CN106110340B - A kind of method and device preparing target drug-carrying microbubble - Google Patents
A kind of method and device preparing target drug-carrying microbubble Download PDFInfo
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- CN106110340B CN106110340B CN201610546835.6A CN201610546835A CN106110340B CN 106110340 B CN106110340 B CN 106110340B CN 201610546835 A CN201610546835 A CN 201610546835A CN 106110340 B CN106110340 B CN 106110340B
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- phase
- acid
- microbubble
- oil
- phosphatide
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- 238000000034 method Methods 0.000 title claims abstract description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 27
- 239000003814 drug Substances 0.000 claims abstract description 23
- 238000002360 preparation method Methods 0.000 claims abstract description 17
- 238000010438 heat treatment Methods 0.000 claims abstract description 11
- 239000002872 contrast media Substances 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 5
- 230000002209 hydrophobic effect Effects 0.000 claims abstract description 5
- 238000007711 solidification Methods 0.000 claims abstract description 4
- 230000008023 solidification Effects 0.000 claims abstract description 4
- 239000002120 nanofilm Substances 0.000 claims abstract description 3
- 239000007789 gas Substances 0.000 claims description 43
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 claims description 36
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 claims description 28
- 239000005639 Lauric acid Substances 0.000 claims description 18
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims description 15
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 claims description 14
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 12
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 9
- 229940079593 drug Drugs 0.000 claims description 9
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 claims description 9
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 claims description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- 235000012000 cholesterol Nutrition 0.000 claims description 6
- 239000003921 oil Substances 0.000 claims description 6
- 230000002269 spontaneous effect Effects 0.000 claims description 6
- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 239000004615 ingredient Substances 0.000 claims description 4
- 239000004094 surface-active agent Substances 0.000 claims description 4
- 230000008685 targeting Effects 0.000 claims description 4
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 claims description 3
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 claims description 3
- LVNGJLRDBYCPGB-LDLOPFEMSA-N (R)-1,2-distearoylphosphatidylethanolamine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[NH3+])OC(=O)CCCCCCCCCCCCCCCCC LVNGJLRDBYCPGB-LDLOPFEMSA-N 0.000 claims description 2
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 claims description 2
- SLKDGVPOSSLUAI-PGUFJCEWSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine zwitterion Chemical group CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OCCN)OC(=O)CCCCCCCCCCCCCCC SLKDGVPOSSLUAI-PGUFJCEWSA-N 0.000 claims description 2
- WTBFLCSPLLEDEM-JIDRGYQWSA-N 1,2-dioleoyl-sn-glycero-3-phospho-L-serine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCC\C=C/CCCCCCCC WTBFLCSPLLEDEM-JIDRGYQWSA-N 0.000 claims description 2
- TWJNQYPJQDRXPH-UHFFFAOYSA-N 2-cyanobenzohydrazide Chemical compound NNC(=O)C1=CC=CC=C1C#N TWJNQYPJQDRXPH-UHFFFAOYSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- 235000021360 Myristic acid Nutrition 0.000 claims description 2
- TUNFSRHWOTWDNC-UHFFFAOYSA-N Myristic acid Natural products CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 claims description 2
- 101001000212 Rattus norvegicus Decorin Proteins 0.000 claims description 2
- 208000007536 Thrombosis Diseases 0.000 claims description 2
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims description 2
- 229940041181 antineoplastic drug Drugs 0.000 claims description 2
- 239000000470 constituent Substances 0.000 claims description 2
- 238000005520 cutting process Methods 0.000 claims description 2
- BIABMEZBCHDPBV-UHFFFAOYSA-N dipalmitoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCCCC BIABMEZBCHDPBV-UHFFFAOYSA-N 0.000 claims description 2
- FVJZSBGHRPJMMA-UHFFFAOYSA-N distearoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCCCCCC FVJZSBGHRPJMMA-UHFFFAOYSA-N 0.000 claims description 2
- 239000003527 fibrinolytic agent Substances 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 210000004209 hair Anatomy 0.000 claims description 2
- 239000002502 liposome Substances 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 239000006188 syrup Substances 0.000 claims description 2
- 235000020357 syrup Nutrition 0.000 claims description 2
- 229960000103 thrombolytic agent Drugs 0.000 claims description 2
- 210000005239 tubule Anatomy 0.000 claims description 2
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 claims 1
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 claims 1
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 claims 1
- FVJZSBGHRPJMMA-IOLBBIBUSA-N PG(18:0/18:0) Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@@H](O)CO)OC(=O)CCCCCCCCCCCCCCCCC FVJZSBGHRPJMMA-IOLBBIBUSA-N 0.000 claims 1
- 235000021314 Palmitic acid Nutrition 0.000 claims 1
- 125000001924 fatty-acyl group Chemical group 0.000 claims 1
- 239000000835 fiber Substances 0.000 claims 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 claims 1
- 150000008104 phosphatidylethanolamines Chemical class 0.000 claims 1
- 238000005538 encapsulation Methods 0.000 abstract description 4
- 239000012071 phase Substances 0.000 description 99
- 230000001681 protective effect Effects 0.000 description 11
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 8
- 238000002347 injection Methods 0.000 description 8
- 239000007924 injection Substances 0.000 description 8
- 238000010586 diagram Methods 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 239000011521 glass Substances 0.000 description 5
- 229940009456 adriamycin Drugs 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 150000004665 fatty acids Chemical class 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000000823 artificial membrane Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 238000011017 operating method Methods 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000010412 perfusion Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- LVNGJLRDBYCPGB-UHFFFAOYSA-N 1,2-distearoylphosphatidylethanolamine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(COP([O-])(=O)OCC[NH3+])OC(=O)CCCCCCCCCCCCCCCCC LVNGJLRDBYCPGB-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 244000270834 Myristica fragrans Species 0.000 description 1
- 235000009421 Myristica fragrans Nutrition 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000000889 atomisation Methods 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000002086 nanomaterial Substances 0.000 description 1
- 239000001702 nutmeg Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 238000001259 photo etching Methods 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 210000000998 shell membrane Anatomy 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010408 sweeping Methods 0.000 description 1
- 239000012780 transparent material Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/223—Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
-
- 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
- A61K9/5015—Organic compounds, e.g. fats, sugars
Abstract
A kind of method and device preparing target drug-carrying microbubble, the load medicine microbubble are the three-phase microbubbles by the gas phase kernel of microfluidic methods preparation, oily phase middle layer, shell for phosphatide and targeted molecular film layer；Its preparation process is: while heating to micro-fluidic chip and water, oil, gas three-phase, each leading into oily, gas and water to each channel and mutually prepares three-phase microbubble, the solidification that cools down again after the completion of preparation is collected, and wherein heating temperature is higher than oily phase fusing point；The oil is mutually the hydrophobic compound that fusing point is not less than 20 DEG C；Each access port of micro-fluidic chip clearance distance at the center of intersection be not higher than 10 μm, wherein gas phase, oily phase channel port at control at capillary dimensions.Method of the invention can effectively prepare that partial size is small, and encapsulation rate is complete, and the good three-phase of stability carries medicine micro air bubble ultrasonic contrast medium.
Description
Technical field
The present invention relates to a kind of methods for preparing target drug-carrying microbubble, are especially applicable in and prepare micro air bubble ultrasonic contrast medium
Method, and be applicable to the device of this method.
Background technique
The method for commonly preparing micro air bubble ultrasonic contrast medium has ultrasonic cavitation method, freeze-drying, coaxial electrostatic atomization
Method, high-shear emulsifying method etc..And microbubble size prepared by these methods is inhomogenous, partial size is uncontrollable, and can not resonate increasing
Strong ultrasonic imaging, and entrapment efficiency is not high, and stability is poor, and targeting is not also strong, can not prepare ideal target drug-carrying
Acoustic contrast agent.
Microfluidic chip technology has started the research prepared for micro Nano material in recent years, for applying microfluidic methods
The research for preparing micro air bubble ultrasonic contrast medium has also started to walk.Micro-fluidic chip refers to through technologies such as photoetching at several square centimeters
Glass or Polymer Surface portray the tens microscale experiment platforms that fluid control is used for several hundred microns of sized passageways.In miniflow
It controls in chip channel, after gas enters liquid flow with certain flow rate, under surface tension effects, gas stream can spontaneous disruption shape
At microbubble one by one.It is compared with the traditional method, for microflow control technique because being to prepare microbubble in continuous flow, preparation condition is equal
One is controllable, therefore microbubble obtained has the monodispersity and dimensional homogeneity of height.If drug is dissolved in oily phase, utilize
Water, oil, gas three-phase fluid microfluidic chip technology, then theoretically can by drug controllable encapsulation in the oil film of lipid microbubble,
The three-phase microbubble that phosphatide package carries medicine oil layer, kernel is gas is formed, guarantees good entrapment efficiency.
At present both at home and abroad generally using flow focusing type and built-in capillary T-type structure both common micro-fluidic chips
Microbubble is prepared, but prepared microbubble partial size is larger, while it is much lower compared with conventional method to prepare yield, leads to low efficiency
Under.Scale, integrated micro-fluidic chip can be relied on the basis of improving single micro-fluidic chip yield by improving yield
Group is realized, and preparing the more stable microbubble of nominal particle size, property is then that current microflow control technique preparation carries medicine microbubble institute
Facing challenges.Have been able to realize 5 μm or less seminars of microbubble of preparation and few using microfluidic chip technology at present,
Foreign countries mainly by sweeping along gas to prepare small particle microbubble by the nozzle of several microns of sizes in micro-fluidic chip, make in this way
Standby microbubble stability is poor and cannot be used for carrying medicine, while its special micro-fluidic chip nozzle needs the light of superhigh precision
Carve technology of preparing, expensive unsuitable volume production.Especially, microfluidic control Preparation Method is solving microbubble stability and is possessing use
In carry medicine oil reservoir structure the problems such as on there is no effective ways.
Summary of the invention
The purpose of the present invention is intended to provide a kind of good method for possessing three-phase and carrying medicine microbubble structure of stability.
The further object of the present invention, which also resides in, to be provided one kind and can effectively prepare that partial size is small, and encapsulation rate is complete, and stability
The good method for possessing three-phase and carrying medicine microbubble structure.
Another object of the present invention is intended to provide a kind of special device suitable for the above method.
The scheme of the invention is the load medicine microbubble is by the gas phase kernel of microfluidic methods preparation, oily phase middle layer, outer
Shell is the three-phase microbubble of phosphatide and targeted molecular film layer；Its preparation process is: to micro-fluidic chip and water, oil, gas three-phase
While heating, oily, gas and water is each led into each channel and mutually prepares three-phase microbubble, cool down solidification again after the completion of preparation
It collects, wherein heating temperature is higher than oily phase fusing point；The oil is mutually the hydrophobic compound that fusing point is not less than 20 DEG C；Micro-fluidic core
Each access port of piece clearance distance at the center of intersection be not higher than 10 μm, wherein gas phase, oily phase channel port at set
It is set to capillary dimensions.
The gas phase of micro-fluidic chip, the port in oil phase channel can directly be prepared into capillary dimensions, or in gas phase, oil
Trace interpolation is communicated equipped with capillary.
The inner passage of the micro-fluidic chip of the invention can be cross, rice font or other achievable systems
The shape of standby three-phase microbubble.
Being added in the oily phase has drug, phosphatide and targeted molecular ingredient, and water phase is cut at oil, gas and water three phase boundary
It cuts gas phase and mutually forms microbubble with oil,
Inventor is found surprisingly that the oil of above scheme, gas phase channel port are in intersection through the invention by research
Capillary dimensions controls and can solve the prior art to the control of micro-fluidic chip heating condition and the selection of oily phase at the heart
In perplex technical staff's three-phase microbubble stability problem always, to micro-fluidic chip heating process, oily phase is heated
It is played in cool down to the good stability action of three-phase microbubble.
Each access port of the preferred micro-fluidic chip of present invention clearance distance at the center of intersection is 1~10 μm of
The present invention is inserted into hair in two channels of cross micro-fluidic chip or so preferably in cross micro-fluidic chip respectively
At tubule to cross junction center, clearance distance of the port of two capillaries at the cross junction center is 1
~10 μm；The internal diameter of capillary is 1~20 μm, and capillary is tightly attached on cross micro-fluidic chip conduit wall；To cross micro-
While fluidic chip and water, oil, gas three-phase are heated, divide into the capillary in two channel of cross micro-fluidic chip or so
It is not passed through oily phase and gas phase, the Upper passage of cross micro-fluidic chip are then passed through continuous phase water phase；It is added in the oily phase
There are phosphatide and targeted molecular ingredient, water phase cuts gas phase at oily, gas and water three phase boundary and oil mutually forms microbubble, and oil phase is certainly
Give out a contract for a project and wraps up in gas phase and form film layer middle layer, phosphatide and targeted molecular is spontaneous is distributed in water-oil interface outer layer.
Preferred oil is mutually the hydrophobic compound that fusing point is not less than 30 DEG C in the solution of the present invention.It is of the present invention oil mutually into
One step is preferably 30-90 DEG C of molten point of hydrophobic compound.
Oil of the invention can be mutually fatty acid etc..
The phosphatide be dipalmitoylphosphatidylethanolamine DPPE, dipalmitoylphosphatidylcholine (DPPC), two oil
Acyl phospholipids acyl serine DOPS, distearoyl phosphatidylcholine DSPC, 1,2- palmityl phosphatidyl glycerol DPPG, distearyl
The PEGylated production of acyl phosphatidyl glycerol DSPG, dipalmitophosphatidic acid DPPA, distearoylphosphatidylethanolamine DSPE and phosphatide
One or more of object.
The oil is mutually preferably capric acid, lauric acid, myristic acid or palmitinic acid；Or in capric acid, lauric acid, nutmeg
Added with mass content for one of after 1%-20% phosphatide in acid, palmitinic acid；Or capric acid, lauric acid, myristic acid,
Add mass content for one of after 0.1%-10% cholesterol in palmitinic acid；Or capric acid, lauric acid, myristic acid,
Added simultaneously in palmitinic acid mass content be 0.1%-10% cholesterol and mass content be after 1%-20% phosphatide in one
Kind；One of or added simultaneously after the phosphatide of 1%-20% in capric acid, lauric acid, myristic acid, palmitinic acid；Or
Add that mass content is 0.1%-10% cholesterol and mass content is simultaneously in capric acid, lauric acid, myristic acid, palmitinic acid
One of after the phosphatide of 1%-20%.
For the oil mutually for carrying drug, the drug is thrombolytic agent and/or anti-tumor drug.
The gas phase is air, nitrogen, SF6 or C3F8.
Surfactant is added in the continuous phase water phase.The surfactant is polysorbas20, propylene glycol+sweet
Oil, PEG, PVA, glycerol+PVA, liposome, one or more of glucose syrup.
The targeted constituent is targeting thrombus molecule and target tumor molecule；
The temperature heated to cross micro-fluidic chip is 20~99 DEG C；Preferably 20~90 DEG C；The present invention is into one
Step is preferably 30~80 DEG C.
When being flowed out at the collection port that microbubble passes through cross micro-fluidic chip, it is cooled to -5~25 DEG C and carries out at solidification
Reason；Preferably -5~5 DEG C.
The flow velocity of currently preferred water phase is 1-1000 μ l/min.The flow velocity of preferred oil phase is 0.1-100 μ l/min.
The pressure of preferred gas phase is 0.1-50atm.
The flow velocity of the preferred water phase of the present invention is 50-100 μ l/min.The flow velocity of preferred oil phase is 1-10 μ l/
min.The pressure of preferred gas phase is 2-10atm.
The micro-fluidic chip that the present invention passes through setting capillary inner diameter.It is flat that it is inserted into port respectively in two channels of chip or so
Neat capillary, compact to intersect at cross junction center, two capillary exits are accurately controlled in 1-10 μm.Firstly, will dispersion
Mutually and continuous phase introduces cross cake core, wherein the oil phase and gas phase as dispersed phase are logical from chip left and right ends capillary respectively
Road is passed through, and continuous phase (water phase) is passed through from Upper passage.At three phase boundary, oil is mutually squeezed out from capillary with gas phase,
Under the action of surface tension, be initially formed the interface of oil and gas, when relative to the faster gas phase of Oil phase flow rate by water phase " cutting " formed
When bubble, the mutually spontaneous package gas phase of oil forms the bubble of oily packet gas.Wherein, the ingredient of oily phase can be fatty acid, in oily phase
Phosphatide is added, can be formed using phosphatide as nucleocapsid, oil mutually surrounds the three-phase microbubble of gas phase.Oil-soluble medicine is added in oily phase
The load medicine microbubble that encapsulation rate is complete, has phosphatide to protect as nucleocapsid can be made in object.Meanwhile if phosphatide being matched with corresponding
Body is combined the target drug-carrying function, it can be achieved that microbubble.Finally, microbubble is at collection port by flowing out, with ice cube by its
Cooling, is solidified, and the controllable stable microbubble of size uniformity is prepared.In this process, the present invention passes through heating temperature control
Liquefaction phase simultaneously cooperates phosphatide to spontaneously form stable monomolecular film in oil-water interfaces, after microbubble to be prepared is cooling, by solid
The oil phase and immobilized artificial membrane jointly stabilizing microbubble of change.
It is a kind of for the perseverance for preparing target drug-carrying micro air bubble ultrasonic contrast medium method the present invention also provides devising
Warm device, including constant temperature protective case, heater, temperature controller, Miniature injection pump；Constant temperature protective case includes support base, heater
Cover board, constant temperature protective case cover board；Support base bottom is equipped with heater, is covered with heater cover board above heater, chip is set
It sets on heater cover board；The heater is circumscribed with temperature controller；It is Miniature injection pump that upper layer one end of support base, which is equipped with, micro-
Type syringe pump is connected by silica gel perfusion tube with the channel in chip.
The Miniature injection pump includes water phase syringe pump, gaseous injection pump, oily phase syringe pump.
The thermostat, constant temperature protective case cover board correspond to and are set as transparent material at chip upper end position.
The thermostat is provided with multiple hollow apertures on the heater cover board.The aperture of hollow aperture can
It is set as 0.4-1cm.
There are a hollow cylinder, diameter 2.5cm, for laying in oily phase on heater cover board.Solid oil is mutually packed into injection
In device, after syringe be put on heater cover board in cylindrical hole be fixed.After placement, lid mounted device cover board, with
Guarantee heat insulation effect.
The silica gel perfusion tube of chip gas phase dispersion phase and water phase continuous phase is pierced by by cover board aperture, outside connection injection
Pump.Finally, covering organic glass cover board in the vacancy that constant temperature protective case cover board upper layer corresponds to chip, microbubble is facilitated look at
The condition of production and to carry out some simple chips mobile.
Detailed description of the invention
Fig. 1 is a kind of micro-fluidic chip floor map that the generation of medicine microbubble is carried for three-phase.Wherein a enters for continuous phase
Mouth and channel, b, c are dispersed phase entrance and channel, and d is two dispersed phase capillary interfaces, and e is microbubble channel and microbubble.
Fig. 2 is microbubble figure prepared by embodiment 1.
Fig. 3 is load medicine microbubble figure prepared by embodiment 1.
Fig. 4 is the microbubble preparation facilities system structure diagram that the present invention designs.Reactor, that is, constant temperature protection in figure
Set.
Fig. 5 is constant temperature protective case support base schematic diagram；The settable Miniature injection pump in left part upper layer in figure；Right part lower layer sets
It is equipped with heater.
Heater cover board is equipped with the schematic diagram of hollow cylinder in Fig. 6, and wherein hollow cylinder is for laying in oily phase.
Fig. 7 is the schematic diagram of heater cover board.
Fig. 8 is the schematic diagram of constant temperature protective case cover board, and a part of top surface can correspond to chip position, and be set as
Bright material.
Fig. 9 is the three-phase microbubble stability control that (a) is prepared with (b) under 60 degree of constant temperature under room temperature.
Figure 10 is to adjust the control of aqueous hydrocarbon condition to generate different size of microbubble.
Figure 11 is the various sizes of microbubble being collected into.
It is oily phase that Figure 12, which is respectively using capric acid, lauric acid, palmitinic acid, respectively in 40 DEG C of (a), 60 DEG C of (b), 70 DEG C of (c)
Under prepare microbubble.
Specific embodiment
Embodiment 1
Heater is put into constant temperature protective case support base bottom right end vacancy (as shown in Figure 4), heater connecting line
By being removed at right end square aperture, temperature controller is connected outside and is heated.Cover heater cover board (as shown in Figure 7).In perseverance
Warm protective case support base upper layer left end is put into miniature oily phase syringe pump, is fixed with screw.Micro-fluidic chip is put in
The heater cover board center of right end, by four biggish circular holes, is fixed with screw.By the lauric acid containing 5%DPPC
(44-46 DEG C of fusing point) is packed into micro glass bottle, then is placed in the heart cylinder of right end heater cover board overhead, at oily phase storage
It is attached with oily injection pump.After the completion of fixation, constant temperature protective case cover board (as shown in Figure 8), chip infusion silicone tube are covered
It is attached by being exported at cover board aperture with extraneous syringe pump.Cover the organic glass cover board of constant temperature protective case cover board.Glass
It is connected above plate with observation devices such as microscopes, constitutes entire microbubble preparation system (as shown in Figure 4).
Heating, is maintained at 60 DEG C or so for temperature, lauric acid is enable to be completely melt.The width and height of micro-fluidic chip are
It is 100 μm.Such as Fig. 2, it is passed through the aqueous solution containing 5%PEG at the channel chip a, it is logical by 20 μm of internal diameter capillary tubes at the channel chip b
Enter to contain the lauric acid of 5% phosphatide DPPC, is passed through air by 20 μm of internal diameter capillary tubes at the channel chip c.Wherein aqueous phase flow rate is
80 μ L/min, Oil phase flow rate are 0.5 μ L/min, and the air pressure being passed through is 2atm.In the nozzle of triple channel convergence, dissolved with phosphorus
For the oil of rouge mutually under surface tension effects power, spontaneous encirclement gas phase forms microbubble, and phosphatide occurs certainly between water phase and oily phase
At immobilized artificial membrane, to be obtained in three-phase junction super using phosphatide as the microbubble of the size uniformity comprising gas phase in shell membrane, oily phase
Sound contrast agent.Obtained microbubble is collected and by the capillary export of 100 μm of internal diameters with ice block cooling outside, make containing
The lauric acid of phosphatide solidifies in time, improves its stability.The microbubble of collection is taken pictures under microscope, as shown in Figure 2.Pass through
The size that the size of adjusting aqueous phase flow rate can change microbubble prepares micro- gas of 5 μm to 100 μm sizes as shown in Figure 10
Bubble (as shown in figure 11, bubble size is respectively 5 μm, 10 μm, 50 μm).
Embodiment 2
For other operating procedures with embodiment 1, bulk pharmaceutical chemicals are adriamycin.Method is that adriamycin is dissolved in oily mutually preparation to carry Ah mould
Plain microbubble.As shown in figure 3, the microbubble periphery for being loaded with adriamycin glows, and solution does not shine under green light excitation, card
Bright drug 100% is wrapped in the oil reservoir of microbubble.Also, oil film thickness is controlled by changing Oil phase flow rate, finds adriamycin
Corresponding change has occurred in fluorescence intensity, it was demonstrated that the preparation method has the ability of regulation microbubble drugloading rate.
Comparative example 1
Other operating procedures are that three-phase microbubble is prepared under room temperature with embodiment 1.
It is the micro- gas of three-phase prepared under room temperature by the three-phase microbubble prepared under 60 degree of constant temperature of embodiment 1 and comparative example 1
Bubble stability is compared.As shown in figure 9, significant component of microbubble has been not present after the placement of Fig. 9 (a) 24 hours,
And Fig. 9 (b) place 24 hours or even 18 days after still without disappearance, be stabilized.Preparation temperature is made more than after oily phase fusing point
Standby three-phase microbubble stability greatly improves.
Inventor configures the raw material of different gas phases, water phase, oily phase by means of the present invention, can successfully prepare at present
The microbubble of stable storage 20 days at normal temperature (as shown in figure 12, bubble standing time is respectively 1 minute, 1 day, 20 days).Make
When using the fatty acid of different melting points as oily phase, heating temperature is different.Capric acid (32 DEG C of fusing point) is used respectively, lauric acid (fusing point
44~46 DEG C), palmitinic acid (63 DEG C of fusing point) is oily phase, prepares microbubble at 40 DEG C, 60 DEG C, 70 DEG C respectively.(such as Figure 12,
(a), (b), (c) are shown).
Claims (8)
1. a kind of method for preparing target drug-carrying micro air bubble ultrasonic contrast medium, which is characterized in that the load medicine microbubble is by miniflow
The gas phase kernel of prosecutor method preparation, oily phase middle layer, the three-phase microbubble that shell is phosphatide and targeted molecular film layer；It is prepared
Process is: is inserted at capillary to cross junction center respectively in two channels of cross micro-fluidic chip or so, two hairs
Clearance distance of the port of tubule at the cross junction center is 1~10 μm；The internal diameter of capillary is 1~20 μm,
Capillary is tightly attached on cross micro-fluidic chip conduit wall；Cross micro-fluidic chip and water, oil, gas three-phase are heated
While, oily phase and gas phase are each led into the capillary in two channel of cross micro-fluidic chip or so, it is cross micro-fluidic
The Upper passage of chip is then passed through continuous phase water phase；Being added in the oily phase has drug, phosphatide and targeted molecular ingredient,
Water phase cutting gas phase mutually forms microbubble with oil at oil, gas and water three phase boundary, and the mutually spontaneous package gas phase of oil is formed among film layer
Layer, phosphatide and targeted molecular is spontaneous is distributed in water-oil interface outer layer；The solidification that cools down again after the completion of preparation is collected；Wherein heating temperature
Higher than oily phase fusing point, the oil is mutually the hydrophobic compound that fusing point is not less than 20 DEG C.
2. the method according to claim 1, wherein the phosphatide is dipalmitoylphosphatidylethanolamine
DPPE, dipalmitoylphosphatidylcholine DPPC, di-oleoyl phosphatidylserine DOPS, distearoyl phosphatidylcholine
DSPC, 1,2- palmityl phosphatidyl glycerol DPPG, distearoylphosphatidylglycerol DSPG, dipalmitophosphatidic acid DPPA, two are firmly
One or more of fatty acyl group phosphatidyl-ethanolamine DSPE and the PEGylated product of phosphatide.
3. the method according to claim 1, wherein the oil is mutually capric acid, lauric acid, myristic acid or palm fibre
Palmitic acid acid；Or in capric acid, lauric acid, myristic acid, palmitinic acid added with mass content be 1%-20% phosphatide after one of；Or
It is to add mass content for one of after 0.1%-10% cholesterol in capric acid, lauric acid, myristic acid, palmitinic acid；Or
Capric acid, myristic acid, has added that mass content is 0.1%-10% cholesterol and mass content is 1%- in palmitinic acid at lauric acid simultaneously
One of after 20% phosphatide；Or after the phosphatide that capric acid, lauric acid, myristic acid, palmitinic acid have added 1%-20% in one
Kind；Or mass content has been added to be 0.1%-10% cholesterol and quality simultaneously in capric acid, lauric acid, myristic acid, palmitinic acid
Content is one of after the phosphatide of 1%-20%.
4. the drug is the method according to claim 1, wherein the oil is mutually for carrying drug
Thrombolytic agent and/or anti-tumor drug；The gas phase is air, nitrogen, SF6 or C3F8.
5. the method according to claim 1, wherein in the water phase be added with surfactant, it is described
Surfactant is polysorbas20, propylene glycol+glycerol, PEG, PVA, glycerol+PVA, liposome, one of glucose syrup or several
Kind.
6. the method according to claim 1, wherein the targeted constituent is that targeting thrombus molecule and targeting are swollen
Oncocyte molecule.
7. the method according to claim 1, wherein being 20~99 to the temperature of cross micro-fluidic chip heating
DEG C, the temperature for the collection that cools down is -5~25 DEG C.
8. the method according to claim 1, wherein the flow velocity of water phase is 1-100 μ l/min, the flow velocity of oily phase
For 0.1-10 μ l/min, the pressure of gas phase is 0.1-10atm.
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Citations (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998051284A1 (en) * | 1997-05-13 | 1998-11-19 | Imarx Pharmaceutical Corp. | Novel acoustically active drug delivery systems |
| WO2011017524A1 (en) * | 2009-08-05 | 2011-02-10 | The Trustees Of The University Of Pennsylvania | Microfluidic-based generation of functionalized microbubbles for ultrasound imaging and therapy |
| CN102008983A (en) * | 2010-11-01 | 2011-04-13 | 武汉大学 | Microfluidic chip suitable for producing microcapsules |
| CN102373153A (en) * | 2010-08-18 | 2012-03-14 | 国家纳米科学中心 | Bubble removing device used for microfluidic channel |
| CN102573797A (en) * | 2009-07-17 | 2012-07-11 | 国家科学研究中心 | Emulsion activatable by ultrasounds and method for producing same |
| CN102974411A (en) * | 2012-11-22 | 2013-03-20 | 清华大学 | Microfluidic device and method for preparing monodispersed bubble covered with liquid film by utilizing same |
| WO2013141695A1 (en) * | 2012-03-22 | 2013-09-26 | Universiteit Twente | Apparatus and method for mass producing a monodisperse microbubble agent |
| CN103386333A (en) * | 2013-08-07 | 2013-11-13 | 苏州扬清芯片科技有限公司 | Micro-fluidic liquid drop production chip |
| CN103386336A (en) * | 2013-08-07 | 2013-11-13 | 苏州扬清芯片科技有限公司 | Microfluidic chip for producing droplets with concentration gradients |
| CN103816881A (en) * | 2014-03-10 | 2014-05-28 | 厦门大学 | Method for preparing controllable chromatographic packing with uniform particle size based on droplet microfluidic technology |
| CN104549585A (en) * | 2014-12-31 | 2015-04-29 | 国家纳米科学中心 | Micro-fluidic chip and method for preparing nanocapusule by using same |
| WO2015196065A1 (en) * | 2014-06-19 | 2015-12-23 | The Trustees Of The University Of Pennsylvania | Apparatus and methods for making recombinant protein-stabilized monodisperse microbubbles |
| CN105535999A (en) * | 2016-01-11 | 2016-05-04 | 中国科学院化学研究所 | Intelligent magnetic single-hole hollow nanosphere and preparation method and application thereof |
| CN105688721A (en) * | 2016-01-06 | 2016-06-22 | 中国计量学院 | Micro-fluidic chip for generating spherical microbubbles |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101520443B1 (en) * | 2013-11-06 | 2015-05-14 | 서울대학교산학협력단 | Preparation method of organic mircro-bubble complex particle, organic mircro-bubble complex particle, and ultrasound contrast agent |
-
2016
- 2016-07-12 CN CN201610546835.6A patent/CN106110340B/en active Active
Patent Citations (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998051284A1 (en) * | 1997-05-13 | 1998-11-19 | Imarx Pharmaceutical Corp. | Novel acoustically active drug delivery systems |
| CN102573797A (en) * | 2009-07-17 | 2012-07-11 | 国家科学研究中心 | Emulsion activatable by ultrasounds and method for producing same |
| WO2011017524A1 (en) * | 2009-08-05 | 2011-02-10 | The Trustees Of The University Of Pennsylvania | Microfluidic-based generation of functionalized microbubbles for ultrasound imaging and therapy |
| CN102373153A (en) * | 2010-08-18 | 2012-03-14 | 国家纳米科学中心 | Bubble removing device used for microfluidic channel |
| CN102008983A (en) * | 2010-11-01 | 2011-04-13 | 武汉大学 | Microfluidic chip suitable for producing microcapsules |
| WO2013141695A1 (en) * | 2012-03-22 | 2013-09-26 | Universiteit Twente | Apparatus and method for mass producing a monodisperse microbubble agent |
| CN102974411A (en) * | 2012-11-22 | 2013-03-20 | 清华大学 | Microfluidic device and method for preparing monodispersed bubble covered with liquid film by utilizing same |
| CN103386333A (en) * | 2013-08-07 | 2013-11-13 | 苏州扬清芯片科技有限公司 | Micro-fluidic liquid drop production chip |
| CN103386336A (en) * | 2013-08-07 | 2013-11-13 | 苏州扬清芯片科技有限公司 | Microfluidic chip for producing droplets with concentration gradients |
| CN103816881A (en) * | 2014-03-10 | 2014-05-28 | 厦门大学 | Method for preparing controllable chromatographic packing with uniform particle size based on droplet microfluidic technology |
| WO2015196065A1 (en) * | 2014-06-19 | 2015-12-23 | The Trustees Of The University Of Pennsylvania | Apparatus and methods for making recombinant protein-stabilized monodisperse microbubbles |
| CN104549585A (en) * | 2014-12-31 | 2015-04-29 | 国家纳米科学中心 | Micro-fluidic chip and method for preparing nanocapusule by using same |
| CN105688721A (en) * | 2016-01-06 | 2016-06-22 | 中国计量学院 | Micro-fluidic chip for generating spherical microbubbles |
| CN105535999A (en) * | 2016-01-11 | 2016-05-04 | 中国科学院化学研究所 | Intelligent magnetic single-hole hollow nanosphere and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| Controllable Microfluidic Synthesis of Multiphase Drug-Carrying Lipospheres for Site-Targeted Therapy;Kanaka Hettiarachchi et al;《Biotechnol. Prog》;20090519;第25卷(第4期);摘要，第940"lipid materials and preparation",figure2;第942页"structure visualization"小节，figure3，第939页左栏第3段 |
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