CN102293751A - Preparation method of chitosan microsphere used for anti-cancer drug release - Google Patents
Preparation method of chitosan microsphere used for anti-cancer drug release Download PDFInfo
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- CN102293751A CN102293751A CN2011101687169A CN201110168716A CN102293751A CN 102293751 A CN102293751 A CN 102293751A CN 2011101687169 A CN2011101687169 A CN 2011101687169A CN 201110168716 A CN201110168716 A CN 201110168716A CN 102293751 A CN102293751 A CN 102293751A
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Abstract
The invention discloses a preparation method of a chitosan microsphere used for anti-cancer drug release. By employing a water in oil technology, the method comprises the steps of: dissolving chitosan in a dilute acid solution of 2wt% so as to prepare a dilute acid solution of chitosan of 2% (w/v) as a water phase, dissolving paclitaxel and lecithin in ethanol or acetone as an oil phase, adding a proper amount of Span 80 into the oil phase, and stirring mechanically for 5-30min to make the Span 80 dispersed uniformly, adding the water phase drop by drop into the oil phase, conducting water bath heating with the temperature controlled from 30 to 70 DEG C and stirring the oil phase for 20-50min, gradually adding a proper amount of a genipin water solution for crosslinking, and after a certain period of rapid stirring, adjusting the pH value of the reaction system with a NaHCO3 solution of 0.5-5% by mass, carrying out rapid stirring for reaction for 1-10h, removing ethanol or acetone, thus obtaining the chitosan nano-microsphere after drying.
Description
Technical field
The present invention relates to a kind of preparation method that is used for the chitosan microball of cancer therapy drug release.
Background technology
Paclitaxel is a kind of diterpene-kind compound for the treatment of cancer of the extraction in the Chinese yew genus plants, has stabilize microtubules and promotes the effect of its polymerization and assembling, is the anticarcinogen that solid tumor and leukemia is had good prospect.Lecithin is the fatty compound that a class contains P elements, not only can the liver protecting, can also reduce serum cholesterol content, and in addition, can also promote brain development, memory reinforcing.Lecithin has the good health care effect, and it is applied in microsphere system as oil phase, does not need extra removal.
Chitosan has superior bioactive, as performances such as biocompatibility, degradability, anti-inflammation, avirulence and promotion wound healings, more and more favored at biomedical sector in recent years, be can be used as tissue engineering bracket material, skin histology wound adjuvant, pharmaceutical carrier etc.
Chitosan microball is the more medicament slow release form of using at present, it is with the extensive use in clinical medicine of good sustained release performance, but its targeting is distributed in tumor tissues, can strengthen the penetrance and the anelasticity of medicine, improve stability of drug and bioavailability, reduce whole body blood drug level, reduce side reaction.The distinctive character of chitosan makes it become the novel medicament carrier, except that the general characteristic that possesses chitosan, the universals that also have some nano materials, as surface and interfacial effect, small-size effect and quantum size effect etc., so in organizational project and medicine delivery, show good prospects for application.The preparation method of chitosan rice microsphere mainly contains following several: emulsion-crosslinking method, emulsified solvent evaporation, emulsifying internal gelation method, multi-emulsion method, ion exchange, spray drying method, freeze-drying and coating method etc.
The sustained release performance of chitosan derivatives was also better in recent years, extensive use in slow release formulations such as microsphere, microcapsule, nanosphere, floating tablets.Microsphere is present focus as slow release formulation research, manufacture method is the most commonly used with emulsion-crosslinking method, its basic skills is that medicine is scattered in the acetum of chitosan, after the oil phase mixed processing that contains surfactant, becomes and can make with emulsification and cross linkeds such as cross-linking agent such as glutaraldehyde again.Chitosan microball more and more is subjected to people's attention as the advantage that a kind of novel medicament and genophore are shown, along with the development of science and technology progress, the chitosan microball carrier will enter Drug therapy field more widely, make a breakthrough in numerous chemical synthetic drugs and natural drug.The uses advanced synthetic technology is modified the chitosan microball surface, makes it have the desired selectivity of target organ, target tissue and target cell, also is development in future trend.
Summary of the invention
The purpose of this invention is to provide a kind of preparation method that is used for the chitosan microball of cancer therapy drug release:
(1) chitosan is dissolved in the dilute acid soln of 2wt%, the chitosan dilute acid soln that is mixed with 2% (w/v) is dissolved in ethanol or the acetone paclitaxel and lecithin as oil phase as water.
(2) an amount of emulsifying agent is joined oil phase, mechanical agitation 5-30min is uniformly dispersed it, and water is dropwise added oil phase, and heating in water bath control temperature stirs 20-50min for 30-70 ℃.
(3) dropwise add an amount of genipin aqueous solution and carry out crosslinkedly, and stir fast.
(4) NaHCO of usefulness 0.5-5wt%
3Solution is transferred pH value of reaction system, and stirring reaction 1-10h removes ethanol or acetone fast, is drying to obtain the chitosan nano microsphere.
The major advantage of this method is: the first, and lecithin is one of necessary for human body material, and is nontoxic to human body, have no side effect, we adopt lecithin is to be the oil phase non-emulsifiers.The second, genipin is a kind of iridoid heterocyclic compounds, is the cross-linking agent of natural biological.Adopt genipin to make cross-linking agent and further reduce cytotoxicity.The 3rd, in preparation process, add paclitaxel, pharmaceutical pack is overlayed on the inside of microsphere, improve the drug loading of particle, thereby improve the effective rate of utilization of medicine.
The specific embodiment:
Embodiment 1
(molecular weight is 50 with chitosan, 000) is dissolved in the acetic acid aqueous solution of 2wt%, the chitosan acetic acid aqueous solution that is mixed with 2% (w/v) is as water, paclitaxel and lecithin are dissolved in the ethanol as oil phase, class of department 80 joins oil phase, 1000r/min mechanical agitation 20min is uniformly dispersed it, water is dropwise added oil phase, wherein water/oil phase is 1: 2, the addition of paclitaxel is 0.01% of an ethanol quality, soft phospholipid is 2% of ethanol quality, and the addition of class of department is 0.5% (v/v) of oil phase.Heating in water bath control temperature stirs 20min for 30 ℃.Dropwise add 2% genipin solution and carry out crosslinkedly, stir 30min fast.NaHCO with mass fraction 5%
3It is 9 that solution is transferred pH value of reaction system, and fast reaction 10h removes ethanol, and vacuum drying gets final product.The mean diameter of thus obtained microsphere is 5 μ m.
Embodiment 2
(molecular weight is 100 with chitosan, 000) is dissolved in the aqueous formic acid of 2wt%, the chitosan aqueous formic acid 10ml that is mixed with 2% (w/v) is as water, paclitaxel and lecithin are dissolved in the ethanol as oil phase, class of department 80 joins oil phase, 2000r/min mechanical agitation 5min is uniformly dispersed it, water is dropwise added oil phase, wherein water/oil phase is 1: 2, the addition of paclitaxel is 0.5% of an ethanol quality, soft phospholipid is 6% of ethanol quality, and the addition of class of department is 2% (v/v) of oil phase.Heating in water bath control temperature stirs 30min for 40 ℃.The genipin solution that dropwise adds 1mL2% is carried out crosslinked, stirs 30min fast.NaHCO with mass fraction 1%
3It is 7.5 that solution is transferred pH value of reaction system, and fast reaction 1h removes ethanol, and vacuum drying gets final product.The mean diameter of thus obtained microsphere is 2 μ m.
Embodiment 3
(molecular weight is 3 with chitosan, 000) is dissolved in the aqueous citric acid solution of 2wt%, the chitosan aqueous citric acid solution 10ml that is mixed with 2% (w/v) is as water, paclitaxel and lecithin are dissolved in the ethanol as oil phase, class of department 80 joins oil phase, 2500r/min mechanical agitation 30min is uniformly dispersed it, water is dropwise added oil phase, wherein water/oil phase is 1: 8, the addition of paclitaxel is 2% of an ethanol quality, soft phospholipid is 3% of ethanol quality, and the addition of class of department is 6% (v/v) of oil phase.Heating in water bath control temperature stirs 50min for 50 ℃.The genipin solution that dropwise adds 1mL2% is carried out crosslinked, stirs 30min fast.NaHCO with mass fraction 1%
3It is 6.5 that solution is transferred pH value of reaction system, and fast reaction 2h removes ethanol, and vacuum drying gets final product.The mean diameter of thus obtained microsphere is 830nm.
Embodiment 4
(molecular weight is 5 with chitosan, 000) is dissolved in the hydroxy acid solution of 2wt%, the chitosan hydroxyl acetic acid aqueous solution 10ml that is mixed with 2% (w/v) is as water, paclitaxel and lecithin are dissolved in the ethanol as oil phase, the class of department 85 is joined oil phase, 2000r/min mechanical agitation 10min is uniformly dispersed it, water is dropwise added oil phase, wherein water/oil phase is 1: 4, the addition of paclitaxel is 1% of an ethanol quality, soft phospholipid is 10% of ethanol quality, and the addition of class of department is 10% (v/v) of oil phase.Heating in water bath control temperature stirs 30min for 40 ℃.The genipin solution that dropwise adds 1mL2% is carried out crosslinked, stirs 50min fast.NaHCO with mass fraction 2%
3It is 7 that solution is transferred pH value of reaction system, and fast reaction 2h removes ethanol, and vacuum drying gets final product.The mean diameter of thus obtained microsphere is 1 μ m.
Embodiment 5
(molecular weight is 200 with chitosan, 000) is dissolved in the lactic acid aqueous solution of 2wt%, the chitosan lactic acid aqueous solution 10ml that is mixed with 2% (w/v) is as water, paclitaxel and lecithin are dissolved in the acetone as oil phase, class of department 83 joins oil phase, 2500r/min mechanical agitation 20min is uniformly dispersed it, water is dropwise added oil phase, wherein water/oil phase is 1: 3, the addition of paclitaxel is 2% of an acetone quality, soft phospholipid is 8% of acetone quality, and the addition of class of department is 1% (v/v) of oil phase.Heating in water bath control temperature stirs 50min for 70 ℃.Dropwise add 2% genipin solution and carry out crosslinkedly, stir 20min fast.NaHCO with mass fraction 0.5%
3It is 5 that solution is transferred pH value of reaction system, and fast reaction 5h removes acetone, and vacuum drying gets final product.The mean diameter of thus obtained microsphere is 2.5 μ m.
Embodiment 6
(molecular weight is 10 with chitosan, 000) is dissolved in the malonic acid aqueous solution of 2wt%, the chitosan malonic acid aqueous solution 10ml that is mixed with 2% (w/v) is as water, paclitaxel and lecithin are dissolved in the ethanol as oil phase, class of department 80 joins oil phase, 1500r/min mechanical agitation 5min is uniformly dispersed it, water is dropwise added oil phase, wherein water/oil phase is 1: 5, the addition of paclitaxel is 0.7% of an ethanol quality, soft phospholipid is 5% of ethanol quality, and the addition of class of department is 3% (v/v) of oil phase.Heating in water bath control temperature stirs 50min for 40 ℃.Dropwise add 1% genipin solution and carry out crosslinkedly, stir 30min fast.NaHCO with mass fraction 1%
3It is 4.5 that solution is transferred pH value of reaction system, and fast reaction 7h removes ethanol, and vacuum drying gets final product.The mean diameter of thus obtained microsphere is 3 μ m.
Claims (8)
1. preparation method that is used for the chitosan microball that cancer therapy drug discharges, its method following steps:
(1) chitosan is dissolved in the dilute acid soln of 2wt%, the chitosan dilute acid soln that is mixed with 2% (w/v) is dissolved in ethanol or the acetone paclitaxel and lecithin as oil phase as water.
(2) an amount of emulsifying agent is joined oil phase, mechanical agitation 5-30min is uniformly dispersed it, and water is dropwise added oil phase, and heating in water bath control temperature stirs 20-50min for 30-70 ℃.
(3) dropwise add the genipin aqueous solution and carry out crosslinkedly, and stir fast.
(4) NaHCO of usefulness 0.5-5wt%
3Solution is transferred pH value of reaction system, and stirring reaction 1-10h removes ethanol or acetone fast, is drying to obtain the chitosan nano microsphere.
2. preparation method as claimed in claim 1, the molecular weight that it is characterized in that the chitosan in the step 1 is 3000-200,000.
3. preparation method as claimed in claim 1 is characterized in that the acid of the dilute acid soln in the step 1 comprises: formic acid, acetic acid, citric acid, hydroxyacetic acid, lactic acid, malonic acid.
4. preparation method as claimed in claim 1 is characterized in that the water/oil phase in the step 1 is 1: 2-1: 8, and the addition of paclitaxel is the 0.01-1% of ethanol or acetone quality, soft phospholipid is the 2-10% of ethanol or acetone quality.
5. preparation method as claimed in claim 1 is characterized in that class of department emulsifying agent comprises in the step 2: class of department 80, class of department 83 or class of department 85, and the addition of its class of department is the 0.5%-10% (v/v) of oil phase.
6. preparation method as claimed in claim 1 is characterized in that step 3 Zhong jing Buddhist nun's par solution is 1wt%-2wt%.
7. preparation method as claimed in claim 1 is characterized in that the rotating speed 1000-2500rpm that stirs in the step 2,3,4.
8. preparation method as claimed in claim 1, the pH value that it is characterized in that reaction system in the step 4 is 4-9.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103920149A (en) * | 2014-04-25 | 2014-07-16 | 浙江中医药大学 | Preparation method of chitosan photosensitive microspheres |
| CN104208757A (en) * | 2014-08-29 | 2014-12-17 | 石家庄亿生堂医用品有限公司 | Chitosan microspheres and preparation method thereof |
| CN104208755A (en) * | 2014-08-29 | 2014-12-17 | 石家庄亿生堂医用品有限公司 | Preparation method of chitosan microsphere |
| CN104208756A (en) * | 2014-08-29 | 2014-12-17 | 石家庄亿生堂医用品有限公司 | Preparation method of carboxymethyl chitosan microspheres |
-
2011
- 2011-06-17 CN CN2011101687169A patent/CN102293751A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103920149A (en) * | 2014-04-25 | 2014-07-16 | 浙江中医药大学 | Preparation method of chitosan photosensitive microspheres |
| CN104208757A (en) * | 2014-08-29 | 2014-12-17 | 石家庄亿生堂医用品有限公司 | Chitosan microspheres and preparation method thereof |
| CN104208755A (en) * | 2014-08-29 | 2014-12-17 | 石家庄亿生堂医用品有限公司 | Preparation method of chitosan microsphere |
| CN104208756A (en) * | 2014-08-29 | 2014-12-17 | 石家庄亿生堂医用品有限公司 | Preparation method of carboxymethyl chitosan microspheres |
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Application publication date: 20111228 |