CN105694120B - A kind of preparation method of chitosan oligosaccharide hyaluronic acid composite nano particle - Google Patents
A kind of preparation method of chitosan oligosaccharide hyaluronic acid composite nano particle Download PDFInfo
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- CN105694120B CN105694120B CN201410699380.2A CN201410699380A CN105694120B CN 105694120 B CN105694120 B CN 105694120B CN 201410699380 A CN201410699380 A CN 201410699380A CN 105694120 B CN105694120 B CN 105694120B
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Abstract
The invention discloses a kind of technology of preparing of the nanoparticle in high molecular material field, i.e., a kind of preparation method of chitosan oligosaccharide hyaluronic acid composite nano particle, the present invention, as raw material, synthesizes target product by polymer agglomerates method using chitosan oligosaccharide and hyaluronic acid.Specific steps are as follows: be dissolved in chitosan oligosaccharide, hyaluronic acid in deionized water respectively, obtain chitosan oligosaccharide solution and hyaluronic acid solution, one of above two solution is slowly dropped under agitation in another solution, carry out polymer precipitation reaction, when dripping quantity is close to half, stop being added dropwise, then resulting reaction system is reversely added drop-wise in former solution, and is kept stirring.The mass ratio of speed of agitator, the concentration of chitosan oligosaccharide, the concentration of hyaluronic acid, chitosan oligosaccharide and hyaluronic acid and the rate of addition of solution are controlled, to end of reaction, ultrasonic disperse is isolated and purified, and is dried to obtain product of the invention.The average grain diameter of product is -20mV-+30mV in 120-200nm, Zeta potential, can be used as pharmaceutical carrier and biomaterial for medical purpose, has good research and development prospect.
Description
Technical field
The invention belongs to a kind of preparation methods of chitosan oligosaccharide hyaluronic acid composite nano particle of technical field of biological material.
Background technique
Chitosan oligosaccharide is called Chitosan poly oligosaccharide, chitosan oligomer, is using chitosan as raw material, one made of degrading through biotechnology
Kind oligosaccharide product.Good water solubility, the bioactivity of chitosan oligosaccharide are high, and in human body internal absorption factor nearly 100%, effect is chitosan
Decades of times, the effect to human body includes immunological regulation, antitumor, reducing blood lipid, adjust blood glucose, improve liver and cardio-pulmonary function and its
His different physiological roles.In existing research invention, once had been reported that and chitosan oligosaccharide nanoparticle is prepared for by solvent diffusion method, and
The case where human lung adenocarcinoma cell absorbs it has been investigated, has disclosed chitosan oligosaccharide nanoparticle as biopharmaceutical macromolecular drug carrier
Potential function.It also has been reported that and glycosyl galactose chitosan oligosaccharide nanoparticle is prepared for by microemulsified-gelling process, be with diammonium glycyrrhizinate
Model drug has investigated its liver target function.However, the nanoparticle stability of above method preparation is poor, preparation process phase
It is not easy to remove to complexity, using emulsifier and dispersing agent etc., reduces its biocompatibility, affect it and be used as drug in vivo
The application of carrier.Therefore, the present invention is directed to prepare a kind of stability is strong, good dispersion, preparation process are simple, mild condition and
Nanoparticle with certain targeting is of great significance for drug encapsulation, release and the targeted delivery under physiological condition.
Summary of the invention
It is existing to make up the object of the present invention is to provide a kind of preparation method of chitosan oligosaccharide hyaluronic acid composite nano particle
The shortcomings that technique.
The present invention, as raw material, synthesizes chitosan oligosaccharide hyaluronic acid by polymer agglomerates method using chitosan oligosaccharide and hyaluronic acid
Composite nano particle.Specific steps are as follows: chitosan oligosaccharide, hyaluronic acid are dissolved in deionized water respectively, obtain chitosan oligosaccharide solution and
One of above two solution is slowly dropped in another solution under agitation, is gathered by hyaluronic acid solution
Object precipitation reaction is closed, when dripping quantity is close to half, stops being added dropwise, resulting reaction system is reversely then added drop-wise to former
In solution, and it is kept stirring.Control speed of agitator, the concentration of chitosan oligosaccharide, the concentration of hyaluronic acid, chitosan oligosaccharide and hyaluronic acid
The rate of addition of mass ratio and solution, to end of reaction, ultrasonic disperse is isolated and purified, and is dried to obtain chitosan oligosaccharide hyaluronic acid
Composite nano particle.
The present invention have it is easy to operate, low in cost, preparation condition is mildly quick, and it is excellent not add emulsifier and dispersing agent etc.
Point, raw material-chitosan oligosaccharide and hyaluronic acid used in the present invention have preferable biocompatibility, low toxicity, under physiological condition
It is solvable, there is significant advantage as the application of drug delivery carrier in vivo.Significance of the invention is to prepare
Obtained nanoparticle has well-regulated spherical shape, can be stabilized under neutrallty condition, be conducive to carry out drug under physiological condition
Contain and discharge.In cell surface, there are the receptor CD44 of hyaluronic acid simultaneously, and it is multiple that this also gives chitosan oligosaccharide hyaluronic acid
The intracorporal targeting of nanoparticle is closed, there is good research application prospect in biomaterial and cancer diagnosis and treatment.
Detailed description of the invention
Fig. 1: the schematic diagram (method one) of chitosan oligosaccharide hyaluronic acid composite nano particle
Fig. 2: the schematic diagram (method two) of chitosan oligosaccharide hyaluronic acid composite nano particle.
Specific embodiment
The present invention, as raw material, synthesizes target product by polymer agglomerates method using chitosan oligosaccharide.Specific embodiment are as follows:
Step 1: chitosan oligosaccharide and hyaluronic acid are dissolved in deionized water respectively, the concentration of chitosan oligosaccharide is 0.2%-1.2%,
The concentration of hyaluronic acid is 0.2%-1.2%
Step 2:
Method one:
Hyaluronic acid solution is slowly dropped in chitosan oligosaccharide solution, the mass ratio of chitosan oligosaccharide and hyaluronic acid is 0.2-1:
1, when the dripping quantity of hyaluronic acid solution reaches 40%-60%, remaining hyaluronic acid is added drop-wise to by resulting reaction system is counter
It in solution, completes to be added dropwise in 15-30 min, revolving speed is 200-500 revs/min, and the reaction time is 1-5 hours, and ultrasonic power is
100-150w, ultrasonic time are 5-10 minutes, and 20000 revs/min are centrifuged 20 minutes, discard supernatant liquid, are freeze-dried
Obtain target product.
Method two:
Chitosan oligosaccharide solution is slowly dropped in hyaluronic acid solution, dripping quantity is the mass ratio of chitosan oligosaccharide and hyaluronic acid
For 0.2-1:1, when the dripping quantity of chitosan oligosaccharide solution reaches 40%-60%, remaining shell is added drop-wise to by resulting reaction system is counter
It in oligosaccharide solution, completes to be added dropwise in 15-30 min, revolving speed is 200-500 revs/min, and the reaction time is 1-5 hours, ultrasonic function
Rate is 100-150w, and ultrasonic time is 5-10 minutes, and 20000 revs/min are centrifuged 20 minutes, discard supernatant liquid, is freeze-dried,
Target product can be obtained.
The molecular weight of chitosan oligosaccharide in the present invention is 1000-5000Da, 90% or more deacetylation, the molecule of hyaluronic acid
Amount is 10000-50000Da, the structural schematic diagram of products therefrom as shown in Figure 1, product is carried out partial size and Zeta potential is analyzed,
The result shows that the uniform particle diameter of prepared nanoparticle, the coefficient of dispersion is in 0.093-0.195, and average grain diameter is in 120-200
Nm, nanometer system is more stable, Zeta potential -20mV -+30mV (table 1).The observation that transmission electron microscope is carried out to product, receives
Rice particle is spherical in shape, and size is uniform, and be uniformly dispersed (Fig. 2).
The manufacturing method of the present invention is further provided for following specific embodiment.
Embodiment 1:
Taking 0.01 g molecular weight is that the chitosan oligosaccharide of 1500Da is dissolved in 5mL deionized water, under agitation, is slowly added dropwise
(w/v) molecular weight of 2mL 0.4% is that it is transparent to be then added drop-wise to 3mL by the hyaluronic acid solution of 10000Da for resulting reaction system
It in matter acid solution, drips off within 20 minutes, mixing speed is 300 revs/min, is reacted 2 hours, 100w ultrasound 5 minutes, 20000 revs/min
Zhongli's heart 20 minutes, liquid is discarded supernatant, is freeze-dried up to chitosan oligosaccharide hyaluronic acid composite nano particle.
Embodiment 2:
Taking 0.02 g molecular weight is that the chitosan oligosaccharide of 2500Da is dissolved in 5mL deionized water, under agitation, is slowly added dropwise
(w/v) molecular weight of 3mL 0.6% is that resulting reaction system is then added drop-wise to remaining by the hyaluronic acid solution of 20000Da
In 2mL hyaluronic acid solution, dripping off within 30 minutes, mixing speed is 400 revs/min, it reacts 3 hours, 120w ultrasound 5 minutes,
20000 revs/min are centrifuged 20 minutes, discard supernatant liquid, are freeze-dried up to chitosan oligosaccharide hyaluronic acid composite nano particle.
Embodiment 3:
Taking 0.05g molecular weight is that the hyaluronic acid of 40000Da is dissolved in 5mL deionized water, under agitation, is slowly dripped
Add 2mL 0.2%(w/v) molecular weight be 3500Da chitosan oligosaccharide solution it is few that resulting reaction system is then added drop-wise to 3mL shell
It in sugar juice, drips off within 30 minutes, mixing speed is 200 revs/min, is reacted 4 hours, 120w ultrasound 10 minutes, 20000 revs/min
Zhongli's heart 20 minutes, liquid is discarded supernatant, is freeze-dried up to chitosan oligosaccharide hyaluronic acid composite nano particle.
Embodiment 4:
Taking 0.06g molecular weight is that the hyaluronic acid of 50000Da is dissolved in 5mL deionized water, under agitation, is slowly dripped
Add 3mL 0.3%(w/v) molecular weight be 5000Da chitosan oligosaccharide solution it is few that resulting reaction system is then added drop-wise to 2mL shell
In sugar juice, being dripped off in 20 minutes, mixing speed is 500 revs/min, it reacts 5 hours, 150w ultrasound 10 minutes, 20000 turns/
Minute centrifugation 20 minutes, discards supernatant liquid, is freeze-dried up to chitosan oligosaccharide hyaluronic acid composite nano particle.
Subordinate list explanation
Table 1: average grain diameter, the coefficient of dispersion and the Zeta potential of chitosan oligosaccharide hyaluronic acid composite nano particle
Claims (1)
1. a kind of preparation method of chitosan oligosaccharide hyaluronic acid composite nano particle, it is characterized in that with polymer agglomerates method, it is specific to walk
Suddenly are as follows: chitosan oligosaccharide, hyaluronic acid are dissolved in deionized water respectively, obtain chitosan oligosaccharide solution and hyaluronic acid solution, by shell widow
Sugar juice is slowly dropped in hyaluronic acid solution under agitation, carries out polymer precipitation reaction, is dripped to chitosan oligosaccharide solution
When dosage reaches 40-60%, stop being added dropwise, then resulting reaction system is reversely added drop-wise in chitosan oligosaccharide solution, and keeps stirring
It mixes, the chitosan oligosaccharide hyaluronic acid composite nano particle of positive surface charge is prepared, or by hyaluronic acid solution in stirring bar
It is slowly dropped under part in chitosan oligosaccharide solution, carries out polymer precipitation reaction and stop when hyaluronic acid dripping quantity reaches 40-60%
It is only added dropwise, then resulting reaction system is reversely added drop-wise in hyaluronic acid solution, and is kept stirring, surface is prepared
The molecular weight of the chitosan oligosaccharide hyaluronic acid composite nano particle of negative electrical charge, the chitosan oligosaccharide is 1000-5000Da, and deacetylation is big
The concentration of chitosan oligosaccharide is 0.2%-1.2% in 90%, chitosan oligosaccharide solution, and the molecular weight of the hyaluronic acid is 10000-
50000Da, the concentration of hyaluronic acid is 0.2%-1.2% in hyaluronic acid solution, and the total mass ratio of chitosan oligosaccharide and hyaluronic acid is
0.2-1:1。
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CN103656653A (en) * | 2013-12-05 | 2014-03-26 | 天津大学 | Polyelectrolyte compound based on hyaluronic acid drug-loading nano particles, preparation method and application thereof |
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