CN105963275B - The controllable fibroin albumen micro-capsule of shell and preparation method - Google Patents
The controllable fibroin albumen micro-capsule of shell and preparation method Download PDFInfo
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- CN105963275B CN105963275B CN201610377106.2A CN201610377106A CN105963275B CN 105963275 B CN105963275 B CN 105963275B CN 201610377106 A CN201610377106 A CN 201610377106A CN 105963275 B CN105963275 B CN 105963275B
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- 239000003094 microcapsule Substances 0.000 title claims abstract description 111
- 108010022355 Fibroins Proteins 0.000 title claims abstract description 104
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- 239000002245 particle Substances 0.000 claims abstract description 92
- 239000000243 solution Substances 0.000 claims abstract description 30
- 238000005119 centrifugation Methods 0.000 claims abstract description 20
- 239000002904 solvent Substances 0.000 claims abstract description 19
- 238000005406 washing Methods 0.000 claims abstract description 17
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims abstract description 16
- 239000007853 buffer solution Substances 0.000 claims abstract description 16
- 239000006228 supernatant Substances 0.000 claims abstract description 16
- 239000000725 suspension Substances 0.000 claims abstract description 14
- BHTJEPVNHUUIPV-UHFFFAOYSA-N pentanedial;hydrate Chemical compound O.O=CCCCC=O BHTJEPVNHUUIPV-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000004132 cross linking Methods 0.000 claims abstract description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 40
- 238000000034 method Methods 0.000 claims description 35
- 235000019441 ethanol Nutrition 0.000 claims description 20
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 230000000694 effects Effects 0.000 claims description 9
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 9
- 239000004626 polylactic acid Substances 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 7
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 6
- 239000011859 microparticle Substances 0.000 claims description 5
- 150000004676 glycans Chemical class 0.000 claims description 3
- 229920001282 polysaccharide Polymers 0.000 claims description 3
- 239000005017 polysaccharide Substances 0.000 claims description 3
- 239000003814 drug Substances 0.000 abstract description 8
- 238000002156 mixing Methods 0.000 abstract description 7
- 239000000463 material Substances 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 4
- 230000000857 drug effect Effects 0.000 abstract description 2
- 230000005847 immunogenicity Effects 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 230000001151 other effect Effects 0.000 abstract description 2
- 239000010410 layer Substances 0.000 description 53
- 230000035699 permeability Effects 0.000 description 12
- 229920002307 Dextran Polymers 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 229920001503 Glucan Polymers 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 6
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 5
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 4
- 229910052737 gold Inorganic materials 0.000 description 4
- 239000010931 gold Substances 0.000 description 4
- 229920000867 polyelectrolyte Polymers 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 229940098773 bovine serum albumin Drugs 0.000 description 3
- 230000007812 deficiency Effects 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000002105 nanoparticle Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000002604 ultrasonography Methods 0.000 description 3
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 2
- 240000002853 Nelumbo nucifera Species 0.000 description 2
- 235000006508 Nelumbo nucifera Nutrition 0.000 description 2
- 235000006510 Nelumbo pentapetala Nutrition 0.000 description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 230000003796 beauty Effects 0.000 description 2
- 239000012620 biological material Substances 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- 235000013601 eggs Nutrition 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- 239000010703 silicon Substances 0.000 description 2
- 239000002356 single layer Substances 0.000 description 2
- 238000000935 solvent evaporation Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- QCVGEOXPDFCNHA-UHFFFAOYSA-N 5,5-dimethyl-2,4-dioxo-1,3-oxazolidine-3-carboxamide Chemical compound CC1(C)OC(=O)N(C(N)=O)C1=O QCVGEOXPDFCNHA-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 238000007334 copolymerization reaction Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 235000014103 egg white Nutrition 0.000 description 1
- 210000000969 egg white Anatomy 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 108010006205 fluorescein isothiocyanate bovine serum albumin Proteins 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- 239000010954 inorganic particle Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000011146 organic particle Substances 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000001338 self-assembly Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5052—Proteins, e.g. albumin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
- A61K8/11—Encapsulated compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/10—General cosmetic use
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
- A61K2800/56—Compounds, absorbed onto or entrapped into a solid carrier, e.g. encapsulated perfumes, inclusion compounds, sustained release forms
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Dermatology (AREA)
- Birds (AREA)
- Manufacturing Of Micro-Capsules (AREA)
- Medicinal Preparation (AREA)
- Cosmetics (AREA)
Abstract
The invention discloses a kind of fibroin albumen micro-capsules that shell is controllable and preparation method to be added dropwise the poor solvent of albumen the preparation method comprises the following steps: fibroin albumen, template particles and carbonate buffer solution are mixed to obtain mixed liquor one by (1), mixing, centrifugation remove supernatant, washing, obtains the first particle；(2) the first particle, fibroin albumen and carbonate buffer solution are mixed, obtains mixed liquor two, be centrifuged, remove supernatant, washing obtains second of particle；(3) step (2) are repeated；(4) add glutaraldehyde water solution to carry out protein-crosslinking in the particle obtained to step (3), be centrifuged, washing obtains final particle；Template particles are removed, then wash to obtain the controllable fibroin albumen micro-capsule suspension of shell.Micro-capsule of the invention is a kind of hollow micro-capsule, can load large biological molecule class drug or other effect components.Easily operated, time-saving energy-saving is suitable for large-scale production, and material therefor has good biocompatibility, biodegradability and non-immunogenicity.
Description
Technical field
The invention belongs to medicine and beauty and skin care fields, more particularly to a kind of fibroin albumen micro-capsule that shell is controllable and system
Preparation Method
Background technique
The carrier of hollow structure has a wide range of applications in fields such as drug delivery, bioreactor, biosensors.Its
In, micro-capsule class carrier is receive more and more attention.Using LBL self-assembly (Layer-by-layer, LbL) technology, by band
The polyelectrolyte of positive and negative charge is alternately deposited on template surface and again removes template, is to prepare to obtain polyelectrolyte microcapsule
The most common method of such carrier.This method is simple, applied widely, accurately controls the size, shape, group of micro-capsule
Point etc., and the number of plies can be deposited by changing, the thickness of micro-capsule is controlled, and then adjust the permeability and other functional characteristics of micro-capsule.
However, LbL method synthesizes micro-capsule base carrier there are inherent shortcoming, as there are potential source biomolecule poison for the introducing of polyelectrolyte of lotus positive electricity
Property.To overcome the above deficiency, researcher prepares one pack system micro-capsule, such as 2008 using a variety of interaction mechanisms,
H.J. group glutaraldehyde processing is adsorbed in the bovine serum albumin(BSA) of template surface, covers active aldehydes in outermost layer while crosslinking
Base, and lower layer's BSA covalent bond, to be prepared for bovine serum albumin(BSA) one-component micro-capsule (Tong with the LbL method that glutaraldehyde mediates
W.；Gao C.；H.,Colloid Polym.Sci.2008,286,1103-1109.)；2011, Tsukruk group
The characteristic that can be physical crosslinking by hydrogen bond and β-pleated sheet using fibroin albumen, is not introduced lotus positive electrical polyelectrolyte, is prepared with LbL method
Fibroin albumen one-component micro-capsule, avoids potential bio-toxicity, while it is logical by changing the regulation of the shell number of plies to save LbL method
Ability (Shchepelina, the O. of permeability；Drachuk,I.；Gupta,M.K.；Lin,J.；Tsukruk,V.V.,
Adv.Mater.2011,23,4655-4660.)；Germershaus group in 2014 prepares the fibroin egg of load plasmid with LbL method
White micro-capsule realizes effective low toxicity transfection (Li L. of gene；Puhl S.；Meinel L.；Germershaus O.,
Biomaterials,2014,35,7929-7939.).However, LbL method is there are still cumbersome, time consumption and energy consumption, and yield with
The deficiency that deposition number of plies increase substantially reduces, it would be highly desirable to LbL derivatization method or other methods are developed, to improve its practical application in industry
Value (Tong W,；Song X,；Gao C.；Chem.Soc.Rev.,2012,41,6103.Zhu,Y.；Tong,W.；Gao,C.；H.J.Mater.Chem.2008,18,1153-1158).Therefore, one-step synthesis method micro-capsule is by more and more
Concern, this method is simple and efficient to handle and time saving and energy saving, and can be by adjusting molecular weight and the amount of solvent being gone to adjust micro-capsule
Thickness, and then adjust its permeability (Zhu Y.；Tong W,Gao C.； H.J.,Mater.Chem.2008,18,
1153-1158.Wang Y.；Bansal V.；Zelikin AN.；Caruso F.,Nano Lett.2008,8,1741-
1745.)；This seminar spends solvent method and prepares fibroin albumen one-component micro-capsule, and a step goes solvent to generate micro-capsule thickness to be about
22.42 ± 8.45nm, the 8-10 layer fibroin albumen for being equivalent to the preparation of LbL method deposits to obtain the thickness of micro-capsule, although this single group
Part micro-capsule hole is larger, but this seminar modified nano gold adjusts its permeability (ZL201410066374.3；Du,B.；Wang,
J.；Zhou,Z.；Tang,H.；Li,X.；Liu,Y.；Zhang,Q.Chem.Commun.,2014,50,4423-4426.).So
And one-component micro-capsule and its system that material non-toxic is degradable, mild easy, the micro-capsule permeability controllable precise of method is integrated in one
Preparation Method has not been reported.
Fibroin albumen has brilliant mechanical stability, good biocompatibility, biodegradability, is bioactivity
The ideal material of component carrier.Therefore, using organic and inorganic particle as template, using going solvent method combination LbL method (to go layer by layer molten
Agent method) the controllable fibroin albumen one-component micro-capsule of permeability is efficiently synthesized as effect component carrier in medicine and beauty and skin care neck
Domain research has not been reported.
Summary of the invention
It is adjustable object of the present invention is to overcome the deficiencies of the prior art and provide a kind of simple and direct technique, time-saving energy-saving, permeability
The controllable fibroin albumen micro-capsule of shell preparation method.
A second object of the present invention is to provide a kind of fibroin albumen micro-capsules that shell is controllable.
Third object of the present invention is to provide a kind of applications of fibroin albumen micro-capsule that shell is controllable.
Technical solution of the present invention is summarized as follows:
A kind of preparation method for the fibroin albumen micro-capsule that shell is controllable, includes the following steps:
(1) carbonate buffer solution of fibroin albumen, template particles and pH=9-11 are mixed into obtain mixed liquor one, makes mixed liquor
The concentration of fibroin albumen is 0.4-1.5mg/mL in one, the concentration of template particles is 6-15mg/mL；Egg is added dropwise into mixed liquor one
White poor solvent is uniformly mixed, and the volume ratio of the mixed liquor one and the poor solvent of albumen is 1:6-10；Centrifugation removes
Supernatant is washed, and centrifugation obtains the first particle；
(2) it is mixed by the first particle, with the carbonate buffer solution of the fibroin albumen of step (1) equivalent and pH=9-11,
Mixed liquor two is obtained, keeps the volume of mixed liquor two equal with the volume of mixed liquor one, the bad molten of albumen is added dropwise into mixed liquor two
The volume ratio of agent mixing, the mixed liquor two and the poor solvent of albumen is 1:6-10；Centrifugation, removes supernatant, and washing obtains
Second of particle；
(3) it repeats step (2) 0,1,2,3,4 or 5 times；
(4) glutaraldehyde water solution is added in the particle obtained to step (3) and carries out protein-crosslinking, be centrifuged, washing obtains most
Whole particle；Final particle is washed, removes template particles, then wash to obtain the controllable fibroin albumen micro-capsule suspension of shell.
The preferred methanol of the poor solvent of albumen or ethyl alcohol.
The preferred calcium carbonate microparticle of template particles, the poly lactide-glycolide acid particle that molecular weight is 5000-50000
Or molecular weight is the polylactic acid particle of 5000-50000.
The controllable fibroin albumen micro-capsule of the shell of above method preparation.
The controllable fibroin albumen micro-capsule of shell carries the application in effect component micro-capsule in preparation.
Effect component optimization protein or polysaccharide.
The controllable fibroin albumen micro-capsule of shell of the invention is a kind of hollow micro-capsule, can load large biological molecule class drug or
Other effect components.Preparation process universality is strong, easily operated, time-saving energy-saving, is suitable for large-scale production, and material therefor
With good biocompatibility, biodegradability and non-immunogenicity.
12 layers of fibroin albumen that seven layers of fibroin albumen micro-capsule permeability prepared by the present invention is equivalent to the preparation of document LbL method are micro-
The permeability of capsule, the 8-10 layer fibroin albumen micro-capsule permeability that the permeability of five layers of fibroin albumen micro-capsule is prepared between LbL method it
Between, simplify preparation flow.Compared with the patent that this study group authorizes before this, single layer goes to solvent micro-capsule aperture to be greater than 31.8nm,
It modifies gold nanoparticle and blocks single lamellar vesicles back aperture less than 8nm.In the present invention, go solvent deposition regulation more accurate thin layer by layer
It causes, such as aperture of five layers of fibroin albumen micro-capsule is in 22.9nm or so, and the aperture of seven layers of fibroin albumen micro-capsule is less than 8nm, with single layer
Effect after adding gold nanoparticle modification to block is suitable, but without introducing gold nanoparticle, on the basis of reducing cost, reduces
The application of non-degradable material.The present invention is more suitable for applying in effect component carrier, targeted delivery and cosmetology field.
Detailed description of the invention
Fig. 1 is the transmission electron microscope photo of the controllable fibroin albumen micro-capsule (three layers) of the shell of the preparation of embodiment 5；Fibroin albumen
Concentration be respectively (a) 0.4mg/mL；(b)0.7mg/mL；(c)1mg/mL；(d)1.3mg/mL.
Fig. 2 is the stereoscan photograph of the controllable fibroin albumen micro-capsule of the shell of the preparation of embodiment 6；(a) single lamellar vesicles are (right
Than)；(b) three layers of micro-capsule；(c) five layers of micro-capsule；(d) seven layers of micro-capsule.
Fig. 3 is the stereoscan photograph for the fibroin albumen micro-capsule that embodiment 7 uses calcium carbonate microparticle to prepare for template；(a)
Calcium carbonate template；(b) three layers of micro-capsule.
Fig. 4 is copolymerization of the three layers of fibroin albumen micro-capsule of the preparation of embodiment 6 in FITC-dextran 2000KDa solution
Focusing microscope photo.
Fig. 5 is five layers of fibroin albumen micro-capsule of the preparation of embodiment 6 in FITC-dextran 500KDa (a) and FITC-
Laser Scanning Confocal Microscope photo in dextran 2000KDa (b) solution.
Fig. 6 is seven layers of fibroin albumen micro-capsule of the preparation of embodiment 6 in FITC-dextran 250KDa (a) and FITC-
Laser Scanning Confocal Microscope photo in BSA (b) solution.
Specific embodiment
The present invention is further illustrated combined with specific embodiments below, and the embodiment of the present invention is to make this field
Technical staff better understood when the present invention, but the present invention is not imposed any restrictions.
The preparation of 1 silk fibroin water solution of embodiment:
Take 1g fibroin powder, be placed in 5mL LiBr (9.3M) solution, 60 DEG C of slow magnetic agitation 4h, be made 20% it is molten
Acquired solution is transferred to bag filter (MWCO 3500) by liquid, and distilled water is dialysed 4d (it is primary that every 4h changes water), acquired solution 8,
000rpm is centrifuged 20min, is repeated 3 times, and removes insoluble matter, then acquired solution is crossed 0.45 μm of filter membrane.Finally obtained fibroin egg
White water solution concentration is about 6%.Concentration mensuration is to calculate institute by weight after measurement certain volume silk fibroin water solution freeze-drying
?.Storing liquid deposit in 4 DEG C it is spare.
The preparation of embodiment 2PLGA particle:
PLGA particle is prepared using classical lotion-solvent evaporation method:
By the PLGA of 150mg (ten thousand) 50:50, weight average molecular weight 5 are dissolved in 10mL methylene chloride, instill dropwise to
In the polyvinyl alcohol that 100mL concentration is 1%, the homogeneous formation lotion of high speed is transferred on blender and continues to stir 18h, makes dichloro
Completely, 10,000rpm centrifugation 15min add water ultrasound to disperse again, repeat this process three times, freeze-drying, low-temperature storage for methane volatilization.
(ten thousand) 50:50, weight average molecular weight 1.5, are prepared poly lactide-glycolide acid particle referring to the above method.
Poly lactide-glycolide acid particle (50:50, weight average molecular weight 5000) is prepared referring to the above method.
The preparation of 3 calcium carbonate microparticle of embodiment:
While stirring by 0.33M calcium chloride water, it is added in the isometric aqueous sodium carbonate of isoconcentration,
30S is mixed, 800rpm is centrifuged 3min, water ultrasound is added to disperse again, repeats this process three times, is lyophilized, and stores at drying.
The preparation of 4 polylactic acid particle of embodiment:
Polylactic acid particle is prepared using classical lotion-solvent evaporation method:
The PLA (molecular weight 50,000) of 150mg is dissolved in 10mL methylene chloride, is instilled dropwise to the poly- second of 100mL 1%
In enol aqueous solution, the homogeneous formation lotion of high speed is transferred on magnetic stirring apparatus and continues to stir 18h, is evaporated completely methylene chloride
Entirely, 10,000rpm is centrifuged 15min, and water ultrasound is added to disperse again, repeats this process three times, freeze-drying, low-temperature storage.
Polylactic acid particle (molecular weight 5000) is prepared referring to embodiment 4.
The method of the particle of embodiment 2-4 preparation is to enable those skilled in the art to more fully understand this hair
It is bright, but the present invention is not imposed any restrictions, the particle identical with above-mentioned particle prepared with other methods may be used to this
Invention.
Embodiment 5
A kind of preparation method for the fibroin albumen micro-capsule that shell is controllable, includes the steps that:
(1) by fibroin albumen, the poly lactide-glycolide acid particle (template particles) of molecular weight 50000 and pH=9
Carbonate buffer solution mix to obtain mixed liquor one, make the concentration 0.4mg/mL of fibroin albumen in mixed liquor one, template particles
Concentration is 7mg/mL；Ethyl alcohol is added dropwise into mixed liquor one to be uniformly mixed, the volume ratio of the mixed liquor one and ethyl alcohol is 1:7；From
The heart removes supernatant, washes, and centrifugation obtains the first particle (one layer)；
(2) it mixes, obtains by the first particle, with the carbonate buffer solution of the fibroin albumen of step (1) equivalent and pH=9
Mixed liquor two keeps the volume of mixed liquor two equal with the volume of mixed liquor one, and ethyl alcohol mixing is added dropwise into mixed liquor two, described mixed
The volume ratio for closing liquid two and ethyl alcohol is 1:7；Centrifugation, removes supernatant, and washing obtains second of particle (two layers)；
(3) step (2) 1 times (three layers) are repeated；
(4) 2% glutaraldehyde water solution of mass concentration is added in the particle obtained to step (3) and carries out protein-crosslinking, be centrifuged,
Washing, obtains final particle；The acetone for being 1:1 with volume ratio and N-Methyl pyrrolidone mixed liquor wash final particle, remove mould
Plate particle, then wash to obtain the controllable fibroin albumen micro-capsule suspension of shell.
The volume ratio of mixed liquor one in 2% glutaraldehyde water solution of mass concentration and step (1) is 1:1.
The amount for the fibroin albumen being added in the present embodiment step (1) is different, it may be assumed that makes the concentration of fibroin albumen in mixed liquor one
0.4mg/mL is substituted for 0.7mg/mL, 1mg/mL, 1.3mg/mL, other same the present embodiment prepare the controllable fibroin of shell respectively
Albumen micro-capsule suspension.
The controllable fibroin albumen micro-capsule suspension of above-mentioned shell is dripped and is spontaneously dried on copper mesh, takes pictures, sees under transmission electron microscope
Fig. 1.
The present embodiment utilizes hydrophobic interaction (Wang, the X. of fibroin albumen and PLGA；Wenk,E.；Hu,X.；
Castro,G.R.；Meinel,L.；Wang,X.；Li,C.；Merkle,H.；Kaplan,D.L.,Biomaterials 2007,
28 (28), 4161-4169) fibroin albumen of precipitation is deposited on PLGA microsphere surface, then cross-linking solidification, it is allowed to no longer solve
Poly-, dissolution template ultimately forms fibroin albumen micro-capsule, therefore the PLGA microballoon of other scales is for example: being 5000- in molecular weight
50000 any particle can also serve as template and prepare various sizes of fibroin albumen micro-capsule.
Embodiment 6
A kind of preparation method for the fibroin albumen micro-capsule that shell is controllable, includes the following steps:
(1) by fibroin albumen, the poly lactide-glycolide acid particle (template particles) of molecular weight 50000 and pH=9
Carbonate buffer solution mix to obtain mixed liquor one, make the concentration 1mg/mL of fibroin albumen in mixed liquor one, template particles it is dense
Degree is 7mg/mL；Ethyl alcohol is added dropwise into mixed liquor one to be uniformly mixed, the volume ratio of the mixed liquor one and ethyl alcohol is 1:7；Centrifugation,
Supernatant is removed, is washed, centrifugation obtains the first particle (one layer)；
(2) it mixes, obtains by the first particle, with the carbonate buffer solution of the fibroin albumen of step (1) equivalent and pH=9
Mixed liquor two keeps the volume of mixed liquor two equal with the volume of mixed liquor one, and ethyl alcohol mixing is added dropwise into mixed liquor two, described mixed
The volume ratio for closing liquid two and ethyl alcohol is 1:7；Centrifugation, removes supernatant, and washing obtains second of particle (two layers)；
(3) step (2) 1 times (three layers) are repeated；
(4) 2% glutaraldehyde water solution of mass concentration is added in the particle obtained to step (3) and carries out protein-crosslinking, be centrifuged,
Washing, obtains final particle；The acetone for being 1:1 with volume ratio and N-Methyl pyrrolidone mixed liquor wash final particle, remove mould
Plate particle, then wash to obtain the controllable fibroin albumen micro-capsule suspension of shell.
The volume ratio of mixed liquor one in 2% glutaraldehyde water solution of mass concentration and step (1) is 1:1.
1 time of 3,5 substitution the present embodiment of duplicate number in the present embodiment step (3), other same the present embodiment are made
The standby controllable fibroin albumen micro-capsule suspension of shell.
Above-mentioned fibroin albumen micro-capsule suspension drop is spontaneously dried on silicon wafer, takes pictures under scanning electron microscope, sees Fig. 2.
Embodiment 7
A kind of preparation method for the fibroin albumen micro-capsule that shell is controllable, includes the steps that:
(1) carbonate buffer solution of fibroin albumen, calcium carbonate microparticle (template particles) and pH=9 is mixed into obtain mixed liquor
One, the concentration of the concentration 1mg/mL, template particles that make fibroin albumen in mixed liquor one are 6mg/mL；It is added dropwise into mixed liquor one
Ethyl alcohol is uniformly mixed, and the mixed liquor one is 1:6 with ethyl alcohol volume ratio；Centrifugation removes supernatant, washes, and centrifugation obtains first
Kind particle (one layer)；
(2) it mixes, obtains by the first particle, with the carbonate buffer solution of the fibroin albumen of step (1) equivalent and pH=9
Mixed liquor two keeps the volume of mixed liquor two equal with the volume of mixed liquor one, and ethyl alcohol mixing is added dropwise into mixed liquor two, described mixed
The volume ratio for closing the poor solvent of liquid two and albumen is 1:6；Centrifugation, removes supernatant, and washing obtains second of particle (two
Layer)；
(3) repeat step (2) 1 times (three layers)；
(4) 2% glutaraldehyde water solution of mass concentration is added in the particle obtained to step (3) and carries out protein-crosslinking, be centrifuged,
Washing, obtains final particle；Final particle is washed with EDTA aqueous solution (0.2M, pH=7.5), removes template particles, then wash
The fibroin albumen micro-capsule suspension controllable to shell.The body of mixed liquor one in 2% glutaraldehyde water solution of mass concentration and step (1)
Product is than being 1:1.
Above-mentioned fibroin albumen micro-capsule suspension drop is spontaneously dried on silicon wafer, takes pictures under scanning electron microscope, sees Fig. 3.
It is demonstrated experimentally that the poor solvent of albumen selects methanol to can be used for the present invention.
Embodiment 8
The aperture indirect analysis of three layers of fibroin albumen micro-capsule
1) three layers of fibroin albumen micro-capsule for preparing embodiment 6 are put into container, and it is that 2000kDa mass is dense that molecular weight, which is added,
Glucan (FITC-dextran 2000KDa) aqueous solution that the FITC that degree is 2mg/mL is marked, mixes to obtain mixed liquor, after 30min
Take pictures (Fig. 4) is placed under Laser Scanning Confocal Microscope.
In the mixed liquor of three layers of fibroin albumen micro-capsule and FITC-dextran 2000KDa, have inside micro-capsule and external solution
The fluorescence signal of same intensity, it is known that molecular weight is that the glucan of 2000kDa can be by the hole of micro-capsule wall, into micro-capsule
Portion, according to the literature (Shchepelina, O.；Drachuk,I.；Gupta,M.K.；Lin,J.；Tsukruk,V.V.,
Adv.Mater.2011,23,4655-4660.) three layers of fibroin albumen micro-capsule aperture are greater than 31.8nm.
Embodiment 9
The aperture indirect analysis of five layers of fibroin albumen micro-capsule
1) five layers of fibroin albumen micro-capsule for preparing embodiment 6 are put into container, and it is that 500kDa mass is dense that molecular weight, which is added,
Glucan (FITC-dextran 500KDa) aqueous solution that the FITC that degree is 2mg/mL is marked, mixes to obtain mixed liquor, after 30min
It is placed under Laser Scanning Confocal Microscope and takes pictures (Fig. 5 a).
2) five layers of fibroin albumen micro-capsule for preparing embodiment 6 are put into container, and it is that 2000kDa mass is dense that molecular weight, which is added,
Glucan (FITC-dextran 2000KDa) aqueous solution that the FITC that degree is 2mg/mL is marked, mixes to obtain mixed liquor, after 30min
It is placed under Laser Scanning Confocal Microscope and takes pictures (Fig. 5 b).
In the mixed liquor of five layers of fibroin albumen micro-capsule and FITC-dextran 2000KDa, micro-capsule intrinsic fluorescence intensity is lower than
The fluorescence intensity of external solution, it is known that molecular weight is that the glucan of 2000kDa can not be by the hole of micro-capsule wall, into micro-capsule
Portion；In the mixed liquor of five layers of fibroin albumen micro-capsule and FITC-dextran 500KDa, have inside the micro-capsule of part and external solution phase
With the fluorescence signal of intensity, and part micro-capsule intrinsic fluorescence intensity is lower than the fluorescence intensity of external solution, it is known that molecular weight is
The hydrated diameter of the glucan sugar of 500kDa is near five layers of fibroin albumen micro-capsule aperture.According to the literature
(Shchepelina,O.；Drachuk,I.；Gupta,M.K.；Lin,J.；Tsukruk,V.V.,Adv.Mater.2011,23,
4655-4660.) five layers of controllable fibroin albumen micro-capsule aperture of shell are in 22.9nm or so.
Embodiment 10
The aperture indirect analysis of seven layers of fibroin albumen micro-capsule
1) seven layers of fibroin albumen micro-capsule for preparing embodiment 6 are put into container, and it is that 250kDa mass is dense that molecular weight, which is added,
Glucan (FITC-dextran250KDa) aqueous solution that the FITC that degree is 2mg/mL is marked, mixes to obtain mixed liquor, 30min postposition
It takes pictures under Laser Scanning Confocal Microscope (Fig. 6 a).
2) bovine serum albumin(BSA) (FITC- for marking the FITC that seven layers of fibroin albumen micro-capsule and mass concentration are 2mg/mL
BSA mixed liquor) is mixed to obtain, 30min is placed under Laser Scanning Confocal Microscope and takes pictures (Fig. 6 b).
In the mixed liquor of seven layers of fibroin albumen micro-capsule and FITC-dextran 250KDa, micro-capsule intrinsic fluorescence intensity is lower than
The fluorescence intensity of external solution, it is known that molecular weight is that the glucan of 250kDa can not be by the hole of micro-capsule wall, into micro-capsule
Portion；In the mixed liquor of seven layers of fibroin albumen micro-capsule and FITC-BSA, micro-capsule intrinsic fluorescence intensity is strong lower than the fluorescence of external solution
Degree, it is known that BSA can not be by the hole of micro-capsule wall, into inside micro-capsule.(Shchepelina, O. according to the literature；
Drachuk,I.；Gupta,M.K.；Lin,J.；Tsukruk, V.V., Adv.Mater.2011,23,4655-4660.) seven layers of silk
Fibroin micro-capsule aperture is less than 8nm.
Embodiment 8-10 show method of the invention can effective adjustment aperture size, to make it to different molecular weight
Molecule has different permeabilities.Further, since it is known in the art that model drug glucan is the representative of polysaccharide, model drug
BSA is the representative of albumen, and the controllable fibroin albumen micro-capsule of shell of the invention can be used as polyose medicament and protein medicaments
Carrier.
Embodiment 11
A kind of preparation method for the fibroin albumen micro-capsule that shell is controllable, includes the steps that:
(1) by fibroin albumen, the poly lactide-glycolide acid particle (template particles) of molecular weight 50000 and pH=9
Carbonate buffer solution mix to obtain mixed liquor one, make the concentration 1.5mg/mL of fibroin albumen in mixed liquor one, template particles
Concentration is 15mg/mL；Ethyl alcohol is added dropwise into mixed liquor one to be uniformly mixed, the volume ratio of the mixed liquor one and ethyl alcohol is 1:7；From
The heart removes supernatant, washes, and centrifugation obtains the first particle (one layer)；
(2) it mixes, obtains by the first particle, with the carbonate buffer solution of the fibroin albumen of step (1) equivalent and pH=9
Mixed liquor two keeps the volume of mixed liquor two equal with the volume of mixed liquor one, and ethyl alcohol mixing is added dropwise into mixed liquor two, described mixed
The volume ratio for closing liquid two and ethyl alcohol is 1:7；Centrifugation, removes supernatant, and washing obtains second of particle (two layers)；
(3) 2% glutaraldehyde water solution of mass concentration is added in the particle obtained to step (2) and carries out protein-crosslinking, be centrifuged,
Washing, obtains final particle；The acetone for being 1:1 with volume ratio and N-Methyl pyrrolidone mixed liquor wash final particle, remove mould
Plate particle, then wash to obtain the controllable fibroin albumen micro-capsule suspension of shell.
The volume ratio of mixed liquor one in 2% glutaraldehyde water solution of mass concentration and step (1) is 1:1.
The micro-capsule that the present embodiment obtains is similar to the micro-capsule form that embodiment 6 obtains, and effect is suitable.
Embodiment 12
A kind of preparation method for the fibroin albumen micro-capsule that shell is controllable, includes the steps that:
(1) by fibroin albumen, the carbonate buffer solution of polylactic acid particle (template particles) and pH=11 of molecular weight 50000
Mixed liquor one is mixed to obtain, the concentration of the concentration 1mg/mL, template particles that make fibroin albumen in mixed liquor one are 7mg/mL；To mixed
It closes dropwise addition ethyl alcohol in liquid one to be uniformly mixed, the volume ratio of the mixed liquor one and ethyl alcohol is 1:10；Centrifugation removes supernatant, water
It washes, is centrifuged, obtains the first particle (one layer)；
(2) it mixes, obtains by the first particle, with the carbonate buffer solution of the fibroin albumen of step (1) equivalent and pH=11
Mixed liquor two keeps the volume of mixed liquor two equal with the volume of mixed liquor one, and ethyl alcohol mixing is added dropwise into mixed liquor two, described mixed
The volume ratio for closing the poor solvent of liquid two and albumen is 1:10；Centrifugation, removes supernatant, and washing obtains second of particle (two
Layer)；
(3) step (2) 1 times (three layers) are repeated；
(4) 2% glutaraldehyde water solution of mass concentration is added in the particle obtained to step (3) and carries out protein-crosslinking, be centrifuged,
Washing, obtains final particle；The acetone for being 1:1 with volume ratio and N-Methyl pyrrolidone mixed liquor wash final particle, remove mould
Plate particle, then wash to obtain the controllable fibroin albumen micro-capsule suspension of shell.
The volume ratio of mixed liquor one in 2% glutaraldehyde water solution of mass concentration and step (1) is 1:1.
The polylactic acid particle of the molecular weight 50000 of the present embodiment, Qi Tatong are substituted with the polylactic acid particle of molecular weight 5000
The present embodiment prepares the controllable fibroin albumen micro-capsule suspension of shell.
The micro-capsule that the present embodiment obtains is similar to the micro-capsule form that embodiment 6 obtains, and effect is suitable.
Claims (6)
1. a kind of preparation method for the fibroin albumen micro-capsule that shell is controllable, it is characterised in that include the following steps:
(1) carbonate buffer solution of fibroin albumen, template particles and pH=9-11 are mixed into obtain mixed liquor one, made in mixed liquor one
The concentration of fibroin albumen is 0.4-1.5mg/mL, the concentration of template particles is 6-15mg/mL；Albumen is added dropwise into mixed liquor one
Poor solvent is uniformly mixed, and the volume ratio of the mixed liquor one and the poor solvent of albumen is 1:6-10；Centrifugation removes supernatant
Liquid is washed, and centrifugation obtains the first particle；
(2) it mixes, obtains mixed by the first particle, with the carbonate buffer solution of the fibroin albumen of step (1) equivalent and pH=9-11
Liquid two is closed, keeps the volume of mixed liquor two equal with the volume of mixed liquor one, the poor solvent that albumen is added dropwise into mixed liquor two is mixed
It closes, the volume ratio of the mixed liquor two and the poor solvent of albumen is 1:6-10；Centrifugation, removes supernatant, and washing obtains second
Kind particle；
(3) it repeats step (2) 1,2,3,4 or 5 times；
(4) glutaraldehyde water solution is added in the particle obtained to step (3) and carries out protein-crosslinking, be centrifuged, washing, obtain final micro-
Grain；Final particle is washed, removes template particles, then wash to obtain the controllable fibroin albumen micro-capsule suspension of shell.
2. according to the method described in claim 1, it is characterized in that the poor solvent of the albumen is methanol or ethyl alcohol.
3. according to the method described in claim 1, it is characterized in that template particles are calcium carbonate microparticle, molecular weight 5000-50000
Poly lactide-glycolide acid particle or molecular weight be 5000-50000 polylactic acid particle.
4. the controllable fibroin albumen micro-capsule of shell prepared by the method for claim 1,2 or 3.
5. the controllable fibroin albumen micro-capsule of the shell of claim 4 carries the application in effect component micro-capsule in preparation.
6. application according to claim 5, it is characterized in that effect component is albumen or polysaccharide.
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| CN107982239B (en) * | 2017-12-08 | 2020-02-21 | 中国医学科学院生物医学工程研究所 | Protein-based non-spherical microcapsule with hydrophobic drug crystal as template and preparation method thereof |
| CN108479650B (en) * | 2018-03-26 | 2021-02-23 | 上海应用技术大学 | A kind of sweet-scented osmanthus essence-silk fibroin microcapsule and preparation method thereof |
| CN109126650A (en) * | 2018-08-24 | 2019-01-04 | 浙江理工大学 | A kind of preparation method of the microcapsules based on fibroin albumen regulation |
| EP3843708A4 (en) * | 2018-10-01 | 2022-02-23 | Ege Universitesi | BIOPOLYMER-BASED VECTOR SYSTEM |
| CN110327307B (en) * | 2019-06-26 | 2020-06-23 | 浙江大学 | A kind of preparation method and product of silk fibroin drug-loaded nano-microcapsules |
| CN115612124B (en) * | 2022-10-31 | 2025-06-10 | 徐州医科大学 | Preparation method of injectable hyaluronic acid hydrogel containing BMP2 mimetic peptide and SDF-1 |
| CN116473945A (en) * | 2023-03-01 | 2023-07-25 | 中国人民解放军联勤保障部队第九〇四医院 | A kind of PLGA drug-loaded microspheres with delayed initial burst release and its preparation method and application |
| CN116421727B (en) * | 2023-04-28 | 2025-08-01 | 中国医学科学院生物医学工程研究所 | Filiform silk fibroin calcium carbonate hybrid particles and preparation method thereof |
| CN120093993A (en) * | 2025-03-04 | 2025-06-06 | 苏州祥利医疗科技有限公司 | Drug balloon, drug coating and preparation method thereof |
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