CN1320036C - Medical intelligent nano-gel material and its preparation method - Google Patents
Medical intelligent nano-gel material and its preparation method Download PDFInfo
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- CN1320036C CN1320036C CNB2005100408897A CN200510040889A CN1320036C CN 1320036 C CN1320036 C CN 1320036C CN B2005100408897 A CNB2005100408897 A CN B2005100408897A CN 200510040889 A CN200510040889 A CN 200510040889A CN 1320036 C CN1320036 C CN 1320036C
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Abstract
The present invention relates to a medical intelligent nanometer gel material which is provided with a composite structure of a core and a shell. The core adopts cross linking or non cross linking polysaccharide macromolecules, and the shell adopts an acrylic three-dimensional polymer. The mole percentage of the core and the shell is 10 to 90% and 90 to 10%. A preparation method of the medical intelligent nanometer gel material comprises the steps: acrylic acid or derivatives thereof are added in the water suspension liquid of polysaccharide nanometer particles, and cross-linking agents and initiating agents are added after nitrogen deoxidization and react with the liquid for 1 hour to 48 hours under the condition of 25DEG C to 80DEG C. The present invention uses the temperature-sensitive polysaccharide as the core and the pH-sensitive acrylic three-dimensional polymer as the shell, so the intelligent performance of gel, namely fast response to the outside temperature and pH change, is ensured, and low critical temperature is adjusted between 30DEG C and 50DEG C. The swelling ratio reaches 10<3> times. The present invention has the advantage of certain strength, is suitable for the separation and purification of certain protein, enzyme and other active biological macromolecules and the embedment and controlled release of certain medicine.
Description
One, technical field
The present invention relates to a kind of pharmaceutical polymers and preparation method thereof, particularly medicinal gelatinous material and preparation method thereof, a kind of medical intelligent nano-gel material and preparation method thereof specifically.
Two, background technology
Intelligent gel rubber material is a class for external environment such as, the variation in temperature, pressure, pH, electric field, magnetic field etc., and its volume or aperture produce material jumpy.Intelligent gel rubber material has important use in fields such as the immobilization of controlled delivery of pharmaceutical agents release, organized enzyme and cell, the macromolecular separation and purification of active bio, has become the focus of material area research in recent years.Be that the research of temperature-sensitive hydrogel of representative is the most deep wherein with poly N-isopropyl acrylamide (PNIPAm), its lower critical solution temperature (LCST) is 32 ℃, in this temperature gel is shunk-the swollen transformation, thereby realize the embedding and the controlled delivery of pharmaceutical agents of some organized enzyme are discharged.Dextran is that the good plasma volume of a kind of biocompatibility expands agent, has the porousness three-dimensional space net structure through crosslinked dextrane gel, play molecular sieve, being widely used in protein/enzyme in the biological chemistry, nucleic acid, amino acid, cholesterol separates with polyose polymer substance and many medicines, but need adopt the material of different size for the protein separation of different molecular weight, also be the range of application relative narrower of the dextrane gel of every kind of specification.
Park T G (Temperature modulated protein release to pH/temperature-sensitive hydrogels.Biomaterials.1999,20:517-521) reported hydrogel, and investigated sustained release behavior Regular Insulin with temperature and pH responsive type.(USP 6 for people such as Alexander V., 696,089 B2) at least a crosslinked Ionomer fragment and another water-soluble nonionic polymer segments have at least been adopted, at a kind of nanometer network gel that added a kind of biodegradable reagent preparation, this gel has biodegradability, can be used for the sustained release of some drugs.The Liu Lanzhi of Wuhan University, Hu Han, Zhuo Renxi etc. (publication number CN 1594384A) have prepared a kind of macropore konjac glucomannan and the crosslinked biodegradable hydrogel of N-N-isopropylacrylamide, can be used for embeddings such as antitumour drug 5 FU 5 fluorouracil.(USP 6 for Guy Chauveteau etc., 579,909 B1) invented a kind of single preparation method who disperses the controlled polyacrylamide microgel of particle diameter, rely on and in the flow velocity in the control porous permeable media polymer monomer is prepared in limiting time under the effect that contains the zirconium ion complex crosslinking agent, the porousness media mainly contains particulate matter such as the particle diameter grains of sand at 50-2000um, can consider and remove excessive linking agent in the prepared microgel solution.
Above-mentioned existing these gelatinous materials, existing certain advantage also exists many shortcoming gesture to be solved,, bad mechanical property slow such as prepared gel response speed, have a large amount of hazardous solvents residual be not suitable for medicinal etc.
Three, summary of the invention
The preparation method who the object of the present invention is to provide a kind of novel medicinal intelligent nano-gel material and this class intelligent nano-gel material is provided is to overcome the deficiency of prior art.The present invention adopts novel material and novel method to prepare that response speed is fast, the medical intelligent nano-gel material of good combination property; It is that base material not only has excellent biological compatibility and biodegradability that the present invention selects the polyose macromolecular material for use, and change very sensitive to environmental factorss such as temperature, employing is a shell to the acrylic acid or the like three-dimensional polymer of pH sensitivity, and preparation has the gelatinous material of nano level nucleocapsid structure in aqueous phase system.Described nuclear is crosslinked or non-crosslinked polyose polymer, and described shell is the three-dimensional polymer of vinylformic acid or derivatives thereof, and both have following molar percentage (in monomer):
Polyose polymer 10～90%
Acrylic acid or the like three-dimensional polymer 90～10%.
Preferably
Polyose polymer 20～30%
Acrylic acid or the like three-dimensional polymer 80～70%.
Described polyose polymer can be cross-linked polysaccharides family macromolecule or non-crosslinked polyose polymer.
Described polyose nanometer nuclear is selected from dextran, starch, starch derivative, Mierocrystalline cellulose, derivatived cellulose, gum arabic, chitin, chitosan and derivative thereof, hyaluronic acid, sodium alginate and other salt etc.
Described three-dimensional polymer shell is synthetic to be selected from vinylformic acid, methacrylic acid and derivative thereof etc. with monomer and to contain carboxyl (unsaturated carbon-carbon double bond (C=C) monomer COOH).
The preparation method of the intelligent nano-gel material of above-mentioned nucleocapsid structure comprises polymerization, separation and dry each unit process, and described polymerization is to add vinylformic acid or derivatives thereof, logical nitrogen (N in the aqeous suspension of polyose nanoparticle
2) deoxidation makes and be uniformly dispersed, at N
2Add linking agent and initiator under the atmosphere, in 25～80 ℃ of following polyreactions 1～48 ℃ hour, at the outside vinylformic acid or derivatives thereof three-dimensional polymer shell that forms of polysaccharide nano granule.After reaction finished, with centrifugation in the gel grain autoreaction liquid of nucleocapsid structure, oven dry promptly in the most rearmounted vacuum drying oven.
The molar percentage (in monomer) of nuclear and shell is 10～90: 90～10, preferred 20～30: 80～70.
Described linking agent is to be selected from N, N '-methylene-bisacrylamide (Bis), CH
2-CH-R-CH=CH
2, CH
2-CH-CO-X-CO-CH=CH
2Contain the chain compound of carbon-carbon double bond (C=C) etc. such two ends, preferred Bis; Its consumption is 1: 2～50 for the mol ratio with vinylformic acid or derivatives thereof (monomer).R is meant phenyl or derivatives thereof aromatic base etc.; X is meant-NH-(CH
2)
m-NH-or-O-(CH
2-CH
2-O)
n-,
M=0～10 wherein, n=1～10.
Described initiator is the redox system of ammonium persulphate (APS) or Potassium Persulphate (KPS) and Tetramethyl Ethylene Diamine (TEMED) formation, and its consumption APS or KPS and monomeric mol ratio are 1: 20～100, and TEMED and monomeric mol ratio are 1: 50～100.
Described cross-linked polysaccharides family macromolecule nanoparticle is the polyose polymer aqueous solution through leaving standstill, obtaining after crosslinked, the precipitate and separate.Promptly at first prepare 1～5% polyose polymer aqueous solution, left standstill 12～48 hours, it is even to add emulsifier for mixing emulsification then, add linking agent again under 25～35 ℃ of conditions, reacted 24～48 hours, obtain crosslinked polyose high molecular nanometer grain, standby after making it to precipitate, separate with the acetone or alcohol condensation at last.
Described linking agent is that epoxy chloropropane, glycidyl methacrylate etc. contain the material more than the bifunctional.
Described emulsifying agent is class nonionic surface active agent such as tween, sapn, and its consumption is 0～0.5%.
Described non-crosslinked polyose high molecular nanometer grain is that the polyose polymer aqueous solution is standby after the condensation of usefulness acetone or alcohol, the precipitate and separate after leaving standstill, and perhaps leaves standstill the back and directly uses.
The prepared intelligent nano-gel material of the present invention is compared with gelatinous material in the past, and size is little, can reach nanoscale, because the response speed of gelatinous material and its size are negative correlation, therefore has better environmental stimulus responsiveness; Gel material of the present invention be with temperature sensitive property polysaccharose substance serve as nuclear and pH susceptibility acrylic acid or the like material be shell, guaranteed the intelligent of material, the i.e. variation of temperature to external world and pH produces corresponding response, can effectively regulate its responsiveness to a certain stimulation by the nuclear-shell molar percentage that changes this gel simultaneously; Can realize intelligent control to drug release; Intelligent nano-gel material of the present invention can be regulated low critical temperature (LCST) as required between 30 ℃-50 ℃, and swelling ratio can reach 10
3Doubly, far above more existing gelatinous materials (publication number CN1526747A); The prepared nano-gel material of the present invention can be used for many controlled delivery of pharmaceutical agents as a kind of novel pharmaceutical modified release solid support material and discharges, and particularly reaction medium is a water, can introduce or not introduce other solvents according to the different needs of medicine.Can make the nanogel particle diameter of preparation littler when introducing other solvents, ball shape higher (seeing accompanying drawing), the load of beneficial drug; And do not introduce other solvents, the nanogel for preparing in the aqueous systems is fit to embedding and the sustained release to some protein, enzyme and the macromolecular separation and purification of some other active bio and many medicines.Also can be used for the embedding of organized enzyme and bacterium in addition, certain application prospect is also arranged in fields such as chemical sensors.
In summary, this nano-gel material has intelligent to the stimuli responsive of environment, also promptly produces different responses according to the kind of outside stimulus with degree; This product has quick response, good comprehensive performances and wide application prospect such as physical strength preferably; In addition present method also have easy and simple to handle, reaction conditions is gentle, need not especial equipment requirements, advantage such as suitability for industrialized production is easy.
Four, description of drawings
Accompanying drawing is depicted as the TEM photo of the dextran/acrylate/nano gel for preparing under the different solvents system
Figure A-pure water phase; Figure B-mixed solvent;
Five, embodiment
Embodiment 1: the water of dextran/acrylate/nano gel is synthetic
Getting the 1.5g dextran is dissolved in the 100ml deionized water, place the 250ml there-necked flask, left standstill 24 hours, drip the 1ml epoxy chloropropane under at the uniform velocity stirring, reaction 48h goes out crosslinked dextran nanoparticle with acetone precipitation at last under 30 ℃, centrifugation final vacuum drying, be scattered in the 100ml deionized water, in this suspension, add vinylformic acid 3ml, feed N then
2Gas 30min, continue to add 1.0g N respectively, N '-methylene-bisacrylamide (Bis), 0.1g ammonium persulphate (APS) and 1 Tetramethyl Ethylene Diamine (TEMED) stop behind the reaction 2h, with the centrifugation from reaction solution of nuclear shell structure nano grain, place the vacuum drying oven oven dry promptly.
Embodiment 2: prepare dextran/acrylate/nano gel in the mixed solvent
Get in the mixed solvent that the 2.5g dextran is dissolved in 100ml deionized water and acetone, left standstill 24 hours, slow dropwise addition of acrylic acid 2ml in this system feeds N then in solution
2Gas 30min, continue to add 1.0g N respectively, N '-methylene-bisacrylamide (Bis), 0.2g ammonium persulphate (APS) and 2 Tetramethyl Ethylene Diamines (TEMED) stop behind the reaction 4h, with the centrifugation from reaction solution of nuclear shell structure nano grain, place vacuum drying oven dry the dry powder body.
Embodiment 3: the preparation of HPMC/acrylate/nano gel
Get the 5g HPMC and be dissolved in the 100ml deionized water, in solution, add acetone to system then and turbid white just occurred, left standstill 24 hours; Continuation adds vinylformic acid 2ml in this system, feed N then in solution
2Gas 30min, continue to add 1.0g N respectively, N '-methylene-bisacrylamide (Bis), 0.3g ammonium persulphate (APS) and 2 Tetramethyl Ethylene Diamines (TEMED) stop behind the reaction 4h, with the centrifugation from reaction solution of nuclear shell structure nano grain, place the vacuum drying oven oven dry promptly.
Embodiment 4: the preparation of HPMC/methacrylic acid nanogel
Get the 1g HPMC and be dissolved in the 100ml deionized water, in solution, add acetone to system then and turbid white just occurred, left standstill 24 hours; Continuation adds methacrylic acid 2ml in this system, feed N then in solution
2Gas 30min, continue to add 1.0gN respectively, N '-methylene-bisacrylamide (Bis), 0.2g ammonium persulphate (APS) and 2 Tetramethyl Ethylene Diamines (TEMED) stop behind the reaction 2h, with the centrifugation from reaction solution of nuclear shell structure nano grain, place the vacuum drying oven oven dry promptly.
Embodiment 5: contain the preparation of Ibuprofen BP/EP nanogel
Getting the 1.5g dextran is dissolved in the 100ml deionized water, place the 250ml there-necked flask, left standstill 24 hours, and under at the uniform velocity stirring, dripped the 1ml epoxy chloropropane, react 48h down in 30 ℃, go out crosslinked dextran nanoparticle with ethanol sedimentation at last, after the vacuum-drying, be scattered in the 100ml deionized water, in solution, add 1g Ibuprofen BP/EP ethanolic soln, and then add vinylformic acid 3ml, lead to N
2Gas 30min, continue to add 1.0g N respectively, N '-methylene-bisacrylamide (Bis), 0.1g ammonium persulphate (APS) and 1 Tetramethyl Ethylene Diamine (TEMED) stop behind the reaction 2h, with the centrifugation from reaction solution of nuclear shell structure nano grain, place the vacuum drying oven oven dry promptly.
Embodiment 6: contain the preparation of interferon nano gel
Getting the 2.5g dextran is dissolved in the 100ml deionized water, place the 250ml there-necked flask, left standstill 24 hours, under at the uniform velocity stirring, drip the 1ml epoxy chloropropane, react 48h down in 30 ℃, go out crosslinked dextran nanoparticle with ethanol sedimentation at last, fully washing is after the vacuum-drying, be scattered in the 100ml deionized water, in solution, add the 1ml Interferon, rabbit, slow then dropwise addition of acrylic acid 3ml, logical N
2Gas 30min, continue to add 1.0g N respectively, N '-methylene-bisacrylamide (Bis), 0.1g ammonium persulphate (APS) and 1 Tetramethyl Ethylene Diamine (TEMED) stop behind the reaction 2h, nuclear shell structure nano grain low-temperature centrifugation from reaction solution is separated, and freeze-drying promptly.
Claims (4)
1, a kind of medical intelligent nano-gel material has the nucleocapsid composite structure, it is characterized in that: described nuclear is the polyose polymer, and described shell is the three-dimensional polymer of vinylformic acid or derivatives thereof, and both in the molar percentage of monomer are
Polyose polymer 10～90%
Acrylic acid or the like three-dimensional polymer 90～10%;
Polyose is selected from dextran, starch, starch derivative, Mierocrystalline cellulose, derivatived cellulose, gum arabic, chitin, chitosan and derivative thereof, hyaluronic acid, Na-alginate;
Acrylic acid or the like is selected from vinylformic acid, methacrylic acid and derivative thereof.
2, gelatinous material according to claim 1 is characterized in that: the molar percentage of nuclear and shell is
Polyose polymer 20～30%
Acrylic acid or the like three-dimensional polymer 80～70%.
3, by the preparation method of the described medical intelligent nano-gel material of claim 1, comprise polymerization, separation and dry each unit process, it is characterized in that: described polymerization is to add vinylformic acid or derivatives thereof, logical nitrogen (N in the aqeous suspension of crosslinked or non-crosslinked polyose nanoparticle
2) deoxidation, at N
2Add linking agent and initiator under the atmosphere, under 25～80 ℃ of conditions, reacted 1～48 hour;
The molar percentage of nuclear, shell is 10～90: 90～10;
Linking agent is to be selected from CH
2=CH-R-CH=CH
2, CH
2=CH-CO-X-CO-CH=CH
2The chain compound of carbon-carbon double bond (C=C) is contained at such two ends; The mol ratio of itself and shell monomer is 1: 2～50; R is meant phenyl or derivatives thereof aromatic base; X is meant-NH-(CH
2) m-NH-or-O-(CH
2-CH
2-O) n-, m=0～10 wherein, n=1～10;
Initiator is the redox system of ammonium persulphate (APS) or Potassium Persulphate (KPS) and Tetramethyl Ethylene Diamine (TEMED) formation, and the mol ratio of APS or KPS and shell monomer is 1: 2～100, and the mol ratio of TEMED and shell monomer is 1: 50～100.
4, preparation method according to claim 3 is characterized in that: the molar percentage of nuclear and shell is 20～30: 80～70.
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| CN101830992B (en) * | 2010-04-03 | 2012-01-25 | 大连理工大学 | PH-/temperature dual-sensitive starch derivative and preparation method thereof |
| CN101857683A (en) * | 2010-06-09 | 2010-10-13 | 中国科学院青岛生物能源与过程研究所 | Different types of chitosan methacrylate and preparation method thereof |
| CN103665400B (en) * | 2013-11-12 | 2016-01-13 | 张家界本草科技有限公司 | The preparation method of hyacinth bletilla hemostatic gel and application |
| CN104857574B (en) * | 2015-06-04 | 2017-08-11 | 中国人民解放军第三军医大学第三附属医院 | Intelligent nano-hydrogel topological structure antibacterial bone plate and its manufacture method |
| CN105126157B (en) * | 2015-09-17 | 2018-02-09 | 爱美客技术发展股份有限公司 | Medical injectable adhesive gel and preparation method thereof |
| CN107474263B (en) * | 2016-06-08 | 2019-06-21 | 中国科学院武汉物理与数学研究所 | The preparation method of temperature-pH sensitivity block nano-hydrogel using polyion polysaccharide as macromolecules cross-linking agent |
| CN109133781B (en) * | 2018-08-28 | 2021-12-07 | 新昌县天姥园艺发展有限公司 | Preparation method of environment-friendly dry powder crack sealer |
| CN109354455B (en) * | 2018-08-29 | 2021-11-12 | 佛山瓷牛新材料有限公司 | Ceramic tile crack sealer and preparation method thereof |
| CN109762567B (en) * | 2019-02-22 | 2021-03-02 | 山东省农业科学院农业资源与环境研究所 | Temperature-sensitive gel type heavy metal curing agent, heavy metal contaminated soil curing and repairing method and curing agent recycling method |
| CN110025580A (en) * | 2019-03-06 | 2019-07-19 | 武汉职业技术学院 | A kind of porous dextran of pH responsiveness is microsphere supported and preparation method thereof, application |
| CN116082713B (en) * | 2022-12-06 | 2024-03-01 | 浙江工业大学 | PH/temperature dual-response intelligent hydrogel and preparation method thereof |
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| 珠状交联丙烯基葡聚糖凝胶的合成 宋国强，王钒 等，江苏石油化工学院学报，第9卷第2期 1997 * |
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