and preparation method thereof |
| CN110538349A (en) * | 2019-08-28 | 2019-12-06 | 温州医科大学 | MSCs cell membrane integrated with gelatin-silk fibroin composite microspheres and preparation method thereof |
| CN111012942B (en) * | 2020-02-05 | 2022-01-25 | 重庆理工大学 | Hemostatic microsphere for bleeding of artery and vein and viscera and preparation method thereof |
| CN113274561B (en) * | 2021-05-20 | 2022-07-26 | 江苏英伟医疗有限公司 | Medical intravascular stent material and preparation method thereof |
| CN113663119A (en) * | 2021-07-07 | 2021-11-19 | 核工业总医院 | Preparation method of iodized oil silk fibroin embolism microsphere with perspective developing function |
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| CN113730599A (en) * | 2021-10-08 | 2021-12-03 | 苏州大学 | Functional silk fibroin drug carrier and preparation method thereof |
| CN114748671B (en) * | 2022-03-22 | 2022-11-25 | 德晟康(苏州)生物科技有限公司 | Compound protein slow-release hydrocolloid application and preparation method thereof |
| CN117283608B (en) * | 2023-11-22 | 2024-03-05 | 微纳动力(北京)科技有限责任公司 | Preparation method of medicine-carrying magnetic fluid robot |
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