CN107049987A - A kind of preparation method of the double structure nano-particle with multiple response - Google Patents
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- 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
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Abstract
The invention discloses a kind of preparation method of the double structure nano-particle of multiple response, pH sensitive cyclodextrine derivatives and double bond containing natural macromolecular are synthesized first.The present invention prepares double bond containing gelatin using gelatin as model.First the sensitive cyclodextrine derivatives of pH are dissolved in dichloromethane using double emulsion methods；GM is dissolved in PVA (polyvinyl alcohol)/PBS (pH=7.5) solution again, while adding ammonium persulfate initiator.Above-mentioned two solution is mixed by different proportion, Ultrasonic Pulverization formation water-in-oil emulsion.Add PVA/PBS solution, Ultrasonic Pulverization formation oil-in-water emulsion, and be added into the PVA solution of the reducing agent containing tetramethylethylenediamine, organic solvent, which fully evaporates, forms the cyclodextrin nano particle with pH sensitivity characteristics, and the gelatin solution for being wrapped in inside particles triggers double-bond polymerization formation nanogel structure in the presence of redox initiator.It is freeze-dried with after the multiple centrifuge washing of alkaline water, obtains the double structure nano-particle with multiple response.
Description
Technical field
The invention belongs to new material technology field, and in particular to a kind of preparation of the nano-particle of double structure.
Background technology
Nano-particle due to its big specific surface area, flexible operating characteristic and enjoy favor.But single structure is received
Rice corpuscles often only has single function, it is impossible to meet the multi-functional demand of nano-carrier.The invention provides one kind is multiple
The double structure nano-particle of response meets many demands of carrier material.
PH sensitivity cyclodextrin is a kind of a kind of cyclodextrine derivatives with the pH characteristics responded occurred recently, due to it
PH responses, good biocompatibility, as the new of controlled drug delivery system particularly medicine controlled releasing micro-/ nano particles fields
Dote on.And the preparation of the sensitive cyclodextrin nano-particles of pH is to continue to use the side originally with oil-soluble polylactic acid nano nano-particle
Solvent, the temperature of environment, the species of stabilizer and the stir speed (S.S.) used in method, and preparation process finally can influence to prepare
The various aspects of performance of obtained particle.It is the most frequently used in numerous preparation methods that emulsification-evaporation method, which prepares polymer particle,
A kind of method.Its prepare general process be：Using emulsification method by the organic phase that solution has polymer be distributed to containing point
Emulsion is formed in the continuous phase of powder or emulsifying agent, after the organic solvent in emulsion droplet volatilizees, the polymerization solidified
A kind of method of thing particle.It is divided into two kinds of aqueous phase and oil phase according to the different this methods of continuous facies type used, when aqueous phase is
During continuous phase, single emulsion and double classes of emulsion emulsifiers-solvent evaporation method two can be divided into again.
Single emulsion (O/W) method：In this approach, the oil phase of polymer is dissolved with first in the aqueous phase containing dispersant
It is emulsified to form emulsion, afterwards, due to the volatilization of organic solvent in emulsion droplet, makes the emulsion droplet dissolved with polymer slowly solid
Change, diminish, eventually become the polymer micron or nano-particle for being embedded with medicine, this method applies in general to oil-soluble medicine
The embedding of thing.
Double emulsion (W/O/W) methods：By single emulsion method, further development is obtained this method for preparing polymer particle,
Profit can realize the bag of water soluble drug or protein and other in polymer micron/nano particle in this way
Bury.Its basic process is that medicine or large biological molecule are dissolved in the water to form interior aqueous phase first, and polymer is dissolved in organic solvent
Middle formation oil phase, both are mixed, emulsification is formed after colostrum (W/O), and colostrum is poured into rapidly in the water containing dispersant to (outer water
Phase), by emulsifying, disperseing again, lasting stirring is finally utilized, it is ensured that the stabilization of emulsion and promotion solvent volatilization, so that solid
Change forms polymer micron/nano particle.
On the other hand, another three-dimensional netted Hydrogels nano material (nanogel) is due to in analogue body
Physiological environment, the various diaphragms for being easily phagocytized by cells, penetrating readily through in human body, also progress into the advantages of carrier medicine carrying efficiency is high
The visual field of researcher.But preparing nanogel by natural polysaccharide and protein also has low intensity, easily by internal enzyme drop
Solve, be difficult to be stabilized.
It is an object of the invention to overcome the shortcomings of above two nano-carrier, therefore, a kind of method preparation pH is found quick
Sense and the composite carrier of nanogel, make nano-particle while having pH sensitive and gel bionical characteristic, while making load
Body material has multiple or Multilevel Response characteristic, and the preparation for NEW TYPE OF COMPOSITE carrier material has great significance.This hair
It is bright to intend combining the preparation that double emulsion methods realize composite nanoparticle with radical polymerization in situ.
Another object of the present invention is to provide a kind of preparation method of composite nano materials.
The content of the invention
It is an object of the invention to provide a kind of preparation method of composite nano materials, to prepare, a kind of pH is sensitive and nanometer
The composite carrier of gel, makes nano-particle while having pH sensitive and gel bionical characteristic, while having carrier material
There is multiple or Multilevel Response characteristic.The present invention combines the system that double emulsion methods realize composite nanoparticle with radical polymerization in situ
It is standby.
The technical scheme is that：
The present invention by acetalation by obtaining the cyclodextrin with pH sensitivity characteristics (see number of patent application：
2010101817859), have by preparing to contain using emulsion volatility process by emulsifying agent of the large biological molecule with parents' group
The cyclodextrin nano particle of pH sensitivity characteristics.
The purpose of the present invention is realized through the following steps：
Step 1：The preparation of material：
I has the cyclodextrin of pH sensitivity characteristics (see number of patent application：2010101817859)
The synthesis (GM) of the double bond containing natural macromoleculars of ii
Using gelatin as model, the gelatin of preparation double bond, specific method reference (Hu little Hong, repair of cartilage hydrogel
Preparing and performance study, Zhejiang University's thesis for the doctorate, 2009) specific method is as follows：Acrylic acid (AA) is grafted to gelatin point
GM is obtained in subchain.Weigh gelatin 1g to be placed in 250mL conical flasks, add after 100mL tri-distilled waters heating for dissolving, add 800 μ
L (8.7mmol) AA, then adds the water miscible carbodiimides of 400mg (EDC), then at room temperature, stirring reaction 8h.For
Unreacted MA and other small molecule products are removed, mixed liquor cutoff is inserted into in 10,000Da bag filters, big
Tri-distilled water and the 3d that dialyses at room temperature are measured, 2~3 tri-distilled waters are changed daily.Finally this liquid is freezed, freezed, MA grafting is obtained
Chitosan (GM).
Step 2：The preparation of multiple response composite nanoparticle
Cyclodextrin/dichloromethane solution will be formed in the sensitive cyclodextrine derivatives dissolving dichloromethane of certain mass pH, its
It is preferred that concentration be 1%-20% (w/v), further concentration is 5%-15% (w/v), and optimal concentration is 9%-11% (w/
v).A certain amount of GM is dissolved in 1%PVA (polyvinyl alcohol)/PBS (pH=7.5) solution, its preferred concentration is 1%-25%
(w/v), further concentration is 10%-20% (w/v), and optimal concentration is 15%-20% (w/v), adds 0.05%w/v over cures
Sour ammonium (initiator).Above-mentioned solution is pressed into different water (GM solution)：Oily (cyclodextrin/dichloromethane) is than mixing, water preferably
Oil is than being 1：2-1：15, it is further 1：5-1：10, it is optimal for 1：10, crush 2min, shape with sealing ice-bath ultrasonic after mixing
Into water-in-oil emulsion.
Above-mentioned solution is added into finite concentration and PVA (polyvinyl alcohol)/PBS (pH=7.5) solution of volume, its is preferred
Concentration be 0.1%-10% (w/v), further concentration is 0.1%-1% (w/v), and optimal concentration is 0.8%-1.0% (w/
v)；It is preferred that water-oil factor be 2：1-20：1, it is further 5：1-15：1, it is optimal for 6:1；Seal supersonic cell and crush 3min
The second phase oil-in-water emulsion is formed, the tetramethyl that certain volume 0.3% (w/v) PVA/PBS (pH=7.5) contains 0.05% is subsequently added into
Base ethylenediamine (reducing agent) solution obtains whole emulsion emulsion；It is preferred that the second phase emulsion and PVA solution ratio be 2：1-1：10, enter one
Walk as 1：1-1：5, it is optimal for 1：2-1：3；10h is stirred under magnetic stirring apparatus 1300r/min at a certain temperature, allows organic molten
The cyclodextrin nano particle to form pH sensitivity characteristics is fully evaporated in agent, while the gelatin solution for being wrapped in inside particles is gone back in oxidation
Trigger double-bond polymerization formation nanogel structure under the left and right of former initiator；It is preferred that temperature 0-60 degree, further 20-50 degree,
Optimal 30-40 degree.Then liquid is centrifuged into (10000r/min) 10min, obtains sediment, wash many with alkaline water again afterwards
It is secondary, centrifugation, except emulsion breaker.
The present invention has the advantages that：
1st, the characteristic of the enzyme response of the composite nanoparticle prepared by the present invention；Nano-particle prepared by the present invention is in pH
(specific manifestation is quickly dissolved in the aqueous solution less than 6：Nanoparticle dispersion liquid becomes clear solution by white emulsion), after dissolving
The hydration radius of nanogel can be still detected by DLS, nanogel was in the presence of lysozyme, in the time of 3 days
It is interior quick
2nd, the presence that nano-particle prepared in the solution that ph is more than 7 can be stablized.
Brief description of the drawings
Fig. 1 a are the scanning electron microscope (SEM) photographs of the composite nanoparticle prepared by embodiment 1；
Fig. 1 c are the transmission electron microscope pictures of the composite nanoparticle prepared by embodiment 1；
Fig. 1 b are the scanning electron microscope (SEM) photographs of the composite nanoparticle prepared by embodiment 2；
Fig. 1 d are the transmission electron microscope pictures of the composite nanoparticle prepared by embodiment 2；
Embodiment
Below in conjunction with drawings and the specific embodiments, the present invention will be further described, but following embodiments are not to the present invention
Protection domain limitation.
Embodiment 1
Cyclodextrin/dichloromethane solution will be formed in the sensitive cyclodextrine derivatives dissolving dichloromethane of certain mass pH, it is dense
Spend for 10% (w/v) 1mL；A certain amount of GM is dissolved in 1%PVA (polyvinyl alcohol)/PBS (pH=7.5) solution, over cure is added
Sour ammonium (initiator), final GM concentration is 20% (w/v), and ammonium persulfate concentrations are 0.05%w/v, and volume is 0.1mL；Two solution
After mixing, sealing ice-bath ultrasonic crushes 2min；This solution is added into 6mL 1%PVA/PBS (pH=7.5) solution again, sealing is super
Sound wave cell pulverization 3min forms second layer emulsion, then 20mL 0.3% (w/v) PVA/PBS (pH=7.5) solution, this solution
In contain 0.05% tetramethylethylenediamine (reducing agent), obtain mixed emulsion, stirring under 20 degree lower magnetic stirring apparatus 1300r/min
10h, allows organic solvent fully to evaporate the composite nanoparticle to form the double structure with multiple response.Then liquid is centrifuged
(10000r/min) 10min, obtains sediment, is washed, centrifuged with alkaline water again afterwards, except emulsion breaker, this process repeatedly 5
It is secondary.
Embodiment 2
Cyclodextrin/dichloromethane solution will be formed in the sensitive cyclodextrine derivatives dissolving dichloromethane of certain mass pH, it is dense
Spend for 10% (w/v) 1mL；A certain amount of GM is dissolved in 1%PVA (polyvinyl alcohol)/PBS (pH=7.5) solution, over cure is added
Sour ammonium (initiator), final GM concentration is 20% (w/v), and ammonium persulfate concentrations are 0.05%w/v, and volume is 0.1mL；Two solution
After mixing, sealing ice-bath ultrasonic crushes 2min；This solution is added into 6mL 1%PVA/PBS (pH=7.5) solution again, sealing is super
Sound wave cell pulverization 3min forms second layer emulsion, then 20mL 0.3% (w/v) PVA/PBS (pH=7.5) solution, this solution
In contain 0.05% tetramethylethylenediamine (reducing agent), obtain mixed emulsion, stirring under 40 degree lower magnetic stirring apparatus 1300r/min
10h, allows organic solvent fully to evaporate the composite nanoparticle to form the double structure with multiple response.Then liquid is centrifuged
(10000r/min) 10min, obtains sediment, is washed, centrifuged with alkaline water again afterwards, except emulsion breaker, this process repeatedly 5
It is secondary.
Embodiment 3
Cyclodextrin/dichloromethane solution will be formed in the sensitive cyclodextrine derivatives dissolving dichloromethane of certain mass pH, it is dense
Spend for 10% (w/v) 1mL；A certain amount of GM is dissolved in 1%PVA (polyvinyl alcohol)/PBS (pH=7.5) solution, over cure is added
Sour ammonium (initiator), final GM concentration is 15% (w/v), and ammonium persulfate concentrations are 0.05%w/v, and volume is 0.2mL；Two solution
After mixing, sealing ice-bath ultrasonic crushes 2min；This solution is added into 6mL 1%PVA/PBS (pH=7.5) solution again, sealing is super
Sound wave cell pulverization 3min forms second layer emulsion, then 20mL 0.3% (w/v) PVA/PBS (pH=7.5) solution, this solution
In contain 0.05% tetramethylethylenediamine (reducing agent), obtain mixed emulsion, stirring under 20 degree lower magnetic stirring apparatus 1300r/min
10h, allows organic solvent fully to evaporate the composite nanoparticle to form the double structure with multiple response.Then liquid is centrifuged
(10000r/min) 10min, obtains sediment, is washed, centrifuged with alkaline water again afterwards, except emulsion breaker, this process repeatedly 5
It is secondary.
Embodiment 4
Cyclodextrin/dichloromethane solution will be formed in the sensitive cyclodextrine derivatives dissolving dichloromethane of certain mass pH, it is dense
Spend for 10% (w/v) 1mL；A certain amount of GM is dissolved in 1%PVA (polyvinyl alcohol)/PBS (pH=7.5) solution, over cure is added
Sour ammonium (initiator), final GM concentration is 15% (w/v), and ammonium persulfate concentrations are 0.05%w/v, and volume is 0.2mL；Two solution
After mixing, sealing ice-bath ultrasonic crushes 2min；This solution is added into 6mL 1%PVA/PBS (pH=7.5) solution again, sealing is super
Sound wave cell pulverization 3min forms second layer emulsion, then 20mL 0.3% (w/v) PVA/PBS (pH=7.5) solution, this solution
In contain 0.05% tetramethylethylenediamine (reducing agent), obtain mixed emulsion, stirring under 40 degree lower magnetic stirring apparatus 1300r/min
10h, allows organic solvent fully to evaporate the composite nanoparticle to form the double structure with multiple response.Then liquid is centrifuged
(10000r/min) 10min, obtains sediment, is washed, centrifuged with alkaline water again afterwards, except emulsion breaker, this process repeatedly 5
It is secondary.
Embodiment 5
Cyclodextrin/dichloromethane solution will be formed in the sensitive cyclodextrine derivatives dissolving dichloromethane of certain mass pH, it is dense
Spend for 10% (w/v) 1mL；A certain amount of GM is dissolved in 1%PVA (polyvinyl alcohol)/PBS (pH=7.5) solution, over cure is added
Sour ammonium (initiator), final GM concentration is 20% (w/v), and ammonium persulfate concentrations are 0.05%w/v, and volume is 0.2mL；Two solution
After mixing, sealing ice-bath ultrasonic crushes 2min；This solution is added into 6mL 1%PVA/PBS (pH=7.5) solution again, sealing is super
Sound wave cell pulverization 3min forms second layer emulsion, then 15mL 0.3% (w/v) PVA/PBS (pH=7.5) solution, this solution
In contain 0.05% tetramethylethylenediamine (reducing agent), obtain mixed emulsion, stirring under 40 degree lower magnetic stirring apparatus 1300r/min
10h, allows organic solvent fully to evaporate the composite nanoparticle to form the double structure with multiple response.Then liquid is centrifuged
(10000r/min) 10min, obtains sediment, is washed, centrifuged with alkaline water again afterwards, except emulsion breaker, this process repeatedly 5
It is secondary.
The present embodiment is not construed as limiting the scope of the present invention, and the present invention is successfully prepared for a kind of with multiple sound
The double structure nano-particle answered.
Claims (4)
1. a kind of preparation method of the double structure nano-particle with multiple response, comprises the following steps：
Step 1：The preparation of material
I, cyclodextrin with pH sensitivity characteristics preparation；
Ii, double bond containing natural macromolecular synthesis；
Using gelatin as model, the gelatin of double bond is prepared, is specifically included：Weigh gelatin 1g to be placed in 250mL conical flasks, add
After 100mL tri-distilled waters are dissolved by heating, 800 μ L acrylic acid AA are added, the water miscible carbodiimides EDC of 400mg are then added,
Then at room temperature, stirring reaction 8h；To remove unreacted acrylic acid AA and other small molecule products, mixed liquor is inserted and cut
During only molecular weight is 10,000Da bag filters, dialysis 3 days, change 2~3 tri-distilled waters daily in a large amount of tri-distilled waters and at room temperature；Will
This liquid freezes, and freezes, and obtains the gelatin GM of acrylic acid AA grafting；
Step 2：The preparation of multiple response composite nanoparticle
I, cyclodextrin/dichloromethane solution, concentration will be formed in the sensitive cyclodextrine derivatives dissolving dichloromethane of certain mass pH
W/v is 1%-20%；
Ii, by a certain amount of acrylic acid AA be grafted gelatin GM be dissolved in 1% PVAC polyvinylalcohol/PBS, pH=7.5 solution,
The concentration of GM solution is 1%-25%w/v, adds 0.05%w/v ammonium persulfate initiators；
Iii, the GM solution in 2ii and cyclodextrin/dichloromethane solution in 2i mixed by different water-oil factors, i.e., GM is molten
Liquid：Cyclodextrin/dichloromethane solution presses different water：The volume ratio mixing of oil, water-oil factor is 1：2-1：15, with sealing after mixing
Ice-bath ultrasonic crushes 2min, forms water-in-oil emulsion；
Iv, the water-in-oil emulsion in 2iii is added to the molten of the PVA polyvinyl alcohol of finite concentration and volume/PBS, pH=7.5
Liquid, the concentration of PVA/PBS solution is 0.1%-10%w/v；Water-oil factor, i.e. PVA/PBS solution：Water-in-oil emulsion in 2iii
Water：The volume ratio of oil is 2：1-20：1；
V, by 2iv resulting solutions sealing supersonic cell crush 3min formation the second phase oil-in-water emulsion, be subsequently added into certain body
Product concentration obtains whole breast for 0.3%w/v PVA/PBS, pH=7.5, the solution containing 0.05% tetramethylethylenediamine reducing agent
Change liquid emulsion；Second phase oil-in-water emulsion with containing 0.05% tetramethylethylenediamine reducing agent, pH=7.5 PVA/PBS solution
Volume ratio be 2：1-1：10；
10h is stirred under vi, at a certain temperature magnetic stirring apparatus 1300r/min, allows organic solvent fully to evaporate to form pH sensitivities
The cyclodextrin nano particle of characteristic, while the gelatin solution for being wrapped in inside particles triggers in the presence of redox initiator
Double-bond polymerization formation nanogel structure, temperature is 0-60 DEG C；
Vii and then the rotating speed that liquid is pressed into 10000r/min centrifuge 10min, obtain sediment, wash many with alkaline water again afterwards
It is secondary, centrifugation, except emulsion breaker.
2. a kind of preparation method of double structure nano-particle with multiple response according to claim 1, its feature exists
In：
In the step 2i, the concentration of the cyclodextrin/dichloromethane solution is 5%-15%w/v；
In the step 2ii, the concentration of described GM solution is 15%-20%w/v；
In the step 2iii, the volume ratio of described water-oil factor is 1：5-1：10；
In the step 2iv, described finite concentration and the PVAC polyvinylalcohol of volume/PBS, pH=7.5 solution, its concentration is
0.1%-1%w/v；Described water-oil factor is 5：1-15：1；
In the step 2v, described the second phase oil-in-water emulsion with containing 0.05% tetramethylethylenediamine reducing agent, pH=7.5
PVA/PBS solution volume ratio be 1：1-1：5；
In the step 2vi, described temperature is 20-50 DEG C.
3. according to a kind of preparation method of the double structure nano-particle with multiple response according to claim 2, it is special
Levy and be：
In the step 2i, the concentration of the cyclodextrin/dichloromethane solution is 9%-11%w/v；
In the step 2ii, the concentration of described GM solution is 10%-20%w/v；
In the step 2iii, the volume ratio of described water-oil factor is 1：10；
In the step 2iv, described finite concentration and the PVAC polyvinylalcohol of volume/PBS, pH=7.5 solution, its concentration is
0.8%-1.0%w/v；Described water-oil factor is 6:1；
In the step 2v, described the second phase oil-in-water emulsion with containing 0.05% tetramethylethylenediamine reducing agent, pH=7.5
PVA/PBS solution volume ratio be 1：2-1：3；
In the step 2vi, described temperature is 30-40 DEG C.
4. the double structure nano-particle with multiple response according to prepared by the mode of claim 1,2 or 3.
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| CN107998102A (en) * | 2017-12-13 | 2018-05-08 | 金陵科技学院 | A kind of nano-particle pharmaceutical carrier with pH and magnetic double-response and preparation method thereof |
| CN108721695A (en) * | 2018-05-29 | 2018-11-02 | 金陵科技学院 | A kind of preparation method of syringeability composite hydrogel cell carrier holder |
| CN114574175A (en) * | 2022-04-26 | 2022-06-03 | 中国石油大学胜利学院 | pH value responsive reversible emulsifier based on waste argil for drilling fluid and application |
| CN114574175B (en) * | 2022-04-26 | 2022-07-15 | 中国石油大学胜利学院 | pH value responsive reversible emulsifier based on waste argil for drilling fluid and application |
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