CN104138356A - Cinnamaldehyde crosslinked chitosan drug-loading microsphere preparation method - Google Patents
Cinnamaldehyde crosslinked chitosan drug-loading microsphere preparation method Download PDFInfo
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- CN104138356A CN104138356A CN201310167563.5A CN201310167563A CN104138356A CN 104138356 A CN104138356 A CN 104138356A CN 201310167563 A CN201310167563 A CN 201310167563A CN 104138356 A CN104138356 A CN 104138356A
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Abstract
The invention discloses a chitosan drug-loading microsphere preparation method using cinnamaldehyde as a cross linking agent and using emulsification crosslinking method, and the method is as follows: first, chitosan and a target drug are dissolved in a 0.1-2wt% acetic acid solution, after fully dissolving, the mixture as a water phase is added dropwise into an emulsifier-containing oil phase, the emulsifier-containing oil phase is stirred in a constant speed at 20-70 DEG C to form emulsus water-in-oil emulsion; then, the emulsus water-in-oil emulsion is added into a cinnamaldehyde acetone solution reaction system, and continued stirring for 1-5h; and finally, centrifugal separation is performed, the prepared drug loading microspheres are collected, fully washed respectively with petroleum ether, isopropyl alcohol and other organic solvents, and then freeze-dried to obtain chitosan drug-loading microsphere powder. The particle size of the chitosan drug-loading microspheres is 30 to 150 mu m, the chitosan drug-loading microspheres are good in degree of sphericity, the encapsulation efficiency is 90-96%, the drug loading amount is 20-25%, the sustained release performance is good, the antibacterial performance is significant, and the method has the advantages of simple process and easy scale production.
Description
Technical field
The present invention relates to the preparation method of chitosan drug-loading microsphere, particularly a kind of method that adopts emulsion-crosslinking method to prepare chitosan drug-loading microsphere.
Background technology
Chitosan claims again soluble chitin, chitosan, chitosan etc., it is unique alkaline polysaccharide that nature exists, nontoxic, there is biological degradability and biocompatibility in body, its chemistry by name (1,4)-2-amino-2-deoxidation--D-Glucose, its similar is in cellulose, and chitosan has many physiologically actives, at aspects such as medicine, food, cosmetics and agriculturals, has extensive and important using value.Chitosan can wrap pharmaceutical pack by model of action such as chemical crosslinking, Electrostatic Absorption, ion condensations, thereby forms the network microcapsule structure of bag medicine carrying thing.During due to drug release, to overcome the obstruction of macromolecular skeleton, thereby make pharmaceutical release time significant prolongation, reach the object of sustained-release and controlled release.At present, the preparation method of conventional chitosan drug-loading microsphere mainly adopts chemical crosslink technique, and adopting formaldehyde, glutaraldehyde etc. is cross-linking agent, and these cross-linking agent have stronger toxicity.
Therefore, also need to provide a kind of toxic and side effects little, microsphere drug loading is high, the preparation method of the significant chitosan drug-loading microsphere of slow release effect.
Summary of the invention
The object of the present invention is to provide the preparation method of the crosslinked chitosan drug-loading microsphere of a kind of novel cinnamic aldehyde, this method can make chitosan drug-loading microsphere reach micro/nano level, favorable dispersibility, controlled-release effect is remarkable, is expected to reach the oral needs with injecting clinically.
The invention provides and a kind ofly take cinnamic aldehyde as cross-linking agent, load water soluble drug and prepare the method for chitosan drug-loading microsphere, chitosan nano microspherulite diameter prepared by the method is 30 ~ 150 μ m, and sphericity is good, and envelop rate is 90-96%, and drug loading is 20 ~ 25%.
The preparation method of chitosan drug-loading microsphere of the present invention, specific embodiments is as follows:
First, use 0.1 ~ 2wt% acetum to make the chitosan-acetic acid solution (A) of 2 ~ 20wt%; In A solution, add drug target B, after fully dissolving, as water (C); Water C is dropwise joined in the oil phase (E) that contains 0.1 ~ 10wt% emulsifying agent (D), 20 ~ 70 ℃ of constant speed, stir 0.5 ~ 1h, form emulsus water-in-oil emulsion (F).Then, in emulsion F, add cross-linking agent solution (G), and continue to stir 1 ~ 5 h; Finally, prepared medicine carrying microballoons is collected in centrifugalize, and respectively with the fully washing such as petroleum ether, isopropyl alcohol, obtains yellow chitosan drug-loading microsphere powder after lyophilization.
The preparation method of chitosan drug-loading microsphere of the present invention, wherein as chitosan, its viscosity-average molecular weight >=340,000, deacetylation >=90%; Its drug target B can be the water soluble drugs such as azithromycin, levofloxacin hydrochloride; Its emulsifying agent D can be sorbitol anhydride oleate (span-80), anhydrous sorbitol stearate monoesters (span-60), anhydrous sorbitol Palmic acid monoesters (span-40), anhydrous sorbitol lauric acid monoester (span-20), polyoxyethylene sorbitan monooleate dehydration (tween-80), sorbitan monostearate polyoxyethylene (20) ether (tween-60), polyoxyethylene sorbitol acid anhydride monopalmitate (tween-40) and polyoxyethylene (20) sorbitan monolaurate (tween-20) etc., 0.1 ~ 10wt% that emulsifying agent D consumption is oil phase; Described oil phase E can be liquid paraffin, Oleum Arachidis hypogaeae semen, soybean oil or other commercially available edible oil; The mass ratio of oil phase E/ water C is 1:1 ~ 6:1; The cinnamic aldehyde acetone soln that its cross-linking agent solution G is 0.2 ~ 5wt%, wherein chitosan/cinnamic aldehyde mass ratio is 3:1 ~ 8:1.
Key problem in technology point of the present invention is:
The present invention adopts cinnamic aldehyde to be cross-linked and to prepare chitosan microball as cross-linking agent and chitosan.Western Buddhist alkali reaction occurs the amino part of the aldehyde radical of cinnamic aldehyde and chitosan and acetalation occurs part, makes the chitosan drop crosslinking curing of water in w/o type emulsion form microsphere.
The cinnamic aldehyde acetone soln that the cross-linking agent solution that the present invention uses is 0.2 ~ 5wt%, wherein chitosan/cinnamic aldehyde mass ratio is 3:1 ~ 8:1.Acetone is easy to remove from microsphere after follow-up processed, and can be not residual.
The emulsifying agent that the present invention uses, can be sorbitol anhydride oleate (span-80), anhydrous sorbitol stearate monoesters (span-60), anhydrous sorbitol Palmic acid monoesters (span-40), anhydrous sorbitol lauric acid monoester (span-20), polyoxyethylene sorbitan monooleate dehydration (tween-80), sorbitan monostearate polyoxyethylene (20) ether (tween-60), polyoxyethylene sorbitol acid anhydride monopalmitate (tween-40) and polyoxyethylene (20) sorbitan monolaurate (tween-20) etc., emulsifier is 0.1 ~ 10wt% of oil phase, emulsifying effectiveness increases greatly, can form emulsion droplet comparatively uniformly, by the acetone soln curing cross-linked of cinnamic aldehyde, thereby form the microsphere of good sphericity.
Cinnamic aldehyde cross-linked chitosan medicine carrying microballoons prepared by the present invention, drug loading and envelop rate are higher, and drug release curve is good.
At this, it is worthy of note that cinnamic aldehyde itself has anti-corrosive antibacterial effect, and chitosan is natural antibacterial, the anti-microbial property potentiation of the medicine carrying microballoons after the two is crosslinked; Cinnamic aldehyde cross-linked chitosan is prepared medicine carrying microballoons and is had no report.
The inventive method and art methods have following significant effect:
The features such as 1, the present invention be take cinnamic aldehyde as cross-linking agent, and the novel chitosan medicine carrying microballoons surface compact, the good sphericity that prepare, have drug loading high, and drug release curve is good;
2, the speed of cinnamic aldehyde crosslinking curing chitosan formation microsphere is fast, consuming time short, and the medicine carrying microballoons antibacterial effect of formation is remarkable;
3, utilization of the present invention has good biocompatibility, and in low toxicity and body, the chitosan of energy self degradation is carrier, has increased the permeability on medicine cell membrane surface, and slowly discharges to improve drug effect, reduce toxic and side effects.
4, the present invention does not relate to poisonous material (cross-linking agent, surfactant), and the organic solvent of use is all easier to remove.
5, lower cost for material, preparation technology is simple, and mild condition is applicable to large-scale production.
Accompanying drawing explanation
The chitosan drug-loading microsphere scanning electron microscope (SEM) photograph of Fig. 1 for adopting the inventive method to prepare, as can be seen from the figure, prepared chitosan nano drug-carrying microsphere sphericity is good;
Fig. 2 is the particle size distribution figure of prepared chitosan drug-loading microsphere, as can be seen from the figure, and prepared chitosan drug-loading microsphere good dispersion degree.
Fig. 3 is pure medicine and the release profiles of chitosan drug-loading microsphere in simulation human gastric juice, from figure, can find, the drug release curve b of prepared chitosan drug-loading microsphere is larger at the slope of the release profiles in simulation human gastric juice than pure medicine, and therefore prepared chitosan drug-loading microsphere extends than pure medicine release time in simulation human gastric juice greatly.
Fig. 4 be chitosan drug-loading microsphere and chitosan to the comparison of Escherichia coli Growth inhibition, chitosan drug-loading microsphere is more remarkable than the fungistatic effect of simple chitosan as seen from the figure.
The specific embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Except as otherwise noted, these embodiment are only not used in and limit the scope of the invention for the present invention is described.
Embodiment 1
First, by 100mg viscosity-average molecular weight >=340,000, it is in 2% acetum that the chitosan of deacetylation >=90% and 4mg azithromycin are dissolved in 4g mass fraction, after fully dissolving, as water, dropwise joining 25g contains in the liquid paraffin oil phase that mass fraction is 2% sorbitol anhydride oleate, rapid stirring 60min at 20 ℃, forms yellow emulsus Water-In-Oil (W/O) emulsion; Then, add 20g mass fraction be 2.5% cinnamic aldehyde acetone soln in reaction system, and continue to stir 4h; Finally, adopt low-temperature and high-speed centrifuge at 10000rpm centrifugalize 10min, collect prepared medicine carrying micro-and nano-particles, with petroleum ether, isopropyl alcohol, fully wash respectively, after lyophilization, obtain yellow chitosan drug-loading Nano microsphere powder.This microspherulite diameter is 30-150 μ m, and sphericity is good, and envelop rate is 90.1%, and carrying drug ratio is 20.1%.
Embodiment 2
First, by 200mg viscosity-average molecular weight >=340,000, it is in 2% acetum that the chitosan of deacetylation >=90% and 20mg azithromycin are dissolved in 10g mass fraction, after fully dissolving, as water, dropwise joining 50g contains in the liquid paraffin oil phase that mass fraction is 2% sorbitol anhydride oleate, rapid stirring 60min at 30 ℃, forms yellow emulsus Water-In-Oil (W/O) emulsion; Then, add 40g mass fraction be 2.5% cinnamic aldehyde acetone soln in reaction system, and continue to stir 4h; Finally, adopt low-temperature and high-speed centrifuge at 10000rpm centrifugalize 10min, collect prepared medicine carrying micro-and nano-particles, with petroleum ether, isopropyl alcohol, fully wash respectively, after lyophilization, obtain yellow chitosan drug-loading Nano microsphere powder.This microspherulite diameter is 30-150 μ m, and sphericity is good, and envelop rate is 95.6%, and carrying drug ratio is 21.6%.
Embodiment 3
First, by 300mg viscosity-average molecular weight >=340,000, it is in 2% acetum that the chitosan of deacetylation >=90% and 30mg azithromycin are dissolved in 16g mass fraction, after fully dissolving, as water, dropwise joining 60g contains in the liquid paraffin oil phase that mass fraction is 2% sorbitol anhydride oleate, rapid stirring 60min at 40 ℃, forms yellow emulsus Water-In-Oil (W/O) emulsion; Then, add 48g mass fraction be 2.5% cinnamic aldehyde acetone soln in reaction system, and continue to stir 4h; Finally, adopt low-temperature and high-speed centrifuge at 10000rpm centrifugalize 10min, collect prepared medicine carrying micro-and nano-particles, with petroleum ether, isopropyl alcohol, fully wash respectively, after lyophilization, obtain yellow chitosan drug-loading Nano microsphere powder.This microspherulite diameter is 30-150 μ m, and sphericity is good, and envelop rate is 94.6%, and carrying drug ratio is 21.4%.
Embodiment 4
First, by 200mg viscosity-average molecular weight >=340,000, it is in 2% acetum that the chitosan of deacetylation >=90% and 30mg azithromycin are dissolved in 10g mass fraction, after fully dissolving, as water, dropwise joining 50g contains in the liquid paraffin oil phase that mass fraction is 2% sorbitol anhydride oleate, rapid stirring 60min at 50 ℃, forms yellow emulsus Water-In-Oil (W/O) emulsion; Then, add 50g contain mass fraction be 3% cinnamic aldehyde acetone soln in reaction system, and continue to stir 3h; Finally, adopt low-temperature and high-speed centrifuge at 10000rpm centrifugalize 10min, collect prepared medicine carrying micro-and nano-particles, with petroleum ether, isopropyl alcohol, fully wash respectively, after lyophilization, obtain yellow chitosan drug-loading Nano microsphere powder.This microspherulite diameter is 30-150 μ m, and sphericity is good, and envelop rate is 91.9%, and carrying drug ratio is 20.4%.
Embodiment 5
First, by 200mg viscosity-average molecular weight >=340,000, it is in 2% acetum that the chitosan of deacetylation >=90% and 20mg azithromycin are dissolved in 10g mass fraction, after fully dissolving, as water, dropwise joining 50g contains in the liquid paraffin oil phase that mass fraction is 2% sorbitol anhydride oleate, rapid stirring 60min at 70 ℃, forms yellow emulsus Water-In-Oil (W/O) emulsion; Then, add 50g contain mass fraction be 3% cinnamic aldehyde acetone soln in reaction system, and continue to stir 4h; Finally, adopt low-temperature and high-speed centrifuge at 10000rpm centrifugalize 10min, collect prepared medicine carrying micro-and nano-particles, with petroleum ether, isopropyl alcohol, fully wash respectively, after lyophilization, obtain yellow chitosan drug-loading Nano microsphere powder.This microspherulite diameter is 30-150 μ m, and sphericity is good, and envelop rate is 94.9%, and carrying drug ratio is 22.1%.
Claims (6)
1. a preparation method for cinnamic aldehyde cross-linked chitosan medicine carrying microballoons, is characterized in that comprising the following steps:
First, use 0.1 ~ 2wt% acetum to make the chitosan-acetic acid solution (A) of 2 ~ 20wt%; In A solution, add drug target B, after fully dissolving, as water (C); Water C is dropwise joined in the oil phase (E) that contains 0.1 ~ 10wt% emulsifying agent (D), 20 ~ 70 ℃ of constant speed, stir 0.5 ~ 1h, form emulsus water-in-oil emulsion (F).
2. then, in emulsion F, add cross-linking agent solution (G), and continue to stir 1 ~ 5 h; Finally, prepared medicine carrying microballoons is collected in centrifugalize, and respectively with the fully washing such as petroleum ether, isopropyl alcohol, obtains yellow chitosan drug-loading microsphere powder after lyophilization;
Described drug target B can be the water soluble drugs such as azithromycin, levofloxacin hydrochloride; Described emulsifying agent D can be sorbitol anhydride oleate (span-80), anhydrous sorbitol stearate monoesters (span-60), anhydrous sorbitol Palmic acid monoesters (span-40), anhydrous sorbitol lauric acid monoester (span-20), polyoxyethylene sorbitan monooleate dehydration (tween-80), sorbitan monostearate polyoxyethylene (20) ether (tween-60), polyoxyethylene sorbitol acid anhydride monopalmitate (tween-40) and polyoxyethylene (20) sorbitan monolaurate (tween-20) etc., 0.1 ~ 10wt% that its consumption is oil phase; Described oil phase E can be liquid paraffin, Oleum Arachidis hypogaeae semen, soybean oil or other commercially available edible oil; The mass ratio of oil phase E/ water C is 1:1 ~ 6:1; The cinnamic aldehyde acetone soln that described cross-linking agent solution G is 0.2 ~ 5wt%, wherein chitosan/cinnamic aldehyde mass ratio is 3:1 ~ 8:1.
3. the preparation method of chitosan drug-loading microsphere according to claim 1, is characterized in that viscosity-average molecular weight >=340,000 of described chitosan, deacetylation >=90%.
4. the preparation method of chitosan drug-loading microsphere according to claim 1, is characterized in that drug target B/ chitosan mass than being 1:30 ~ 1:1.
5. the preparation method of chitosan drug-loading microsphere according to claim 1, is characterized in that reaction temperature is 20 ~ 70 ℃.
6. the chitosan drug-loading microsphere that prepared by method according to claim 1, is characterized in that sustained release performance is good, anti-microbial property is remarkable.
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Cited By (5)
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| CN105030696A (en) * | 2015-09-11 | 2015-11-11 | 江苏锦宇环境工程有限公司 | Preparation method of azithromycin slow-release dry suspension agent |
| CN107233330A (en) * | 2017-06-14 | 2017-10-10 | 广西大海阳光药业有限公司 | A kind of azithromycin granule and preparation method thereof |
| CN112169756A (en) * | 2020-09-29 | 2021-01-05 | 四川大学 | Microporous granular carbon and preparation method thereof |
| CN112294870A (en) * | 2020-11-06 | 2021-02-02 | 江苏省中医药研究院 | Cinnamon oil microsphere inclusion compound and preparation method and application thereof |
| CN113476425A (en) * | 2021-08-05 | 2021-10-08 | 江西农业大学 | PH-responsive enrofloxacin nanoparticles and preparation method and application thereof |
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| CN102885379A (en) * | 2012-09-29 | 2013-01-23 | 渤海大学 | Preparation method of dual bacteriostatic cinnamyl aldehyde microcapsule |
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| CN102885379A (en) * | 2012-09-29 | 2013-01-23 | 渤海大学 | Preparation method of dual bacteriostatic cinnamyl aldehyde microcapsule |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105030696A (en) * | 2015-09-11 | 2015-11-11 | 江苏锦宇环境工程有限公司 | Preparation method of azithromycin slow-release dry suspension agent |
| CN107233330A (en) * | 2017-06-14 | 2017-10-10 | 广西大海阳光药业有限公司 | A kind of azithromycin granule and preparation method thereof |
| CN112169756A (en) * | 2020-09-29 | 2021-01-05 | 四川大学 | Microporous granular carbon and preparation method thereof |
| CN112169756B (en) * | 2020-09-29 | 2021-11-09 | 四川大学 | Microporous granular carbon and preparation method thereof |
| CN112294870A (en) * | 2020-11-06 | 2021-02-02 | 江苏省中医药研究院 | Cinnamon oil microsphere inclusion compound and preparation method and application thereof |
| CN113476425A (en) * | 2021-08-05 | 2021-10-08 | 江西农业大学 | PH-responsive enrofloxacin nanoparticles and preparation method and application thereof |
| CN113476425B (en) * | 2021-08-05 | 2022-08-05 | 江西农业大学 | PH-responsive enrofloxacin nanoparticles and preparation method and application thereof |
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Application publication date: 20141112 |