CN104208711A - Chitosan semi-fluid slow release gel and application - Google Patents
Chitosan semi-fluid slow release gel and application Download PDFInfo
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- CN104208711A CN104208711A CN201410505063.2A CN201410505063A CN104208711A CN 104208711 A CN104208711 A CN 104208711A CN 201410505063 A CN201410505063 A CN 201410505063A CN 104208711 A CN104208711 A CN 104208711A
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Abstract
The invention discloses a chitosan semi-fluid slow release gel. The chitosan semi-fluid slow release gel comprises an ingredient I and an ingredient II, wherein the ingredient I is obtained by dissolving 0.5020g/ml of prepared chitosan solution at the temperature of 4 DEG C with normal saline or distilled water as a solvent, and the ingredient II is obtained by dissolving 0.251g/ml of prepared hyaluronic acid chitosan solution at the temperature of 4 DEG C with mixed liquid formed by saturated sodium bicarbonate water solution and distilled water at the volume ratio of 1:1 as a solvent. The chitosan semi-fluid slow release gel is prepared by the steps that the ingredient I and the ingredient II are proportionally mixed at the normal temperature before usage to form a mixture in an injectable semi-fluid state, the injected position gradually solidifies and is finally cured when the temperature rises in a range from 26 DEG C to 40 DEG C, and slow drug release can be controlled. A semi-fluid gel preparation prepared by the gel can serve as a drug carrier and a scaffold for tissue engineering. The chitosan semi-fluid slow release gel is biodegradable and good in biocompatibility.
Description
Technical field
The invention belongs to a kind of chitosan semifluid preparation, relate to particularly a kind of chitosan semifluid gel and purposes.
Background technology
Chitosan semifluid sustained-release gel is a kind of semifluid shape that at room temperature becomes, and in 37 ℃ or body, becomes a kind of of solid can temperature-responsive sustained-release preparation.An its large advantage is lazy flow, avoid carrying medicine runs off when flowable state, and when being expelled to human body sufferer place, can well carry out slow release (Emily Mastronardi by packaging medicine, Amand aFoster, Xueru Zhang, MariaC.DeRosa.Smart Materials Based on DNA Aptamers:Taking Aptasensing to the Next Level.Sensors, 2014; 14:3156-3171.).This property class is similar to temperature sensitive hydrogel, is easy to wrap medicine carrying thing, administration, good biocompatibility and degradability.Material main source is natural and synthetic material, chitosan chitosan claims again chitosan, chitosan has good biocompatibility and degradability as the macromolecular material of natural origin, a kind of nontoxic, nonirritant, no antigen, there is good biocompatibility, the material that degradable absorbs (
fizyki Medycznej, Uniwersytet Adama Mickiewicza w Poznaniu, Pozna ń, 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 source is abundant, and extraction process is simple, and derivant kind is various, can heat-resisting sterilizing.Utilize the gel-like preparation that chitosan is made at aspects such as pharmaceutical carrier, organization brackets, to have research and development (hee Dong han very widely, 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 contains two kinds, matrix type and depots type.Matrix type sustained-release and controlled release preparation is that the form with molecule or microgranule is dispersed in carrier material by medicine.Reservoir devices sustained-release and controlled release preparation is that pharmaceutical pack is rolled in high molecular polymer.The release principle of sustained-release and controlled release preparation is mainly stripping, diffusion, corrosion, osmotic pressure and ion exchange.The main feature of sustained-release preparation is 1) to half-life medicine short or that need frequent drug administration, can reduce medicining times, improve the compliance that patient takes medicine, easy to use.2) blood drug level " peak valley " fluctuates littlely, and blood concentration is steady, within valid density scope, maintains curative effect.3) minimum dose reaches maximum drug effect (pharmaceutics/Cui Fude edits .-6 version .-Beijing: People's Health Publisher, 2007.8).Also exist problem, owing to having concentrated acid, concentrated base and organic reagent in manufacturing process, therefore water-solubility protein class medicine easy inactivation in preparation bag carries process simultaneously.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, a kind of chitosan semifluid sustained-release gel is provided.
Second object of the present invention is to provide the purposes of chitosan semifluid sustained-release gel.
Technical scheme of the present invention is summarized as follows:
A chitosan semifluid sustained-release gel, by following component, make:
Component 1: take the chitosan solution that normal saline or distilled water be that the concentration of solvent preparation is 0.5020g/ml, the molecular weight of described chitosan is 3-8kDa, and deacetylation is 65%-98%, dissolves under 4 ℃ of conditions;
Component 2: the saturated sodium bicarbonate aqueous solution that the volume ratio of take is 1:1 and the mixed liquor of distilled water are solvent, the hyaluronic acid chitosan solution that the concentration of preparation is 0.2510g/ml, the molecular weight of described hyaluronic acid chitosan is 500kDa, and intrinsic viscosity 3000g/ml dissolves and obtains under 4 ℃ of conditions.
The molecular weight of chitosan is preferably 5kDa, and deacetylation is preferably 95%.
Chitosan semifluid sustained-release gel is prepared pharmaceutical carrier or is prepared the purposes of tissue engineering bracket.
Advantage of the present invention:
1, chitosan semifluid sustained-release gel of the present invention, before use under room temperature, by component 1 and component 2, be the ratio mixing of 1:1 by volume, mixture is injectable semi-fluid condition, after injection when temperature rises to 26-40 ℃, in injection site, solidify gradually, finally solidify, and controlled pharmacy slowly discharges.
2, the semifluid gel preparation that prepared by chitosan semifluid sustained-release gel of the present invention can be used as pharmaceutical carrier and tissue engineering bracket is used.
3, chitosan semifluid sustained-release gel biodegradable of the present invention, good biocompatibility, can carry fat-soluble medicine and protein medicaments.
Accompanying drawing explanation
Fig. 1 for semifluid gel preparation at ambient temperature and at 37 ℃ the preparation photo after solidifying for 3 hours, wherein A is semifluid gel preparation, B is coagulation agent (37 ℃ 3 hours).
Fig. 2 is the slow release behavior figure of the Cumulative release amount of bag year bovine serum albumin.
Fig. 3 is the unit interval burst size slow release behavior figure of bag year fluorescin.
Fig. 4 is the slow release behavior figure of the Cumulative release amount of bag year paclitaxel.
Fig. 5 is the unit interval burst size slow release behavior figure of bag year paclitaxel.
The specific embodiment
Embodiment 1
A chitosan semifluid sustained-release gel, by following component, make:
Component 1: the chitosan solution that the concentration that the normal saline of take is solvent preparation is 0.5020g/ml, the molecular weight of chitosan is 5kDa, deacetylation is 95%, under 4 ℃ of conditions, dissolves and obtains;
Component 2: the saturated sodium bicarbonate aqueous solution that the volume ratio of take is 1:1 and the mixed liquor of distilled water are solvent, the hyaluronic acid chitosan solution that the concentration of preparation is 0.2510g/ml, the molecular weight of described hyaluronic acid chitosan is 500kDa, and intrinsic viscosity 3000g/ml dissolves acquisition under 4 ℃ of conditions.
Before using, under room temperature, the ratio of 1:1 mixes by component 1 and component 2 gel that is semi-fluid condition by volume, sees Figure 1A, can be for injection.By mixed liquor be warming up to 37 ℃ 3 hours, be curdled appearance, see Figure 1B.
Bovine serum albumin fluorescence labeling method is that 20mg albumen is dissolved in to 5mLpH9.5 is in carbonate buffer solution, places 4 ℃ of 30min.Add the 0.4mg Fluorescein isothiocyanate dissolving with 1 DMSO, then add 0.5mL carbonate buffer solution.After mixing, dropwise add in protein solution, lucifuge is spent the night in 4 ℃.Second day liquid packs chromatography bag lucifuge dialysis 3 days into.-20 ℃ of preservations.
Get the gel that 1ml is semi-fluid condition, add the fluorescently-labeled bovine serum albumin of 0.08g, by stirring, fluorescently-labeled bovine serum albumin is mixed completely with gel.Add 1mlPBS, under 37 ℃ of conditions, place, every 24h, get supernatant 1ml, add again the PBS that 1ml is new, after 168h, the supernatant of collection is detected by microplate reader respectively simultaneously.Carry albumen simulation release and see Fig. 2.
Getting volume is the gel that 100 μ l are semi-fluid condition, adds the 7.5mg paclitaxel with the DMSO dissolving of 25 μ l, by stirring, paclitaxel is mixed completely with gel.Add 200 μ lPBS, under 37 ℃ of conditions, place, every 24h sampling supernatant 200 μ l, add again the new PBS of 200 μ l simultaneously.After 168h, the supernatant of collection is detected by high performance liquid chromatography respectively.Carry taxol drug simulation release and see Fig. 4.
Embodiment 2
A chitosan semifluid sustained-release gel, by following component, make:
Component 1: the chitosan solution that the concentration that the distilled water of take is solvent preparation is 0.5020g/ml, the molecular weight of chitosan is 5kDa, deacetylation is 95%, under 4 ℃ of conditions, dissolves and obtains;
Component 2: the saturated sodium bicarbonate aqueous solution that the volume ratio of take is 1:1 and the mixed liquor of distilled water are solvent, the hyaluronic acid chitosan solution that the concentration of preparation is 0.2510g/ml, the molecular weight of described hyaluronic acid chitosan is 500kDa, and intrinsic viscosity 3000g/ml dissolves acquisition under 4 ℃ of conditions.
Before using, under room temperature, the ratio of 1:1 mixes by component 1 and component 2 gel that is semi-fluid condition by volume, can be for injection.
Bovine serum albumin fluorescence labeling method is that 20mg albumen is dissolved in to 5mLpH9.5 is in carbonate buffer solution, places 4 ℃ of 30min.Add the 0.4mg Fluorescein isothiocyanate dissolving with 1 DMSO, then add 0.5mL carbonate buffer solution.After mixing, dropwise add in protein solution, lucifuge is spent the night in 4 ℃.Second day liquid packs chromatography bag lucifuge dialysis 3 days into.-20 ℃ of preservations.
Get the gel that 1ml is semi-fluid condition, add the fluorescently-labeled bovine serum albumin of 0.08g, by stirring, bovine serum albumin is mixed completely with gel.Add 1mlPBS, under 37 ℃ of conditions, place, every 24h, get supernatant 1ml, add again the PBS that 1ml is new, after 168h, the supernatant of collection is detected by microplate reader respectively simultaneously.Carry albumen simulation release and see Fig. 3.
Getting volume is the gel that 100 μ l are semi-fluid condition, adds the 7.5mg paclitaxel with the DMSO dissolving of 25 μ l, by stirring, paclitaxel is mixed completely with gel.Add 200 μ lPBS, under 37 ℃ of conditions, place, every 24h sampling supernatant 200 μ l, add again the new PBS of 200 μ l simultaneously.After 168h, the supernatant of collection is detected by high performance liquid chromatography respectively.Carry taxol drug simulation release and see Fig. 5.
Embodiment 3
A chitosan semifluid sustained-release gel, by following component, make:
Component 1: the chitosan solution that the concentration that the normal saline of take is solvent preparation is 0.5020g/ml, the molecular weight of chitosan is 3kDa, deacetylation is 65%, under 4 ℃ of conditions, dissolves and obtains;
Component 2: the saturated sodium bicarbonate aqueous solution that the volume ratio of take is 1:1 and the mixed liquor of distilled water are solvent, the hyaluronic acid chitosan solution that the concentration of preparation is 0.2510g/ml, the molecular weight of hyaluronic acid chitosan is 500kDa, and intrinsic viscosity 3000g/ml dissolves acquisition under 4 ℃ of conditions.
Before using, under room temperature, the ratio of 1:1 is injectable semi-fluid condition by component 1 and component 2 mixing by volume.
Experimental results show that, with the kin fat-soluble medicine of paclitaxel: the chitosan semifluid sustained-release gel embedding of embodiment 1 preparation for rapamycin, methotrexate, fluorouracil, mercaptopurine, hydroxyurea, cytosine arabinoside, methotrexate, fluorouracil, mercaptopurine, hydroxyurea, cytosine arabinoside, adrenocortical hormone, androgen, corticosteroid, steroid etc., each simulation releasing effect is similar to embodiment 1.
Experimental results show that, with the kin water-solubility protein medicine of bovine serum albumin: protein medicaments, the chitosan semifluid sustained-release gel embedding of embodiment 1 preparation for BMP (bone morphogenetic protein), OVA (chicken egg white), BSA (bovine serum albumin), vaccine (such as bacillus calmette-guerin vaccine), cytokine (such as cell interleukin), recombinant polypeptide (such as Human Inter Leukin-2) etc., each simulation releasing effect is similar to embodiment 1.
Embodiment 4
A chitosan semifluid sustained-release gel, by following component, make:
Component 1: the chitosan solution that the concentration that the distilled water of take is solvent preparation is 0.5020g/ml, the molecular weight of chitosan is 8kDa, deacetylation is 98%, under 4 ℃ of conditions, dissolves and obtains;
Component 2: the saturated sodium bicarbonate aqueous solution that the volume ratio of take is 1:1 and the mixed liquor of distilled water are solvent, the hyaluronic acid chitosan solution that the concentration of preparation is 0.2510g/ml, the molecular weight of hyaluronic acid chitosan is 500kDa, and intrinsic viscosity 3000g/ml dissolves acquisition under 4 ℃ of conditions.
Before using, under room temperature, the ratio of 1:1 is injectable semi-fluid condition by component 1 and component 2 mixing by volume.
Experiment showed, a kind of chitosan semifluid sustained-release gel embedding fat-soluble medicine of preparing with the present embodiment: rapamycin is similar to embodiment 1 with each simulation releasing effect of embedding protein medicaments BMP.
Claims (3)
1. a chitosan semifluid sustained-release gel, is characterized in that making by following component:
Component 1: take the chitosan solution that normal saline or distilled water be that the concentration of solvent preparation is 0.5020g/ml, the molecular weight of described chitosan is 3-8kDa, and deacetylation is 65%-98%, dissolves under 4 ℃ of conditions;
Component 2: the saturated sodium bicarbonate aqueous solution that the volume ratio of take is 1:1 and the mixed liquor of distilled water are solvent, the hyaluronic acid chitosan solution that the concentration of preparation is 0.2510g/ml, the molecular weight of described hyaluronic acid chitosan is 500kDa, and intrinsic viscosity 3000g/ml dissolves and obtains under 4 ℃ of conditions.
2. a kind of chitosan semifluid sustained-release gel according to claim 1, the molecular weight that it is characterized in that described chitosan is 5kDa, deacetylation is 95%.
3. claim 1 or a kind of chitosan semifluid sustained-release gel of 2 are prepared pharmaceutical carrier or are prepared the purposes of tissue engineering bracket.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109310800A (en) * | 2016-07-29 | 2019-02-05 | 医药研究产品有限公司 | Rotator cuff tear reparation composition 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 |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109310800A (en) * | 2016-07-29 | 2019-02-05 | 医药研究产品有限公司 | Rotator cuff tear reparation composition comprising nucleic acid and chitosan |
| 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 |
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