CN104208711B - Chitosan semifluid sustained-release gel and purposes - Google Patents
Chitosan semifluid sustained-release gel and purposes Download PDFInfo
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- CN104208711B CN104208711B CN201410505063.2A CN201410505063A CN104208711B CN 104208711 B CN104208711 B CN 104208711B CN 201410505063 A CN201410505063 A CN 201410505063A CN 104208711 B CN104208711 B CN 104208711B
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Abstract
The invention discloses a kind of chitosan semifluid sustained-release gel, make by following component: component 1: concentration prepare with normal saline or distilled water for the solvent chitosan solution as 0.5020g/ml, dissolving under the conditions of 4 DEG C；Component 2: saturated sodium bicarbonate aqueous solution with volume ratio as 1:1 and the mixed liquor of distilled water are as solvent, and the concentration of preparation is the hyaluronic acid chitosan solution of 0.2510g/ml, dissolves under the conditions of 4 DEG C and obtains.The chitosan semifluid sustained-release gel of the present invention, is before use under room temperature, component 1 and component 2 is mixed in proportion, mixture is injectable semi-fluid condition, after injection when temperature rises to 26 40 DEG C, gradually solidifies in injection site, finally solidification, and controlled pharmacy thing slowly discharges.Semifluid gel preparation prepared by the gel of the present invention can use as pharmaceutical carrier and tissue engineering bracket.Biodegradable, good biocompatibility.
Description
Technical field
The invention belongs to a kind of chitosan semiliquid preparations, more particularly to a kind of chitosan semifluid gel and purposes.
Background technology
Chitosan semifluid sustained-release gel is that one at room temperature becomes semifluid shape, and permissible in the one of 37 DEG C or internal one-tenth solid
Temperature-responsive sustained-release preparation.Its one is big, and advantage is lazy flow, it is to avoid carries medicine and runs off when flowable state, and works as
When being expelled at human body sufferer, slow release (Emily Mastronardi, Amand a can well be carried out by packaging medicine
Foster,Xueru Zhang,MariaC.DeRosa.Smart Materials Based on DNA Aptamers:Taking
Aptasensing to the Next Level.Sensors,2014；14:3156-3171.).It is quick that this characteristic is similar to temperature
Perception hydrogel, is i.e. prone to bag medicine carrying thing, administration, good biocompatibility and degradability.Material main source is natural
And synthetic material, chitosan chitosan has well as the macromolecular material of natural origin also known as chitosan, chitosan
Biocompatibility and degradability, be a kind of nontoxic, nonirritant, no antigen, there is good biocompatibility, can
The material of degraded and absorbed (Fizyki Medycznej,Uniwersytet Adama Mickiewicza w Poznaniu,
Poznań,Polska.The Use of Shells Made of Poly(EthyleneGlycol) and Chitosan to Ensure
the Biocompatibility of Nanoparticles in Biomedical Applications.Polim.Med.
2014；44(2):119-127.).Its abundance, extraction process is simple, and derivant wide variety can be with resistance to heat sterilization.
The gel type formulations utilizing chitosan to be fabricated to has research and development (hee the most widely at the aspect such as pharmaceutical carrier, organization bracket
Dong han,ednaM.Mora,Ju Won Roh,Masato Nishimura,sun Joo Lee,Rebecca L.
stone,Menashe Bar-eli,Gabriel Lopez-Berestein,anil K.sood.Chitosan hydrogel for
localized gene silencing.Cancer Biology & Therapy,2011:9,839-845.)。
Sustained-release preparation mainly has matrix type and reservoir type two kinds.Matrix type sustained-release and controlled release preparation is with molecule or microgranule by medicine
Form be dispersed in carrier material.Reservoir devices sustained-release and controlled release preparation is pharmaceutical pack to be rolled in high molecular polymer.Slow release
The release principle of controlled release preparation is mainly dissolution, diffusion, corrosion, osmotic pressure and ion exchange.Sustained-release preparation is main
Feature is 1) medicine that is short or that need frequent drug administration to the half-life, it is possible to reduce medicining times, what raising patient took medicine complies with
Property, easy to use.2) blood drug level " peak valley " fluctuates little, and blood concentration is steady, maintains curative effect within Valid concentration.3)
Minimum dose reaches maximum drug effect (pharmaceutics/Cui Fude edits .-6 version .-Beijing: People's Health Publisher, 2007.8).Simultaneously
There is also problem, owing to there is concentrated acid, concentrated base and organic reagent in manufacturing process, therefore water-solubility protein class medicine is at preparation bag
Easily inactivate during load.
Summary of the invention
It is an object of the invention to overcome the deficiencies in the prior art, it is provided that a kind of chitosan semifluid sustained-release gel.
Second object of the present invention is to provide the purposes of chitosan semifluid sustained-release gel.
Technical scheme is summarized as follows:
A kind of chitosan semifluid sustained-release gel, makes by following component:
Component 1: the concentration prepared with normal saline or distilled water for the solvent chitosan solution as 0.5020g/ml, described shell gathers
The molecular weight of sugar is 3-8kDa, and deacetylation is 65%-98%, dissolves under the conditions of 4 DEG C；
Component 2: saturated sodium bicarbonate aqueous solution with volume ratio as 1:1 and the mixed liquor of distilled water as solvent, the concentration of preparation
For the hyaluronic acid chitosan solution of 0.2510g/ml, the molecular weight of described hyaluronic acid chitosan is 500kDa, intrinsic viscosity
3000g/ml, dissolves under the conditions of 4 DEG C and obtains.
The molecular weight of chitosan is preferably 5kDa, and deacetylation is preferably 95%.
Chitosan semifluid sustained-release gel is prepared pharmaceutical carrier or prepares the purposes of tissue engineering bracket.
Advantages of the present invention:
1, the chitosan semifluid sustained-release gel of the present invention, is before use under room temperature, by component 1 and component 2 is by volume
The ratio mixing of 1:1, mixture is injectable semi-fluid condition, after injection when temperature rises to 26-40 DEG C, in injection site
Gradually solidify, finally solidify, and controlled pharmacy thing slowly discharges.
2, semifluid gel preparation prepared by the chitosan semifluid sustained-release gel of the present invention can prop up as pharmaceutical carrier and organizational project
Frame uses.
3, chitosan semifluid sustained-release gel biodegradable of the present invention, good biocompatibility, can carry fat-soluble medicine and egg
White class medicine.
Accompanying drawing explanation
Fig. 1 is semifluid gel preparation at ambient temperature and the preparation photo after 37 DEG C of solidifications in 3 hours, and wherein A is half
Fluid gel preparation, B is coagulation agent (37 DEG C 3 hours).
Fig. 2 is the slow release behavior figure that bag carries the Cumulative release amount of bovine serum albumin.
Fig. 3 is the unit interval burst size slow release behavior figure that bag carries fluorescin.
Fig. 4 is the slow release behavior figure that bag carries the Cumulative release amount of paclitaxel.
Fig. 5 is the unit interval burst size slow release behavior figure that bag carries paclitaxel.
Detailed description of the invention
Embodiment 1
A kind of chitosan semifluid sustained-release gel, makes by following component:
Component 1: the concentration prepared with normal saline for the solvent chitosan solution as 0.5020g/ml, the molecular weight of chitosan is
5kDa, deacetylation is 95%, dissolves and obtain under the conditions of 4 DEG C；
Component 2: saturated sodium bicarbonate aqueous solution with volume ratio as 1:1 and the mixed liquor of distilled water as solvent, the concentration of preparation
For the hyaluronic acid chitosan solution of 0.2510g/ml, the molecular weight of described hyaluronic acid chitosan is 500kDa, intrinsic viscosity
3000g/ml dissolves acquisition under the conditions of 4 DEG C.
Component 1 and component 2 are mixed the gel in semi-fluid condition by the ratio using 1:1 by volume under front room temperature, see Figure 1A,
It is available for injection to use.Mixed liquor is warming up to 37 DEG C 3 hours, in curdled appearance, sees Figure 1B.
Bovine serum albumin fluorescence labeling method is that 20mg albumen is dissolved in 5mLpH9.5 is in carbonate buffer solution, places 4
℃30min.Add the 0.4mg Fluorescein isothiocyanate dissolved with 1 DMSO, add 0.5mL carbonate buffer solution.
Being added dropwise over after mixing in protein solution, in 4 DEG C, lucifuge is overnight.Second day liquid loads chromatography bag lucifuge and dialyses 3 days.-20℃
Preserve.
Take the gel that 1ml is semi-fluid condition, add the fluorescently-labeled bovine serum albumin of 0.08g, by stirring, make fluorescence
The bovine serum albumin of labelling is thoroughly mixed with gel.Add 1mlPBS, place under the conditions of 37 DEG C, take supernatant every 24h
1ml, is added the new PBS of 1ml simultaneously, is detected by microplate reader respectively by the supernatant of collection after 168h.Carry albumen mould
Intend release and see Fig. 2.
Take volume be 100 μ l be the gel of semi-fluid condition, add the 7.5mg paclitaxel dissolved with the DMSO of 25 μ l, lead to
Cross stirring, make paclitaxel be thoroughly mixed with gel.Add 200 μ lPBS, place under the conditions of 37 DEG C, in 24h sampling
Clear 200 μ l, add 200 PBS new for μ l simultaneously.After 168h, the supernatant of collection is entered by high performance liquid chromatography respectively
Row detection.Carry taxol drug simulation release and see Fig. 4.
Embodiment 2
A kind of chitosan semifluid sustained-release gel, makes by following component:
Component 1: the concentration prepared with distilled water for the solvent chitosan solution as 0.5020g/ml, the molecular weight of chitosan is
5kDa, deacetylation is 95%, dissolves and obtain under the conditions of 4 DEG C；
Component 2: saturated sodium bicarbonate aqueous solution with volume ratio as 1:1 and the mixed liquor of distilled water as solvent, the concentration of preparation
For the hyaluronic acid chitosan solution of 0.2510g/ml, the molecular weight of described hyaluronic acid chitosan is 500kDa, intrinsic viscosity
3000g/ml dissolves acquisition under the conditions of 4 DEG C.
Component 1 and component 2 are mixed the gel in semi-fluid condition by the ratio using 1:1 by volume under front room temperature, are available for note
Penetrate use.
Bovine serum albumin fluorescence labeling method is that 20mg albumen is dissolved in 5mLpH9.5 is in carbonate buffer solution, places 4
℃30min.Add the 0.4mg Fluorescein isothiocyanate dissolved with 1 DMSO, add 0.5mL carbonate buffer solution.
Being added dropwise over after mixing in protein solution, in 4 DEG C, lucifuge is overnight.Second day liquid loads chromatography bag lucifuge and dialyses 3 days.-20℃
Preserve.
Take the gel that 1ml is semi-fluid condition, add the fluorescently-labeled bovine serum albumin of 0.08g, by stirring, make Sanguis Bovis seu Bubali
Pure albumen is thoroughly mixed with gel.Add 1mlPBS, place under the conditions of 37 DEG C, take supernatant 1ml every 24h, the most again
Add the new PBS of 1ml, after 168h, the supernatant of collection is detected by microplate reader respectively.Carry albumen simulation release and see figure
3。
Take volume be 100 μ l be the gel of semi-fluid condition, add the 7.5mg paclitaxel dissolved with the DMSO of 25 μ l, lead to
Cross stirring, make paclitaxel be thoroughly mixed with gel.Add 200 μ lPBS, place under the conditions of 37 DEG C, in 24h sampling
Clear 200 μ l, add 200 PBS new for μ l simultaneously.After 168h, the supernatant of collection is entered by high performance liquid chromatography respectively
Row detection.Carry taxol drug simulation release and see Fig. 5.
Embodiment 3
A kind of chitosan semifluid sustained-release gel, makes by following component:
Component 1: the concentration prepared with normal saline for the solvent chitosan solution as 0.5020g/ml, the molecular weight of chitosan is
3kDa, deacetylation is 65%, dissolves and obtain under the conditions of 4 DEG C；
Component 2: saturated sodium bicarbonate aqueous solution with volume ratio as 1:1 and the mixed liquor of distilled water as solvent, the concentration of preparation
For the hyaluronic acid chitosan solution of 0.2510g/ml, the molecular weight of hyaluronic acid chitosan is 500kDa, intrinsic viscosity
3000g/ml dissolves acquisition under the conditions of 4 DEG C.
Component 1 and component 2 are mixed in injectable semi-fluid condition by the ratio using 1:1 by volume under front room temperature.
It is demonstrated experimentally that fat-soluble medicine kin with paclitaxel: rapamycin, methotrexate, fluorouracil, mercaptopurine,
Hydroxyurea, cytosine arabinoside, methotrexate, fluorouracil, mercaptopurine, hydroxyurea, cytosine arabinoside, adrenocortical hormone,
The chitosan semifluid sustained-release gel embedding of embodiment 1 preparation such as androgen, corticosteroid, steroid, each simulation discharges
Effect is similar to Example 1.
It is demonstrated experimentally that water-soluble protein drugs kin with bovine serum albumin: protein medicaments, BMP (Bones morphology generation egg
In vain), OVA (chicken egg white), BSA (bovine serum albumin), vaccine (such as bacillus calmette-guerin vaccine), cytokine are (such as
Interleukin), the chitosan semifluid slow release of embodiment 1 preparation such as recombinant polypeptide (such as Human Inter Leukin-2) coagulates
Glue embeds, and each simulation releasing effect is similar to Example 1.
Embodiment 4
A kind of chitosan semifluid sustained-release gel, makes by following component:
Component 1: the concentration prepared with distilled water for the solvent chitosan solution as 0.5020g/ml, the molecular weight of chitosan is
8kDa, deacetylation is 98%, dissolves and obtain under the conditions of 4 DEG C；
Component 2: saturated sodium bicarbonate aqueous solution with volume ratio as 1:1 and the mixed liquor of distilled water as solvent, the concentration of preparation
For the hyaluronic acid chitosan solution of 0.2510g/ml, the molecular weight of hyaluronic acid chitosan is 500kDa, intrinsic viscosity
3000g/ml dissolves acquisition under the conditions of 4 DEG C.
Component 1 and component 2 are mixed in injectable semi-fluid condition by the ratio using 1:1 by volume under front room temperature.
It is demonstrated experimentally that a kind of chitosan semifluid sustained-release gel embedding fat-soluble medicine prepared with the present embodiment: rapamycin and
Embedding protein medicaments BMP each simulation releasing effect is similar to Example 1.
Claims (3)
1. a chitosan semifluid sustained-release gel, is characterized in that making by following component:
Component 1: the concentration prepared with normal saline or distilled water for the solvent chitosan solution as 0.5020g/ml, described chitosan
Molecular weight is 3-8kDa, and deacetylation is 65%-98%, dissolves under the conditions of 4 DEG C；
Component 2: saturated sodium bicarbonate aqueous solution with volume ratio as 1:1 and the mixed liquor of distilled water are as solvent, and the concentration of preparation is
The hyaluronic acid chitosan solution of 0.2510g/ml, the molecular weight of described hyaluronic acid chitosan is 500kDa, intrinsic viscosity
3000g/ml, dissolves under the conditions of 4 DEG C and obtains.
A kind of chitosan semifluid sustained-release gel the most according to claim 1, is characterized in that the molecular weight of described chitosan is 5kDa,
Deacetylation is 95%.
3. a kind of chitosan semifluid sustained-release gel of claim 1 or 2 is prepared pharmaceutical carrier or prepares the purposes of tissue engineering bracket.
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| CN109310800B (en) * | 2016-07-29 | 2022-01-07 | 医药研究有限公司 | Composition for rotator cuff tear repair comprising nucleic acid and chitosan |
| CN113456882A (en) * | 2021-06-30 | 2021-10-01 | 南开大学 | Chitosan sponge material modification method and application |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102321248A (en) * | 2011-06-10 | 2012-01-18 | 冯淑芹 | Injectable temperature sensitive gel used for filling and repairing damaged tissues |
| CN102755662A (en) * | 2012-07-25 | 2012-10-31 | 福州乾正药业有限公司 | Medical gel film prepared by compounding chitosan and preparation method of same |
| CN103202802A (en) * | 2013-04-22 | 2013-07-17 | 南京农业大学 | In-situ gel formulation for florfenicol injection and preparation method thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102321248A (en) * | 2011-06-10 | 2012-01-18 | 冯淑芹 | Injectable temperature sensitive gel used for filling and repairing damaged tissues |
| CN102755662A (en) * | 2012-07-25 | 2012-10-31 | 福州乾正药业有限公司 | Medical gel film prepared by compounding chitosan and preparation method of same |
| CN103202802A (en) * | 2013-04-22 | 2013-07-17 | 南京农业大学 | In-situ gel formulation for florfenicol injection and preparation method thereof |
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