CN101066457A - Injectable temperature-sensitive chitosan/methyl cellulose gel and its prepn process - Google Patents
Injectable temperature-sensitive chitosan/methyl cellulose gel and its prepn process Download PDFInfo
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- CN101066457A CN101066457A CN 200710052449 CN200710052449A CN101066457A CN 101066457 A CN101066457 A CN 101066457A CN 200710052449 CN200710052449 CN 200710052449 CN 200710052449 A CN200710052449 A CN 200710052449A CN 101066457 A CN101066457 A CN 101066457A
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Abstract
The present invention discloses one kind of injectable temperature-sensitive chitosan/methyl cellulose gel and its preparation process. The gel is physical gel and has effective components including chitosan in 0.25-2 wt% and methyl cellulose in 0.25-5 wt%. It is prepared through dissolving chitosan in acid solution to prepare 0.5-4 wt% concentration chitosan solution set in ice bath; dissolving basic salt in 0.5-10 wt% concentration methyl cellulose solution and setting in ice bath too; dropping the methyl cellulose solution into the chitosan solution slowly through constant stirring for complete mixing, centrifuging to deair and setting the mixture solution in gel temperature to form gel. The preparation process has mild condition and can avoid contamination of chemical reagent and harmful matter, and the gel is suitable for carrying sensitive macro molecules, such as protein and may be also used in injecting medical material and tissue engineering rack material.
Description
Technical field
The present invention relates to a kind of Injectable temperature-sensitive chitosan/methyl cellulose gel and preparation method thereof.Belong to polymer chemistry and biomedical sector.
Background technology
Hydrogel has hydrophilic three-dimensional polymer network structure, can absorb a large amount of moisture.Interchain physical crosslinking of polymer and chemical crosslinking effect can make hydrogel keep certain shape, can not be dissolved in the water.Because hydrogel has excellent biological compatibility, obtained to use widely at biomedical sector.Wherein, it is the focus of a research that original position forms gel rubber system, has multiple biological use, is mainly used in medicament slow release, cell culture and organizational project.Original position forms gel rubber system and keep solution state before injection, can form gel under human body temperature after the injection.Factors such as solvent, ultraviolet radiation, ion crosslinking agent, pH and temperature can both cause the formation of situ-gel.Above generation type does not need chemical reagent such as organic solvent, copolymerizing agent and initiator, can reduce the bio-toxicity of hydrogel.Wherein, but carrying out the temperature sensitive type material that solution-gel conversion original position is solidified by temperature change, also is the research focus of injectable embedded material.Chitosan has good biocompatibility and biodegradability, contains amino and hydroxyl on the macromolecular chain, is a kind of natural cationic polysaccharide, has the response of unique pH value and temperature dual, is the very wide biomaterial of a kind of purposes.Methylcellulose also is the natural macromolecular material of a kind of good biocompatibility and biodegradability, has temperature-sensitive equally, but its phase transition temperature does not have application value in injectable organizational project and drug-supplying system between 50-70 ℃.
Summary of the invention
The objective of the invention is to make full use of chitosan, methylcellulose advantage separately, and provide a kind of novel Injectable temperature-sensitive chitosan/methyl cellulose gel and preparation method thereof, it is liquid that this gel low-temperature keeps down, can form gel under the human body temperature, meet the requirement of injectable embedded material.And its preparation method process safety, simple effective, compliance with environmental protection requirements, form physical gel this preparation under neutrallty condition, can avoid the side effect of organic solvent, is suitable for the delivery of sensitive kinds medicine, had good sustained release effect.
The technical scheme that realizes the object of the invention is: the Injectable temperature-sensitive chitosan/methyl cellulose gel is a physical gel, it is effectively formed and comprises chitosan and methylcellulose, the mass percentage content of chitosan is 0.25～2% in the gel, and the mass percentage content of methylcellulose is 0.25～5%.
The concrete steps of above-mentioned gel process for preparing provided by the invention are as follows: chitosan is dissolved in concentration can guarantees that chitosan fully dissolves and dissolve back gained solution pH value greater than in 5.0 the hydrochloric acid or acetum, make weight percent concentration and be 0.5～4% chitosan acid solution, in ice bath, place; It is to get the methylcellulose saline solution in 0.5～10% methocel solution that basic salt is dissolved in weight percent concentration, places in ice bath equally; Then under constantly stirring, the methylcellulose saline solution is slowly splashed into the chitosan acid solution, keep solution not have muddiness, be stirred to both and fully mix, behind the centrifugal removal bubble, blend solution is positioned over promptly forms the Injectable temperature-sensitive chitosan/methyl cellulose gel under the gelling temp.
Wherein, used basic salt is NaHCO
3, Na
3PO
4Or the glyceryl sodium phosphate, the basic salt consumption must guarantee that chitosan and methylcellulose blend solution pH value are between 6.5～7.2.
And chitosan and methocel solution all need ice bath to place 15min at least, and drip the methylcellulose saline solution under condition of ice bath in the chitosan acid solution.
Gelling temp is relevant with the basic salt kind that is adopted among the present invention, and when used chitosan is identical with the volume of methylcellulose, concentration respectively is 1% o'clock, and basic salt is NaHCO
3The time, gelling temp is about 24 ℃; Basic salt is Na
3PO
4The time, gelling temp is about 27 ℃; When basic salt was the glyceryl sodium phosphate, gelling temp was about 33 ℃.
This novel chitosan that the present invention provides first and the physical gel of methylcellulose blend adopt the method preparation of chitosan and methylcellulose blend, have temperature sensitivity, and suitable human body temperature can form gel under human body temperature.And the easy gentleness of its preparation condition, process safety, can avoid organic chemical reagent and other deleterious material, compliance with environmental protection requirements, can be used as pharmaceutical carrier, the slow release that is used for the sensitive kinds medicine, be particularly suitable for the delivery of responsive macromole such as protein drug, also can be used as the injectable type medical material, as the reparation of injections in articular cavity in articular cartilage, the pore space structure of gel densification and higher mechanical strength, make it also can be used as tissue engineering bracket material, be used for the cultivation of cell, so the present invention is at medicament slow release, biomedical sector such as organizational project and cell culture has a wide range of applications.
The specific embodiment
Embodiment 1: the 200mg chitosan is dissolved in the hydrochloric acid solution that 10ml concentration is 0.1mol/l, after the dissolving fully, places 15min in ice bath; After the methylcellulose dissolving, be mixed with 2wt% solution; Sodium bicarbonate 84mg is added in the methocel solution, in ice bath, place 15min equally; Under continuous stirring, condition of ice bath, the methylcellulose saline solution is slowly splashed in the chitosan salt acid solution then, keep solution not have muddiness, be stirred to both and fully mix, chitosan and methylcellulose blend solution pH value are 6.7, centrifugal again removal bubble.At last, blend solution is positioned under the gelling temp can forms the Injectable temperature-sensitive chitosan/methyl cellulose gel, the mass percentage content of chitosan is 1% in the gel, and the mass percentage content of methylcellulose is 1%, and gelling temp can record by dynamic rheometer.
Embodiment 2: the 200mg chitosan is dissolved in the acetum that 10ml concentration is 0.12mol/l, after the dissolving fully, places 15min in ice bath; After the methylcellulose dissolving, be mixed with 2wt% solution; Sodium phosphate 100mg is added in the methocel solution, in ice bath, place 15min equally; Under continuous stirring, condition of ice bath, the methylcellulose saline solution is slowly splashed in the chitosan salt acid solution then, keep solution not have muddiness, be stirred to both and fully mix, chitosan and methylcellulose blend solution pH value are 6.8, centrifugal again removal bubble.At last, blend solution is positioned over forms Injectable temperature-sensitive chitosan/methyl cellulose gel gel under the gelling temp, the mass percentage content of chitosan is 1% in the gel, and the mass percentage content of methylcellulose is 1%, and gelling temp can record by dynamic rheometer.
Embodiment 3: the 100mg chitosan is dissolved in the hydrochloric acid solution that 10ml concentration is 0.05mol/l, after the dissolving fully, places 15min in ice bath; After the methylcellulose dissolving, be mixed with 3wt% solution; Glyceryl sodium phosphate 500mg is added in the methocel solution, in ice bath, place 15min equally; Under continuous stirring, condition of ice bath, the methylcellulose saline solution is slowly splashed in the chitosan salt acid solution then, keep solution not have muddiness, be stirred to both and fully mix, chitosan and methylcellulose blend solution pH value are 6.7, centrifugal again removal bubble.At last, blend solution is positioned over forms Injectable temperature-sensitive chitosan/methyl cellulose gel gel under the gelling temp, the mass percentage content of chitosan is 0.5% in the gel, and the mass percentage content of methylcellulose is 1.5%, and gelling temp can record by dynamic rheometer.
Embodiment 4: the 200mg chitosan is dissolved in the hydrochloric acid solution that 10ml concentration is 0.1mol/l, after the dissolving fully, places 15min in ice bath; After the methylcellulose dissolving, be mixed with 1wt% solution; Sodium bicarbonate 84mg and bovine serum albumin are added in the methocel solution, in ice bath, place 15min equally; Under continuous stirring, condition of ice bath, the methylcellulose saline solution is slowly splashed in the chitosan salt acid solution then, keep solution not have muddiness, be stirred to both and fully mix, chitosan and methylcellulose blend solution pH value are 6.7, centrifugal again removal bubble.At last, it is 1% that blend solution is positioned over the mass percentage content that can form chitosan in the Injectable temperature-sensitive chitosan/methyl cellulose gel gel gel under the gelling temp, and the mass percentage content of methylcellulose is 0.5%.The envelop rate of BSA can reach 90%, and gel two days accumulation slow release in the phosphate buffered solution (PBS) of pH 7.4 reach more than 80%.
Embodiment 5: behind the gel autoclaving after the lyophilization, under the aseptic condition, will cultivate triple-substituted rabbit knee cartilage cell inoculation on gel stent, and place 37 ℃, 5%CO
2, cultivate in the incubator of 95% humidity.Visible cell relatively is uniformly distributed on the support after cultivating for two weeks, and along the gel stent growth, how spherical in shape cell is, and minority is a fusiformis, and visible cell stretches out pseudopodium, attaches to support.
Claims (5)
1, a kind of Injectable temperature-sensitive chitosan/methyl cellulose gel, it is characterized in that: chitosan/methyl cellulose gel is a physical gel, it is effectively formed and comprises chitosan and methylcellulose, the mass percentage content of chitosan is 0.25～2% in the gel, and the mass percentage content of methylcellulose is 0.25～5%.
2, the preparation method of the described Injectable temperature-sensitive chitosan/methyl cellulose gel of a kind of claim 1, it is characterized in that adopting following concrete steps: chitosan is dissolved in concentration can guarantees that chitosan fully dissolves and dissolve back gained solution pH value greater than in 5.0 the hydrochloric acid or acetum, make weight percent concentration and be 0.5～4% chitosan acid solution, in ice bath, place; It is to get the methylcellulose saline solution in 0.5～10% methocel solution that basic salt is dissolved in weight percent concentration, places in ice bath equally; Then under constantly stirring, the methylcellulose saline solution is slowly splashed into the chitosan acid solution, keep solution not have muddiness, be stirred to both and fully mix, behind the centrifugal removal bubble, blend solution is positioned over promptly forms the Injectable temperature-sensitive chitosan/methyl cellulose gel under the gelling temp.
3, the preparation method of Injectable temperature-sensitive chitosan/methyl cellulose gel according to claim 2 is characterized in that: used basic salt is NaHCO
3, Na
3PO
4Or glyceryl sodium phosphate.
4, the preparation method of Injectable temperature-sensitive chitosan/methyl cellulose gel according to claim 2 is characterized in that: the basic salt consumption must guarantee that chitosan and methylcellulose blend solution pH value are between 6.5～7.2.
5, the preparation method of Injectable temperature-sensitive chitosan/methyl cellulose gel according to claim 2, it is characterized in that: chitosan and methocel solution all need ice bath to place 15min at least, and drip the methylcellulose saline solution under condition of ice bath in the chitosan acid solution.
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101215389B (en) * | 2008-01-14 | 2010-06-02 | 浙江大学 | Chitosan hydrogel and preparation method thereof |
| CN102827446A (en) * | 2012-09-14 | 2012-12-19 | 武汉大学 | Temperature response type injectable hydrogel and preparation method and usage thereof |
| CN106667986A (en) * | 2017-01-24 | 2017-05-17 | 中南大学湘雅医院 | Rhein/chitosan hydrogel and preparation method and application thereof |
| CN110215542A (en) * | 2018-03-02 | 2019-09-10 | 成都远睿生物技术有限公司 | A method of forming the interim obturator of blood vessel |
| CN110215255A (en) * | 2018-03-02 | 2019-09-10 | 成都远睿生物技术有限公司 | A method of forming the interim obturator of urethra |
| CN113429589A (en) * | 2021-06-29 | 2021-09-24 | 华南理工大学 | Glycyrrhetinic acid-based pH-sensitive slow-release hydrogel material and preparation method and application thereof |
| CN113679878A (en) * | 2021-08-16 | 2021-11-23 | 稳健医疗用品股份有限公司 | Injectable temperature-sensitive hydrogel and preparation method thereof |
| CN114316306A (en) * | 2021-12-30 | 2022-04-12 | 普丽妍（南京）医疗科技有限公司 | Preparation method of injectable temperature-sensitive hydrogel |
| CN114652895A (en) * | 2020-12-23 | 2022-06-24 | 上海其胜生物制剂有限公司 | Preparation method of injectable tissue regeneration type chitosan composite gel scaffold |
-
2007
- 2007-06-11 CN CNB2007100524492A patent/CN100522247C/en not_active Expired - Fee Related
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101215389B (en) * | 2008-01-14 | 2010-06-02 | 浙江大学 | Chitosan hydrogel and preparation method thereof |
| CN102827446A (en) * | 2012-09-14 | 2012-12-19 | 武汉大学 | Temperature response type injectable hydrogel and preparation method and usage thereof |
| CN102827446B (en) * | 2012-09-14 | 2014-06-18 | 武汉大学 | Temperature response type injectable hydrogel and preparation method and usage thereof |
| CN106667986A (en) * | 2017-01-24 | 2017-05-17 | 中南大学湘雅医院 | Rhein/chitosan hydrogel and preparation method and application thereof |
| CN106667986B (en) * | 2017-01-24 | 2019-03-19 | 中南大学湘雅医院 | Rhein/chitosan hydrogel and preparation method and application thereof |
| CN110215542A (en) * | 2018-03-02 | 2019-09-10 | 成都远睿生物技术有限公司 | A method of forming the interim obturator of blood vessel |
| CN110215255A (en) * | 2018-03-02 | 2019-09-10 | 成都远睿生物技术有限公司 | A method of forming the interim obturator of urethra |
| CN114652895A (en) * | 2020-12-23 | 2022-06-24 | 上海其胜生物制剂有限公司 | Preparation method of injectable tissue regeneration type chitosan composite gel scaffold |
| CN113429589A (en) * | 2021-06-29 | 2021-09-24 | 华南理工大学 | Glycyrrhetinic acid-based pH-sensitive slow-release hydrogel material and preparation method and application thereof |
| CN113679878A (en) * | 2021-08-16 | 2021-11-23 | 稳健医疗用品股份有限公司 | Injectable temperature-sensitive hydrogel and preparation method thereof |
| CN114316306A (en) * | 2021-12-30 | 2022-04-12 | 普丽妍（南京）医疗科技有限公司 | Preparation method of injectable temperature-sensitive hydrogel |
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| CN100522247C (en) | 2009-08-05 |
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