CN110025580A - A kind of porous dextran of pH responsiveness is microsphere supported and preparation method thereof, application - Google Patents
A kind of porous dextran of pH responsiveness is microsphere supported and preparation method thereof, application Download PDFInfo
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- CN110025580A CN110025580A CN201910168938.7A CN201910168938A CN110025580A CN 110025580 A CN110025580 A CN 110025580A CN 201910168938 A CN201910168938 A CN 201910168938A CN 110025580 A CN110025580 A CN 110025580A
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
Abstract
The present invention provides that a kind of porous dextran of pH responsiveness is microsphere supported, the porous dextran it is microsphere supported for the porous dextran with pH responsiveness that is generated by dextran, pore-foaming agent, emulsion oil phase, acrylic acid phase, crosslinking agent, initiator for reaction it is microsphere supported.The present invention also provides a kind of preparation methods that the porous dextran of pH responsiveness is microsphere supported.Preparation method provided by the invention is microsphere supported with inverse suspension method reaction synthesis dextran, pass through freeze-drying and add pore-foaming agent and prepare that porous dextran is microsphere supported, and improves the microsphere supported irritability to environmental stimulus of porous dextran in the microsphere supported upper introduction acrylic acid.The porous dextran of pH responsiveness prepared by the present invention is microsphere supported to have broad application prospects as the Potential Vector of drug controlled release in many fields such as medicine and biotechnology.
Description
Technical field
The present invention relates to polymer carrier fields, and in particular to a kind of porous dextran of pH responsiveness is microsphere supported
And preparation method thereof, application.
Background technique
Pharmaceutical carrier is to be embedded in drug inside microballoon or be supported on microsphere surface, has the advantage that (1) improves medicine
The targeting of object；(2) absorbability of drug is improved；(3) change the distribution of drug in vivo；(4) drug is protected, drug is improved and exists
Intracorporal half-life period.Porous microsphere profile material due to its inner void structure particularity, as the carrier material of drug,
There to be unique advantage to the controlled release or sustained release of realizing drug.It can control the rate of release of drug in vivo, make drug
It is able to maintain effective concentration in vivo, reduces or eliminates side effect, especially when being implanted into or investing lesion, then can more show it
Superiority.And dextran is one of the carrier that current medical release field is concerned.
Dextran, also known as glucan are a kind of straight-chain polysaccharides being polymerized by several glucose molecules.Dextran
Since the different degree of polymerization has different molecular weight, mainly it is keyed by D- glucopyanosyl with α, 1 → 6, branch point has 1
→ 2,1 → 3,1 → 4 connection.There is tridimensional network in molecule by the dextran of chemical crosslinking, molecular sieve can be made,
Separate the compound of different molecular weight, therefore manufactured dextran gel micro-ball is commonly used to carry out bio-chemistry separation (such as: column layer
Analysis).Dextran has fine biodegradability and hydrophily, and the glycosidic bond in structure is easily by dextranase water
Solution.Its structural formula is as shown in Figure 1.
Due to containing a large amount of hydrophilic hydroxyls on the strand of dextran, so it is with biological tissue with good
Compatibility, and being degraded in designated position by enzyme, thus dextran is often treated as a kind of drug control and releases
The Potential Vector put has been more and more widely used in many fields such as medicine and biotechnology.
105111512 A of Chinese patent literature CN (application number 201510572711.0) discloses a kind of chemical crosslinking
Dextran hydrogel and preparation method thereof is subsequently placed in ice-water bath by the way that dextran to be dissolved in water at room temperature
Be added sodium metaperiodate obtain mixed liquor, by mixed liquor room temperature, be protected from light under the conditions of be stirred to react to obtain aldehyde radical dextran, so
Afterwards at room temperature, polyamino crosslinking agent is added into aldehyde radical dextran aqueous solution and dextran is prepared after mixing
Hydrogel.The program is only using the dextran natural polymer of good biological safety as material foundation, and being prepared can
Biodegradable hydrogel, but and not yet explicitly specifically use approach and use field.
105348548 A of Chinese patent literature CN (application number 201510704378.4) discloses a kind of based on dextrose
Hydrogel microsphere of acid anhydride and preparation method thereof is added sodium metaperiodate and obtains by the way that dextran to be dissolved in water at room temperature
Mixed liquor is dialysed after stirring, freeze-drying obtains part aldehyde radical dextran solid；The part aldehyde radical dextrose that will be obtained
Acid anhydride is dissolved in deionized water and is added the cyclohexane solution for having dissolved emulsifier, and amine cross-linking agent stirring is added, finally by from
The heart collects sediment, and chemical crosslinking dextran hydrogel microsphere is obtained after cleaning；To obtaining being scattered in deionized water
Sodium borohydride is added in chemical crosslinking dextran hydrogel microsphere, is stirred at room temperature for 24 hours, it is heavy finally by being collected by centrifugation
Starch, the dextran hydrogel microsphere after being restored after deionized water is cleaned.The program proposes inversed phase emulsification preparation
Gel micro-ball, but research not yet is made to the control of microspherulite diameter, and the gel stability prepared is poor, it is micro- in Ph < 4.0
Spherical structure is easy to be destroyed.
It is micro- that 105153440 A of Chinese patent literature CN (application number 201510404680.8) discloses a kind of dextran
The preparation method of ball gel, firstly, preparing dispersed phase dextran solution and continuous phase solution；Dispersed phase solution is at the uniform velocity added dropwise
Make the fully emulsified addition N of mixture, N'- methylene-bisacrylamide into continuous phase solution, while using emulsifying equipment
Crosslinking agent, mechanical stirring keep mixture full cross-linked, and dextran microsphere gel is made.This method is although cheap, production
Period is short, but use emulsifying method will lead to microballoon form and cannot be effectively controlled, the residue removal mode of crosslinking agent
It does not refer to, and the stability under acid or alkali environment is not also studied.
To sum up, the polyalcohol stephanoporate microballoons preparation method multiplicity of the prior art, there is traditional suspension polymerization, micro-fluidic conjunction
Cheng Fa, freeze-drying and self-assembly method etc., but stability of the obtained gel porous microballoon under different soda acid degree is not
It obtains and knows, the homogeneity distribution of grain diameter also not yet discloses.And as pharmaceutical carrier, it is necessary to have certain degrees
With guarantee drug can normal transport to destination, therefore, research dextran microballoon pH be of great significance.
Summary of the invention
In view of this, the present invention provides a kind of porous dextran of pH responsiveness is microsphere supported, it can be as drug
Carrier material guarantees that drug normal transport to destination, realizes the controlled release or slow releasing function of drug；The present invention also provides one kind
The microsphere supported preparation method of the porous dextran of pH responsiveness of simple process.
The present invention provides that a kind of porous dextran of pH responsiveness is microsphere supported, and the porous dextran is microsphere supported is
It is generated by dextran, pore-foaming agent, emulsion oil phase, acrylic acid phase, crosslinking agent, initiator for reaction more with pH responsiveness
Hole dextran is microsphere supported.
Further, the pore-foaming agent is polyethylene glycol dimethyl ether.
Further, the emulsion oil is mutually the mixed liquor of atoleine and sorbester p17.
Further, the acrylic acid mutually is neutralized to obtain by acrylic monomers through NaOH solution, the acrylic acid and dextrorotation
The mass ratio of sugared acid anhydride is 1:2~5:2.
Further, the crosslinking agent is N ,-N ' methylene-bisacrylamide, polyethylene glycol, glutaraldehyde or acrylamide
Any one or more of mixture.
Further, the initiator is potassium peroxydisulfate, sodium hydrogensulfite, tetramethylethylenediamine or N, N, N', N'- tetramethyl
The mixture of any one or more of base ethylenediamine.
The present invention also provides a kind of preparation methods that the above-mentioned porous dextran of pH responsiveness is microsphere supported, including following step
It is rapid:
S1 prepares dextran/pore-foaming agent water phase: weighing dextran and pore-foaming agent dissolution in deionized water, obtains
Dextran/pore-foaming agent water phase；
S2 prepares emulsion oil phase: weighing atoleine and sorbester p17 is uniformly mixed, obtain emulsion oil phase；
S3 prepares acrylic acid phase: acrylic monomers weighed, NaOH solution is added and neutralizes acrylic monomers, cooling standby
With；
S4, into the acrylic acid phase of step S3 preparation, addition crosslinking agent is stirred evenly spare；
The solution of step S4 is poured into dextran/pore-foaming agent water phase of step S1 and is stirred evenly by S5；
The emulsion oil phase of S6, heating stepses S2 are simultaneously sufficiently stirred；
S7 drops evenly the solution of step S5 in the emulsion oil phase of step S6；
Initiator is added into the solution of step S7 by S8, and then heating carries out curing reaction, obtains reaction product:
S9, washing and drying: using the reaction product of dehydrated alcohol and acetone soak and constantly washing step S8, after dry
Obtain having the porous dextran of pH responsiveness microsphere supported.
Further, in step S1, the pore-foaming agent is polyethylene glycol dimethyl ether.
Further, in step S4, the crosslinking agent be N ,-N ' methylene-bisacrylamide, polyethylene glycol, glutaraldehyde or
The mixture of any one or more of acrylamide.
Further, in step S4, the crosslinking agent used is N ,-N ' methylene-bisacrylamide and polyethylene glycol-6000
Mixture.
Further, in step S6, by emulsion oil heat phase to 40~60 DEG C.
Further, in step S8, the initiator is potassium peroxydisulfate, sodium hydrogensulfite, tetramethylethylenediamine or N, N,
The mixture of any one or more of N', N'- tetramethylethylenediamine.
Further, in step S8,80 are warming up to after potassium peroxydisulfate and sodium hydrogensulfite is added into the solution of step S7
The molar ratio of~100 DEG C of progress curing reactions, potassium peroxydisulfate and sodium hydrogensulfite is 5:1~1:5.
Further, in step S8, curing reaction carries out under nitrogen protection.
The present invention also provides answer using the porous dextran of pH responsiveness is microsphere supported made from above-mentioned preparation method
With the microsphere supported controlled release that as the carrier of drug, can realize drug of the porous dextran of pH responsiveness or sustained release are made
With.
Compared with the existing technology, the invention has the following advantages that
1) raw material used in preparation process of the present invention are easy to get and price is low, with short production cycle, are convenient for industrialization；
2) for the present invention using atoleine and sorbester p17 mixing as oily phase, oily substance is not soluble in water, many kinds of, and
Safety and environmental protection is easy to get, can be to avoid the safety in production of the organic solvents bring such as chlorobenzene, toluene and environmental pollution hidden danger；
3) present invention forms oil packet using stable effective surfactant sorbester p17 under alkaline condition as dispersing agent
The emulsification system of water, effectively prevents the reunion of pre-dispersed good dextran droplet, and the partial size that microballoon can be effectively controlled is big
Small and distribution；
4) present invention is with N ,-N ' methylene-bisacrylamide (MBA) is used as crosslinking agent, and it is auxiliary to consolidate in polyethylene glycol-6000
Change microballoon size, promote the mechanical strength of microballoon, cross-linking reaction only plays the role of solidification, promotes microballoon mechanical strength, will not
The size of microballoon is had an impact；
It include acrylic acid groups in the microsphere supported chemical structure of the porous dextran of pH responsiveness prepared by the present invention, because
The enzyme degradability of dextran had not only been utilized in this, but also the pH responsiveness of acrylic acid is utilized.
In the present invention, the graft copolymerization mechanism category free radical polymerization of dextran and acrylic acid, initiator persulfuric acid
Potassium-sodium hydrogensulfite generates two kinds of free radical SO by redox4- and HSO3, free radical can be under hydrogen bond action
It is adsorbed onto the intramolecular of dextran, captures the hydrogen in dextran molecule on hydroxyl, so that dextran is become macromolecular free
Base is copolymerized to cause acrylic acid with it, and finally being formed in inverse suspension system has spacial framework
Acid-sensitive dextran microballoon.
Detailed description of the invention
Fig. 1 is the structural formula of dextran.
Fig. 2 is the microsphere supported scanning electron microscope (SEM) photograph of the pH responsiveness porous dextran of the invention being prepared.
Fig. 3 is the microsphere supported FT-IR (Fourier of the pH responsiveness porous dextran of the invention being prepared
Transform infrared spectroscopy, the infrared conversion spectrum of Fourier) map.
Specific embodiment
To make the object, technical solutions and advantages of the present invention clearer, below in conjunction with attached drawing to embodiment party of the present invention
Formula is further described.
The embodiment provides a kind of porous dextran of pH responsiveness is microsphere supported, by dextran, pore
Agent, emulsion oil phase, acrylic acid phase, crosslinking agent, initiator for reaction generate, and the dextran is microsphere supported to have pH responsiveness.
Wherein, pore-foaming agent is polyethylene glycol dimethyl ether；Emulsion oil is mutually the mixed liquor of atoleine and sorbester p17；Propylene
It is sour mutually to neutralize to obtain through NaOH solution by acrylic acid；Crosslinking agent is N ,-N ' methylene-bisacrylamide, polyethylene glycol, glutaraldehyde
Or the mixture of any one or more of acrylamide；Initiator be potassium peroxydisulfate, sodium hydrogensulfite, tetramethylethylenediamine or
The mixture of any one or more of N, N, N', N'- tetramethylethylenediamine.
The embodiment provides a kind of preparation methods that the porous dextran of pH responsiveness is microsphere supported, including with
Lower step:
Step S1 prepares dextran/pore-foaming agent water phase: precise 5g dextran and 2g pore-foaming agent polyethylene glycol two
Methyl ether is dissolved in spare in 10mL ± 5mL deionized water；
Step S2, prepare emulsion oil phase: precise 100mL ± 10mL atoleine and 10g ± 0.5g sorbester p17 are mixed
It closes uniformly mutually spare as oil；
Step S3 prepares the acrylic acid phase with pH responsiveness: weighing 10g ± 7.5g acrylic monomers, uses mass fraction
22%~50% NaOH solution is neutralized, spare after cooling；
Crosslinking agent is added in step S4: 0.1~5g crosslinking agent N ,-N ' methylene-bisacrylamide being added into step S3
(MBA) and 0.1~2g polyethylene glycol-6000 stir evenly it is spare；
Step S5 mixes acrylic acid phase and water phase: on magnetic agitation instrument, the solution of step S4 being poured into the molten of step S1
Pre- stirring 10~60 minutes is carried out in liquid, is mixed them thoroughly as water phase；
The emulsion oil of step S2 is mutually poured into four-hole bottle and is warming up to 40~60 DEG C and is sufficiently stirred by step S6；
Step S7, miscella phase and water phase: in the four-hole bottle that the water phase of step S5 is dropped evenly to step S6；
Initiation reaction: step S8 is added potassium peroxydisulfate and sodium hydrogensulfite, and is warming up in the four-hole bottle into step S7
80~100 DEG C are solidified, and reaction product is obtained；
In step S8, the molar ratio of potassium peroxydisulfate and sodium hydrogensulfite is 5:1~1:5；Solidification process is under nitrogen protection
It carries out.
Step S9, washing and drying: with dehydrated alcohol and acetone soak and continuous washing reaction product, had after dry
There is the porous dextran of pH responsiveness microsphere supported.
It is microsphere supported to the porous dextran of pH responsiveness provided by the invention and preparation method thereof below with reference to embodiment
It is described in detail.
Embodiment 1:
100mL atoleine and 10g sorbester p17 are uniformly mixed as oily phase；
It weighs 5g dextran and 2g pore-foaming agent polyethylene glycol dimethyl ether is dissolved in 10mL deionized water for use；
Weigh 2.5g acrylic monomers, neutralized with the NaOH solution of mass fraction 22%, this operation in cold water into
Row, obtains the acrylic acid solution of neutralization, and when the temperature of acrylic acid solution to be neutralized is down to room temperature, 0.25g crosslinking agent N is added ,-
N ' methylene-bisacrylamide (MBA) and 1g polyethylene glycol-6000 stir evenly；On magnetic agitation instrument, by and good third
Olefin(e) acid solution, which pours into dextran solution, carries out pre- stirring 10 minutes, mixes them thoroughly as water phase；Oil is mutually poured into four
It is heated up and is sufficiently stirred in mouth bottle, the water phase stirred in advance is added when temperature rises to 60 DEG C；Sequentially add a certain amount of draw
Hair agent potassium peroxydisulfate and sodium hydrogensulfite (keeping the molar ratio of potassium peroxydisulfate and sodium hydrogensulfite is 1:1) initiation reaction, one section
Visible a large amount of solid spheres generate after time, are warming up to 80 DEG C after this thermotonus 2h and are solidified, and whole process nitrogen is protected
Shield；Finally with dehydrated alcohol and acetone soak and continuous washing reaction product, obtain that there are the more of pH responsiveness after freeze-drying
Hole dextran is microsphere supported.
Embodiment 2:
Embodiment 2 and the difference of embodiment 1 are only that: the dosage of acrylic acid is 5g in embodiment 2, and crosslinking agent N ,-N ' are sub-
The dosage of bisacrylamide is 0.5g；Remaining is then substantially the same manner as Example 1.
Embodiment 3:
Embodiment 3 and the difference of embodiment 1 are only that: the dosage of acrylic acid is 7.5g, crosslinking agent N ,-N ' in embodiment 3
The dosage of methylene-bisacrylamide is 0.75g；Remaining is then substantially the same manner as Example 1.
Embodiment 4:
Embodiment 4 and the difference of embodiment 1 are only that: the dosage of acrylic acid is 10g in embodiment 4, and crosslinking agent N ,-N ' are sub-
The dosage of bisacrylamide is 1g；Remaining is then substantially the same manner as Example 1.
Embodiment 5:
Embodiment 5 and the difference of embodiment 1 are only that: the dosage of acrylic acid is 12.5g, crosslinking agent N ,-N ' in embodiment 5
The dosage of methylene-bisacrylamide is 1.25g；Remaining is then substantially the same manner as Example 1.
Embodiment 6:
Embodiment 6 and the difference of embodiment 1 are only that: the dosage of acrylic acid is 5g in embodiment 6, and crosslinking agent N ,-N ' are sub-
The dosage of bisacrylamide is 0.125g；Remaining is then substantially the same manner as Example 1.
Embodiment 7:
Embodiment 7 and the difference of embodiment 1 are only that: the dosage of acrylic acid is 5g in embodiment 7, and crosslinking agent N ,-N ' are sub-
The dosage of bisacrylamide is 0.25g；Remaining is then substantially the same manner as Example 1.
Embodiment 8:
Embodiment 8 and the difference of embodiment 1 are only that: the dosage of acrylic acid is 5g in embodiment 7, and crosslinking agent N ,-N ' are sub-
The dosage of bisacrylamide is 0.75g；Remaining is then substantially the same manner as Example 1.
Embodiment 9:
Embodiment 9 and the difference of embodiment 1 are only that: the dosage of acrylic acid is 5g in embodiment 9, and crosslinking agent N ,-N ' are sub-
The dosage of bisacrylamide is 1g；Remaining is then substantially the same manner as Example 1.
The dosage of dextran, acrylic acid and crosslinking agent N ,-N ' methylene-bisacrylamide in 1~embodiment of embodiment 9
As shown in table 1.
The use of dextran, acrylic acid and crosslinking agent N ,-N ' methylene-bisacrylamide in 1 1~embodiment of embodiment 9 of table
Amount
Note: in table 1, the dosage of crosslinking agent refers to crosslinking agent N, and the quality of-N ' methylene-bisacrylamide accounts for acrylic monomers
The percentage of quality.
For the microsphere supported property of the porous dextran with pH responsiveness for understanding preparation, to embodiment 1~implementation
Example 9 in accordance with the following methods detects it:
1, the microsphere supported water absorption rate measurement of the porous dextran of pH responsiveness:
The specific detection method is as follows:
Microsphere supported 50 mesh of mistake of dextran prepared by 1~embodiment of embodiment 9 weighs 1g respectively and is put into 100mL
In beaker, it is swollen sufficiently with deionized water immersion, until the quality of microballoon is no longer changed, that is, reach water suction balance.
The calculation formula of the water absorption rate Q of dextran microballoon are as follows:
Q=(Ws-Wd)/Wd
Wherein: WdIt is the dry mass of dextran microballoon when not absorbing water, WsIt is dextran microballoon when reaching water suction balance
Hygrometric state quality.
The water absorption rate Q of dextran microballoon prepared by 1~embodiment of embodiment 9 is as shown in table 2.
The water absorption rate of the dextran microballoon of 2 1~embodiment of embodiment 9 of table preparation
| Embodiment | Water absorption rate |
| 1 | 21.3 |
| 2 | 23.0 |
| 3 | 28.9 |
| 4 | 31.5 |
| 5 | 38.8 |
| 6 | 20.7 |
| 7 | 11.3 |
| 8 | 11.0 |
| 9 | 9.1 |
As can be seen from Table 2: in 1~embodiment of embodiment 5, when the proportion of dextran and acrylic monomers is dropped from 2:1
When as low as 2:5, the water absorption rate of dextran microballoon is gradually increased, and is increased to 38.8g/g from 21.3g/g, is illustrated: with acrylic acid
The amount of the increase of monomer concentration, the polyacrylic acid being grafted on dextran matrix also increases, finally formed dextran microballoon
Average molecular weight increase, while network structure number increase, so water absorption rate enhance；And in 6~embodiment of embodiment 9, when
The dosage of crosslinking agent N ,-N ' methylene-bisacrylamide from 2.5% increase to 20% when, under the water absorption rate of dextran microballoon is in
Drop trend is reduced to 9.1g/g from 20.7g/g, this is because the crosslink density of microballoon becomes larger with the increase of dosage of crosslinking agent,
Skeleton becomes finer and close, and the micropore in network structure becomes smaller, difficult so as to cause microballoon water absorption and swelling, therefore water absorption rate declines.
Therefore, the quality of crosslinking agent N ,-N ' methylene-bisacrylamide accounts for best when acrylic monomers quality 10%.
2, the measurement of the microsphere supported water absorption rate at various ph values of the porous dextran of pH responsiveness:
The specific detection method is as follows:
By the trishydroxymethylaminomethane (Tris) of the 0.12g standard titration with hydrochloric acid of 0.1mol/l to required pH value,
After mixing plus water is settled to 100mL, is configured to the Tris buffer solution of the different pH value of 0.01mol/L；It will be in embodiment 2
The microsphere supported Tris for being put into pH value and being respectively 3,4,5,6,7,8,9,10 of the pH responsiveness dextran of several parts of 0.5g obtained
Buffer solution is sufficiently swollen, and is reached water suction balance until the quality of microballoon is no longer changed, is weighed dextran at this time
Microsphere supported hygrometric state quality calculates the water absorption rate that dextran is microsphere supported under different pH value using water absorption rate calculation formula,
The microsphere supported water absorption rate of dextran is as shown in table 3 under different pH value.
The microsphere supported water absorption rate at various ph values of 3 dextran of table
| pH | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 |
| Q | 11.60 | 11.75 | 12.04 | 12.20 | 12.69 | 13.17 | 13.68 | 15.21 |
As shown in Table 3, when pH increases to 10 from 3, the microsphere supported water absorption rate of dextran is gradually increased, from
11.60g/g increasing to 15.21g/g.In lower pH value, the dissociation of the microsphere supported middle carboxyl of dextran is restricted, again
Hydrogen bond easy to form causes water absorption rate lower so that microballoon network structure is shunk；With the increase of pH value, especially when environment
When pH value is higher than (4.75) pKa of polyacrylic acid, the water absorption rate of microballoon is obviously increased, because of the carboxyl under alkaline condition in microballoon
Sufficiently dissociation, swellbility become larger and expand network structure.This, which illustrates that the dextran of this experiment preparation is microsphere supported, has acid
Quick property can make corresponding response according to the change of external environment acidity.This dextran is microsphere supported to be expected to become intestines
The excellent carrier of road target administration, microballoon deflation does not release the drug when pH is lower in gastric juice, and microballoon is in expansion when pH higher in intestinal juice
State, drug can be with slow releases.
3, in the microsphere supported different salinity environment of the porous dextran of pH responsiveness water absorption rate measurement:
The specific detection method is as follows:
The NaCl for weighing different quality is dissolved in the deionized water of 100g, so that the mass fraction of NaCl solution is respectively
0%, 1%, 2%, 3% and 4%.By the dextran of several parts of 0.5g obtained in embodiment 2, microsphere supported to be put into different salt dense
The NaCl solution of degree is sufficiently swollen, and is reached water suction balance until the quality of microballoon is no longer changed, is weighed dextrorotation at this time
The hygrometric state quality of sugared acid anhydride microballoon calculates the water suction that dextran is microsphere supported under different salinity using water absorption rate calculation formula
Rate, the microsphere supported water absorption rate of dextran is as shown in table 4 under different salinity.
The microsphere supported water absorption rate in different salinity environment of 4 dextran of table
| Salinity | 0% | 1% | 2% | 3% | 4% |
| Q | 15.58 | 10.21 | 9.05 | 8.34 | 7.7 |
It is found that when NaCl salinity gradually increases, the microsphere supported water absorption rate of dextran is gradually reduced analytical table 4
(being reduced to 7.7g/g from 15.58g/g).On the one hand the addition of NaCl generates common-ion effect, so that in microballoon network structure
Segment turgor movement ability reduces, and another aspect inorganic ion can reduce in solution hydrone to expanding inside dextran microballoon
Scattered osmotic pressure, the water absorption rate that the two influence factors result in dextran microballoon are reduced with the increase of salinity.This hair
When NaCl concentration is 1% (close to the salinity 0.9% of human body cell external solution) in bright, the water absorption rate of dextran microballoon is
10.21g/g has substantial degradation compared with the water absorption rate in pure water, this is conducive to the progress for carrying medicine test in vivo.
4, the microsphere supported scanning electron microscope measurement of the porous dextran of pH responsiveness:
The specific detection method is as follows:
The microsphere supported sample surfaces of dry state dextran made from embodiment 2 are subjected to metal spraying with ion sputtering instrument, are utilized
PHILIPS XL_30ESEM environmental scanning electron microscope observes the microsphere supported configuration of surface of dextran, and dextran is micro-
For the scanning electron microscope (SEM) photograph of balloon borne body as shown in Fig. 2, analysis attached drawing 2 illustrates, dextran microballoon has preferable pattern, spherical regular
And particle diameter distribution is relatively uniform, and the particle size of microballoon illustrates that pH responsiveness prepared by the present invention is more between 5 μm -10 μm
Dextran microsphere supported particle diameter distribution in hole is visibly homogeneous.
5, the microsphere supported Fourier spectrum measurement of the porous dextran of pH responsiveness:
The specific detection method is as follows:
Spectrometer uses the infrared transform spectrometer of tradition FT-IR Fourier, and dextran made from embodiment 2 is microsphere supported
After sample drying and KBr grinds tabletting together, carries out infrared spectroscopy on Bio-Rad FTS135 type Fourier infrared spectrograph
Test, for the microsphere supported FT-IR map of dextran as shown in figure 3, in Fig. 3, a is the FT-IR map of dextran, and b is real
The microsphere supported FT-IR map of dextran made from example 2 is applied, it can be seen from Fig. 3 that the graft polymerization of dextran and acrylic acid produces
Still there is 3430cm during object dextran is microsphere supported-1The characteristic absorption peak of place-OH, but the intensity at this peak and width are with respect to dextrorotation
The absorption peak of-OH is all substantially reduced in sugared acid anhydride raw material, illustrates in dextran that a large amount of hydroxyl has occurred cross-linking reaction, in a
2926cm-1The absorption peak at place is the methylene (- CH in dextran molecule2) stretching vibration absworption peak, this peak is split point in b
For 2928cm-1And 2852cm-1Two peaks illustrate that the intensity of methylene further increases, this is because acrylic acid is being graft-polymerized
CH in the process2=CH- double bond, which is opened, generates a large amount of-CH2Group, 1718cm in b-1Left and right is the stretching vibration of C=O group
Absorption peak because acrylic acid using when have certain degree of neutralization, most carboxyls lose proton to be existed in the form of COO-,
1566cm in b-1It is COO- symmetric vibration absorption peak, 1460cm-1It is COO- antisymmetric vibration absorption peak.All illustrate dextrorotation above
Successfully acrylic acid has been gone up in grafting on sugared acid anhydride molecule.
Preparation method provided by the invention is microsphere supported with inverse suspension method reaction synthesis dextran, passes through freeze-drying
Method simultaneously adds pore-foaming agent to prepare porous dextran microsphere supported, and improves the porous right side in the microsphere supported upper introduction acrylic acid
Revolve the microsphere supported irritability to environmental stimulus of sugared acid anhydride.
Preparation method provided by the invention is original with the dextran natural macromolecular material with good biological safety
Material, the composite porous microspheres obtained after being chemically modified have both the good biodegradability properties of dextran and the pH response of acrylic acid
Property；The porous dextran of pH responsiveness prepared by the present invention it is microsphere supported can as the Potential Vector of drug controlled release,
Many fields such as medicine and biotechnology have broad application prospects.
In the absence of conflict, the feature in embodiment and embodiment herein-above set forth can be combined with each other.
The foregoing is merely presently preferred embodiments of the present invention, is not intended to limit the invention, it is all in spirit of the invention and
Within principle, any modification, equivalent replacement, improvement and so on be should all be included in the protection scope of the present invention.
Claims (10)
1. a kind of porous dextran of pH responsiveness is microsphere supported, which is characterized in that the porous dextran is microsphere supported to be
It is generated by dextran, pore-foaming agent, emulsion oil phase, acrylic acid phase, crosslinking agent, initiator for reaction more with pH responsiveness
Hole dextran is microsphere supported.
2. the porous dextran of pH responsiveness according to claim 1 is microsphere supported, which is characterized in that the pore-foaming agent is
Polyethylene glycol dimethyl ether.
3. the porous dextran of pH responsiveness according to claim 1 is microsphere supported, which is characterized in that the emulsion oil
It is mutually the mixed liquor of atoleine and sorbester p17.
4. the porous dextran of pH responsiveness according to claim 1 is microsphere supported, which is characterized in that the acrylic acid phase
It neutralizes to obtain through NaOH solution by acrylic acid, the mass ratio of the acrylic acid and dextran is 1:2~5:2.
5. the porous dextran of pH responsiveness according to claim 1 is microsphere supported, which is characterized in that the crosslinking agent is
The mixture of any one or more of N ,-N ' methylene-bisacrylamide, polyethylene glycol, glutaraldehyde or acrylamide.
6. the porous dextran of pH responsiveness according to claim 1 is microsphere supported, which is characterized in that the initiator is
Potassium peroxydisulfate, sodium hydrogensulfite, tetramethylethylenediamine or N, N, N', any one or more of N'- tetramethylethylenediamine mix
Close object.
7. the microsphere supported preparation method of the porous dextran of pH responsiveness described in any one of claims 1-6, feature exist
In, comprising the following steps:
S1 prepares dextran/pore-foaming agent water phase: weighing dextran and pore-foaming agent dissolution in deionized water, obtains dextrorotation
Sugared acid anhydride/pore-foaming agent water phase；
S2 prepares emulsion oil phase: weighing atoleine and sorbester p17 is uniformly mixed, obtain emulsion oil phase；
S3 prepares acrylic acid phase: acrylic monomers weighed, NaOH solution is added and neutralizes acrylic monomers, it is spare after cooling；
S4, into the acrylic acid phase of step S3 preparation, addition crosslinking agent is stirred evenly spare；
The solution of step S4 is poured into dextran/pore-foaming agent water phase of step S1 and is stirred evenly by S5；
The emulsion oil phase of S6, heating stepses S2 are simultaneously sufficiently stirred；
S7 drops evenly the solution of step S5 in the emulsion oil phase of step S6；
Initiator is added into the solution of step S7 by S8, and then heating carries out curing reaction, obtains reaction product:
S9, washing and drying: it using the reaction product of dehydrated alcohol and acetone soak and constantly washing step S8, is obtained after dry
Porous dextran with pH responsiveness is microsphere supported.
8. the microsphere supported preparation method of the porous dextran of pH responsiveness according to claim 7, which is characterized in that step
In rapid S6, by emulsion oil heat phase to 40~60 DEG C.
9. the microsphere supported preparation method of the porous dextran of pH responsiveness according to claim 7, which is characterized in that step
In rapid S8,80~100 DEG C of progress curing reactions are warming up to after potassium peroxydisulfate and sodium hydrogensulfite is added into the solution of step S7,
The molar ratio of potassium peroxydisulfate and sodium hydrogensulfite is 5:1~1:5.
10. using the microsphere supported application of the porous dextran of pH responsiveness made from preparation method as claimed in claim 7,
Be characterized in that, the microsphere supported controlled release that as the carrier of drug, can realize drug of the porous dextran of pH responsiveness or
Slow releasing function.
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| WO2005116084A1 (en) * | 2004-05-24 | 2005-12-08 | University Of Bath | Process |
| CN1718616A (en) * | 2005-06-30 | 2006-01-11 | 合肥工业大学 | Medical intelligent nano-gel material and its preparation method |
| CN102258787A (en) * | 2011-06-01 | 2011-11-30 | 天津大学 | Hydrophilic porous dextran-based microsphere and preparation method thereof |
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2019
- 2019-03-06 CN CN201910168938.7A patent/CN110025580A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005116084A1 (en) * | 2004-05-24 | 2005-12-08 | University Of Bath | Process |
| CN1718616A (en) * | 2005-06-30 | 2006-01-11 | 合肥工业大学 | Medical intelligent nano-gel material and its preparation method |
| CN102258787A (en) * | 2011-06-01 | 2011-11-30 | 天津大学 | Hydrophilic porous dextran-based microsphere and preparation method thereof |
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