CN102813931B - Chitosan nanoparticles and their preparation method and use - Google Patents
Chitosan nanoparticles and their preparation method and use Download PDFInfo
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- CN102813931B CN102813931B CN201210281009.5A CN201210281009A CN102813931B CN 102813931 B CN102813931 B CN 102813931B CN 201210281009 A CN201210281009 A CN 201210281009A CN 102813931 B CN102813931 B CN 102813931B
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Abstract
The invention discloses chitosan nanoparticles and their preparation method and use. The chitosan nanoparticles comprise 5 to 50wt% of chitosan and 95 to 50wt% of polymethacryloylpolyoxalic acid or polyacryloylpolyoxalic acid and have an average particle size of 100 to 300nm. The preparation method allows mild conditions and has simple processes. The chitosan nanoparticles obtained by the preparation method have good biocompatibility, can be used as drug carriers, and have performances of slow release of drugs and pH value-responsive release of drugs.
Description
Technical field
The invention belongs to medical art, relate to a kind of chitin nanometer and preparation method thereof, and apply as pharmaceutical carrier.
Background technology
In recent years, nanoparticle medicine-carried system is widely used at biomedicine field.Nanoparticle drug-loading system is various informative: as nano-emulsion, nano-micelle, nanogel, nanocrystal, lipid nanoparticle etc.Nanoparticle drug-loading system has following advantage: (1) increases the water solublity of insoluble drug, improves dispersibility; (2) slow release and the controlled release of medicine can be realized after vivo medicine-feeding; (3) strengthen target-oriented drug, improve medicine stability, reduce toxic and side effects.
The key of development nanoparticle medicine-carried system is the selection of the material preparing nanoparticle.Prepare in the material of nanoparticle numerous, chitosan, as the natural polycation polysaccharide of one, has the features such as good bond properties, readily degradable, biocompatibility, is subject to paying close attention to widely and studying because of it.In addition, PEG (Polyethylene Glycol) is also subject to the favor of numerous researcher as a kind of hydrophilic and the good macromolecular compound of biocompatibility.Research shows; introduce the biocompatibility [Biomaterials that hydrophilic PEG long-chain can improve chitin nanometer; 23 (2002); 2641 – 2648] and stability in body fluid and circulation time [Carbohudr.Polym; 32 (1997), 193-199; European Journal of Pharmacology, 670 (2011), 372 – 383].
But, the nanoparticle main method that current preparation is made up of Polyethylene Glycol or polyethyleneglycol derivative and chitosan carries out chemical modification with PEG to chitosan, chitosan after modification is at ion crosslinking agent sodium tripolyphosphate or adopt solvent replacement technique to be prepared into nanoparticle, DMF, DMSO etc. are applied as solvent in this method preparation process, post-processing difficulty is large, and operating procedure is complicated.[Polymer,39(1998),5171-5175,1998；European?Journal?of?Pharmaceutics?and?Biopharmaceutics，68（2008），526-534]。
When the nanoparticle medicine-carried system of development of new, also require to give medicine-carried nano particles new performance to a certain degree, as pH value sensitivity, temperature sensitivity etc., the controlled release acquired a certain degree.There is bibliographical information [colloids and surfaces B:Biointerfaces, 90 (2012), 102-108], chitosan, Polyethylene Glycol, acrylic acid and ethylene glycol dimethacrylate are carried out polyreaction and obtain polyacrylamide-chitosan-Polyethylene Glycol nanoparticle, there is the performance of certain pH value response release medicine, under different PH condition, the burst size of medicine is different.But this nanoparticle slow release effect is bad, when PH6.8, within 24 hours, just release the medicine of about 60%; Meanwhile, the cycle that the method prepares nanoparticle is long, needs reaction to spend the night.
Summary of the invention
The object of this invention is to provide the chitin nanometer that a kind of biocompatibility is good, it can be applied as pharmaceutical carrier, has the performance of slow releasing pharmaceutical and pH value response release medicine.
Another object of the present invention is to provide a kind of method preparing above-mentioned chitin nanometer, and it can carry out in aqueous phase, mild condition, and technique is simple, and manufacturing cycle is short.
Another object of the present invention is to provide above-mentioned chitin nanometer purposes.
To achieve these goals, the present invention adopts following technical scheme:
A kind of chitin nanometer, it is characterized in that: form primarily of chitosan and polymethyl acyl polyglycolic acid or polyacrylamide polyglycolic acid, wherein the content of chitosan accounts for 5 ~ 50wt%, polymethyl acyl polyglycolic acid or polyacrylamide polyglycolic acid account for 95 ~ 50wt%, and the mean diameter of chitin nanometer is 100 ~ 300nm.
The viscosity-average molecular weight of described chitosan 5000 ~ 500000, especially 5000,50000 or 300000, deacetylation is greater than 50%, especially more than 85%.
The structural formula of described polymethyl acyl polyglycolic acid or polyacrylamide polyglycolic acid is as follows:
Wherein, R=H or CH
3, m, n are the degree of polymerization of Polyethylene Glycol used and acrylate or methacrylic acid acid esters respectively, and x, y represent CH
2quantity, x>=1, y>=1, especially x=2 or 3, y=1 or 2.
The number-average molecular weight of described polymethyl acyl polyglycolic acid or polyacrylamide polyglycolic acid Polyethylene Glycol used 200 ~ 200000, especially 200,400,800 or 2000.
Described chitin nanometer is the chitin nanometer through cross-linking agents, especially through the chitin nanometer of glutaraldehyde or ethylene glycol dimethacrylate cross-linking agents.
The preparation method of chitin nanometer; chitosan is dissolved in aqueous together with methacryl polyglycolic acid or acryloyl polyglycolic acid, heating, after stirring a period of time; initiator is added under nitrogen protection; after continuing reaction a period of time, there is opalescence in system, cooling; reaction completes; filter, dialysis or centrifugal, namely obtains chitin nanometer.
Described initiator is the salt causing carbon-to-carbon double bond polymerization, and mainly persulfate, refers in particular to potassium peroxydisulfate or Ammonium persulfate..
Mol ratio is that the chitosan of 1:1 dissolves in aqueous together with methacryl polyglycolic acid or acryloyl polyglycolic acid by the preparation method of chitin nanometer, 70 DEG C of heating, stir after 1 ~ 2 hour, add potassium peroxydisulfate under nitrogen protection, after continuing reaction a period of time, there is opalescence in system, cool to 60 DEG C, continue reaction 2 hours, reaction completes, and filters, dialysis or centrifugal, namely obtains chitin nanometer; Wherein, the amino number that the molal quantity of chitosan is pressed in chitosan calculates.
The preparation method of chitin nanometer; chitosan is dissolved in aqueous together with methacryl polyglycolic acid or acryloyl polyglycolic acid, heating, after stirring a period of time; initiator is added under nitrogen protection; after continuing reaction a period of time, there is opalescence in system, adds cross-linking agents; reaction completes; filter, dialysis or centrifugal, namely obtains chitin nanometer.
Described initiator is the salt causing carbon-to-carbon double bond polymerization, and mainly persulfate, refers in particular to potassium peroxydisulfate or Ammonium persulfate..
Mol ratio is that the chitosan of 1:1 dissolves in aqueous together with methacryl polyglycolic acid or acryloyl polyglycolic acid by the preparation method of chitin nanometer, 70 DEG C of heating, stir after 1 ~ 2 hour, under nitrogen protection, add potassium peroxydisulfate, after continuing reaction a period of time, there is opalescence in system, cool to 60 DEG C, add cross-linking agent, continue reaction 2 hours, reaction completes, filter, dialysis or centrifugal, namely obtains chitin nanometer; Wherein, the amino number that the molal quantity of chitosan is pressed in chitosan calculates.
The preparation method of chitin nanometer, chitosan is dissolved in aqueous together with polymethyl acyl polyglycolic acid or polyacrylamide polyglycolic acid, heating, after stirring reaction a period of time, there is opalescence in system, cooling, reaction completes, filter, dialysis or centrifugal, namely obtains chitin nanometer.
The preparation method of chitin nanometer, chitosan is dissolved in aqueous together with polymethyl acyl polyglycolic acid or polyacrylamide polyglycolic acid, heating, after stirring reaction a period of time, there is opalescence in system, adds cross-linking agents, reaction completes, filter, dialysis or centrifugal, namely obtains chitin nanometer.
The purposes of chitin nanometer, as pharmaceutical carrier, parcel chemicals, genomic medicine or protein drug, have slow-release function and pH value response release pharmaceutical properties.
As the carrier of medicine, the medicine wanting load can be added in chitin nanometer solution of the present invention, through standing adsorption or ultrasonic absorption, centrifugally can obtain the chitin nanometer that load has medicine.
As the carrier of medicine, the medicine wanting load can be added in chitin nanometer solution of the present invention, after standing adsorption or ultrasonic absorption, add cross-linking agent and react a period of time, dialysis, centrifugally can obtain the chitin nanometer that load has medicine.
As the carrier of medicine, also before methacryl polyglycolic acid or the polymerization of acryloyl polyglycolic acid, (before adding initiator) medicine wanting load can be added, as 5-fluorouracil, and then add initiator, cross-linking agent.After filtration, the chitin nanometer that load has medicine is obtained after dialysis and the mode purification such as centrifugal.
Nanoparticle after medicine carrying has certain pH value sensitivity, and in different pH value buffer, under identical release time, the burst size of medicine is relevant with the size of pH value, and pH value is large, and drug release is many.Meanwhile, there is certain sustained release performance.
After adopting such scheme, chitin nanometer of the present invention, form primarily of chitosan and polymethyl acyl polyglycolic acid or polyacrylamide polyglycolic acid, nanoparticle mean diameter is 100 ~ 300nm, biocompatibility is good, can apply as pharmaceutical carrier, there is the performance of slow releasing pharmaceutical and pH value response release medicine.Preparation method of the present invention is carried out in aqueous phase, mild condition, and technique is simple, and manufacturing cycle is short.
Accompanying drawing explanation
Fig. 1 is the infrared figure of the chitosan of middle-molecular-weihydroxyethyl 50000 of the present invention;
Fig. 2 is the infrared figure of methacryl PEG400 butanoic acid in the present invention;
Fig. 3 is the infrared figure of the chitin nanometer that in the present invention prepared by embodiment 1;
Fig. 4 is the grain size distribution of the chitin nanometer that in the present invention prepared by embodiment 1;
Fig. 5 is the transmission electron microscope picture (amplification 50000 times) of the chitin nanometer that in the present invention prepared by embodiment 2;
Fig. 6 is the grain size distribution of the chitin nanometer that in the present invention prepared by embodiment 3;
Fig. 7 is the grain size distribution of the load 5-fluorouracil chitin nanometer that in the present invention prepared by embodiment 6;
Fig. 8 is the drug release patterns figure of load 5-fluorouracil chitin nanometer in vitro in PH5.5 buffer in embodiment 9 in the present invention;
Fig. 9 is the drug release patterns figure of load 5-fluorouracil chitin nanometer in vitro in PH7.4 buffer in embodiment 9 in the present invention;
Figure 10 is the drug release patterns figure of load 5-fluorouracil chitin nanometer in vitro in PH8.0 buffer in embodiment 9 in the present invention.
Detailed description of the invention
Elaborate to embodiments of the present invention below, the present embodiment is carried out under the prerequisite of technical solution of the present invention, provides following examples to be in order to further elaboration, instead of the invention scope of restriction the application.
Step one: the synthesis of methacryl PEG400 monoesters
Getting 5g PEG400 joins in the round-bottomed flask of 100ml, adds 50ml dichloromethane, under condition of ice bath, adds 2ml triethylamine, stirs.Slowly drip the dichloromethane that 15ml is dissolved with methacrylic chloride 0.5ml under constant voltage, be naturally warming up to room temperature, continue stirring reaction 24 hours.After, steam except dichloromethane, remaining liq is proceeded to separatory funnel, adds 50ml ethyl acetate, with the washing of 30ml saturated sodium-chloride, then use 30ml deionized water wash, combining water layer; Use 50ml dichloromethane extraction water layer again, merge organic layer, with anhydrous sodium sulfate drying, remove solvent under reduced pressure, obtain colourless viscous liquid, be methacryl PEG400 monoesters.
Step 2: the synthesis of methacryl PEG400 butanoic acid
The product 1.0g getting step one preparation joins 100ml round-bottomed flask, adds 40ml dichloromethane stirring and dissolving; Add 0.21g DMAP(4-dimethylamino naphthyridine more successively) and 0.23g succinic anhydride, continue stirring reaction 36 hours.After reaction terminates, reactant liquor is moved into separatory funnel, and the hydrochloric acid solution 5ml adding 1mol/L washs, then washs organic layer with saturated sodium-chloride.Organic over anhydrous dried over sodium sulfate, removes solvent under reduced pressure, obtains colourless viscous liquid, is methacryl PEG400 butanoic acid.The infrared figure of methacryl PEG400 butanoic acid as shown in Figure 2.
Methacryl polyglycolic acid or acryloyl polyglycolic acid obtain, for the preparation of nanoparticle of the present invention with reference to the synthesis of identical method.
Step 3: the synthesis of polymethyl acyl PEG400 butanoic acid
Get 0.2376g methacryl PEG400 butanoic acid in 100ml four-hole bottle, add 50ml deionized water.Be heated to 50 DEG C, magnetic agitation, under nitrogen protection, add initiator potassium persulfate 0.005g, continue stirring reaction.After reaction terminates, product is the bag filter dialysis of 3500 through molecular cut off, can be directly used in and prepare nanoparticle.
Polymethyl acyl polyglycolic acid or polyacrylamide polyglycolic acid obtain, for the preparation of nanoparticle of the present invention with reference to the synthesis of identical method.
embodiment 1
Get methacryl PEG400 butanoic acid 0.2376g and viscosity-average molecular weight is 50000, deacetylation be the chitosan 0.0888g of 90% in four-hole bottle, add 50ml deionized water.Be heated to 70 DEG C, stir 4h.Add initiator potassium persulfate 0.005g under nitrogen protection, continue under 70 DEG C of conditions to stir 1.5h, there is opalescence in system, is cooled to 60 DEG C, continues to stir 2h.After reaction terminates, first remove insoluble matter with filter paper filtering, then nano-particle solution to be loaded molecular cut off be in the bag filter of 3500, dialysis 48h, in bag filter contained by solution, be chitin nanometer.Mean diameter is about 193nm.
In the present embodiment, number-average molecular weight be the infrared figure of the chitosan of 50000 as shown in Figure 1, as shown in Figure 3, the grain size distribution of the chitin nanometer of gained is as shown in Figure 4 for the infrared figure of the chitin nanometer of gained.
embodiment 2
Get methacryl PEG400 butanoic acid 0.2376g and number-average molecular weight is 5000, deacetylation be the chitosan 0.1g of 90% in four-hole bottle, add 50ml deionized water.Be heated to 70 DEG C, stir 4h.Add initiator potassium persulfate 0.005g under nitrogen protection, continue under 70 DEG C of conditions to stir 1.5h, there is opalescence in system, is cooled to 60 DEG C, adds 0.001g glutaraldehyde, continues to stir 2h.After reaction terminates, first remove insoluble matter with filter paper filtering, then nano-particle solution to be loaded molecular cut off be in the bag filter of 3500, dialysis 48h, in bag filter contained by solution, be chitin nanometer.Mean diameter is about 100nm.
In the present embodiment, the transmission electron microscope picture of the chitin nanometer of gained as shown in Figure 5.
embodiment 3
Get acryloyl PEG400 butanoic acid 0.2376g and number-average molecular weight is 300000, deacetylation be the chitosan 0.09g of 85% in four-hole bottle, add 50ml deionized water.Be heated to 70 DEG C, stir 4h.Add initiator ammonium persulfate 0.004g under nitrogen protection, continue under 70 DEG C of conditions to stir 1h, there is opalescence in system, is cooled to 60 DEG C, adds 0.001g ethylene glycol dimethacrylate, continues to stir 2h.After reaction terminates, cross and filter larger polymer, nano-particle solution being loaded molecular cut off is in the bag filter of 3500, and dialysis 48h, is chitin nanometer in bag filter contained by solution.Mean diameter is about 181nm.
In the present embodiment, the grain size distribution of the chitin nanometer of gained as shown in Figure 6.
embodiment 4
Get acryloyl Macrogol 2000 butanoic acid 1g and number-average molecular weight is 5000, deacetylation be the chitosan 0.1g of 90% in four-hole bottle, add 50ml deionized water.Be heated to 70 DEG C, stir 4h.Add initiator potassium persulfate 0.008g under nitrogen protection, continue under 70 DEG C of conditions to stir 2h, there is opalescence in system, is cooled to 60 DEG C, continues to stir 2h.After reaction terminates, remove insoluble matter with filter paper filtering, nano-particle solution being loaded molecular cut off is in the bag filter of 3500, and dialysis 48h, is chitin nanometer in bag filter contained by solution.Mean diameter is about 256nm.
embodiment 5
Get polymethyl acyl Macrogol 2000 butanoic acid 1g and number-average molecular weight is 5000, deacetylation be the chitosan 0.1g of 90% in four-hole bottle, add 50ml deionized water.Be heated to 70 DEG C, stirring 4h, there is opalescence in system.After reaction terminates, remove insoluble matter with filter paper filtering, nano-particle solution being loaded molecular cut off is in the bag filter of 10000, and dialysis 48h, is chitin nanometer in bag filter contained by solution.Mean diameter is about 260nm.
embodiment 6
In Example 1, chitin nanometer (solution) 25ml of preparation is in 50ml centrifuge tube, adds the 5-FU(5-fluorouracil that concentration is 5mg/ml) solution 2.5ml, carries out ultrasonic medicine carrying (power: 90W; Time: 30min).After, centrifugal 20min under 10000r/min 4 DEG C of conditions, abandoning supernatant, obtains medicine-carried nano particles.The nanoparticle drug loading of the above-mentioned 5-FU of being loaded with reaches about 16%, envelop rate 32%, and mean diameter is about 214nm.
In the present embodiment, the grain size distribution of load 5-fluorouracil chitin nanometer as shown in Figure 7.
embodiment 7
In Example 1, chitin nanometer (solution) 25ml of preparation is in 50ml centrifuge tube, adds the 5-FU solution 2.5ml that concentration is 5mg/ml, carries out standing medicine carrying 24 hours.After, centrifugal 20min under 10000r/min 4 DEG C of conditions, abandoning supernatant, obtains medicine-carried nano particles.The nanoparticle drug loading of the above-mentioned 5-FU of being loaded with reaches about 15%, envelop rate 30%, and mean diameter is about 207nm.
embodiment 8
Get acryloyl Macrogol 2000 butanoic acid 1g and number-average molecular weight is 5000, deacetylation be the chitosan 0.1g of 90% in four-hole bottle, add 50ml deionized water.Be heated to 70 DEG C, stir 4h.Add the 5-FU solution 2.5ml that concentration is 5mg/ml, add initiator potassium persulfate 0.008g under nitrogen protection, continue under 70 DEG C of conditions to stir 2h, there is opalescence in system, is cooled to 60 DEG C, continues to stir 2h.After reaction terminates, insoluble matter is removed with filter paper filtering, nano-particle solution being loaded molecular cut off is in the bag filter of 3500, dialysis 48h, chitin nanometer is in bag filter contained by solution, the nanoparticle drug loading being loaded with 5-FU reaches about 20%, envelop rate 40%, and mean diameter is about 285nm.
embodiment 9
By the medicine-carried nano particles of preparation in embodiment 6, get 3 parts, every part of 20mg.The phosphate buffer being 5.5,7.4,8.0 at PH respectively carries out drug release patterns mensuration, measures uv absorption at 265nm place, calculates cumulative release amount.When being discharged into the 5th day, medicine-carried nano particles is discharge 34% in the dissolution medium of 5.5 at PH, is discharge 45% in the dissolution medium of 7.4 at PH, is discharge 60% in the dissolution medium of 8.0 at PH.
In the present embodiment, the drug release patterns figure of load 5-fluorouracil chitin nanometer in vitro in PH5.5 buffer as shown in Figure 8, as shown in Figure 9, the drug release patterns figure of load 5-fluorouracil chitin nanometer in vitro in PH8.0 buffer as shown in Figure 10 for the drug release patterns figure of load 5-fluorouracil chitin nanometer in vitro in PH7.4 buffer.
Claims (1)
1. a preparation method for chitin nanometer, is characterized in that: get acryloyl Macrogol 2000 butanoic acid 1g and number-average molecular weight is 5000, deacetylation be the chitosan 0.1g of 90% in four-hole bottle, add 50ml deionized water; Be heated to 70 DEG C, stir 4h; Add the 5-FU solution 2.5ml that concentration is 5mg/ml, add initiator potassium persulfate 0.008g under nitrogen protection, continue under 70 DEG C of conditions to stir 2h, there is opalescence in system, is cooled to 60 DEG C, continues to stir 2h; After reaction terminates, insoluble matter is removed with filter paper filtering, nano-particle solution being loaded molecular cut off is in the bag filter of 3500, dialysis 48h, chitin nanometer is in bag filter contained by solution, the nanoparticle drug loading being loaded with 5-FU reaches about 20%, envelop rate 40%, and mean diameter is about 285nm.
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| CN1314430A (en) * | 2001-04-26 | 2001-09-26 | 南京大学 | Nanometer microball of chitosan-polyacrylic acid composite and its producing method and use |
| CN1446832A (en) * | 2003-02-08 | 2003-10-08 | 复旦大学 | Gelatin particles and preparation method |
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| CN1314430A (en) * | 2001-04-26 | 2001-09-26 | 南京大学 | Nanometer microball of chitosan-polyacrylic acid composite and its producing method and use |
| CN1446832A (en) * | 2003-02-08 | 2003-10-08 | 复旦大学 | Gelatin particles and preparation method |
| CN1737956A (en) * | 2004-08-19 | 2006-02-22 | 中国人民解放军军事医学科学院毒物药物研究所 | Magnetic Nano material |
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