CN108452376A - A kind of poly-dopamine gelatine microsphere preparation method - Google Patents
A kind of poly-dopamine gelatine microsphere preparation method Download PDFInfo
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Abstract
The present invention relates to a kind of poly-dopamine gelatine microsphere preparation methods, it is characterised in that：Gelatine microsphere obtained is put into pre-configured Tris/HCI, in the buffer solution of pH=8.5,2mg/mL dopamine solutions are then added, 12 are stirred at 37 DEG C for 24 hours, it then centrifuges and is washed with deionized three times, air-dry up to the coated gelatine microsphere of poly-dopamine.The present invention is coated with gelatine microsphere by poly-dopamine well, enhances its surface chemistry multifunctionality, and can succeed supported V c, have potential value in terms of medicament slow release.
Description
Technical field
The invention belongs to biomedical sectors, are related to micro Nano material, and in particular to a kind of poly-dopamine gelatine microsphere system
Preparation Method.
Background technology
The eighties in last century, American scholar Joseph P.Vacanti and Robert Langer take the lead in proposing " group weaver
This concept of journey ", and in the U.S.《Science》Magazine, which is write articles, delivers its achievement in research.Then by famous scientist Chinese descendant in America
Professor Y.C.Fung proposes this term of organizational project and can determine whether by national science foundation of the US committee member in 1987.It is general next
It says, it includes three aspects that we, which define organizational project mainly,：Seed cell, biomaterial and growth factor.It is wherein main
While be also research emphasis be exactly biomaterial, that is, we " holder " often said.One good to can be used in reality
The biomaterial that border produces and uses needs to have following characteristic：One, biocompatibility and histocompatbility；Two, biology drop
Solution property and absorbability；Three, the three-dimensional space structure of holder.Biomaterial mainly divides two major classes：Natural macromolecular material
(such as de- cell epimatrix and collagen) and artificial synthesized degradation material (such as polylactic acid, polyglycolic acid and its are answered
Close object, polylactic acid and polyglycolic acid copolymers etc.).Wherein the advantages of natural macromolecular material includes good biocompatibility, with
Extra-cellular matrix structure is similar, sticking, be proliferated and breaking up conducive to cell, so having artificial synthesized material in organizational project
The incomparable advantage of material.
With the reach of science, people also deepen continuously for the cognition and transformation in the world, from macroscopic view to microcosmic, from substance
To particle.Recently in decades micro Nano material due to its unique physics, chemical property and be widely used in multiple fields,
And then as a big hot topic of current scientific research.Microballoon belongs to a kind of spherical grain being made of polymer in micro Nano material
Son, size is between 20nm to 2000 μm.The research of microballoon is derived from the research to natural polymer, previously to natural rubber
Latex formation just proposes when being studied it is assumed that just worked out the heterogeneous polymerization technology for preparing microballoon later, until it is current this
Technology still produces the main method of microballoon.
Gelatine microsphere：Natural polymer is prepare microballoon one due to its good biocompatibility and biodegradability
Class important materials.Collagen is relatively common in natural biologic material, it is the master of skin, bone, tendon, cartilage, blood vessel and tooth
Want fibre composition, the important component of cytoskeleton.Its biological function includes：The skeleton structure of extracellular matrix is constituted, and it is thin
Born of the same parents interact and influence the form of cell, skeleton assembling and proliferation and differentiation；Have with the matrix of cell peripheral good mutual
Effect shows interactional harmony, and as cell and tissue normal physiological function part of the whole；It biological can drop
Solution property and cell growth can be promoted to be metabolized.M.Stol et al. has found that the compound that can synthesize collagen and HEMA arbitrary proportions
Method, and find that it can promote myocyte's differentiation in vitro and be used for cell culture[4].It is studied not with to collagen
Disconnected to go deep into and develop, untwist product of the gelatin as collagen, other than the excellent performance for having collagen, also outstanding is molten
Xie Xing, the reversible transition of gel-sol and higher chemical reactivity.Flocculating agent or tune are added in aqueous gelatin solution
It saves its pH value and is allowed to agglomerate again and can be prepared by gelatine microsphere.In addition, also emulsification-cross-linking method, agent approach, spray drying process etc.
All it is the common method for preparing gelatine microsphere.Gelatine microsphere is due to its special shape, the size and excellent reason of Jie's sight state
Change property and biological nature, so having a wide range of applications in biology, medicine, chemical industry etc., such as：Organizational project, medicine
Object sustained release, embolotherapy, tracing in vivo, chromatographic isolation etc..
Dopamine：Dopamine is a kind of biological neural mediator, is the catechol derivatives of L-DOPA, the meeting under wet condition
Oxidative polymerization occurs, polymerizate can anchor at stromal surface, show superpower adhesion characteristic.Based on to ocean
Mussel the study found that the pedal gland cell of marine mussel can secrete a kind of byssus gland, this gland liquid also has superpower adherency
Characteristic.The component of both analyses learns that catechol and its derivative energy spontaneous polymerization, formation are adhered tightly to solid matrix table
The polymer coating in face.With the continuous deepening of research, this characteristic of dopamine makes solid material surface modification
It is popular.
Gelatin is as a kind of natural macromolecular material with characteristic property, the gelatin made of the material based on gelatin
Application prospect is extensive in microballoon, therefore, how to improve preparation method or to improve its performance most important.Peking University's pharmacy
Institute just once made improvement to the preparation method of gelatine microsphere, they change the castor oil as oil phase in original emulsion-crosslinking method into
Atoleine, while in crosslinking agent formaldehyde not being mixed into isopropanol.Although adjustment is few, prepared by improved method
The gelatine microsphere gone out all makes moderate progress in pattern etc..Ratanavaraporn, J. et al. are also studied and are prepared gelatin/fibroin
Protein microsphere loads curcumin, and for the anti-inflammatory treatment of the osteoarthritis in rat model.Make a general survey of research in recent years we
It was found that the most of improvement also in preparation method of research for gelatine microsphere.The application direction of current gelatine microsphere is come
It sees, there is conduct in future very much in the medicament slow release of medicine and embolotherapy etc..In recent years, dopamine is due to its superpower adherency
Characteristic and the surface modification for being widely used in solid material, but dopamine is aggregated in gelatine microsphere surface to strongly combine
The research report of functional molecular is actually rare.Medicament slow release is a big hot topic project of gelatine microsphere application development research.Section
It is all continuous that personnel, which are ground, from being initially modified, modifying to gelatine microsphere by now to the research of gelatine microsphere preparation process etc.
Exploration.
Invention content
The purpose of the present invention is to provide a kind of poly-dopamine gelatine microsphere preparation methods, and poly-dopamine is successfully coated on
On gelatine microsphere, drug carrying ability is excellent, sustained drug release effect is good.
The technical solution adopted by the present invention is as follows：A kind of poly-dopamine gelatine microsphere preparation method, gelatin obtained is micro-
Ball is put into pre-configured Tris/HCI, in the buffer solution of pH=8.5,2mg/mL dopamine solutions is then added, at 37 DEG C
Lower stirring 12-24h is then centrifuged and is washed with deionized three times, air-dries up to the coated gelatine microsphere of poly-dopamine.
The poly-dopamine gelatine microsphere that the above method using the present invention is prepared is used for medicament slow release；For carrying Vc：
It takes the coated gelatine microsphere of poly-dopamine and Vc to be mixed in distilled water, and fully infiltrates 20-24h at 4 DEG C, it later will mixing
Object centrifuges, and takes part supernatant, and label is for use, remaining to be placed in minus 80 DEG C of ultra low temperature freezers freezing 6h or more, takes out, is placed on cold
Dry 12-24h on lyophilizer, obtains the poly-dopamine gelatine microsphere for carrying Vc.
In the step (1), gelatin solution is added to as water phase and is pre-configured with using emulsification-cross-linking method by gelatine microsphere
Good is mixed in the atoleine of span-80, turns ice-water bath after emulsification, adds glutaraldehyde, isopropanol is added after crosslinking curing, quiet
It sets, centrifuge, isopropanol is added to wash, filter, be drying to obtain.
To the assay method of the drugloading rate and embedding rate of the Vc of the load Vc poly-dopamine gelatine microspheres of the above-mentioned preparation of the present invention,
The technical solution of use is as follows：
The supernatant of acquirement is measured into its Vc absorbance on ultraviolet specrophotometer, and is acquired by standard curve
The content of Vc in solution calculates the drugloading rate and embedding rate of Vc；
Quality × 100% of drugloading rate=(remaining Vc contents in Vc gross masses-solution of input)/gelatine microsphere
Vc gross mass × 100% of embedding rate=(remaining Vc contents in Vc gross masses-solution of input)/input.
The method for adding up release rate to the Vc of the load Vc poly-dopamine gelatine microspheres of the above-mentioned preparation of the present invention, specifically include with
Lower step：
Step (1) accurately weighs 0.0132g ascorbic acid (Vc) and is dissolved in 1000mL volumetric flasks with distilled water, is settled to
Graduation mark, a concentration of the 7.5 × 10 of Vc in this solution-5mol/L.Drawn respectively from 1000mL Vc solution 4mL, 6mL, 8mL,
The solution of 10mL is settled to the distilled water of 46mL, 44mL, 42mL, 40mL in the volumetric flask of 50ml, for use；
Step (2) opens ultraviolet specrophotometer, and using distilled water as reference, the suction of Vc is measured within the scope of 220-320nm
The curve of spectrum is received, determines the maximum absorption wavelength of Vc, the absorbance value for measuring 4 Vc standard solution is grown in maximum absorption wave,
The canonical plotting of Vc is drawn according to the data obtained and obtains the equation of linear regression of Vc；
Step (3) takes the poly-dopamine gelatine microsphere of partly lyophilized good load Vc, is divided into 3 groups, every group of sample
Molten with quantitative water phase, interval 10min, 30min, 1h, 2h, 4h, 6h, 8h, 10h take quantitative upper solution label to preserve, and mend
The water of equivalent is filled, the upper solution taken is finally done into fixed wave length analysis, absorbance value is measured, calculates the accumulative of Vc and release
Put rate.
Compared with prior art, the beneficial effects of the present invention are：The present invention prepares gelatine microsphere using emulsification-cross-linking method
(Simple coacervation refers to that hydrophilic Tween-20 is added in solvent gelatin solution, emulsifies certain time compared with Simple coacervation
The metabisulfite solution prepared is added afterwards, goes to ice-water bath, glutaraldehyde is added after a period of time, crosslinking curing is eventually adding certain
Isopropanol is measured, is stood overnight, is centrifuged within second day, isopropanol washing is added and filters afterwards several times, is drying to obtain.) Simple coacervation preparation
Gelatine microsphere grain size it is relatively small, balling ratio is not high, and spherome surface is coarse opaque；Emulsification-cross-linking method through the invention
The gelatine microsphere grain size of preparation is relatively large, and balling ratio is high, and spherome surface is smooth and transparent, and gelatine microsphere obtained is in pattern
Upper difference is small, and obtained gelatine microsphere is more high-quality, can be carried out to the gelatine microsphere of the present invention using poly-dopamine good
Coating modification enhances its surface chemistry multifunctionality, the coated gelatine microsphere of poly-dopamine property in terms of drugloading rate, medicament slow release
Can be excellent, can succeed supported V c, and the coated gelatine microsphere of poly-dopamine of the present invention is notable in terms of Vc controlled releases, through the invention
The poly-dopamine coating gelatine microsphere of preparation is applied has potential value in terms of medicament slow release.
The performance test of poly-dopamine gelatine microsphere of the present invention and characterization
1. carry Vc/macrograph of poly-dopamine/gelatine microsphere
As shown in Figure 1, for the photomacrograph of different gelatine microspheres obtained.Different gelatine microspheres is morphologically without larger
Difference, gelatine microsphere (Fig. 1 a) made from Simple coacervation is in faint yellow, and gelatine microsphere (Fig. 1 b) face made from emulsification-cross-linking method
Color is deeper, and the gelatine microsphere (Fig. 1 c) for carrying Vc is not much different with the former, and poly-dopamine gelatine microsphere (Fig. 1 d) is in black, this is
Because the autoxidation polymerisation of dopamine can form the poly-dopamine film of one layer of black in stromal surface.
2. carry Vc/microgram of poly-dopamine/gelatine microsphere
As shown in Fig. 2, for the photo (20 ×) of each gelatine microsphere under fluorescence microscope.As can be seen that Simple coacervation is made
Gelatine microsphere (Fig. 2 a) good dispersion, but grain size is smaller, and balling ratio is low and rough surface is opaque；But breast through the invention
Gelatine microsphere (Fig. 2 b) good dispersion made from change-cross-linking method, grain size is larger, balling ratio height and surface glossy clear.By poly-
The coated gelatine microsphere (Fig. 2 d) of dopamine, without larger difference, and carries the gelatine microsphere (Fig. 2 c and Fig. 2 e) of Vc in grain on grain size
Have the tendency that significantly becoming larger on diameter, shows that poly-dopamine is to form the film of one layer of oxidation polymerization on gelatine microsphere surface, and Vc
On gelatine microsphere surface constantly by adsorpting aggregation, finally " shell " thick in the formation of gelatine microsphere.
3. carry Vc/histogram of particle size distribution of poly-dopamine/gelatine microsphere
As shown in figure 3, for the distribution situation of different gelatine microsphere grain sizes, the poly-dopamine gelatine microsphere (Vc- of Vc is carried
PDA-GM), poly-dopamine gelatine microsphere (PDA-GM), carry Vc gelatine microspheres (Vc-GM), Simple coacervation gelatine microsphere (GM-D),
The grain size distribution of emulsification-cross-linking method gelatine microsphere (GM-R)；Comparative analysis Simple coacervation gelatine microsphere (GM-D) and emulsification-friendship
Known to the histogram of particle size distribution of connection method gelatine microsphere (GM-R)：The gelatine microsphere grain size made from Simple coacervation is generally smaller,
Size is at 24.40 ± 6.58 μm, and the gelatine microsphere made from emulsification-cross-linking method, more high-quality grain size are relatively large, and size exists
36.53±8.77μm.The gelatine microsphere (Vc-PDA-GM and Vc-GM) of Vc is carried compared with gelatine microsphere (GM-D and GM-R), grain size
Have and become larger, this there are much relations with the amount for carrying Vc.Directly carry the bright of gelatine microsphere (Vc-GM) and the poly-dopamine rear bearing Vc of Vc
There is very big difference in glue microballoon (Vc-PDA-GM), the gelatine microsphere particle diameter distribution for directly carrying Vc is more wide, has in particle diameter distribution
Have greatly it is small, carry Vc amounts it is different, have no regularity；And the gelatine microsphere particle diameter distribution Relatively centralized of poly-dopamine rear bearing Vc,
The coated gelatine microsphere particle diameter distribution of poly-dopamine is stablized relatively, and size is at 43.02 ± 10.34 μm.It can be seen that poly-dopamine is coated with
Gelatine microsphere than the gelatine microsphere for directly carrying Vc it is well many in performance in terms of carrying Vc, microspherulite diameter distribution Relatively centralized,
The amount for averagely carrying Vc is also essentially identical.
4. carrying the chemical constitution characterization of (poly-dopamine) gelatine microsphere of Vc
As shown in figure 4, for the infrared spectrogram of Vc, dopamine, gelatin and its compound.Analysis compare DA, PDA-GM,
Tri- curves of Vc-PDA-GM can be seen that wavelength in 1616cm-1Going out has the stretching vibration peak of apparent amido N-H, in wavelength
3340cm-1Also there is the Absorption Characteristics peak of O-H in place, illustrate poly-dopamine can successfully be coated on the present invention prepare it is bright
On glue microballoon.The curve for comparing Vc, Vc-GM, Vc-PDA-GM again is found in wavelength 3623cm-1Go out to have stretching for enol base O-H
Vibration peak, it was demonstrated that Vc is also successfully loaded on gelatine microsphere.
The standard curve of 5.Vc and gelatine microsphere drugloading rate, embedding rate and the accumulative release rate for carrying Vc
As shown in figure 5, being Vc using distilled water as the uv absorption spectra of reference, find out Vc solution in wavelength by figure
Occurs wave crest at 256nm, this is the maximum absorption bands of Vc in water.
The standard curve of Vc is drawn out further according to the ultraviolet light absorption angle value of the various concentration Vc solution measured.Such as Fig. 6 Vc
Ultraviolet release standard curve
Gelatine microsphere-Vc mixed liquor the supernatants obtained by centrifuging and taking measure：
The Vc drugloading rates for directly carrying the gelatine microsphere of Vc are 2%, embedding rate 5%.
The Vc drugloading rates of the coated gelatine microsphere of poly-dopamine are 31%, embedding rate 44.29%.
Vc adds up release rate as shown in fig. 7, can be seen that by data above：The coated gelatine microsphere of poly-dopamine carries medicine in Vc
Amount ability can be seen that far above the gelatine microsphere for directly carrying Vc by Vc Cumulative release profile figures：The coated gelatin of poly-dopamine
Microballoon its Vc rate of release will be far below the gelatine microsphere for directly carrying Vc, and the directly gelatine microsphere solution of load Vc is from testing at the beginning
The most of Vc for just releasing micro-ball load shows that the gelatine microsphere for directly carrying Vc belongs to burst release type, this kind of administration in administration
Mode can not use under the conditions of certain specific.The coated load Vc gelatine microspheres of poly-dopamine delay at the very start from experiment
On The Drug Release Vc, and gradually stablize over time, illustrate that poly-dopamine truly has remarkable result in terms of Vc controlled releases, also
It is to say that poly-dopamine has huge Development volue on medicament slow release.Simultaneously when the accumulative release rate of Vc reaches a certain level
When, start to tend to a fixed value, that is to say, that no longer release is even recovered the Vc in microballoon again outward, it may be possible to by
The influence (such as temperature, humidity) of extraneous factor causes.
Dopamine solution meeting spontaneous oxidation polymerization in the buffer solution of Tris/HCI (pH=8.5), in gelatine microsphere
Surface formed one layer of black poly-dopamine film.So that gelatine microsphere is fully infiltrated with Vc solution at 4 DEG C, then passes through freezing
It is dry to be made.The gelatine microsphere for having carried Vc has the tendency that becoming larger on grain size.The gelatine microsphere of Vc is directly carried in particle diameter distribution
The upper deviation is larger, and poly-dopamine gelatine microsphere is relatively excellent in load Vc this aspect performance.Poly-dopamine is in drugloading rate, drug
It is had excellent performance in terms of sustained release.
In conclusion method through the invention is prepared for more good gelatine microsphere.In gelatin prepared by the present invention
Microballoon carries out supported V c and poly-dopamine supported V c processing, and by infrared spectrum, uv-spectrophotometric tests its chemical property, carries
The difference of dose and medicament slow release etc..It obtains：Simple coacervation prepares gelatine microsphere and compares with emulsification-cross-linking method, using this
The success rate of gelatine microsphere prepared by the method for invention is high, and both topographically difference is small for gelatine microsphere, more high-quality.Through poly-dopamine
Gelatine microsphere after coating on grain size with gelatine microsphere without larger difference, only will present out black, directly carry the gelatin of Vc
Microspherulite diameter distribution varies, and variation has no rule；And the particle diameter distribution phase after the coated gelatine microsphere of poly-dopamine carries Vc
To stabilization.Ultraviolet release test through Vc shows：The exploitation that the superpower adhesion characteristic of dopamine is suitable for organization material really is excellent
Change etc., especially increases significantly in terms of drugloading rate, and effect is good in terms of medicament slow release.
Description of the drawings
The macrograph of each gelatine microspheres of Fig. 1；
In figure：(a) Simple coacervations gelatine microsphere, (b) emulsifications-cross-linking method gelatine microsphere, (c) loads Vc gelatine microspheres,
(d) poly-dopamines gelatine microsphere, (e) photomacrograph of the poly-dopamine gelatine microsphere of loads Vc；
Fig. 2 are photo (20 ×) photo figure of each gelatine microsphere under fluorescence microscope；
In figure：(a) Simple coacervations gelatine microsphere, (b) emulsifications-cross-linking method gelatine microsphere, (c) loads Vc gelatine microspheres,
(d) poly-dopamines gelatine microsphere, (e) the poly-dopamine gelatine microsphere of loads Vc；
The grain size distribution of each gelatine microspheres of Fig. 3；
In figure：The poly-dopamine gelatine microsphere (Vc-PDA-GM) of Vc is carried, poly-dopamine gelatine microsphere (PDA-GM) carries Vc
Gelatine microsphere (Vc-GM), Simple coacervation gelatine microsphere (GM-D), emulsification-cross-linking method gelatine microsphere (GM-R)；
The infrared spectrogram of Fig. 4 .Vc, dopamine, gelatin and its compound；
The uv absorption spectra of Fig. 5 .Vc；
The ultraviolet release standard curve of Fig. 6 .Vc；
Fig. 7 .Vc add up release rate curve graph.
Specific implementation mode
Embodiment 1
1. preparing gelatine microsphere using emulsification-cross-linking method, it is added to a certain amount of gelatin solution as water phase in advance
What is configured is mixed in the atoleine of span-80, and emulsification turns ice-water bath after a certain period of time, and glutaraldehyde is added after a period of time,
Then crosslinking curing is added a certain amount of isopropanol, stands overnight, centrifuge within second day, and isopropanol washing is added and filters afterwards several times, does
It is dry to obtain the final product.Concrete operation step is as follows：
(1) weighs 0.3g gelatin, is dissolved in 10mL distilled water, is stirred to solution at 50 DEG C.
(2) measures 30mL atoleines, and 0.5mLspan-80 is added, 10min is stirred at 50 DEG C.
(3) gelatin solution is added dropwise in atoleine by, emulsifies 20min.
(4) fast-turn constructions ice-water bath stirs 1h, and 2.5% 200 μ L of glutaraldehyde are added, and is crosslinked 1h.
(5) 5mL isopropanols are added in, stand, overnight.
(6) sample is centrifuged (3000r/min) by, is washed three times with isopropanol, is filtered, be drying to obtain gelatine microsphere.
2. a kind of poly-dopamine gelatine microsphere preparation method carrying Vc, specifically includes following steps,
The preparation of step (1) poly-dopamine gelatine microspheres：Gelatine microsphere obtained is put into pre-configured Tris/
In the buffer solution of HCI, pH=8.5,2mg/mL dopamine solutions are then added, are stirred overnight at 37 DEG C, then centrifugation is used in combination
Deionized water is washed three times, is air-dried up to the coated gelatine microsphere of poly-dopamine；
It is prepared by the poly-dopamine gelatine microsphere that step (2) carries Vc：The coated gelatine microsphere of poly-dopamine and Vc is taken to distill
It is mixed in water, and 20-24h is fully infiltrated at 4 DEG C, later centrifuge mixture, take part supernatant, label is for use, remaining
It is placed in minus 80 DEG C of ultra low temperature freezers freezing 6h or more, is taken out, dry 12-24h is placed on freeze drier, obtains carrying the poly- of Vc
Dopamine gelatine microsphere.
The load Vc and drugloading rate of 2.1 gelatine microspheres, the measurement of embedding rate
Since Vc can be denaturalized at high temperature, so a certain amount of gelatine microsphere and Vc is respectively taken to be mixed in distilled water, and 4
It is fully infiltrated for 24 hours at DEG C.Mixture is centrifuged later, takes part supernatant, label is for use, remaining to be placed in minus 80 DEG C of ultralow temperature ices
Case freezes 6h or more, takes out, is placed on freeze drier and is dried overnight, and obtains the gelatine microsphere for carrying Vc.
The poly-dopamine gelatine microsphere of Vc is carried obtained by above-mentioned steps (2)；
The supernatant of acquirement is measured into its Vc absorbance on ultraviolet specrophotometer (Evolution 300, Uv-vis),
And the standard curve by hereafter having drawn acquires the content of Vc in solution, calculates the drugloading rate and embedding rate of Vc.
Quality × 100% of drugloading rate=(remaining Vc contents in Vc gross masses-solution of input)/gelatine microsphere
Vc gross mass × 100% of embedding rate=(remaining Vc contents in Vc gross masses-solution of input)/input；
2.2 carry Vc/morphology characterization of poly-dopamine/gelatine microsphere
Part is taken to be placed on glass slide different gelatine microspheres obtained, with water infiltration, by fluorescence microscope at 20 times
Lower observation pattern is simultaneously taken pictures, and is measured with ImageJ 1.40G softwares (National Institutes of Health, USA) bright
The grain size of glue microballoon (each sample measures 30).
Gelatine microsphere (Fig. 1 b) color of emulsification-crosslinking legal system is deeper, and the gelatine microsphere (Fig. 1 c) for carrying Vc is differed with the former
Less, and poly-dopamine gelatine microsphere (Fig. 1 d) be in black because the autoxidation polymerisation of dopamine can be in stromal surface shape
At the poly-dopamine film of one layer of black.Dopamine meeting spontaneous oxidation polymerization, coated gelatin of poly-dopamine under hygrometric state condition is micro-
Ball on grain size with gelatine microsphere without larger difference, only will present out black.
2.3 carry Vc/IR Characterization of poly-dopamine/gelatine microsphere
Different gelatine microsphere samples is carried out by FTIR spectrum method (FTIR) (Nexus, Nicolet, USA)
Whether characterization, verification Vc, dopamine have successfully loaded on gelatine microsphere.The measurement range of infrared spectrum is 600-
4000cm-1。
2.4 carry Vc/Vc of poly-dopamine/gelatine microsphere adds up release rate
A method of the Vc measuring the poly-dopamine gelatine microsphere of above-mentioned load Vc adds up release rate, specifically includes following
Step：
Step (1) accurately weighs 0.013g ascorbic acid (Vc) and is dissolved in 1000ml volumetric flasks with distilled water, is settled to quarter
Spend line.A concentration of the 7.5 × 10 of Vc in this solution-5mol/L.4ml, 6ml, 8ml, 10ml are drawn respectively from 1000mlVc solution
The distilled water of solution and 46ml, 44ml, 42ml, 40ml be settled in the volumetric flask of 50ml, for use.
Step (2) opens ultraviolet specrophotometer (Evolution 300), using distilled water as reference, in 220~320nm
The absorption spectrum curve that Vc is measured in range, determines the maximum absorption wavelength of Vc.It is grown in maximum absorption wave and measures 4 Vc standards
The absorbance value of solution draws the canonical plotting of Vc according to the data obtained and obtains the equation of linear regression of Vc.
Step (3) take partly lyophilized good load Vc gelatine microspheres and, be divided into 3 groups, every group of sample with it is quantitative
Water phase is molten, and interval 10min, 30min, 1h, 2h, 4h, 6h, 8h, 10h take quantitative upper solution label to preserve, and supplement equivalent
Water.The poly-dopamine gelatine microsphere for carrying Vc also does same processing.Finally the upper solution taken is all taken away the wavelength that fixes
Analysis, measures absorbance value, calculates the accumulative release rate of Vc.
Fig. 5 is Vc using distilled water as the uv absorption spectra of reference, by figure we can see that Vc solution is in wavelength
There is wave crest in 256nm, this is the maximum absorption bands of Vc in water.Further according to the ultraviolet light absorption of the various concentration Vc solution measured
Angle value draws out the standard curve of Vc.As shown in fig. 6, the ultraviolet release standard curve of Vc
Gelatine microsphere-Vc mixed liquor the supernatants obtained by centrifuging and taking measure：
The Vc drugloading rates for directly carrying the gelatine microsphere of Vc are 2%, embedding rate 5%.
The Vc drugloading rates of the coated gelatine microsphere of poly-dopamine are 31%, embedding rate 44.29%.
Vc adds up release rate, as shown in fig. 7, by data above we can see that：The coated gelatine microsphere of poly-dopamine
To be far above the gelatine microsphere of directly load Vc in terms of Vc drugloading rates, the superpower adhesion characteristic of this and poly-dopamine has very high point
System.Can intuitively it be found out by Vc Cumulative release profiles figure：Its Vc rate of release of the coated gelatine microsphere of poly-dopamine is remote
Less than the gelatine microsphere for directly carrying Vc, the gelatine microsphere solution for directly carrying Vc has been initially released the big of micro-ball load from experiment
Part Vc shows that the gelatine microsphere for directly carrying Vc belongs to burst release type in administration, and this kind of administering mode is in certain specific conditions
Under can not use.The coated load Vc gelatine microspheres of poly-dopamine are from experiment slow release Vc at the very start, and with the time
Passage gradually stablize, illustrate that poly-dopamine truly has remarkable result in terms of Vc controlled releases.
The present invention is relatively large by gelatine microsphere grain size prepared by emulsification-cross-linking method, and balling ratio is high, and spherome surface is smooth
And it is transparent.Dopamine solution meeting spontaneous oxidation polymerization in the buffer solution of Tris/HCI (pH=8.5), in gelatine microsphere
Surface forms the poly-dopamine film of one layer of black.The gelatine microsphere for directly carrying Vc is larger in the particle diameter distribution upper deviation, and poly- DOPA
Amine gelatine microsphere is excellent in load Vc performances.
Reference example
Simple coacervation refers to that hydrophilic Tween-20 is added in solvent gelatin solution, and emulsification is added after a certain period of time
The metabisulfite solution prepared goes to ice-water bath, and glutaraldehyde is added after a period of time, and crosslinking curing is eventually adding a certain amount of isopropyl
Alcohol is stood overnight, and is centrifuged within second day, and isopropanol washing is added and filters afterwards several times, is drying to obtain.Concrete operation step is as follows：
(1) 0.3g gelatin is weighed, is dissolved in 10mL distilled water, is stirred to solution at 50 DEG C.
(2) 2mL Tween-20s are drawn, are added in gelatin solution, 20min is emulsified, it is lasting to stir.
(3) it takes 5% pre-configured metabisulfite solution 1mL to be added, continues to stir 10min.
(4) gelatin solution is quickly transferred in ice-water bath and stirs 1h, 2.5% 200 μ L of glutaraldehyde are added, be crosslinked 1h.
(5) 5mL isopropanols are added, stand, overnight.
(6) sample is centrifuged into (3000r/min), is washed three times with isopropanol, filters, be drying to obtain gelatine microsphere.
Relatively small through characterizing gelatine microsphere grain size prepared by Simple coacervation, balling ratio is not high, and spherome surface is coarse impermeable
It is bright.
Claims (8)
1. a kind of poly-dopamine gelatine microsphere preparation method, it is characterised in that：Gelatine microsphere obtained is put into pre-configured
Tris/HCI, in the buffer solutions of pH=8.5,2mg/mL dopamine solutions are then added, 12-24h are stirred at 37 DEG C, then
It centrifuges and is washed with deionized three times, air-dry up to the coated gelatine microsphere of poly-dopamine.
2. a kind of poly-dopamine gelatine microsphere preparation method according to claim 1, it is characterised in that：It is slow for drug
It releases.
3. a kind of poly-dopamine gelatine microsphere preparation method according to claim 2, it is characterised in that：For carrying Vc：It takes
The coated gelatine microsphere of poly-dopamine and Vc are mixed in distilled water, and 20-24h is fully infiltrated at 4 DEG C, later by mixture
Centrifugation takes part supernatant, and label is for use, remaining to be placed in minus 80 DEG C of ultra low temperature freezers freezing 6h or more, takes out, is placed on freezing
Dry 12-24h on drying machine, obtains the poly-dopamine gelatine microsphere for carrying Vc.
4. according to a kind of poly-dopamine gelatine microsphere preparation method of claim 1-3 any one of them, it is characterised in that：It is described
In step (1), gelatine microsphere is added to pre-configured be mixed with using emulsification-cross-linking method using gelatin solution as water phase
In the atoleine of span-80, turn ice-water bath after emulsification, add glutaraldehyde, isopropanol is added after crosslinking curing, stands, centrifugation, add
Isopropanol is washed, filters, is drying to obtain.
5. a kind of measurement of the drugloading rate and embedding rate of the Vc of poly-dopamine gelatine microsphere carrying Vc according to claim 3
Method, it is characterised in that：The supernatant of acquirement is measured into its Vc absorbance on ultraviolet specrophotometer, and passes through standard
Curve acquires the content of Vc in solution, calculates the drugloading rate and embedding rate of Vc；
Quality × 100% of drugloading rate=(remaining Vc contents in Vc gross masses-solution of input)/gelatine microsphere
Vc gross mass × 100% of embedding rate=(remaining Vc contents in Vc gross masses-solution of input)/input.
6. a kind of method that Vc of the measurement poly-dopamine gelatine microsphere as claimed in claim 3 for carrying Vc adds up release rate,
It is characterized in that：Specifically include following steps：
Step (1) accurately weighs 0.0132g ascorbic acid (Vc) and is dissolved in 1000mL volumetric flasks with distilled water, is settled to scale
Line, a concentration of the 7.5 × 10 of Vc in this solution-5mol/L.4mL, 6mL, 8mL, 10mL are drawn respectively from 1000mL Vc solution
The distilled water of solution and 46mL, 44mL, 42mL, 40mL be settled in the volumetric flask of 50ml, for use；
Step (2) opens ultraviolet specrophotometer, and using distilled water as reference, the absorption light of Vc is measured within the scope of 220-320nm
Spectral curve determines the maximum absorption wavelength of Vc, and the absorbance value for measuring 4 Vc standard solution is grown in maximum absorption wave, according to
The data obtained draws the canonical plotting of Vc and obtains the equation of linear regression of Vc；
Step (3) takes the poly-dopamine gelatine microsphere of partly lyophilized good load Vc, is divided into 3 groups, every group of sample with it is fixed
The water phase of amount is molten, interval 10min, 30min, 1h, 2h, 4h, 6h, 8h, 10h, 12h, quantitative upper solution label is taken to preserve for 24 hours,
And the water of equivalent is supplemented, the upper solution taken is finally done into fixed wave length analysis, measures absorbance value, calculates the tired of Vc
Count release rate.
7. a kind of poly-dopamine gelatine microsphere for the load Vc being prepared by any the methods of claim 1-3.
8. the application of poly-dopamine gelatine microsphere described in claim 1, it is characterised in that：For medicament slow release.
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