CN106214489A - A kind of double-deck emulsion droplet, medicine carrying microballoons and preparation method thereof and device - Google Patents
A kind of double-deck emulsion droplet, medicine carrying microballoons and preparation method thereof and device Download PDFInfo
- Publication number
- CN106214489A CN106214489A CN201610812204.4A CN201610812204A CN106214489A CN 106214489 A CN106214489 A CN 106214489A CN 201610812204 A CN201610812204 A CN 201610812204A CN 106214489 A CN106214489 A CN 106214489A
- Authority
- CN
- China
- Prior art keywords
- microchannel
- phase fluid
- emulsion droplet
- passage
- fluid passage
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000003814 drug Substances 0.000 title claims abstract description 74
- 239000000839 emulsion Substances 0.000 title claims abstract description 70
- 238000002360 preparation method Methods 0.000 title claims abstract description 42
- 239000012530 fluid Substances 0.000 claims abstract description 170
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 55
- 239000003054 catalyst Substances 0.000 claims abstract description 42
- 239000002356 single layer Substances 0.000 claims abstract description 41
- 239000002245 particle Substances 0.000 claims abstract description 24
- 239000007864 aqueous solution Substances 0.000 claims description 50
- 230000001804 emulsifying effect Effects 0.000 claims description 40
- 229920000642 polymer Polymers 0.000 claims description 37
- 239000000243 solution Substances 0.000 claims description 37
- 239000004005 microsphere Substances 0.000 claims description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- 239000003431 cross linking reagent Substances 0.000 claims description 23
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 22
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 22
- 239000010410 layer Substances 0.000 claims description 21
- 239000007787 solid Substances 0.000 claims description 20
- 239000007788 liquid Substances 0.000 claims description 18
- 229920002521 macromolecule Polymers 0.000 claims description 18
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical group CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 17
- 235000010413 sodium alginate Nutrition 0.000 claims description 17
- 239000000661 sodium alginate Substances 0.000 claims description 17
- 229940005550 sodium alginate Drugs 0.000 claims description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 102000004190 Enzymes Human genes 0.000 claims description 15
- 108090000790 Enzymes Proteins 0.000 claims description 15
- 229940079593 drug Drugs 0.000 claims description 15
- 239000004094 surface-active agent Substances 0.000 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 239000007848 Bronsted acid Substances 0.000 claims description 10
- 238000004132 cross linking Methods 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- 239000002202 Polyethylene glycol Substances 0.000 claims description 9
- 229920001223 polyethylene glycol Polymers 0.000 claims description 9
- 238000007711 solidification Methods 0.000 claims description 8
- 230000008023 solidification Effects 0.000 claims description 8
- 235000018102 proteins Nutrition 0.000 claims description 7
- 108090000623 proteins and genes Proteins 0.000 claims description 7
- 102000004169 proteins and genes Human genes 0.000 claims description 7
- 229920001661 Chitosan Polymers 0.000 claims description 6
- 108010010803 Gelatin Proteins 0.000 claims description 6
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical group O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 229920000159 gelatin Polymers 0.000 claims description 6
- 239000008273 gelatin Substances 0.000 claims description 6
- 235000019322 gelatine Nutrition 0.000 claims description 6
- 235000011852 gelatine desserts Nutrition 0.000 claims description 6
- 239000004626 polylactic acid Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 229920002472 Starch Polymers 0.000 claims description 5
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 5
- 230000003197 catalytic effect Effects 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 235000019698 starch Nutrition 0.000 claims description 5
- 239000008107 starch Substances 0.000 claims description 5
- 230000001360 synchronised effect Effects 0.000 claims description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 4
- 235000001014 amino acid Nutrition 0.000 claims description 4
- 150000001413 amino acids Chemical class 0.000 claims description 4
- 239000011575 calcium Substances 0.000 claims description 4
- 229910052791 calcium Inorganic materials 0.000 claims description 4
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical group O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 claims description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 4
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 claims description 4
- 239000011707 mineral Substances 0.000 claims description 4
- 239000002736 nonionic surfactant Substances 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 239000012188 paraffin wax Substances 0.000 claims description 4
- 229920002545 silicone oil Polymers 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 claims description 3
- 229910001422 barium ion Inorganic materials 0.000 claims description 3
- 239000004744 fabric Substances 0.000 claims description 3
- 238000006116 polymerization reaction Methods 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 claims 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims 2
- 229920000344 molecularly imprinted polymer Polymers 0.000 claims 2
- 230000003213 activating effect Effects 0.000 claims 1
- 239000004310 lactic acid Substances 0.000 claims 1
- 235000014655 lactic acid Nutrition 0.000 claims 1
- 239000000843 powder Substances 0.000 claims 1
- 238000010276 construction Methods 0.000 abstract description 2
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 8
- 239000001110 calcium chloride Substances 0.000 description 7
- 229910001628 calcium chloride Inorganic materials 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 238000011068 loading method Methods 0.000 description 6
- -1 polyoxy Ethylene Polymers 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 238000006555 catalytic reaction Methods 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 239000005662 Paraffin oil Substances 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- BHTJEPVNHUUIPV-UHFFFAOYSA-N pentanedial;hydrate Chemical group O.O=CCCCC=O BHTJEPVNHUUIPV-UHFFFAOYSA-N 0.000 description 3
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- NWGKJDSIEKMTRX-MDZDMXLPSA-N Sorbitan oleate Chemical compound CCCCCCCC\C=C\CCCCCCCC(=O)OCC(O)C1OCC(O)C1O NWGKJDSIEKMTRX-MDZDMXLPSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WDIHJSXYQDMJHN-UHFFFAOYSA-L barium chloride Chemical compound [Cl-].[Cl-].[Ba+2] WDIHJSXYQDMJHN-UHFFFAOYSA-L 0.000 description 2
- 229910001626 barium chloride Inorganic materials 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- SNRUBQQJIBEYMU-UHFFFAOYSA-N dodecane Chemical compound CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 239000003292 glue Substances 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 229940057995 liquid paraffin Drugs 0.000 description 2
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 229920001155 polypropylene Polymers 0.000 description 2
- 229920001296 polysiloxane Polymers 0.000 description 2
- 239000010453 quartz Substances 0.000 description 2
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 102000011759 adducin Human genes 0.000 description 1
- 108010076723 adducin Proteins 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 235000010410 calcium alginate Nutrition 0.000 description 1
- 239000000648 calcium alginate Substances 0.000 description 1
- 229960002681 calcium alginate Drugs 0.000 description 1
- OKHHGHGGPDJQHR-YMOPUZKJSA-L calcium;(2s,3s,4s,5s,6r)-6-[(2r,3s,4r,5s,6r)-2-carboxy-6-[(2r,3s,4r,5s,6r)-2-carboxylato-4,5,6-trihydroxyoxan-3-yl]oxy-4,5-dihydroxyoxan-3-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylate Chemical compound [Ca+2].O[C@@H]1[C@H](O)[C@H](O)O[C@@H](C([O-])=O)[C@H]1O[C@H]1[C@@H](O)[C@@H](O)[C@H](O[C@H]2[C@H]([C@@H](O)[C@H](O)[C@H](O2)C([O-])=O)O)[C@H](C(O)=O)O1 OKHHGHGGPDJQHR-YMOPUZKJSA-L 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000007334 copolymerization reaction Methods 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000012567 medical material Substances 0.000 description 1
- 238000001000 micrograph Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 229920002627 poly(phosphazenes) Polymers 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 210000004885 white matter Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- 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
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
-
- 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
- A61K9/5057—Gelatin
Abstract
The present invention relates to a kind of double-deck emulsion droplet, medicine carrying microballoons and preparation method thereof and device, this device is composed in series by first order microchannel and microchannel, the second level；First order microchannel is cross microchannel, T-shaped microchannel, Y type microchannel or is total to flow pattern microchannel；Microchannel, the second level includes A class or the two kinds of microchannel of B class.Double-deck emulsion droplet is to be formed monolayer emulsion droplet in first order microchannel by internal phase fluid and mesophase fluid, and monolayer emulsion droplet forms bilayer emulsion droplet again with catalyst or curing agent solution, continuous phase fluid in the exit of microchannel, the second level.The preparation facilities simple in construction of bilayer emulsion droplet of the present invention, adjusts flexibly, it is easy to accomplish emulsion droplet and medicine carrying microballoons grain size, the flexible control of ectonexine thickness, preparation cost is low, and double-deck emulsion droplet grain size is controlled, particle diameter adjustable extent width.
Description
Technical field
The present invention relates to a kind of double-deck emulsion droplet, medicine carrying microballoons and preparation method thereof and device, belong to biological medicine material
Material and microfluidic art.
Background technology
W/O/W or Water-In-Oil bag oil bilayer emulsifying microlayer model and the medicine carrying microballoons prepared for template with them are being given birth to
The fields such as thing medical material, medicament research and development are widely used.Existing preparation method mainly uses the machinery of tradition large scale to stir
Mix, emulsifying-crosslinking, the volatilization of complex emulsions-solvent, emulsifying-technology such as gel, Inverse suspension copolymerization, the first step first generates bilayer
Emulsifying microlayer model, so by solvent volatilize, be dried etc. method generate microspheres product.Traditional preparation methods lacks Microsphere Size
Be precisely controlled, the microspheres product size range width obtained, uniform particle diameter is poor, often through screening obtain specified particle diameter model
The product enclosed；And the loss of institute's packaging medicine is more in preparation process.
Microfluidic droplet technology can be by between minitype channel (micro-nano-scale) interior hydrodynamic shear and surface tension
Interaction, biphase immiscible liquid (You Heshui) is manipulated, wherein one phase flow know from experience formed highly homogeneous liquid
Drip, to realize size, pattern, the preparation of structure-controllable microsphere.Microfluidic droplet technology is the method preparing emulsion from bottom to top,
Can prepare the drop emulsion of high degree of monodispersity with the highest flux, the medicine carrying microballoons product size homogeneity formed is good
Good.
But, currently with the double-deck emulsifying microlayer model of microflow control technique preparation, the apparatus structure complexity of medicine carrying microballoons, operation
Process steps is many, dumb with controlling, and also can not realize the synchronization solidification of emulsion microlayer model, and preparation cost is higher.
Summary of the invention
For apparatus structure complexity, complex operation, high cost in existing double-deck emulsion droplet and medicine carrying microballoons preparation process
Deng not enough, the present invention provides a kind of double-deck emulsion droplet, medicine carrying microballoons and preparation method thereof and device, and operating procedure is simple, dress
Put can flexible combination, low cost, can prepare the microsphere that particle size range is at 0～1000 micron, and microspherulite diameter homogeneity is good,
Can efficient medicine carrying, solve that the particle diameter that existing microspheres exists is uncontrollable, solidification, medicine carrying cannot be synchronized not exclusively etc. ask
Topic.
Technical scheme is as follows:
The preparation facilities of a kind of double-deck emulsion droplet, this device is by first order microchannel and microchannel, second level series connection group
Become；
Described first order microchannel is cross microchannel, T-shaped microchannel, Y type microchannel or is total to flow pattern microchannel；
Described microchannel, the second level includes A class or the two kinds of microchannel of B class；
Described microchannel, the A class second level includes the discrete phase fluid passage of coaxial connection, continuous phase fluid passage and receipts
Collecting passage, discrete phase fluid passage and collection channel are socketed in continuous phase fluid passage, and discrete phase fluid passage is near collecting
One end of passage is tapered, discrete phase fluid passage along central shaft be bisected into monolayer emulsifying microlayer model be passed through passage and catalyst or
Firming agent passage；
Described microchannel, the B class second level includes that monolayer emulsifying microlayer model is passed through passage, catalyst or firming agent passage, receipts
Collection passage and continuous phase fluid passage, monolayer emulsifying microlayer model is passed through passage, catalyst or firming agent passage and collection channel group
In Y type connectivity structure, described continuous phase fluid passage is arranged on monolayer emulsifying microlayer model and is passed through passage, catalyst or firming agent
Passage and the intersection of collection channel and with collection channel vertical connection.
According to the invention it is preferred to, described cross microchannel includes the mesophase fluid of connection in cross-shaped configuration
Passage, internal phase fluid passage and collection channel.
According to the invention it is preferred to, described T-shaped microchannel includes the mesophase fluid passage of T-shaped fabric connectivity, interior
Phase fluid passage and collection channel.
According to the invention it is preferred to, described Y type microchannel includes in y-type structure the mesophase fluid passage of connection, interior
Phase fluid passage and collection channel.
According to the invention it is preferred to, described common flow pattern microchannel includes the mesophase fluid passage of coaxial connection, internal phase
Fluid passage and collection channel, internal phase fluid passage and collection channel be socketed in mesophase fluid passage, internal phase fluid passage
Trapezoidal and near collection channel one end is smaller diameter end.The fluid flow direction of mesophase fluid passage and internal phase fluid
The fluid flow direction of passage is identical.
According to the invention it is preferred to, behind first order microchannel and the series connection of microchannel, the second level, the receipts in first order microchannel
Monolayer emulsifying microlayer model in collection passage and microchannel, the second level is passed through channel connection.
According to the invention it is preferred to, described first order microchannel and the channel diameter of microchannel, the second level are 20 1000
Micron, further preferred 50 500 microns.
According to the present invention, during using the double-deck emulsion droplet of said apparatus preparation, the flowing of continuous phase fluid is sheared
Interfacial tension between power and/or extruding force and fluid interacts, and drop is handed over continuous phase fluid passage at discrete phase fluid
Generate at remittance.Forming monolayer emulsion droplet in first order microchannel, monolayer emulsion droplet is carried along into the by mesophase fluid
Two grades of microchannels, form double-deck emulsion droplet in the exit of microchannel, the second level, and double-deck emulsion droplet synchronization solidify to form double
Layer microsphere, and the medicine carrying microballoons uniform particle diameter formed (dimensional discrepancy < 5%), size, structure/drug loading are the most controlled；Can carry
Hydrophilic or oleophylic class medicine, and between each microsphere, drug loading is consistent.
It is glass or quartz capillary according to the present invention, first order microchannel and microchannel, the second level, or by light, change
The microchannel that the lithographic methods such as, laser are formed.
A kind of double-deck emulsion droplet, this drop is to be formed list in first order microchannel by internal phase fluid and mesophase fluid
Layer emulsion droplet, monolayer emulsion droplet again with catalyst or curing agent solution, the continuous phase fluid outlet in microchannel, the second level
Place forms double-deck emulsion droplet.
Double-deck emulsion droplet according to the present invention, it is preferred that described internal phase fluid is the biocompatibility containing medicine
Macromolecule polymer solution；Described high molecular polymer is polylactic acid (PLA), Poly(D,L-lactide-co-glycolide (PLGA)
Or Polyethylene Glycol (PEG), the solvent of macromolecule polymer solution is dichloromethane, acetone, dimethylformamide, high molecular polymerization
The mass fraction of thing solution is 0.1 10%.
Double-deck emulsion droplet according to the present invention, it is preferred that described mesophase fluid is that biocompatibility macromolecule gathers
Compound aqueous solution and/or cross-linking agent aqueous solution, high molecular polymer is sodium alginate, polyvinyl alcohol, chitosan, starch or bright
Glue, the mass fraction of high molecular polymer aqueous solution is 0.1 10%；Cross-linking agent is glutaraldehyde, Biformyl or formaldehyde, cross-linking agent
The mass fraction 0.5 80% of aqueous solution.
Double-deck emulsion droplet according to the present invention, it is preferred that described catalyst is Bronsted acid or enzyme aqueous solution, institute
The Bronsted acid stated is for regulating the acidity-basicity ph of mesophase fluid, preferably organic acid or mineral acid, and the pH value of Bronsted acid is preferred
For pH1 4；Described enzyme be preferably able between catalytic proteins molecule or within crosslinking, protein and aminoacid between
The enzyme of connection, most preferably glutamine transaminage, the mass fraction of enzyme aqueous solution preferably 0.1 0.3%.
Double-deck emulsion droplet according to the present invention, it is preferred that described firming agent be water-soluble calcium of bivalence, barium from
Sub-aqueous solution, most preferably calcium chloride or barium chloride solution, the mass fraction of firming agent preferably 0.1 10%.
Double-deck emulsion droplet according to the present invention, it is preferred that described continuous phase fluid is immiscible with water organic molten
Agent, it is further preferred that continuous phase fluidIn contain or not contain surfactant；Described surfactant be water solublity or
Oil soluble surfactant, it is furthermore preferred that described water soluble surfactant active selects nonionic surfactant, including polyoxy
Ethylene type or polyol type；Described oil soluble surfactant selects EM90 (cetyl polyethylene/polypropylene glycol-1,0/1 two
Methylsiloxane), Span 80 (sorbester p17) or DC749 (DOW CORNING silicones XIAMETER RSN 0749)；
Described organic solvent is one of C12 18 liquid alkane, silicone oil, paraffin or combination.
Double-deck emulsion droplet according to the present invention, it is preferred that described size droplet diameter is 160～650 μm, particle diameter deviation≤
2%.
A kind of medicine carrying microballoons, is the kernel being enclosed with drug containing in biocompatibility macromolecule polymer microballoon.
Medicine carrying microballoons according to the present invention, it is preferred that the kernel of described drug containing is to be polymerized with biocompatibility macromolecule
Hydrophilic or the oleophylic class medicine that thing mixes；
Preferably, described medicine carrying microballoons particle diameter is 100～1000 μm, and dimensional discrepancy is less than 5%；Particularly preferred, described
Medicine carrying microballoons particle diameter is 110～530 μm, particle diameter deviation≤4%；
Preferably, described biocompatibility macromolecule polymer is sodium alginate, polyvinyl alcohol, chitosan, starch, bright
Glue, polylactic acid (PLA), Poly(D,L-lactide-co-glycolide (PLGA) are or/and Polyethylene Glycol (PEG).
The medicine carrying microballoons of the present invention, with double-deck emulsion droplet as template, adds in internal phase fluid and mesophase fluid and has
The high molecular polymer of biocompatibility and medicine, solidify to form in having and the medicine carrying microballoons of outer double-layer structure.Microspherulite diameter
Homogeneous, ectonexine thickness is controlled；Through the synchronization curing process of the present invention, produced microsphere features smooth surface, size uniformity, medicine carrying
Measure controlled.Medicine carrying microballoons of the present invention, internal layer and outer layer supporter be high molecular polymer, internal layer bag medicine carrying thing, outward
Layer provides and also contributes to keep internal layer pharmaceutically active while supporting, to realize stablize release, preventing from dashing forward and release, increase safety；
By changing solvent and the character of material, operating parameter etc., can conveniently change the size of microspheres product, ectonexine ratio, with reality
Existing medicine carrying, release are controlled.
The present invention also provides for the preparation method of described medicine carrying microballoons, and the size uniformity of medicine carrying microballoons, structure/drug loading can
Control.
The preparation method of a kind of medicine carrying microballoons, comprises the following steps that
(1) discrete phase fluid and the preparation of continuous phase fluid
Preparation discrete phase fluid and continuous phase fluid respectively；
Described discrete phase fluid is collectively constituted by internal phase fluid, mesophase fluid and catalyst or aqueous solution of curing agent:
Described internal phase fluid is the biocompatibility macromolecule polymer solution containing medicine, described high molecular polymer
For polylactic acid (PLA), Poly(D,L-lactide-co-glycolide (PLGA) or Polyethylene Glycol (PEG), macromolecule polymer solution molten
Agent is dichloromethane, acetone, dimethylformamide, and the mass fraction of macromolecule polymer solution is 0.1 8%；
Described mesophase fluid is biocompatibility macromolecule aqueous solutions of polymers or high molecular polymer aqueous solution and friendship
The mixed liquor of connection agent aqueous solution, high molecular polymer is that sodium alginate, polyvinyl alcohol, chitosan, starch are or/and gelatin, high score
The mass fraction of sub-aqueous solutions of polymers is 0.1 10%；Cross-linking agent is glutaraldehyde, Biformyl or formaldehyde, cross-linking agent aqueous solution
Mass fraction 0.5 80%；
Described catalyst is Bronsted acid or enzyme aqueous solution, and described Bronsted acid is preferably organic acid or mineral acid,
The pH value of Bronsted acid is preferably pH1 4；Described enzyme be preferably able between catalytic proteins molecule or within crosslinking, egg
The enzyme of the connection between white matter and aminoacid, most preferably glutamine transaminage, the mass fraction of enzyme aqueous solution is preferred
0.1 0.3%；
Described firming agent is water-soluble calcium of bivalence, barium ion water solution, most preferably calcium chloride or barium chloride water
Solution, the mass fraction of firming agent preferably 0.1 10%.
Described continuous phase fluid is organic solvent immiscible with water, contains or not contain surface activity in continuous phase fluid
Agent；Described organic solvent is one of C12 18 liquid alkane, silicone oil, paraffin or combination；
(2) double-deck emulsion droplet is formed
Internal phase fluid and mesophase fluid are each led into internal phase fluid passage and the mesophase fluid of first order microchannel
Passage, the intersection in internal phase fluid passage and mesophase fluid passage forms monolayer emulsion droplet, by first order microchannel
Collection channel collect monolayer emulsion droplet；
In microchannel, the second level, monolayer emulsion droplet is passed through monolayer emulsion droplet passage, by catalyst or firming agent
Solution is passed through catalyst or firming agent passage, and continuous phase fluid is passed through continuous phase fluid passage, monolayer emulsion droplet, catalyst
Or firming agent, continuous phase fluid form double-deck emulsion droplet in intersection, collected by the collection channel of microchannel, the second level
To double-deck emulsion droplet；
(3) solidification is synchronized
While forming double-deck emulsion droplet, catalyst or firming agent in microchannel, the second level with in mesophase fluid
High molecular polymer be sufficiently mixed, double-deck emulsion droplet is synchronized and solidify to form microsphere, stands at a temperature of 20 80 DEG C
0.5 24 hours, it is ensured that the fully crosslinked solidification of microsphere, obtain medicine carrying microballoons；
(4) microsphere separates
By the reacting liquid filtering after step (3) crosslinking curing, collect solid particle, successively with organic solvent, water washing, dry
Medicine carrying microballoons product is obtained after dry.
Preparation method according to medicine carrying microballoons of the present invention, it is preferred that containing surface activity in continuous phase fluid in step (1)
During agent, described surfactant is one or more mixing of water solublity or oil soluble surfactant；Further preferably
, described water soluble surfactant active is nonionic surfactant, including polyoxyethylene-type and polyol type nonionic
Surfactant；Described oil soluble surfactant is EM90 (cetyl polyethylene/polypropylene glycol-10/1 dimethyl silica
Alkane), Span 80 (sorbester p17) or DC749 (DOW CORNING silicones XIAMETER RSN 0749).
Preparation method according to medicine carrying microballoons of the present invention, it is preferred that described in step (1), firming agent is that calcium chloride is water-soluble
Liquid, described aqueous solution of curing agent mass concentration is 1 10%, and particularly preferred mass concentration is the calcium chloride water of 2 5%.
Preparation method according to medicine carrying microballoons of the present invention, it is preferred that step (2) controls mesophase in microchannel, the second level
Fluid flow is: 0.5 8mL/h, and catalyst or aqueous solution of curing agent flow be: 0.05 2.0mL/h, controls continuous phase fluid
Flow is: 1 20mL/h；
It is further preferred that it is 2 6mL/h that step (2) controls mesophase fluid flow in microchannel, the second level, catalysis
Agent or aqueous solution of curing agent flow are 0.1 0.5mL/h, and the flow of continuous phase fluid is 5 6mL/h.
According to the present invention, in step (2), the formation of double-deck emulsion droplet is in microchannel, the second level, utilizes cutting of fluid
Shear force and and interfacial tension between interaction discrete phase fluid is divided into the drop of below nanoliter level and nanoliter level.
Preparation method according to medicine carrying microballoons of the present invention, it is preferred that described in step (3), crosslinking curing is: polyphosphazene polymer
Compound and cross-linking agent carry out conventional cross-linking reaction under the effect of catalyst or firming agent, such as: polyvinyl alcohol and aldehydes chemical combination
Thing carries out conventional cross-linking reaction under the catalytic action of acidic catalyst and generates Pioloform, polyvinyl acetal product, or sodium alginate exists
It solidify to form calcium alginate under the catalysis of calcium chloride；Solid particle is obtained, after then carrying out separating, washing, dry after cured
Process, obtain microsphere product.
Preparation method according to medicine carrying microballoons of the present invention, it is preferred that the organic solvent of washing described in step (4) is selected from boiling
Liquid alkane o'clock below 80 DEG C, one or more combinations in 60 90 DEG C of petroleum ether, ethyl acetate.Wash time
It it is 0.5 3 hours.Described being dried refers to vacuum drying, lyophilization or spray drying.
The mode that the present invention uses two-stage microchannel to connect prepares double-deck emulsifying microlayer model, is formed in first order microchannel
Monolayer emulsifying microlayer model, is wrapped by mesophase and carries (or claiming premixed liquid) entrance microchannel, the second level, and being formed, double-deck emulsifying is micro-
While drop, catalyst is had an effect with high molecular polymer, and microlayer model occurs solidification thus forms microsphere.Its ultimate principle
For according to the double-deck emulsifying microlayer model of principle of hydrodynamics preparation, as template, internal phase fluid adds high molecular polymerization
Thing monomer, medicine etc., cured after form medicine carrying microballoons.Owing to microsphere is formed one by one, preparation the most of the present invention
Microsphere Size, ectonexine thickness, drug loading can be precisely controlled by devices and methods therefor, the product good sphericity that formed,
Size uniformity, structure/drug loading are the most controlled.
The invention has the beneficial effects as follows:
1, the present invention is based on the double-deck emulsifying microlayer model of principle of hydrodynamics preparation and medicine carrying microballoons.Internal layer drop is first
Level microchannel in dropwise formed under the effect of liquid liquid surface tension and shearing force, in the passage of the second level internal layer drop by
Between carry mutually and sheared the outer layer being wrapped to form double-deck emulsion droplet together with catalyst or firming agent by continuous phase.Double-deck with this
Emulsifying microlayer model is template, adds high molecular polymer and medicine in a fluid, through catalyst or firming agent effect, can synchronize solid
Change and form medicine carrying microballoons.Obtained medicine carrying microballoons uniform particle diameter (dimensional discrepancy is less than 5%), drug loading is uniform/controlled.
2, the present invention can regulate droplet size by adjusting rate of flow of fluid and microchannel size, therefore by adjusting fluid
Flow velocity or change microchannel size and realize the preparation of different-grain diameter and the medicine carrying microballoons of ectonexine ratio, has grain size, interior
The advantage of the controlled preparation of outer layer thickness.
3, synchronization curing process of the present invention makes the microsphere good sphericity prepared, it is to avoid the operation impact solidified separately
Microsphere pattern.
4, the preparation facilities simple in construction of bilayer emulsion droplet of the present invention, adjusts flexibly, it is easy to accomplish emulsion droplet and load
Medicine microspherulite diameter size, the flexible control of ectonexine thickness, preparation cost is low.
Accompanying drawing explanation
Figure 1A is the structural representation of cross first order microchannel A.
Figure 1B is the structural representation of T-shaped first order microchannel B.
Fig. 1 C is the structural representation of Y type first order microchannel C.
Fig. 1 D is the structural representation of common flow pattern first order microchannel D.
Fig. 2 A is the structural representation of microchannel, the A class second level.
Fig. 2 B is the structural representation of microchannel, the B class second level.
Fig. 3 is the structural representation of the preparation facilities of double-deck emulsifying microlayer model, the most T-shaped first order microchannel B in embodiment 4
The preparation facilities formed with the series connection of microchannel, the B class second level.
Fig. 4,5,6,7 are respectively the microphotograph of the medicine carrying microballoons that embodiment 3,4,5,6 prepares.
Wherein: A1, B1, C1, D1,13 be mesophase fluid passage, A2, B2, C2, D2,14 be internal phase fluid passage, 3,8,
15 are passed through passage for monolayer emulsifying microlayer model, and 4,9,16 is catalyst or firming agent passage, and 5,10,17 lead to for continuous phase fluid
Road, A3, B3, C3, D3,6,11,18 are collection channel, and 7,12,20 is double-deck emulsion droplet, and 19 is monolayer emulsion droplet.
Detailed description of the invention
The present invention will be further described with embodiment below in conjunction with the accompanying drawings, but protection scope of the present invention is not limited to
This.
In embodiment: microchannel, the A class second level is glass or quartz capillary microchannel, microchannel, the B class second level is warp
The microchannel (channel dimension is micron order) that the lithographic techniques such as light, chemistry, laser are formed.
% concentration unit in embodiment is mass percent.
The polyvinyl alcohol molecule amount used in embodiment is 13,000 23,000, hydrolyze more than 99%；Content: >=
99.0%, white particulate.
The sodium alginate molecular formula used in embodiment is (C6H7O6Na) n, molecular weight 398.31；Macromole 32,000
250,000, white particulate.
Embodiment 1, polyvinyl alcohol and the preparation of sodium alginate mixed aqueous solution
Weigh 10 grams of polyvinylalcohol solids granules and add 90 grams of distilled water, stir under the conditions of 75 80 DEG C and be dissolved as
Transparency liquid, obtains the polyvinyl alcohol water solution of 10% mass percent.
Weighing 5 grams of sodium alginate solid particles and add 95 grams of distilled water, stirring at ambient temperature, it is transparent to be dissolved as
Liquid, obtains the sodium alginate aqueous solution of 5% mass percent.
According to mass fraction, above-mentioned polyvinyl alcohol and sodium alginate aqueous solution are configured to final concentration be respectively 1% and
The polyvinyl alcohol of 0.5% and sodium alginate mixed aqueous solution.
The continuous phase fluid used in embodiment is the paraffin oil containing 2%EM90, weighs 98 grams of paraffin oil, adds 2 grams
EM90, obtains the paraffin oil continuous phase fluid of 2% mass percent.
The catalyst used in embodiment is protonic acid aqueous solution, and regulation protonic acid aqueous solution pH value is 16, obtains catalysis
Agent aqueous solution.
The cross-linking agent used in embodiment is glutaraldehyde water solution, calculates polyvinyl alcohol water solution concentration water-soluble with glutaraldehyde
The mass fraction of liquid, according to the proportions cross-linking agent aqueous solution of 3:2.
The firming agent used in embodiment is calcium chloride water, weighs 10 grams of anhydrous calcium chloride solids, adds 90 grams and go
In ionized water, obtain the aqueous solution of curing agent of 10% mass percent.
The internal phase fluid used in embodiment is that the polylactic acid dichloromethane solution containing medicine, the mass fraction of solution are
2%.
Embodiment 2,
The preparation facilities of a kind of double-deck emulsion droplet, this device is by first order microchannel and microchannel, second level series connection group
Become；
Described first order microchannel is cross microchannel A, T-shaped microchannel B, Y type microchannel C or common flow pattern microchannel
D；
Described microchannel, the second level includes A class or the two kinds of microchannel of B class；
Described microchannel, the A class second level includes the discrete phase fluid passage of coaxial connection, continuous phase fluid passage 5 and receives
Collecting passage 6, discrete phase fluid passage and collection channel 6 are socketed in continuous phase fluid passage 5, and discrete phase fluid passage is near receiving
One end of collection passage 6 is tapered, and discrete phase fluid passage is bisected into monolayer emulsifying microlayer model along central shaft and is passed through passage 3 and catalysis
Agent or firming agent passage 4；
Described microchannel, the B class second level include monolayer emulsifying microlayer model be passed through passage 8, catalyst or firming agent passage 9,
Collection channel 11 and continuous phase fluid passage 10, monolayer emulsifying microlayer model is passed through passage 8, catalyst or firming agent passage 9 and receives
Collection 11 groups of passage in Y type connectivity structure, described continuous phase fluid passage 10 be arranged on monolayer emulsifying microlayer model be passed through passage 8,
Catalyst or firming agent passage 9 and the intersection of collection channel 11 and with collection channel 11 vertical connection.
Behind first order microchannel and the series connection of microchannel, the second level, collection channel and the second level in first order microchannel are micro-logical
Monolayer emulsifying microlayer model in road is passed through channel connection.
Described cross microchannel A includes that in cross-shaped configuration the mesophase fluid passage A1 of connection, internal phase fluid lead to
Road A2 and collection channel A3.
Described T-shaped microchannel B includes that the mesophase fluid passage B1 of T-shaped fabric connectivity, internal phase fluid passage B2 receive
Collection passage B3.
Described Y type microchannel C includes that the mesophase fluid passage C1 of connection, internal phase fluid channel C 2 are received in y-type structure
Collection channel C 3.
Described common flow pattern microchannel D includes the mesophase fluid passage D1 of coaxial connection, internal phase fluid passage D2 and receipts
Collection passage D3, internal phase fluid passage D2 and collection channel D3 be socketed in the D1 of mesophase fluid passage, internal phase fluid passage D2 in
Trapezoidal and near collection channel D3 one end is smaller diameter end.The fluid flow direction of mesophase fluid passage D1 and internal phase stream
The fluid flow direction of body passage D2 is identical.
Prepared by embodiment 3, medicine carrying microballoons:
The cross first order microchannel shown in Figure 1A, internal phase fluid passage A2 a diameter of 150 are selected in first order microchannel
Micron, a diameter of 200 microns of mesophase fluid passage A1；The microchannel, the A class second level shown in Fig. 2 A is selected in microchannel, the second level,
A diameter of 250 microns of discrete phase fluid passage, a diameter of 300 microns of continuous phase fluid passage 5.
Polyvinyl alcohol and sodium alginate mixed aqueous solution mass percent concentration are respectively 1.5% and 0.5%, cross-linking agent water
Solution is the glutaraldehyde water solution of 50% mass percent.By solute polyvinyl alcohol: cross-linking agent=3:2 mass ratio is by polyvinyl alcohol
Aqueous solution premixes with glutaraldehyde water solution, and aqueous catalyst solution is the aqueous hydrochloric acid solution of pH=2.0.
Respectively by polyvinyl alcohol, sodium alginate and cross-linking agent mixed liquor, internal phase fluid with the steady flow of 0.3mL/h, 3mL/h
Amount is pumped in first order microchannel, and the monolayer emulsifying microlayer model of formation is passed through passage 3 through monolayer emulsifying microlayer model and is carried along into
In microchannel, the second level (Fig. 2 A), aqueous catalyst solution pumps into catalyst channels 4 with the constant flow rate of 0.8mL/h simultaneously,
Liquid paraffin pumps in continuous phase fluid passage 5 with its constant flow rate 6mL/h, and double-deck emulsifying microlayer model 7 is formed in intersection, logical
Cross collection channel 6 to collect.
White solid is obtained after bilayer emulsifying microlayer model 7 is stood 24 hours under 25 DEG C of room temperature conditions.Then filter, receive
Collection white solid.White solid is washed by ethyl acetate, is adopted by apparatus,Soxhlet's the most again and wash 24 hours with water, very
Empty 4 DEG C obtain white microsphere after drying.Outer layer particle diameter 500 microns, internal layer particle diameter 100 microns (shown in Fig. 4), Microsphere Size deviation
It is 3%.
Prepared by embodiment 4, medicine carrying microballoons:
The T-shaped first order microchannel shown in Figure 1B is selected in first order microchannel, and internal phase fluid passage B2 is a diameter of 100 micro-
Rice, a diameter of 200 microns of mesophase fluid passage B1；Microchannel, the B class second level shown in Fig. 2 B is selected in microchannel, the second level, discrete
Phase fluid channel diameter is 200 microns, a diameter of 300 microns of continuous phase fluid passage 10.First order microchannel and the second level are micro-
After Tandem, as shown in Figure 3.
Polyvinyl alcohol water solution concentration is 2%, and cross-linking agent aqueous solution is that the glutaraldehyde of mass percent concentration 40% is water-soluble
Liquid, by solute polyvinyl alcohol: polyvinyl alcohol water solution is premixed by cross-linking agent=3:2 mass ratio with cross-linking agent aqueous solution, urges
Agent aqueous solution is the aqueous sulfuric acid of pH=1.5.Respectively by polyvinyl alcohol and cross-linking agent mixed liquor, internal phase fluid with 0.5mL/
The constant flow rate of h, 2mL/h pumps into first order microchannel, and the monolayer emulsifying microlayer model 19 of formation is through monolayer emulsifying microlayer model
Being passed through passage 15 and enter in microchannel, the second level, aqueous catalyst solution pumps into catalyst with the constant flow rate of 0.8mL/h simultaneously
In passage 16, dodecane pumps in continuous phase fluid passage 17 with its constant flow rate 8mL/h.Double-deck emulsifying microlayer model 20 is crossing
Place is formed, and is collected by collection channel 18.
White solid is obtained after bilayer emulsifying microlayer model 20 is stood 24 hours under 25 DEG C of room temperature conditions.Then filter,
Collect white solid.White solid is washed by ethyl acetate, is adopted by apparatus,Soxhlet's the most again and wash with water 24 hours,
4 DEG C of vacuum obtains white microsphere after drying.Outer layer particle diameter 300 microns, internal layer particle diameter 120 microns (shown in Fig. 5), Microsphere Size is inclined
Difference is 3%.
Prepared by embodiment 5, medicine carrying microballoons:
The Y type first order microchannel shown in Fig. 1 C is selected in first order microchannel, a diameter of 80 microns of internal phase fluid channel C 2,
A diameter of 100 microns of mesophase fluid passage C1；Microchannel, the B class second level, discrete phase shown in Fig. 2 B are selected in microchannel, the second level
A diameter of 150 microns of fluid passage, a diameter of 200 microns of continuous phase fluid passage 10.
Sodium alginate aqueous solution mass percent concentration is 2%, and aqueous solution of curing agent is the calcium chloride water of 4mol/L.
Respectively sodium alginate aqueous solution, mesophase are pumped into first order microchannel with the constant flow rate of 0.5mL/h, 3mL/h, formed
Microlayer model be passed through passage 8 via monolayer emulsifying microlayer model and enter (Fig. 2 B), aqueous solution of curing agent simultaneously in microchannel, the second level
The constant flow rate of 0.5mL/h pumps into firming agent passage 9, and toluene pumps into continuous phase fluid passage with its constant flow rate 10mL/h
In 10.Double-deck emulsifying microlayer model 12 is formed in intersection, is collected by collection channel 11.
White solid is obtained after bilayer emulsifying microlayer model 12 is stood 24 hours under 25 DEG C of room temperature conditions.Then filter,
Collect white solid.By white solid by petroleum ether, adopted by apparatus,Soxhlet's the most again and wash 24 hours with water, very
Empty 4 DEG C obtain white microsphere after drying.Outer layer particle diameter 120 microns, internal layer particle diameter 95 microns (shown in Fig. 6), Microsphere Size deviation
It is 4%.
Prepared by embodiment 6, medicine carrying microballoons:
The common flow pattern first order microchannel shown in Fig. 1 D, internal phase fluid passage D2 a diameter of 150 are selected in first order microchannel
Micron, a diameter of 130 microns of mesophase fluid passage D1；Microchannel, the A class second level shown in Fig. 2 A is selected in microchannel, the second level, from
A diameter of 150 microns of dephasing fluid passage, a diameter of 400 microns of continuous phase fluid passage 5.
Aqueous gelatin solution mass concentration is 2%, cross-linking agent aqueous solution be mass concentration be the glutamine transaminage of 0.2%
Aqueous solution.Respectively aqueous gelatin solution, mesophase are pumped into first order microchannel with the constant flow rate of 1mL/h, 6mL/h, shape
The microlayer model become is passed through passage 3 via monolayer emulsifying microlayer model and enters (Fig. 2 A) in microchannel, the second level, and cross-linking agent is water-soluble simultaneously
The constant flow rate of liquid 0.8mL/h pumps into catalyst or firming agent passage 4, and liquid paraffin pumps into its constant flow rate 8mL/h
In continuous phase fluid passage 5.Double-deck emulsifying microlayer model 7 generates near discrete phase outlet flow channels, is received by collection channel 6
Collection.
White solid is obtained after bilayer emulsifying microlayer model 12 is stood 24 hours under 25 DEG C of room temperature conditions.Then filter,
Collect white solid.White solid is washed by ethyl acetate, is adopted by apparatus,Soxhlet's the most again and wash with water 24 hours,
4 DEG C of vacuum obtains white microsphere after drying.Outer layer particle diameter 290 microns, internal layer particle diameter 90 microns (Fig. 7), Microsphere Size deviation is
3%.
Claims (10)
1. the preparation facilities of a double-deck emulsion droplet, it is characterised in that this device is micro-logical by first order microchannel and the second level
Road is composed in series；
Described first order microchannel is cross microchannel, T-shaped microchannel, Y type microchannel or is total to flow pattern microchannel；
Described microchannel, the second level includes A class or the two kinds of microchannel of B class；
Described microchannel, the A class second level includes the discrete phase fluid passage of coaxial connection, continuous phase fluid passage and collects logical
Road, discrete phase fluid passage and collection channel be socketed in continuous phase fluid passage, and discrete phase fluid passage is near collection channel
One end tapered, discrete phase fluid passage is bisected into monolayer emulsifying microlayer model along central shaft and is passed through passage and catalyst or solidification
Agent passage；
Described microchannel, the B class second level includes that monolayer emulsifying microlayer model is passed through passage, catalyst or firming agent passage, collects and lead to
Road and continuous phase fluid passage, monolayer emulsifying microlayer model is passed through passage, catalyst or firming agent passage and collection channel composition Y type
Connectivity structure, described continuous phase fluid passage is arranged on monolayer emulsifying microlayer model and is passed through passage, catalyst or firming agent passage
With the intersection of collection channel and with collection channel vertical connection.
The preparation facilities of double-deck emulsion droplet the most according to claim 1, it is characterised in that described cross microchannel
Including the mesophase fluid passage connected in cross-shaped configuration, internal phase fluid passage and collection channel；
Described T-shaped microchannel includes the mesophase fluid passage of T-shaped fabric connectivity, internal phase fluid passage and collection channel；
Described Y type microchannel includes mesophase fluid passage, internal phase fluid passage and the collection channel of connection in y-type structure；
Described common flow pattern microchannel includes the mesophase fluid passage of coaxial connection, internal phase fluid passage and collection channel, interior
Phase fluid passage and collection channel are socketed in mesophase fluid passage, the trapezoidal and close collection channel of internal phase fluid passage
One end be smaller diameter end.
The preparation facilities of double-deck emulsion droplet the most according to claim 1, it is characterised in that first order microchannel and second
After the series connection of level microchannel, the collection channel in first order microchannel and the monolayer emulsifying microlayer model in microchannel, the second level are passed through logical
Road connects.
The preparation facilities of double-deck emulsion droplet the most according to claim 1, it is characterised in that described first order microchannel
It is 20 1000 microns with the channel diameter of microchannel, the second level, preferably 50 500 microns.
5. one kind utilizes the double-deck emulsion droplet that device described in any one of claim 14 prepares, it is characterised in that this drop is
In first order microchannel, formed monolayer emulsion droplet by internal phase fluid and mesophase fluid, monolayer emulsion droplet again with catalyst
Or curing agent solution, continuous phase fluid form double-deck emulsion droplet in the exit of microchannel, the second level.
Double-deck emulsion droplet the most according to claim 5, it is characterised in that described internal phase fluid is the life containing medicine
Thing compatible polymer polymer solution；Described high molecular polymer is polylactic acid, Poly(D,L-lactide-co-glycolide or poly-
Ethylene glycol, the solvent of macromolecule polymer solution is dichloromethane, acetone, dimethylformamide, macromolecule polymer solution
Mass fraction is 0.1 10%.
Double-deck emulsion droplet the most according to claim 5, it is characterised in that described mesophase fluid is biocompatibility
High molecular polymer aqueous solution and/or cross-linking agent aqueous solution, high molecular polymer is sodium alginate, polyvinyl alcohol, chitosan, shallow lake
Powder or gelatin, the mass fraction of high molecular polymer aqueous solution is 0.1 10%；Cross-linking agent is glutaraldehyde, Biformyl or formaldehyde,
The mass fraction 0.5 80% of cross-linking agent aqueous solution；
Preferably, described catalyst is Bronsted acid or enzyme aqueous solution, and described Bronsted acid is organic acid or mineral acid, institute
The enzyme stated be can between catalytic proteins molecule or within crosslinking, protein and aminoacid between the enzyme of connection；
Preferably, described firming agent is water-soluble calcium of bivalence, barium ion water solution；
Preferably, described continuous phase fluid is organic solvent immiscible with water, continuous phase fluidIn contain or not contain table Face activating agent；Described surfactant is water solublity or oil soluble surfactant, and described water soluble surfactant active selects
Nonionic surfactant；Described oil soluble surfactant selects EM90, Span 80 or DC749；Described organic solvent
For one of C12 18 liquid alkane, silicone oil, paraffin or combination.
8. a medicine carrying microballoons, it is characterised in that this microsphere is to be enclosed with to contain in biocompatibility macromolecule polymer microballoon
The kernel of medicine.
Medicine carrying microballoons the most according to claim 8, it is characterised in that the kernel of described drug containing is high with biocompatibility
Hydrophilic or the oleophylic class medicine that Molecularly Imprinted Polymer mixes；
Preferably, described medicine carrying microballoons particle diameter is 100～1000 μm, and dimensional discrepancy is less than 5%；
Preferably, described biocompatibility macromolecule polymer is sodium alginate, polyvinyl alcohol, chitosan, starch, gelatin, gathers
Lactic acid, Poly(D,L-lactide-co-glycolide are or/and Polyethylene Glycol.
10. utilize the method that device described in any one of claim 14 prepares the medicine carrying microballoons described in claim 8 or 9,
Comprise the following steps that
(1) discrete phase fluid and the preparation of continuous phase fluid
Preparation discrete phase fluid and continuous phase fluid respectively；
Described discrete phase fluid is collectively constituted by internal phase fluid, mesophase fluid and catalyst or aqueous solution of curing agent:
Described internal phase fluid is the biocompatibility macromolecule polymer solution containing medicine, and described high molecular polymer is poly-
Lactic acid, Poly(D,L-lactide-co-glycolide or Polyethylene Glycol, the solvent of macromolecule polymer solution be dichloromethane, acetone, two
Methylformamide, the mass fraction of macromolecule polymer solution is 0.1 8%；
Described mesophase fluid is biocompatibility macromolecule aqueous solutions of polymers and/or cross-linking agent aqueous solution, high molecular polymerization
Thing be sodium alginate, polyvinyl alcohol, chitosan, starch or/and gelatin, the mass fraction of high molecular polymer aqueous solution is 0.1
10%；Cross-linking agent is glutaraldehyde, Biformyl or formaldehyde, the mass fraction 0.5 80% of cross-linking agent aqueous solution；
Described catalyst is Bronsted acid or enzyme aqueous solution, and described Bronsted acid is organic acid or mineral acid；Described life
Thing enzyme be can between catalytic proteins molecule or within crosslinking, protein and aminoacid between the enzyme of connection, enzyme
The mass fraction of aqueous solution preferably 0.1 0.3%；
Described firming agent is water-soluble calcium of bivalence, barium ion water solution；
Described continuous phase fluid is organic solvent immiscible with water, contains or not contain surfactant in continuous phase fluid；
Described organic solvent is one of C12 18 liquid alkane, silicone oil, paraffin or combination；
(2) double-deck emulsion droplet is formed
Internal phase fluid and mesophase fluid are each led into internal phase fluid passage and the mesophase fluid passage of first order microchannel,
Intersection in internal phase fluid passage and mesophase fluid passage forms monolayer emulsion droplet, by the collection of first order microchannel
Passage collects monolayer emulsion droplet；
In microchannel, the second level, monolayer emulsion droplet is passed through monolayer emulsion droplet passage, by catalyst or curing agent solution
It is passed through catalyst or firming agent passage, continuous phase fluid is passed through continuous phase fluid passage, monolayer emulsion droplet, catalyst or solid
Agent, continuous phase fluid form double-deck emulsion droplet in intersection, obtain double by the collection channel collection of microchannel, the second level
Layer emulsion droplet；
(3) solidification is synchronized
While forming double-deck emulsion droplet, catalyst or firming agent in microchannel, the second level with the height in mesophase fluid
Molecularly Imprinted Polymer is sufficiently mixed, and double-deck emulsion droplet is synchronized and solidify to form microsphere, stands 0.5 at a temperature of 20 80 DEG C
24 hours, it is ensured that the fully crosslinked solidification of microsphere, obtain medicine carrying microballoons；
(4) microsphere separates
By the reacting liquid filtering after step (3) crosslinking curing, collect solid particle, successively with organic solvent, water washing, after drying
Obtain medicine carrying microballoons product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610812204.4A CN106214489A (en) | 2016-09-09 | 2016-09-09 | A kind of double-deck emulsion droplet, medicine carrying microballoons and preparation method thereof and device |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610812204.4A CN106214489A (en) | 2016-09-09 | 2016-09-09 | A kind of double-deck emulsion droplet, medicine carrying microballoons and preparation method thereof and device |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106214489A true CN106214489A (en) | 2016-12-14 |
Family
ID=58073876
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610812204.4A Pending CN106214489A (en) | 2016-09-09 | 2016-09-09 | A kind of double-deck emulsion droplet, medicine carrying microballoons and preparation method thereof and device |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106214489A (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106669556A (en) * | 2017-01-09 | 2017-05-17 | 中国工程物理研究院激光聚变研究中心 | Method for preparing millimeter-scale granules by changing microfluidic channels |
| CN108403663A (en) * | 2018-06-05 | 2018-08-17 | 广西中医药大学 | GO-PEG gel micro-balls with nucleocapsid and its preparation method and application |
| CN108721684A (en) * | 2018-05-31 | 2018-11-02 | 山东省科学院能源研究所 | Hud typed prepackage chemotherapeutics embolism microball of one kind and preparation method thereof |
| CN109985588A (en) * | 2018-01-02 | 2019-07-09 | 山东省科学院能源研究所 | A kind of micro passage reaction |
| CN109988323A (en) * | 2018-01-02 | 2019-07-09 | 山东省科学院能源研究所 | The method of monodisperse polyvinyl alcohol microparticles is quickly prepared under a kind of room temperature |
| CN110804531A (en) * | 2019-11-15 | 2020-02-18 | 深圳市第二人民医院 | Intestinal microorganism detection system based on micro-droplets |
| CN110819507A (en) * | 2019-11-15 | 2020-02-21 | 深圳市第二人民医院 | Micro-droplet preparation chip for detecting intestinal microorganisms |
| CN113278494A (en) * | 2021-05-07 | 2021-08-20 | 深圳市第二人民医院(深圳市转化医学研究院) | Digital PCR microdroplet generation chip |
| CN115445461A (en) * | 2022-08-17 | 2022-12-09 | 广东省科学院生物与医学工程研究所 | Double-layer micro-droplet generation device and double-layer micro-droplet generation method |
| WO2024007588A1 (en) * | 2022-07-07 | 2024-01-11 | Nanjing Ipe Institute Of Green Manufacturing Industry | Surfactant-free preparation methods of polymer microspheres and microcapsules |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101695646A (en) * | 2009-10-28 | 2010-04-21 | 中国海洋大学 | Device and method for preparing gel microspheres with uniform grain sizes |
| CN102068409A (en) * | 2011-01-13 | 2011-05-25 | 清华大学 | Method for preparing mono-disperse microemulsion, liposome and microsphere based on microfluidic technology |
| CN102392013A (en) * | 2011-11-09 | 2012-03-28 | 华南理工大学 | Magnetic immobilized cross-linking cellulase aggregates (CLEAs), preparation method and application thereof |
| CN103371974A (en) * | 2012-04-25 | 2013-10-30 | 中国科学院大连化学物理研究所 | Drug sustained release polymeric microspheres prepared based on micro-fluidic technology and application |
| CN103536973A (en) * | 2013-10-25 | 2014-01-29 | 北京大学 | Polyvinyl alcohol magnetic particles as well as preparation method and application thereof |
| CN104857576A (en) * | 2015-04-24 | 2015-08-26 | 山东省科学院能源研究所 | Method for preparation of polyvinyl alcohol embolism microball by synchronous solidification |
| KR20150116485A (en) * | 2014-04-07 | 2015-10-16 | 한국과학기술원 | Method for preparing Double Emulsion with multiple innermost drops enveloped by ultrathin shell, and Double Emulsion thereof |
| CN206404046U (en) * | 2016-09-09 | 2017-08-15 | 山东省科学院能源研究所 | A kind of device for preparing double-deck emulsion droplet |
-
2016
- 2016-09-09 CN CN201610812204.4A patent/CN106214489A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101695646A (en) * | 2009-10-28 | 2010-04-21 | 中国海洋大学 | Device and method for preparing gel microspheres with uniform grain sizes |
| CN102068409A (en) * | 2011-01-13 | 2011-05-25 | 清华大学 | Method for preparing mono-disperse microemulsion, liposome and microsphere based on microfluidic technology |
| CN102392013A (en) * | 2011-11-09 | 2012-03-28 | 华南理工大学 | Magnetic immobilized cross-linking cellulase aggregates (CLEAs), preparation method and application thereof |
| CN103371974A (en) * | 2012-04-25 | 2013-10-30 | 中国科学院大连化学物理研究所 | Drug sustained release polymeric microspheres prepared based on micro-fluidic technology and application |
| CN103536973A (en) * | 2013-10-25 | 2014-01-29 | 北京大学 | Polyvinyl alcohol magnetic particles as well as preparation method and application thereof |
| KR20150116485A (en) * | 2014-04-07 | 2015-10-16 | 한국과학기술원 | Method for preparing Double Emulsion with multiple innermost drops enveloped by ultrathin shell, and Double Emulsion thereof |
| CN104857576A (en) * | 2015-04-24 | 2015-08-26 | 山东省科学院能源研究所 | Method for preparation of polyvinyl alcohol embolism microball by synchronous solidification |
| CN206404046U (en) * | 2016-09-09 | 2017-08-15 | 山东省科学院能源研究所 | A kind of device for preparing double-deck emulsion droplet |
Non-Patent Citations (2)
| Title |
|---|
| DITTRICH PS: "A new embedded process for compartmentalized cell-free protein expression and on-line detection in microfluidic devices", 《CHEMBIOCHEM》 * |
| MINSEOK SEO: "Microfluidic consecutive flow-focusing droplet generators", 《SOFT MATTER》 * |
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106669556B (en) * | 2017-01-09 | 2019-05-21 | 中国工程物理研究院激光聚变研究中心 | A method of millimeter grade particles are prepared using transformation microfluidic channel |
| CN106669556A (en) * | 2017-01-09 | 2017-05-17 | 中国工程物理研究院激光聚变研究中心 | Method for preparing millimeter-scale granules by changing microfluidic channels |
| CN109988323B (en) * | 2018-01-02 | 2021-10-08 | 山东省科学院能源研究所 | Method for rapidly preparing monodisperse polyvinyl alcohol microspheres at normal temperature |
| CN109985588A (en) * | 2018-01-02 | 2019-07-09 | 山东省科学院能源研究所 | A kind of micro passage reaction |
| CN109988323A (en) * | 2018-01-02 | 2019-07-09 | 山东省科学院能源研究所 | The method of monodisperse polyvinyl alcohol microparticles is quickly prepared under a kind of room temperature |
| CN108721684A (en) * | 2018-05-31 | 2018-11-02 | 山东省科学院能源研究所 | Hud typed prepackage chemotherapeutics embolism microball of one kind and preparation method thereof |
| CN108403663A (en) * | 2018-06-05 | 2018-08-17 | 广西中医药大学 | GO-PEG gel micro-balls with nucleocapsid and its preparation method and application |
| CN110804531A (en) * | 2019-11-15 | 2020-02-18 | 深圳市第二人民医院 | Intestinal microorganism detection system based on micro-droplets |
| CN110819507A (en) * | 2019-11-15 | 2020-02-21 | 深圳市第二人民医院 | Micro-droplet preparation chip for detecting intestinal microorganisms |
| CN110804531B (en) * | 2019-11-15 | 2023-09-26 | 深圳市第二人民医院 | Intestinal microorganism detection system based on micro-droplets |
| CN110819507B (en) * | 2019-11-15 | 2023-09-26 | 深圳市第二人民医院 | Micro-droplet preparation chip for intestinal microorganism detection |
| CN113278494A (en) * | 2021-05-07 | 2021-08-20 | 深圳市第二人民医院(深圳市转化医学研究院) | Digital PCR microdroplet generation chip |
| WO2024007588A1 (en) * | 2022-07-07 | 2024-01-11 | Nanjing Ipe Institute Of Green Manufacturing Industry | Surfactant-free preparation methods of polymer microspheres and microcapsules |
| CN115445461A (en) * | 2022-08-17 | 2022-12-09 | 广东省科学院生物与医学工程研究所 | Double-layer micro-droplet generation device and double-layer micro-droplet generation method |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106214489A (en) | A kind of double-deck emulsion droplet, medicine carrying microballoons and preparation method thereof and device | |
| Zhao-Miao et al. | Advances in droplet-based microfluidic technology and its applications | |
| Chong et al. | Advances in fabricating double-emulsion droplets and their biomedical applications | |
| Cai et al. | Anisotropic microparticles from microfluidics | |
| Vladisavljević | Structured microparticles with tailored properties produced by membrane emulsification | |
| Wu et al. | Recent studies of Pickering emulsions: particles make the difference | |
| Spyropoulos et al. | Advances in membrane emulsification. Part A: recent developments in processing aspects and microstructural design approaches | |
| CN112275336B (en) | Multi-channel integrated micro-fluidic chip and method for preparing monodisperse gel microspheres by using same in high throughput | |
| CN104857576B (en) | Method for preparation of polyvinyl alcohol embolism microball by synchronous solidification | |
| CN102068409A (en) | Method for preparing mono-disperse microemulsion, liposome and microsphere based on microfluidic technology | |
| CN101392064B (en) | Method for preparing monodisperse polylactic acid microsphere | |
| Chan et al. | Can microfluidics address biomanufacturing challenges in drug/gene/cell therapies? | |
| CN206404046U (en) | A kind of device for preparing double-deck emulsion droplet | |
| CN109652359A (en) | A kind of preparation method of the cell 3D culture hydrogel microsphere based on aqueous two-phase drop | |
| Yamada et al. | Multiphase microfluidic processes to produce alginate-based microparticles and fibers | |
| CN103387691A (en) | Hollow polystyrene plastic spheres, and preparation method and application thereof | |
| CN103374141A (en) | Method for preparing faveolate polymer microsphere on basis of micro-fluidic chip | |
| Luo et al. | Structured microgels through microfluidic assembly and their biomedical applications | |
| Toprakcioglu et al. | Multi-scale microporous silica microcapsules from gas-in water-in oil emulsions | |
| Song et al. | Controlled formation of all-aqueous Janus droplets by liquid–liquid phase separation of an aqueous three-phase system | |
| Zhang et al. | Fast and environmentally friendly microfluidic technique for the fabrication of polymer microspheres | |
| Daradmare et al. | Recent progress in the synthesis of all-aqueous two-phase droplets using microfluidic approaches | |
| CN109988323B (en) | Method for rapidly preparing monodisperse polyvinyl alcohol microspheres at normal temperature | |
| Vladisavljević | Integrated membrane processes for the preparation of emulsions, particles and bubbles | |
| Litina et al. | A novel membrane emulsification technique for microencapsulation in self-healing concrete: development and proof of concept |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20161214 |
|
| RJ01 | Rejection of invention patent application after publication |