CN109701461A - A kind of preparation and its application of the calcium carbonate based on PEG/Dex aqueous two-phase/calcium alginate compounded micro-capsule - Google Patents
A kind of preparation and its application of the calcium carbonate based on PEG/Dex aqueous two-phase/calcium alginate compounded micro-capsule Download PDFInfo
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Abstract
The invention discloses a kind of calcium carbonate based on PEG/Dex aqueous two-phase/calcium alginate compounded micro-capsule preparations and its application.Using aqueous two-phase (glucan/polyethylene glycol) drop as template generation composite microcapsule.The composite microcapsule monodispersity is good, particle size can accuracy controlling from several microns to several millimeters.Micro-capsule is hollow structure, and cyst wall is bilayer, and wall thickness is controllable (account for about microcapsule diameter 1/50~1/4), and intracapsular side is fine and close calcium carbonate layer, is alginic acid calcium layer on the outside of capsule.Compared to simple sodium alginate microcapsule, which has good mechanical strength and fine and close cyst wall structure, avoids shearing force to the broken ring of cystoblast, it is suppressed that the leakage of content.The micro-capsule can construct the drug delivery system of hypotonic leakage, it can also be used to which preparation recycling is often, the holding time is long and is not easy the fixed enzyme vector being swollen.The present invention has expanded application of the sodium alginate microcapsule in the fields such as biological medicine, food service industry, household chemicals industry and enzyme engineering.
Description
Technical field
The invention belongs to the preparations and its application of new material technology field, especially high molecular microcapsule material.
Background technique
Micro-capsule is a kind of carrier material with core-shell structure, is widely used as encapsulation system, for protection activity substance, admittedly
Determine cell, immobilised enzymes and controlled release drug.Alginate is a kind of anion polysaccharide extracted from seaweed, is most by joyous
One of biocompatible materials met, in view of its abundant, nontoxic, non-immunogenicity, good biocompatibility and water solubility, because
This, alginate has been widely used for manufacture micro-capsule.At present production sodium alginate microcapsule frequently with mode have positive drop instillation,
Anti- drop instillation, microflow control technique and coetrusion etc..
Positive drop instillation be will sodium alginate soln instill crosslinking in calcium ions solution (Lin Y H, Liang H F,
Chung C K,et al.Physically crosslinked alginate/N,O-carboxymethyl chitosan
hydrogels with calcium for oral delivery of protein drugs[J].Biomaterials,
2005, 26(14):2105-2113.).However because sodium alginate soln is as drop, cystoblast thickness is difficult to control, and is easily formed
Calcium alginate solid microbeads are low so as to cause the waste of material and the amount of containing.Anti- drop instillation is will be by thickener (such as carboxylic
Methylcellulose) thickening after ionic calcium soln instill sodium alginate soln in crosslink (Jiang Z, Zhang Y, Jian
L,et al.Encapsulation ofβ-Glucuronidase in biomimetic alginate capsules for
bioconversion of baicalin to baicalein[J].European Physical Journal A,2007,45
(1):11-21.).But during micro-capsule generates, cystoblast is shunk, and is squeezed out core solution, is caused encapsulation rate low；And it is formed
Single sodium alginate microcapsule cyst wall is thicker, and network pore size is larger, easily leaks content.Sea is made using microflow control technique
Calcium alginate micro-capsule (Ren P W, Ju X J, Xie R, et al. Monodisperse alginate microcapsules
with oil core generated from a microfluidic device[J].Journal of Colloid&
Interface Science, 2010,343 (1): 392-395.), often using grease multiple emulsion as template, the device is complicated, operation
It is required that it is high, limit its application in the industrial production.Coetrusion is using coaxial bustle pipe arrangement, in nozzle end, inside stream
Body forms aqueous core, and external sodium alginate fluid surrounds core and forms core-shell structure, then instills in calcium chloride solution, leads to
Crossing calcium ion makes sodium alginate gel to form calcium alginate gel (Wang J Y, Jin Y, Xie R, et al.Novel
calcium-alginate capsules with aqueous core and thermo-responsive membrane.
[J].Journal of Colloid &Interface Science,2011,353(1):61-68.).However co-extrusion device
Complexity, microcapsule diameter and wall thickness adjusting are limited by coaxial bustle pipe arrangement size；And after drop is formed in device end, it is
It avoids cystoblast sodium alginate from diffusing into core, need to instill in acceptable solution rapidly, application range is limited.
Aqueous two-phase system is the aqueous medium composition of two kinds of incompatible polymers or a kind of polymer and a kind of salt, when
Its mass concentration ratio has been more than some threshold value to two kinds of solution at a certain temperature, and two kinds of solution of mixing can spontaneous split-phase.
V.Breguet etc. describes a kind of using casein and alginate as the method for aqueous two-phase production sodium alginate microcapsule
(XVth International Workshop on Bioencapsulation, Vienna, Au. Sept 6-8,2007.),
But it is by the way of coextrusion, disadvantage caused by the inevitable technology.
Sodium alginate microcapsule is widely used to drug delivery and fixation because of its fabulous biocompatibility in the prior art
Change zymophore, however due to its own physicochemical properties, there are bad mechanical strength, apertures for micro-capsule greatly, easy the disadvantages of being swollen, and leads
It is caused to contain object easy to leak when being used as pharmaceutical carrier, recycling batch is not high when being used as fixed enzyme vector, these problems one
Directly restrict extensive use of the sodium alginate microcapsule in the industry such as pharmacy and food.
In view of the defect of above-mentioned technology, the present invention is disclosed a kind of based on PEG/ using the bio-compatible interface of aqueous two-phase
Dex aqueous two-phase prepares calcium carbonate/calcium alginate compounded micro-capsule method and its application, provides new way to solve drawbacks described above
Diameter.
Summary of the invention
The purpose of the present invention prepares calcium carbonate/calcium alginate compounded micro-capsule by reacting a step using aqueous two-phase droplet interfaces
And its method is improved, make micro-capsule that there is good mechanical strength, biocompatibility avoids shearing force to the broken ring of content, suppression
The leakage of pharmacy object is conducive to drug delivery or package carrier；Micro-capsule size is controlled by control droplet size, control generates alginic acid
Calcium reaction and the i.e. controllable wall thickness of the speed for generating calcium carbonate reaction, structure and pattern.Another object of the present invention
It is to provide calcium carbonate/calcium alginate compounded micro-capsule application based on the preparation of PEG/Dex aqueous two-phase.
A kind of calcium carbonate/calcium alginate compounded micro-capsule based on the preparation of PEG/Dex aqueous two-phase, micro-capsule is hollow structure,
Cyst wall is inorganic/organic bilayer cyst wall structure, and the 1/50~1/4 of microcapsule diameter, intracapsular side is dense carbon for wall thickness control
Sour calcium layer, capsule outside are alginic acid calcium layer, and composite microcapsule monodispersity particle size can be from several microns of regulations to several millimeters.
The aqueous two-phase be by molecular weight 8kDa, 10~20wt% of mass percent concentration polyethylene glycol PEG solution and
Molecular weight 500kDa, 10~20wt% of mass percent concentration glucan Dex solution mix in equal volume after stand split-phase formed,
Upper phase is that polyethylene glycol is rich in phase, and lower phase is that glucan is rich in phase；Urea and calcium chloride are dissolved in glucan and are rich in phase, seaweed
Sour sodium and urase are dissolved in polyethylene glycol rich in phase.
The urea concentration is 0.005~0.03g/mL, calcium chloride concentration is 0.005~0.03g/mL, and sodium alginate is dense
Degree is 0.005~0.2g/mL and urase concentration is 0.002~0.004g/mL.
A method of calcium carbonate/calcium alginate compounded micro-capsule is prepared based on PEG/Dex aqueous two-phase, the specific steps are that:
Step 1: the preparation of polyethylene glycol-glucan aqueous two-phase:
(1) polyglycol solution of 10~20wt% is prepared, molecular weight 8kDa is denoted as solution A；
(2) dextran solution of 10~20wt% is prepared, molecular weight 500kDa is denoted as B solution；
(3) respectively take solution A and B solution same volume to be sufficiently mixed, stand split-phase 18~24 hours, extract respectively it is upper mutually and
Lower phase transfer is spare into two beakers, is denoted as C solution and solution D respectively.
Step 2: preparing calcium carbonate/calcium alginate compounded micro-capsule:
(4) E solution: weighing 0.05~2g sodium alginate and 0.02~0.04g urase, be added in the C solution of 10mL,
It is uniformly mixed, stands and be used as acceptable solution；
(5) F solution: weighing 0.01~0.06g anhydrous calcium chloride and 0.01~0.06g urea is dissolved in the solution D of 2mL
In, it is uniformly mixed, stands and be used as injection；
(6) preparing diameter using instillation is millimetre-sized composite microcapsule, draws F solution, set with commercially available 10mL syringe
Upper internal diameter is the syringe needle of 0.35~0.45mm, and syringe is maintained at away from 1~3cm of E liquid level of solution at, it is hanging vertically,
It is formed by pushing injector push-rod to instill F solution in E solution with every drop/5-10 seconds speed, after 15~30 minutes straight
Diameter is calcium carbonate/calcium alginate compounded micro-capsule of 2~7mm；
(7) preparing diameter using improved EFI method is micron-sized composite microcapsule, takes F solution that commercially available 10mL note is added
In emitter, syringe is put on syringe pump, and injector head silicone tube is connected with syringe needle, syringe needle internal diameter be 0.35~
0.45mm, for syringe needle perpendicular at away from 5~10cm of E liquid level of solution, adjusting syringe pump parameter feed speed is 20~60 μm/s, will be electric
Source anode is connected on syringe needle, and negative grade is connected to below acceptable solution beaker on masking foil, when the outflow of F solution, adjusts high pressure
Direct current power source voltage parameter is 17.03kV, enables the drop generated at syringe needle that surface tension to be overcome to spray into E solution, 15~30
Calcium carbonate/calcium alginate compounded micro-capsule that diameter is 1~10 μm is formed after minute.
A kind of calcium carbonate/calcium alginate compounded microballoon application based on the preparation of PEG/Dex aqueous two-phase, by controlling poly- second
Glycol PEG is rich in calcium chloride concentration in phase, controllable composite microcapsule wall thickness.
Further, it is prepared for containing calcium carbonate/calcium alginate compounded micro-capsule of rhodamine rhodamine B.
Further, calcium carbonate/calcium alginate compounded micro-capsule is prepared using improved electric jet technology one-step method.
Further, the calcium carbonate/calcium alginate compounded micro-capsule can be biological medicine, food service industry, cosmetics
The particle that hypotonic leakage is constructed in industry and enzyme engineering field contains object or drug particles transport system.
The positive effect of the present invention and remarkable advantage:
1, there is its unique inorganic/organic bilayer cyst wall structure, fine and close double-layer structure, intracapsular side is fine and close calcium carbonate
Layer, capsule outside are alginic acid calcium layer；Micro-capsule mechanical strength is good for this, be not easy to be swollen, percolation ratio is low, and it is excellent to can be used as macromolecular drug
Carrier；The drug delivery system of hypotonic leakage can be constructed, it can also be used to preparation be recycled often, the holding time it is long and less soluble
Swollen fixed enzyme vector.
2, pass through control droplet size, i.e., controllable micro-capsule size；Control generates calcium alginate reaction and generates carbonic acid
The i.e. controllable wall thickness of the speed of calcium reaction, structure and pattern, particle size can accuracy controlling from several microns to several millimeters.
3, by control polyethylene glycol PEG rich in calcium chloride concentration in phase, controllable composite microcapsule wall thickness；It is compound micro-
Capsule wall thickness is controllably accounting for the 1/50~1/4 of microcapsule diameter.
4, composite microcapsule is generated using improved one step of EFI method, equipment requirement is low, composite microcapsule monodispersity obtained
It is good；Can contain to construct the particle of hypotonic leakage in biological medicine, food service industry, cosmetic industry and enzyme engineering field object or
Drug particles transport system.
Detailed description of the invention
The unconverted ingredient of picture sample formulations of the following drawings is PEG mass percent concentration 16wt%, Dex mass
Percent concentration 16wt%, calcium alginate mass concentration 0.01g/mL, urase mass concentration 0.003g/mL, urea quality concentration
0.01g/mL and change ingredient be only calcium chloride mass concentration.
Fig. 1 is that aqueous two-phase droplet interfaces reaction generation calcium carbonate/calcium alginate compounded micro-capsule mechanism of the present invention is shown
It is intended to.
Fig. 2 a, Fig. 2 b are photos under calcium carbonate/calcium alginate compounded micro-capsule digital photograph and microscope；
Fig. 2 c, Fig. 2 d be composite microcapsule cut after digital photograph and microscope under photo.(calcium chloride concentration 0.01g/
mL)。
Fig. 3 a is calcium carbonate/calcium alginate compounded micro-capsule overall picture scanning electron microscope (SEM) photo, and Fig. 3 b is that partial enlargement shines
Piece；Fig. 3 c is the stereoscan photograph after micro-capsule is cut, and Fig. 3 d is partial enlargement photo；Micro-capsule diameter is 2.5mm, wall thickness
It is 50 μm.(calcium chloride concentration 0.01g/mL)
Fig. 4 a, Fig. 4 b, Fig. 4 c, Fig. 4 d, Fig. 4 e, Fig. 4 f were grown under calcium carbonate/calcium alginate compounded micro-capsule microscope
Journey photo, Fig. 4 a~Fig. 4 f are to be denoted as 0min since drop instills receiving liquid to lasting 25min, micro-capsule diameter is reacted to be
6mm, wall thickness 1.5mm.(calcium chloride concentration 0.03g/mL)
Fig. 5 a1, Fig. 5 a2, Fig. 5 a3, Fig. 5 a4 contain FITC-BSA (bovine serum albumin(BSA) of fluorescein isothiocynate grafting)
Calcium carbonate/calcium alginate compounded micro-capsule forming process in, the light field figure under fluorescence microscope, Fig. 5 a1~Fig. 5 a4；It is right therewith
The fluorogram answered, Fig. 5 b1~Fig. 5 b4；The stacking chart of light field figure and fluorogram, Fig. 5 a4 contain macro-molecular protein FITC-BSA
Calcium carbonate/calcium alginate compounded the micro-capsule of (bovine serum albumin(BSA) of fluorescein isothiocynate grafting, 66kDa), starts to instill note
For 0 moment, the light field figure under fluorescence microscope when reacting 30min, calcium chloride concentration 0.02g/mL.
Fluorescence microscope when calcium carbonate/calcium alginate compounded micro-capsule that Fig. 6 a1 contains FITC-BSA saves 0h in water
The light field figure of observation, calcium chloride concentration 0.02g/mL；Fig. 6 b1 is the corresponding fluorogram of Fig. 6 a1.
Calcium carbonate/calcium alginate compounded micro-capsule that Fig. 6 a2 contains FITC-BSA saves in deionized water fluorescence when for 24 hours
The light field figure of micro- sem observation, calcium chloride concentration 0.02g/mL；Fig. 6 b2 is the corresponding fluorogram of Fig. 6 a2.
Calcium carbonate/calcium alginate compounded micro-capsule that Fig. 6 a3 contains FITC-BSA saves fluorescence when 48h in deionized water
Light field figure under microscope, calcium chloride concentration 0.02g/mL；Fig. 6 b3 is the corresponding fluorogram of Fig. 6 a3.
Fig. 7 a1, Fig. 7 a2, Fig. 7 a3, Fig. 7 a4 and Fig. 7 b1, Fig. 7 b2, Fig. 7 b3, Fig. 7 b4 are to load small molecule compound sieve
Calcium carbonate/calcium alginate compounded micro-capsule Fig. 7 a1~Fig. 7 the a4 and calcium alginate microsphere Fig. 7 b1~figure of red bright B (molecular weight 480)
7b4 impregnates the digital photograph comparison of release conditions in deionized water, over time 0~30min.(calcium chloride concentration is
0.02g/mL)
Fig. 8 a1, Fig. 8 a2, Fig. 8 a3, Fig. 8 a4, Fig. 8 a5 and Fig. 8 b1, Fig. 8 b2, Fig. 8 b3, Fig. 8 b4, Fig. 8 b5 be calcium carbonate/
Calcium alginate compounded micro-capsule Fig. 8 a1~figure a5 and sodium alginate microcapsule Fig. 8 b1~Fig. 8 b5 immersion is swollen feelings in deionized water
The digital photograph of condition compares, and 0~9 day over time.(calcium chloride concentration 0.01g/mL)
Fig. 9 a1, Fig. 9 a2, Fig. 9 a3, Fig. 9 b1, Fig. 9 b2, Fig. 9 b3 are that calcium carbonate/calcium alginate compounded micro-capsule is immersed in pH
Sodium hydroxide solution Fig. 9 b1~Fig. 9 b3 of=3 hydrochloric acid solution Fig. 9 a1~Fig. 9 a3 and pH=11, over time 0~
For 24 hours, the digital photograph of composite microcapsule.(calcium chloride concentration 0.02g/mL)
The calcium carbonate of 1~5 μm of size made from Figure 10 EFI method/calcium alginate compounded micro-capsule microphoto.(calcium chloride is dense
Degree is 0.01g/mL)
Specific embodiment
It elaborates below in conjunction with attached drawing to a specific embodiment of the invention.
Embodiment 1
Fig. 1 is that aqueous two-phase droplet interfaces reaction of the present invention generates calcium carbonate/calcium alginate compounded micro-capsule mechanism, i.e.,
A kind of calcium carbonate/calcium alginate compounded micro-capsule and preparation method thereof based on the preparation of PEG/Dex aqueous two-phase the following steps are included:
1. configuring polyethylene glycol/glucan aqueous two-phase
(1) polyglycol solution of 16wt% is prepared, molecular weight 8kDa is denoted as solution A；
(2) dextran solution of 16wt% is prepared, molecular weight 500kDa is denoted as B solution；
(3) respectively take solution A and B solution same volume to be sufficiently mixed, stand split-phase 18~24 hours, extract respectively it is upper mutually and
Lower phase transfer is spare into two beakers, is denoted as C solution and solution D respectively.
2. preparing calcium carbonate/calcium alginate compounded micro-capsule
(4) E solution: weighing 0.108g sodium alginate and 0.03g urase, be added in the C solution of 10mL, is uniformly mixed,
It stands and is used as acceptable solution；
(5) F solution: weighing 0.02g anhydrous calcium chloride and 0.02g urea is dissolved in the solution D of 2mL, is uniformly mixed, quiet
It sets as injection；
(6) F solution is drawn with common commercially available 10mL syringe, puts on the syringe needle that internal diameter is 0.35mm, will injects
Device is maintained at away from 1~3cm of E liquid level of solution, and hanging vertical, promotion injector push-rod is by F solution with every/5~10 seconds speed of drop
Degree instills in E solution, and 15~30min is to form calcium carbonate/calcium alginate compounded micro-capsule that diameter is 2~4mm；
(7) digital camera takes pictures to composite microcapsule in (6), micro- as a result as shown in Fig. 2 a, Fig. 2 b, Fig. 2 c, Fig. 2 d
Capsule good sphericity, is core-shell structure, and cyst wall is relatively thin.Experimental result illustrates micro-capsule good sphericity, and particle diameter distribution is uniform, is hollow
Structure.
Embodiment 2
1. configuring polyethylene glycol/glucan aqueous two-phase
(1) polyglycol solution of 16wt% is prepared, molecular weight 8kDa is denoted as solution A；
(2) dextran solution of 16wt% is prepared, molecular weight 500kDa is denoted as B solution；
(3) respectively take solution A and B solution same volume to be sufficiently mixed, stand split-phase 18~24 hours, extract respectively it is upper mutually and
Lower phase transfer is spare into two beakers, is denoted as C solution and solution D respectively.
2. preparing calcium carbonate/calcium alginate compounded micro-capsule
(4) E solution: weighing 0.108g sodium alginate and 0.03g urase, be added in the C solution of 10mL, is uniformly mixed,
It stands and is used as acceptable solution；
(5) F solution: weighing 0.02g anhydrous calcium chloride and 0.02g urea is dissolved in the solution D of 2mL, is uniformly mixed, quiet
It sets as injection；
(6) F solution is drawn with common commercially available 10mL syringe, puts on the syringe needle that internal diameter is 0.35mm, will injects
Device is maintained at away from 1~3cm of E liquid level of solution, and hanging vertical, promotion injector push-rod is by F solution with every/5~10 seconds speed of drop
Degree instills in E solution, and 15~30min is to form calcium carbonate/calcium alginate compounded micro-capsule that diameter is 2~4mm；
(7) deionization cleans composite microcapsule 3 times, and composite microcapsule is put into culture dish, is freeze-dried；
(8) it is scanned Electronic Speculum to the composite microcapsule after freeze-drying in (7) to take pictures, as a result such as Fig. 3 a, 3b, 3c, 3d institute
Show, it is alginic acid calcium layer on the outside of capsule that micro-capsule diameter, which is 2.5mm, and wall thickness is 50 μm, and intracapsular side is fine and close calcium carbonate layer.
Experimental result corresponding diagram 3a~3d is the stereoscan photograph after composite microcapsule freeze-drying, and displaying micro-capsule diameter is 2.5mm,
Micro-capsule cystoblast is double-layer structure, is calcium alginate on the outside of capsule, and intracapsular side is fine and close calcium carbonate, relatively thin about 50 μm of cystoblast, accounts for micro-capsule
The 1/50 of diameter.
Embodiment 3
1. configuring polyethylene glycol/glucan aqueous two-phase
(1) polyglycol solution of 16wt% is prepared, molecular weight 8kDa is denoted as solution A；
(2) dextran solution of 16wt% is prepared, molecular weight 500kDa is denoted as B solution；
(3) respectively take solution A and B solution same volume to be sufficiently mixed, stand split-phase 18~24 hours, extract respectively it is upper mutually and
Lower phase transfer is spare into two beakers, is denoted as C solution and solution D respectively.
2. preparing calcium carbonate/calcium alginate compounded micro-capsule
(4) E solution: weighing 0.108g sodium alginate and 0.03g urase, be added in the C solution of 10mL, is uniformly mixed,
It stands and is used as acceptable solution；
(5) F solution: weighing 0.06g anhydrous calcium chloride and 0.02g urea is dissolved in the solution D of 2mL, is uniformly mixed, quiet
It sets as injection；
(6) F solution is drawn with common commercially available 10mL syringe, puts on the syringe needle that internal diameter is 0.35mm, will injects
Device is maintained at away from 1~3cm of E liquid level of solution, and hanging vertical, promotion injector push-rod is put into after F solution instillation E solution aobvious
Micro mirror is 0min with the moment, shoots the photo of composite microcapsule in a submicroscope every 5min, as a result such as Fig. 4 a, Fig. 4 b, figure
4c, Fig. 4 d, Fig. 4 e, shown in Fig. 4 f, micro-capsule diameter is 6mm, wall thickness 1.5mm.Illustrate that cystoblast generation is with aqueous two-phase liquid
Drop interface is template, and Fig. 4 (f) micro-capsule diameter is 6mm, and wall thickness 1.5mm accounts for the 1/4 of micro-capsule diameter, with Fig. 2 d and Fig. 3 d
Comparison, by control polyethylene glycol PEG rich in calcium chloride concentration (0.01~0.03g/mL) in phase, controllable composite microcapsule cyst wall
(wall thickness accounts for micro-capsule diameter to thickness: 1/50~1/4), illustrating that cystoblast thickness modification scope is wide.
Embodiment 4
1. configuring polyethylene glycol/glucan aqueous two-phase
(1) polyglycol solution of 16wt% is prepared, molecular weight 8kDa is denoted as solution A；
(2) dextran solution of 16wt% is prepared, molecular weight 500kDa is denoted as B solution；
(3) respectively take solution A and B solution same volume to be sufficiently mixed, stand split-phase 18~24 hours, extract respectively it is upper mutually and
Lower phase transfer is spare into two beakers, is denoted as C solution and solution D respectively.
2. calcium carbonate/calcium alginate compounded micro-capsule that preparation contains FITC-BSA
(4) E solution: weighing 0.108g sodium alginate and 0.03g urase, be added in the C solution of 10mL, is uniformly mixed,
It stands and is used as acceptable solution；
(5) F solution: the FITC-BSA for weighing 0.04g anhydrous calcium chloride, 0.02g urea and 0.004g is dissolved in the D of 2mL
It in solution, is uniformly mixed, stands and be used as injection；
(6) F solution is drawn with common commercially available 10mL syringe, puts on the syringe needle that internal diameter is 0.35mm, will injects
Device is maintained at away from 1~3cm of E liquid level of solution, hanging vertical, after pushing injector push-rod that F solution is instilled E solution, when with this
Carving is 0min, is taken pictures under fluorescence microscope to obtained calcium carbonate/calcium alginate compounded micro-capsule, such as Fig. 5 b1~Fig. 5 b4 institute
Show, fluorescence does not leak in composite microcapsule forming process；
(7) composite microcapsule is washed 3 times, is soaked in deionized water, as shown in Fig. 6 a1~Fig. 6 a3, FITC- in 48 hours
BSA does not leak out micro-capsule yet.
Embodiment 4 illustrates that composite microcapsule has good containment to protein matter.It is to contain macromolecular referring to Fig. 5 a1
The calcium carbonate of protein FITC-BSA (bovine serum albumin(BSA) of fluorescein isothiocynate grafting, 66kDa)/calcium alginate compounded micro-
Capsule, starting instillation was denoted as 0 moment, the light field figure under fluorescence microscope when reacting 3min, calcium chloride concentration 0.02g/mL；Figure
5b1 is the corresponding fluorogram of Fig. 5 a1.
Fig. 5 a2 contains calcium carbonate/calcium alginate compounded micro-capsule of FITC-BSA, starts instillation and was denoted as 0 moment, reacts
Light field figure under fluorescence microscope when 10min, calcium chloride concentration 0.02g/mL；Fig. 5 b2 is the corresponding fluorogram of Fig. 5 a2.
Fig. 5 a3 contains calcium carbonate/calcium alginate compounded micro-capsule of FITC-BSA, starts instillation and was denoted as 0 moment, reacts
Light field figure under the fluorescence microscope of 20min, calcium chloride concentration 0.02g/mL；Fig. 5 b3 is the corresponding fluorogram of Fig. 5 a3.
Fig. 5 a4 contains calcium carbonate/calcium alginate compounded micro-capsule of FITC-BSA, starts instillation and was denoted as 0 moment, reacts
Light field figure under the fluorescence microscope of 30min, calcium chloride concentration 0.02g/mL；Fig. 5 b4 is the corresponding fluorogram of Fig. 5 a4.
Fig. 5 a1~Fig. 5 a4 illustrates that in composite microcapsule forming process, FITC-BSA is not leaked, illustrates to prepare micro-capsule
Method be conducive to encapsulating of the composite microcapsule to protein, help to obtain the medicine carrying microcapsule compared with high encapsulation rate.
Fluorescence microscope when calcium carbonate/calcium alginate compounded micro-capsule that Fig. 6 a1 contains FITC-BSA saves 0h in water
The light field figure of observation, calcium chloride concentration 0.02g/mL；Fig. 6 b1 is the corresponding fluorogram of Fig. 6 a1.
Calcium carbonate/calcium alginate compounded micro-capsule that Fig. 6 a2 contains FITC-BSA saves in deionized water fluorescence when for 24 hours
The light field figure of micro- sem observation, calcium chloride concentration 0.02g/mL；Fig. 6 b2 is the corresponding fluorogram of Fig. 6 a2.
Calcium carbonate/calcium alginate compounded micro-capsule that Fig. 6 a3 contains FITC-BSA saves fluorescence when 48h in deionized water
Light field figure under microscope, calcium chloride concentration 0.02g/mL；Fig. 6 b3 is the corresponding fluorogram of Fig. 6 a3.Fig. 6 a1~Fig. 6 a3 exhibition
Show that the composite microcapsule impregnated in deionized water, the FITC-BSA that its internal layer contains in 48h do not occur obviously to leak, explanation
The double-layer structure of composite microcapsule can effectively prevent the leakage of protein.
Embodiment 5
Following example be it is a kind of based on PEG/Dex aqueous two-phase preparation calcium carbonate/calcium alginate compounded micro-capsule prepare
Using by control polyethylene glycol PEG rich in calcium chloride concentration in phase, controllable composite microcapsule wall thickness；It is prepared for containing
The calcium carbonate of rhodamine rhodamine B/calcium alginate compounded micro-capsule.Specific steps:
1. configuring polyethylene glycol/glucan aqueous two-phase
(1) polyglycol solution of 16wt% is prepared, molecular weight 8kDa is denoted as solution A；
(2) dextran solution of 16wt% is prepared, molecular weight 500kDa is denoted as B solution；
(3) respectively take solution A and B solution same volume to be sufficiently mixed, stand split-phase 18~24 hours, extract respectively it is upper mutually and
Lower phase transfer is spare into two beakers, is denoted as C solution and solution D respectively.
2. calcium carbonate/calcium alginate compounded micro-capsule that preparation contains rhodamine B
(4) E solution: weighing 0.108g sodium alginate and 0.03g urase, be added in the C solution of 10mL, is uniformly mixed,
It stands and is used as acceptable solution；
(5) F solution: weigh 0.04g anhydrous calcium chloride, 0.02g urea and 0.002g rhodamine B be dissolved in 2mL D it is molten
It in liquid, is uniformly mixed, stands and be used as injection；
(6) F solution is drawn with common commercially available 10mL syringe, puts on the syringe needle that internal diameter is 0.35mm, will injects
Device is maintained at away from 1~3cm of E liquid level of solution, and hanging vertical, promotion injector push-rod instills F solution in E solution, and 30min is
Form the calcium carbonate for containing rhodamine B/calcium alginate compounded micro-capsule that diameter is 2~4mm；
(7) it after the calcium carbonate/calcium alginate compounded micro-capsule washing 1 time for containing rhodamine B, is immersed in deionization, with this
Moment is 0min, shoots the photo of composite microcapsule in a submicroscope every 10min, as a result sieve as shown in Fig. 7 a1~Fig. 7 a4
Red bright B does not occur leaking on a large scale in 30min.
3. the calcium alginate microsphere that preparation contains rhodamine B
(8) it G solution: weighs 0.2g anhydrous calcium chloride and is added in the C solution of 10mL, after mixing set aside for use；
(9) H solution: weighing 0.108g sodium alginate, 0.002g rhodamine B is added in the solution D of 2mL, is uniformly mixed,
It is uniformly mixed, set aside for use；
(10) take H solution be added syringe needle internal diameter be 0.35mm syringe in, be vertically put in G liquid level of solution or more 1~
3cm, after pushing injector push-rod that H solution is instilled G solution, 30min is to form diameter to contain rhodamine B for 2~4mm
Calcium alginate microsphere.
(11) it after calcium alginate microsphere washing 1 time for containing rhodamine B, is immersed in deionization, is 0min with the moment,
The photo of composite microcapsule in a submicroscope is shot every 10min, as a result as shown in Fig. 7 b1~Fig. 7 b2, rhodamine B exists
There is obvious leakage phenomenon when 10min, when 30min leaks on a large scale.
Small molecule compound rhodamine in Fig. 7 a1~Fig. 7 a4 composite microcapsule impregnates 30min in deionized water and does not go out
Now apparent leakage, and there is obvious leakage in Fig. 7 b1~Fig. 7 b4 calcium alginate microsphere 10min, illustrates the bilayer of composite microcapsule
The shortcomings that structure effectively hinders the leakage of small molecule, overcomes calcium alginate microsphere encapsulating substance easy to leak.Fig. 7 a1~figure
The initial concentration of rhodamine is consistent in 7a4 micro-capsule and Fig. 7 b1~Fig. 7 b4 microballoon, but because being hollow aqueous core inside micro-capsule
The heart is closely knit gel core inside microballoon, so microballoon internal color is partially deep.
Embodiment 6
1. configuring polyethylene glycol/glucan aqueous two-phase
(1) polyglycol solution of 16wt% is prepared, molecular weight 8kDa is denoted as solution A；
(2) dextran solution of 16wt% is prepared, molecular weight 500kDa is denoted as B solution；
(3) respectively take solution A and B solution same volume to be sufficiently mixed, stand split-phase 18~24 hours, extract respectively it is upper mutually and
Lower phase transfer is spare into two beakers, is denoted as C solution and solution D respectively.
2. preparing calcium carbonate/calcium alginate compounded micro-capsule
(4) E solution: weighing 0.108g sodium alginate and 0.03g urase, be added in the C solution of 10mL, is uniformly mixed,
It stands and is used as acceptable solution；
(5) F solution: weighing 0.02g anhydrous calcium chloride and 0.02g urea is dissolved in the solution D of 2mL, is uniformly mixed, quiet
It sets as injection；
(6) F solution is drawn with common commercially available 10mL syringe, puts on the syringe needle that internal diameter is 0.35mm, will injects
Device is maintained at away from 1~3cm of E liquid level of solution, and hanging vertical, promotion injector push-rod is by F solution with every/5~10 seconds speed of drop
Degree instills in E solution, and 15~30min is to form calcium carbonate/calcium alginate compounded micro-capsule that diameter is 2~4mm；
(7) deionized water is washed composite microcapsule 3 times, is soaked in deionized water, with the moment for 0 day, every 1 day
It takes pictures to composite microcapsule, as a result as shown in Fig. 8 (a1)~(a5), after composite microcapsule saves 9 days in deionized water, pattern is still
It saves complete.
3. preparing sodium alginate microcapsule
(8) G solution: weighing 0.108g sodium alginate and be dissolved in the C solution of 10mL, is uniformly mixed, and stands as receiving
Liquid；
(9) H solution: weighing 0.02g anhydrous calcium chloride and be added in the solution D of 2mL, is uniformly mixed, and stands as injection
Liquid；
(10) H solution is drawn with common commercially available 10mL syringe, puts on the syringe needle that internal diameter is 0.35mm, will injects
Device is maintained at away from G liquid level of solution 1-3cm, and hanging vertical, promotion injector push-rod is by H solution with every/5~10 seconds speed of drop
Degree instills in G solution, and 15~30min is to form calcium carbonate/calcium alginate compounded micro-capsule that diameter is 2~4mm；
(11) deionized water is washed micro-capsule 3 times, is soaked in deionized water, right every 1 day with the moment for 0 day
Composite microcapsule is taken pictures, and as a result as shown in Fig. 8 (b1)~(b5), after saving 3 days, Swelling occurs in micro-capsule, and after 5 days, part is micro-
The rupture of capsule cystoblast, after 9 days, most of micro-capsule cystoblast rupture.
Contrast and experiment corresponding diagram 8a1~Fig. 8 a5, it is unchanged that composite microcapsule impregnates pattern in 9 days in deionized water,
And Fig. 8 b1~Fig. 8 b5 sodium alginate microcapsule, on day 1 when there is cystoblast and be obviously swollen, and often have rupture after 9 days greatly,
Illustrate that calcium carbonate/calcium alginate double-layer structure of composite microcapsule makes it be not easy to be swollen, the holding time is long in water, overcomes alginic acid
Calcium micro-capsule is easily swollen, and impregnates holding time short disadvantage in water.
Embodiment 7
1. configuring polyethylene glycol/glucan aqueous two-phase
(1) polyglycol solution of 16wt% is prepared, molecular weight 8kDa is denoted as solution A；
(2) dextran solution of 16wt% is prepared, molecular weight 500kDa is denoted as B solution；
(3) respectively take solution A and B solution same volume to be sufficiently mixed, stand split-phase 18~24 hours, extract respectively it is upper mutually and
Lower phase transfer is spare into two beakers, is denoted as C solution and solution D respectively.
2. preparing calcium carbonate/calcium alginate compounded micro-capsule
(4) E solution: weighing 0.108g sodium alginate and 0.03g urase, be added in the C solution of 10mL, is uniformly mixed,
It stands and is used as acceptable solution；
(5) F solution: weighing 0.02g anhydrous calcium chloride and 0.02g urea is dissolved in the solution D of 2mL, is uniformly mixed, quiet
It sets as injection；
(6) F solution is drawn with common commercially available 10mL syringe, puts on the syringe needle that internal diameter is 0.35mm, will injects
Device is maintained at away from 1~3cm of E liquid level of solution, and hanging vertical, promotion injector push-rod is by F solution with every/5~10 seconds speed of drop
Degree instills in E solution, and 15~30min is to form calcium carbonate/calcium alginate compounded micro-capsule that diameter is 2~4mm；
3. calcium carbonate/calcium alginate compounded micro-capsule is soaked in acid environment
(7) deionized water is washed composite microcapsule 3 times, is soaked in the hydrochloric acid solution of pH=3, is 0h with the moment,
Over time, take pictures to composite microcapsule, as a result as shown in Fig. 9 a1~Fig. 9 a3, for 24 hours after, composite microcapsule bleach, and cystoblast
It is still intact, illustrate intracapsular survey calcium carbonate layer completely by dissolving with hydrochloric acid；(8) compound after washing immersion hydrochloric acid solution
It micro-capsule 1 time, puts it into the sodium hydroxide solution of pH=11, is 0min with the moment, takes pictures every 1min to composite microcapsule,
As a result as shown in Fig. 9 (b1)~(b3), for 24 hours after, composite microcapsule pattern does not change.
Experimental result corresponding diagram 9a1~Fig. 9 a3, composite microcapsule are immersed in acid solution, although calcium carbonate cystoblast disappears in for 24 hours
It loses, but calcium alginate cystoblast still remains, Fig. 9 b1~Fig. 9 b3 composite microcapsule is immersed in aqueous slkali, for 24 hours interior calcium alginate
Although layer shows slightly swelling, calcium carbonate layer is still remained, and illustrates that the double-layer structure of sodium alginate microcapsule can provide encapsulation object
Duplicate protection.
Embodiment 8
1. configuring polyethylene glycol/glucan aqueous two-phase
(1) polyglycol solution of 16wt% is prepared, molecular weight 8kDa is denoted as solution A；
(2) dextran solution of 16wt% is prepared, molecular weight 500kDa is denoted as B solution；
(3) respectively take solution A and B solution same volume to be sufficiently mixed, stand split-phase 18~24 hours, extract respectively it is upper mutually and
Lower phase transfer is spare into two beakers, is denoted as C solution and solution D respectively.
2. improved electric jet technology prepares calcium carbonate/calcium alginate compounded micro-capsule
(4) E solution: weighing 0.108g sodium alginate and 0.03g urase, be added in the C solution of 10mL, is uniformly mixed,
It stands and is used as acceptable solution；
(5) F solution: weighing 0.02g anhydrous calcium chloride and 0.02g urea is dissolved in the solution D of 2mL, is uniformly mixed, quiet
It sets as injection；
(6) F solution is taken to be added in 10mL syringe, syringe is put in syringe pump, and (Baoding LanGe constant flow pump Co., Ltd is raw
Produce) on, injector head silicone tube is connected (syringe needle internal diameter is 0.35mm) with syringe needle, and syringe needle is perpendicular to away from E solution
At 5~10cm of liquid level, adjusting syringe pump parameter is 50 μm/s of feed speed, positive pole is connected on syringe needle, negative grade
It is connected to below acceptable solution beaker on masking foil, when the outflow of F solution, adjusts high-voltage DC power supply voltage parameter 17.03kV (east text
The production of high voltage power supply Tianjin joint-stock company), the drop of generation overcomes surface tension to spray into E solution, and 15~30min forms straight
Calcium carbonate/calcium alginate compounded micro-capsule that diameter is 1~10 μm.
(7) composite microcapsule is put into microscope, is taken pictures to composite microcapsule, the results are shown in Figure 10, and micro-capsule is spherical
It spends, having a size of 1~10 μm.
Experimental result corresponding diagram 10, Figure 10 are calcium carbonate/calcium alginates of 1~5 μm of size made from improved EFI method
Composite microcapsule microphoto, calcium chloride concentration 0.01g/mL；Figure 10 illustrates this compared with the figure of front grade composite microcapsule
Method can not only make millimetre-sized composite microcapsule, can also be made by EFI method using drop as template micron-sized compound micro-
Capsule, the micro-capsule size range for showing that this method generates are wide.
Claims (8)
1. a kind of calcium carbonate/calcium alginate compounded micro-capsule based on the preparation of PEG/Dex aqueous two-phase, which is characterized in that during micro-capsule is
Hollow structure, cyst wall are inorganic/organic bilayer cyst wall structure, and wall thickness control is the 1/50~1/4 of microcapsule diameter, intracapsular side
For fine and close calcium carbonate layer, capsule outside is alginic acid calcium layer, and composite microcapsule monodispersity particle size can regulate and control from several microns to several
Millimeter.
2. calcium carbonate according to claim 1/calcium alginate compounded micro-capsule, which is characterized in that the aqueous two-phase be by
The polyethylene glycol PEG solution and molecular weight 500kDa, mass percent of molecular weight 8kDa, 10~20wt% of mass percent concentration
The glucan Dex solution of 10~20wt% of concentration stands split-phase after mixing in equal volume and is formed, and upper phase is that polyethylene glycol is rich in phase, under
It is mutually that glucan is rich in phase；Urea and calcium chloride are dissolved in glucan rich in phase, and sodium alginate and urase are dissolved in poly- second two
Alcohol is rich in phase.
3. calcium carbonate according to claim 2/calcium alginate compounded micro-capsule, which is characterized in that the urea concentration is
0.005~0.03g/mL, calcium chloride concentration are 0.005~0.03g/mL, and sodium alginate concentration is 0.005~0.2g/mL and urea
Enzyme concentration is 0.002~0.004g/mL.
4. a kind of prepare calcium carbonate/calcium alginate compounded micro-capsule method based on PEG/Dex aqueous two-phase, which is characterized in that specific
Step are as follows:
Step 1: the preparation of polyethylene glycol-glucan aqueous two-phase:
(1) polyglycol solution of 10~20wt% is prepared, molecular weight 8kDa is denoted as solution A；
(2) dextran solution of 10~20wt% is prepared, molecular weight 500kDa is denoted as B solution；
(3) it respectively takes solution A and B solution same volume to be sufficiently mixed, stands split-phase 18~24 hours, extract upper and lower phase respectively
It is transferred to spare in two beakers, is denoted as C solution and solution D respectively.
Step 2: preparing calcium carbonate/calcium alginate compounded micro-capsule:
(4) E solution: weighing 0.05~2g sodium alginate and 0.02~0.04g urase, be added in the C solution of 10mL, and mixing is equal
It is even, it stands and is used as acceptable solution；
(5) F solution: weighing 0.01~0.06g anhydrous calcium chloride and 0.01~0.06g urea is dissolved in the solution D of 2mL, mixes
It closes uniformly, stands and be used as injection；
(6) preparing diameter using instillation is millimetre-sized composite microcapsule, draws F solution with commercially available 10mL syringe, is put on interior
Diameter is the syringe needle of 0.35~0.45mm, and syringe is maintained at away from 1~3cm of E liquid level of solution, vacantly vertically, is passed through
Injector push-rod is pushed to instill F solution in E solution with every drop/5-10 seconds speed, forming diameter after 15~30 minutes is 2
The calcium carbonate of~7mm/calcium alginate compounded micro-capsule；
(7) preparing diameter using improved EFI method is micron-sized composite microcapsule, takes F solution that commercially available 10mL syringe is added
In, syringe is put on syringe pump, and injector head silicone tube is connected with syringe needle, syringe needle internal diameter be 0.35~
0.45mm, for syringe needle perpendicular at away from 5~10cm of E liquid level of solution, adjusting syringe pump parameter feed speed is 20~60 μm/s, will be electric
Source anode is connected on syringe needle, and negative grade is connected to below acceptable solution beaker on masking foil, when the outflow of F solution, adjusts high pressure
Direct current power source voltage parameter is 17.03kV, enables the drop generated at syringe needle that surface tension to be overcome to spray into E solution, 15~30
Calcium carbonate/calcium alginate compounded micro-capsule that diameter is 1~10 μm is formed after minute.
5. a kind of calcium carbonate/calcium alginate compounded micro-capsule application based on the preparation of PEG/Dex aqueous two-phase, which is characterized in that logical
Control polyethylene glycol PEG is crossed rich in calcium chloride concentration in phase, controllable composite microcapsule wall thickness.
6. a kind of calcium carbonate/calcium alginate compounded microballoon application based on the preparation of PEG/Dex aqueous two-phase, which is characterized in that system
For the calcium carbonate/calcium alginate compounded micro-capsule for containing rhodamine rhodamine B.
7. a kind of calcium carbonate/calcium alginate compounded micro-capsule application based on the preparation of PEG/Dex aqueous two-phase, which is characterized in that benefit
Calcium carbonate/calcium alginate compounded micro-capsule is prepared with electric jet technology one-step method.
8. a kind of calcium carbonate/calcium alginate compounded micro-capsule application based on the preparation of PEG/Dex aqueous two-phase, which is characterized in that institute
Stating calcium carbonate/calcium alginate compounded micro-capsule can be structure in biological medicine, food service industry, cosmetic industry and enzyme engineering field
The particle for building hypotonic leakage contains object or drug particles transport system.
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