CN1290524A - Ion crosslinking process of preparing medicinal slow-releasing chitosan microball - Google Patents
Ion crosslinking process of preparing medicinal slow-releasing chitosan microball Download PDFInfo
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- CN1290524A CN1290524A CN 99121128 CN99121128A CN1290524A CN 1290524 A CN1290524 A CN 1290524A CN 99121128 CN99121128 CN 99121128 CN 99121128 A CN99121128 A CN 99121128A CN 1290524 A CN1290524 A CN 1290524A
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Abstract
Chitosan solution containing medicine in 1-8 % and gelatine, agar or agarose in 1-8 % are mixed through stirring, the mixture is maintained at constant temperature of 30-60 deg.C for 2-5 hr and syringe dripped into cold vegetable oil at the temperature of minus 10 to plus 15 deg.C. After 20-40 min, cold sodium tripolyphosphate, sodium sulfate or sodium cirtrate as crosslinking ion solution in 0.1-5 % is added through slight stirring for 20-40 min, and the mixture is filtered, water washed and dried into the chitosan microball. The persent invention can prepare large-size chitosan microball with high mechanical performance, which may be further produced into chitosan microball with small size and perfect shape.
Description
The present invention relates to the method that a kind of ionomer prepares medicinal slow-releasing chitosan microball.
Chitosan is a kind of natural biological macromolecule from extractions such as shrimp and crab shells, and the nature reserves are abundant, and inexhaustible.Chitosan has the performance of a lot of excellences, as excellent biological compatibility, biological degradability, film property, biological caking property etc.And has unique polycation characteristic.So chitosan has obtained extensive studies and application in chemical industry, agricultural, cosmetics, medicament industry.
Preparation polymer pastille microsphere is one of important channel of realizing medicine controlled releasing.Up to the present, existing a lot of methods are used to prepare chitosan microball, and wherein mainly contain following three kinds: first kind is the most frequently used emulsion-crosslinking method.The organic acid soln of chitosan-containing is emulsifiable in oil phase forms the W/O microemulsion, add chemical cross-linking agent (glutaraldehyde etc.) crosslinking curing.The chitosan microball particle diameter of this method preparation can be as small as several microns, but the remnants of organic crosslinking agent can produce toxic and side effects to organism, and organic crosslinking agent also may make medicine such as polypeptide protein take place crosslinked and lose biological activity simultaneously.Second method is called simple co-agglomeration.Chitosan solution is extruded the formation fine droplet from nozzle, droplet is solidified in solidification liquid.Employed solidification liquid is generally NaOH, NaOH-methanol etc.This method is suitable for preparing the chitosan microball (hundreds of micron～several thousand microns) of greater particle size.But the NaOH of higher concentration and the use of organic solvent also can cause a lot of seondary effects, especially are not suitable as the control-release microsphere of biologically active drugs such as polypeptide protein.
In order to overcome the defective of said method, people have been developed gentle ionic cross-linking and have been used to prepare chitosan microball.Its ultimate principle is to utilize the electrostatic interaction between multivalent anions and the chitosan cation group to make chitosan solution produce reversible physical crosslinking, thereby has avoided the use of chemical covalent crosslinking agent and other organic solvent.Ionic cross-linking prepared chitosan microsphere not only can be used as the slow-released carrier of general medicine, and is having more its superiority aspect the slow release of biologically active drugs such as polypeptide protein.
Bodmeier in 1989 etc. are added dropwise to the sodium tripolyphosphate solidification liquid to chitosan solution, have prepared the ionomer chitosan microball of big particle diameter.Afterwards, the application of this process aspect medicament obtained research.For example Shiraish in 1993 etc. are used for the oral slow-releasing preparation of indomethacin to the crosslinked chitosan microball of sodium tripolyphosphate, and animal test results is good.Nineteen ninety-five Sezer etc. has then studied the feasibility of sodium tripolyphosphate crosslinked chitosan microsphere as the piroxicam slow-released carrier.Simultaneously, the ionomer chitosan microball is also being obtained bigger progress aspect the polypeptide protein medicament slow release, and the medicament categories that is adopted comprises bovine serum albumin, salmon calcitonin, tetanus toxoid or the like.
Yet up to now, the ionomer chitosan microball generally all is directly chitosan solution to be added dropwise to cross-linking ion solution to prepare, and there are two subject matters in this process.The one, be difficult to prepare small particle diameter (tens microns) chitosan microball; The 2nd, prepared big particle diameter microsphere mechanical strength is very poor, and is very easily broken in preparation process.In order to solve second problem, hope such as Aral in 1998 are by improving the microsphere mechanical strength at big particle diameter sodium tripolyphosphate crosslinked chitosan microsphere surface recombination sodium alginate film, but do not obtain ideal results.
The purpose of this invention is to provide the method that a kind of ionomer prepares medicinal slow-releasing chitosan microball.
The present invention takes following measures in order to achieve the above object:
A kind of ionomer prepares the method for medicinal slow-releasing chitosan microball, it is the chitosan solution that contains medicine with 1～8%, add 1～8% gelatin or agarose or agar again, stir, 30～60 ℃ of constant temperature 2～5 hours, be added dropwise in-10～15 ℃ of cold vegetable oil then by syringe needle, after 20～40 minutes, add 0.1～5% cold sodium tripolyphosphate or sodium sulfate or sodium citrate cross-linking ion solution, 20～40 minutes after-filtration of gentle agitation, washing and drying gets final product.
Another kind of ionomer prepares the method for medicinal slow-releasing chitosan microball, it is the chitosan solution that contains medicine with 1～8%, add 1～8% gelatin or agarose or agar again, stirred the back 30～60 ℃ of constant temperature 2～5 hours, the vegetable oil that adds 5～20 times of volumes then, stirred 5～15 minutes down at 30～60 ℃, form the W/O emulsion,-10～15 ℃ of coolings 20～40 minutes, add 0.1～5% cold sodium tripolyphosphate or sodium sulfate or sodium citrate cross-linking ion solution, stirred 20～40 minutes, centrifugalize, washing and drying gets final product.
Advantage of the present invention:
1. the component that passes through to introduce other bio-compatible biodegradation and cohesion takes place at low temperatures in chitosan solution is (as agarose, gelatin etc.), it is crosslinked that uniform static takes place for chitosan macromole and multivalent anions, thereby the mechanical performance that makes the big particle diameter chitosan microball of preparation is significantly improved (tens～hundred times), has reached practical requirement.
2. adopt the present invention can prepare the ionomer chitosan microball that form is good, particle diameter is little (several approximately micron) easily, be suitable for injection to be used.Preparation process is amplified easily simultaneously.
3. prepare microsphere under the LOW TEMPERATURES condition, the loss of contained medicine in preparation process reduces, and significantly improved the embedding rate (greater than 90%) of medicine, and the slow release effect of prolong drug to a certain extent.
4. under low temperature and gentle condition such as solvent-free, prepare microsphere, can effectively keep the biological activity of protein medicaments.So microspheres prepared of the present invention not only is suitable for the slow-released carrier as general small-molecule drug, and have more superiority at the slow release of polypeptide protein class medicine (as GCSF, interferon, vaccine etc.).
Elaborate below in conjunction with embodiment:
Example 1.
4% chitosan solution adds 4% gelatin again, stirs.30～40 ℃ of constant temperature 4 hours, be added dropwise in the cold vegetable oil then by No. 7 syringe needles.After 30 minutes, add the solution of 1.0% cold sodium tripolyphosphate, 30 minutes after-filtration of gentle agitation, washing obtains the big particle diameter ionomer chitosan microball of the about 3mm of particle diameter.The single shaft compressive property of microsphere can reach 0.85 newton/, higher 50～100 times than the microsphere of traditional method preparation.
Example 2.
In the solution of 4% chitosan and 1% model drug (fluorescence glucosan, Mw 71200), add 4% agarose, stir.50～60 ℃ of constant temperature 4 hours, be added dropwise in the cold vegetable oil then by No. 7 syringe needles.After 30 minutes, add 1.0% cold metabisulfite solution, 30 minutes after-filtration of gentle agitation are washed, and obtain the big particle diameter ionomer chitosan microball of the about 3mm of particle diameter.The embedding rate of fluorescence glucosan is up to 90%, and is higher by 20%～40% than preparation under conventional process conditions.Microsphere also improves to the slow release effect of medicine simultaneously.
Example 3.
In the solution of 3% chitosan and 1% model drug (fluorescence glucosan, Mw 71200), add 3% agar, stir.50～60 ℃ of constant temperature 4 hours, be added dropwise in the cold vegetable oil then by No. 8 syringe needles.After 30 minutes, add 2.5% cold sodium citrate solution, 30 minutes after-filtration of gentle agitation are washed, and obtain the big particle diameter ionomer chitosan microball of the about 4mm of particle diameter.The embedding rate of fluorescence glucosan is up to 90%, and is higher by 20%～40% than preparation under conventional process conditions.Microsphere also improves to the slow release effect of medicine simultaneously.
Example 4.
In 4% chitosan and 1% model drug (bright orchid) solution, add 4% gelatin again, the back that stirs was 30～40 ℃ of constant temperature 4 hours.The vegetable oil that adds 10 times of volumes then stirs 10 minutes (100 rev/mins of rotating speeds) down at 30～40 ℃, forms the W/O emulsion.4 ℃ of coolings 30 minutes, add 1.0% cold sodium tripolyphosphate solution, restir 30 minutes, centrifugalize, washing and drying, it is better to obtain form, the particle diameter little (about 10 microns) and the very narrow microsphere that distributes.The embedding rate of model drug surpasses 80% simultaneously.
Example 5.
In 4% chitosan and 1% model drug (bright orchid) solution, add 3% agarose again, the back that stirs was 50～60 ℃ of constant temperature 4 hours.The vegetable oil that adds 15 times of volumes then stirs 10 minutes (100 rev/mins of rotating speeds) down at 50～60 ℃, forms the W/O emulsion.10 ℃ of coolings 30 minutes, add 1.5% cold metabisulfite solution, restir 30 minutes, centrifugalize, washing and drying, it is better to obtain form, the particle diameter little (about 15 microns) and the very narrow microsphere that distributes.The embedding rate of model drug surpasses 80% simultaneously.
Example 6.
In 3% chitosan and 1% model drug (bright orchid) solution, add 2% agar again, the back that stirs was 50～60 ℃ of constant temperature 4 hours.The vegetable oil that adds 15 times of volumes then stirs 10 minutes (200 rev/mins of rotating speeds) down at 50～60 ℃, forms the W/O emulsion.10 ℃ of coolings 30 minutes, add 2% cold sodium citrate solution, restir 30 minutes, centrifugalize, washing and drying, it is better to obtain form, the particle diameter little (about 8 microns) and the very narrow microsphere that distributes.The embedding rate of model drug surpasses 80% simultaneously.
Claims (2)
1. an ionomer prepares the method for medicinal slow-releasing chitosan microball, it is characterized in that: 1～8% contains the chitosan solution of medicine, add 1～8% gelatin or agarose or agar again, stir, 30～60 ℃ of constant temperature 2～5 hours, be added dropwise in-10～15 ℃ of cold vegetable oil then by syringe needle, after 20～40 minutes, add 0.1～5% cold sodium tripolyphosphate or sodium sulfate or sodium citrate cross-linking ion solution, 20～40 minutes after-filtration of gentle agitation, washing and drying gets final product.
2. an ionomer prepares the method for medicinal slow-releasing chitosan microball, it is characterized in that: 1～8% contains the chitosan solution of medicine, add 1～8% gelatin or agarose or agar again, stirred the back 30～60 ℃ of constant temperature 2～5 hours, the vegetable oil that adds 5～20 times of volumes then, stirred 5～15 minutes down at 30～60 ℃, form the W/O emulsion,-10～15 ℃ of coolings 20～40 minutes, add 0.1～5% cold sodium tripolyphosphate or sodium sulfate or sodium citrate cross-linking ion solution, stirred 20～40 minutes, centrifugalize, washing and drying gets final product.
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| CN 99121128 CN1290524A (en) | 1999-09-30 | 1999-09-30 | Ion crosslinking process of preparing medicinal slow-releasing chitosan microball |
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| CN 99121128 CN1290524A (en) | 1999-09-30 | 1999-09-30 | Ion crosslinking process of preparing medicinal slow-releasing chitosan microball |
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| CN100391539C (en) * | 2005-04-08 | 2008-06-04 | 武汉大学 | Chitin tetra ammonium salt nano-particle, its preparation method and use |
| CN100393782C (en) * | 2006-03-29 | 2008-06-11 | 武汉大学 | Carboxymethyl chitosan nanoparticles as medicine carrier and method for preparing same |
| CN100522246C (en) * | 2005-03-18 | 2009-08-05 | 中国科学院过程工程研究所 | Chitosan pellet/microsac and preparation thereof |
| CN100571778C (en) * | 2005-03-18 | 2009-12-23 | 中国科学院过程工程研究所 | A kind of preparation method of chitosan microball of biologically active medicine |
| CN102407089A (en) * | 2011-10-19 | 2012-04-11 | 中国海洋大学 | Method for preparing chitosan compound nano/micron capsule with core-shell structure |
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| CN103145997A (en) * | 2013-04-10 | 2013-06-12 | 山东轻工业学院 | Method for modifying gelatin by binary quaternary ammonium salt compound |
| CN103319733A (en) * | 2013-06-13 | 2013-09-25 | 广东药学院 | Method for preparing glycan-negative ion polysaccharide compound nanoparticles from micro-emulsions |
| CN103386134A (en) * | 2013-07-22 | 2013-11-13 | 沈阳化工大学 | Preparation method for chitosan drug-carrying microspheres by ionic cross-linking method |
| CN105903064A (en) * | 2016-04-12 | 2016-08-31 | 中国科学院深圳先进技术研究院 | Chitosan microsphere, and preparation method and application thereof |
| CN106957448A (en) * | 2017-02-24 | 2017-07-18 | 黄秋丽 | A kind of xanthans modifies the preparation method of chitosan microball |
| CN109316626A (en) * | 2018-10-31 | 2019-02-12 | 杭州艾力康医药科技有限公司 | A kind of preparation method of medicine-carried Gelatin embolism microsphere |
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1999
- 1999-09-30 CN CN 99121128 patent/CN1290524A/en active Pending
Cited By (21)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN100522246C (en) * | 2005-03-18 | 2009-08-05 | 中国科学院过程工程研究所 | Chitosan pellet/microsac and preparation thereof |
| CN100571778C (en) * | 2005-03-18 | 2009-12-23 | 中国科学院过程工程研究所 | A kind of preparation method of chitosan microball of biologically active medicine |
| CN100391539C (en) * | 2005-04-08 | 2008-06-04 | 武汉大学 | Chitin tetra ammonium salt nano-particle, its preparation method and use |
| CN100393782C (en) * | 2006-03-29 | 2008-06-11 | 武汉大学 | Carboxymethyl chitosan nanoparticles as medicine carrier and method for preparing same |
| CN102407089B (en) * | 2011-10-19 | 2014-07-23 | 中国海洋大学 | Method for preparing chitosan compound nano/micron capsule with core-shell structure |
| CN102407089A (en) * | 2011-10-19 | 2012-04-11 | 中国海洋大学 | Method for preparing chitosan compound nano/micron capsule with core-shell structure |
| CN102658072A (en) * | 2012-05-22 | 2012-09-12 | 江南大学 | Preparation method for monodispersed chitosan hollow microspheres |
| CN102658072B (en) * | 2012-05-22 | 2015-12-02 | 江南大学 | The preparation method of single dispersing chitosan hollow microballoon |
| CN103145997A (en) * | 2013-04-10 | 2013-06-12 | 山东轻工业学院 | Method for modifying gelatin by binary quaternary ammonium salt compound |
| CN103319733B (en) * | 2013-06-13 | 2015-05-20 | 广东药学院 | Method for preparing glycan-negative ion polysaccharide compound nanoparticles from micro-emulsions |
| CN103319733A (en) * | 2013-06-13 | 2013-09-25 | 广东药学院 | Method for preparing glycan-negative ion polysaccharide compound nanoparticles from micro-emulsions |
| CN103386134A (en) * | 2013-07-22 | 2013-11-13 | 沈阳化工大学 | Preparation method for chitosan drug-carrying microspheres by ionic cross-linking method |
| CN103386134B (en) * | 2013-07-22 | 2015-05-20 | 沈阳化工大学 | Preparation method for chitosan drug-carrying microspheres by ionic cross-linking method |
| CN105903064A (en) * | 2016-04-12 | 2016-08-31 | 中国科学院深圳先进技术研究院 | Chitosan microsphere, and preparation method and application thereof |
| CN105903064B (en) * | 2016-04-12 | 2019-06-25 | 中国科学院深圳先进技术研究院 | A kind of chitosan microball and its preparation method and application |
| CN106957448A (en) * | 2017-02-24 | 2017-07-18 | 黄秋丽 | A kind of xanthans modifies the preparation method of chitosan microball |
| CN109316626A (en) * | 2018-10-31 | 2019-02-12 | 杭州艾力康医药科技有限公司 | A kind of preparation method of medicine-carried Gelatin embolism microsphere |
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